Spina bifida in Chile: Improving every day

1. Introduction

Spina bifida (SB) is a congenital anomaly. It is the most frequent type of neural tube defect (NTD). SB is characterized by failed closure of the caudal end of the neural tube, and it occurs before the 28th day of gestation [1]. Being considered the most common cause of child disability worldwide [2], SB has wide prevalence.

The following article summarizes the Chilean experience in reference to the aspects related to the implementation of the fortification program of wheat flour with folic acid (FA) and its evolution, genetic studies on patients with SB, improvements in coverage and opportunities for medical management, as well as the creation of associations of families of patients with the condition.

2. Prevention of spina bifida in Chile

After the studies of MRC Vitamin Study Research Group and Czeizel [4, 5], it is strongly recommended that all women of childbearing age intake 400  μ g of folic acid (FA) per day [1, 2, 6] to reduce the risk of a NTD.

As a government initiative, Chile established a national program of fortification of wheat flour with FA, in order to prevent neural tube defects. From January 2000 until 2009, it became mandatory to fortify with 2.2 mg of FA/kg of wheat flour which, according to the average intake of bread by the Chilean population in that period, would result in an average intake of 360 μ g of FA per day [7].

With the purpose of monitoring the impact of the FA fortification program, a study was carried out in the metropolitan region, which covers 50% of the population of the country including Santiago, the capital. This study had two objectives: first, to assess whether the industry was actually fortifying wheat flour with FA and second, to assess the impact of the program on the rate of NTDs.

Two methods were used to achieve the first objective. The first method was to analyze samples of 605 non-pregnant women of reproductive age that were beneficiaries of the public health system. Blood samples were taken from them twice (in September 1999 and in April 2000), in order to measure and compare the pre and post fortification levels of serum folate (9.7 ± 4.3 vs. 37.2 ± 9.5) and erythrocytic folate (290/- 102 nmol/L vs. 707/- 179 nmol/L), revealing a significant increase ( 0.0001). The second method was to take random samples of bread from bakeries in the metropolitan region and measure their folic acid levels. It was verified that the bread indeed contained the expected level of FA. Since the measurement technique was not available in Chile, this phase of the program had the technical assistance of the Centers for Disease Control and Prevention (CDC) in the United States [7]. After confirming that the fortification was being carried out from the date indicated, all that remained was to determine the epidemiological impact of this public health intervention.

In order to evaluate the second objective of the study, and given that Chile did not have a national registry of congenital anomalies, a prospective registry of NTDs was developed. Through this registry, it was demonstrated that only two years after fortification (2002), the NTDs rate had been reduced by 43% [8]. Achieving a cumulative reduction of 50% (RR: 0.5; 95% CI: 0.42–0.59) with a rate of 17.1/ 10,000 births for the pre-fortification period (1999–2000) and a rate of 8.6/10,000 births for the post-fortification period (2001–2009) [3]. The NTD with greater decline in rate was spina bifida with a 52% reduction (RR:0.48, IC 95%: 0.38–0.6) [3]. The results of this study are similar to those reported by the Latin American Collaborative Study of Congenital Malformations (ECLAMC) [9, 10]. In addition, the assessment of the economic impact of this intervention proved to be an effective and cost saving strategy for the primary prevention of NTDs in Chile [11].

Additionally, authorities recommended the supplementation of FA in women of reproductive age with high risk of having children with NTDs (i.e., women with gestational diabetes, women with epilepsy in treatment with antifolinic anticonvulsants such as valproic acid, or with a history of having children with NTDs, have a NTD themselves, or having a first-degree relative with a NTD) through the Guide of Prenatal Care published in 2004 and supported by the guidelines of the Chilean League against Epilepsy.

Furthermore, any fortification program must supervise its fulfillment monitoring the milling industry in the implementation of the norm. Thus, in 2005 the Chilean Institute of Public Health (ISP), implemented the liquid chromatographic method to determine the amount of FA added to fortified wheat flour (UV-HPLC), maintaining control on the levels of fortification in all the mills of the country, posing improvements in each one of them if required.

By 2009, after these implementation strategies, SB in Chile had a rate of 4.2 per 10,000 births, meaning that about 120 children were born with SB per year in the country (52% less than in the previous decade). According to local records of these births, 95% were live newborns and 4% had syndromic SB, meaning they were patients with genetic syndromes that included SB within their overall phenotype [3]. In that same decade, epidemiological studies were published suggesting a possible association between FA and an increased rate of cancer and delay in diagnosis of pernicious anemia [12, 13]. Therefore a different group of specialists of medicine and nutrition requested a re-evaluation of the fortification program to prevent potential hazards [14].

Although studies relating FA to cancer were not conclusive, in 2008, with the assistance of the CDC, an external audit was carried out on the fortification program. As a result it was recommended that the level of fortification should be decreased to 1.8 mg of FA/kg of wheat flour. Subsequently, in November 2009, the Ministry of Health modified the program through Decree 977. The impact of this change in the program is still being evaluated and the results of the study will soon be published. Nevertheless it is relevant to state that recent meta-analysis has not found a relationship between cancer and folic acid and that pernicious anemia could be indentified through routine care; thus the discontinuation of the FA fortification program is not being considered in Chile.

3. Genetic studies of spina bifida in the Chilean population

Given that there was no variation in the curve for NTD rate after 2006 according to the annual registry of NTDs and considering the high survival rate of patients with SB, it was decided to carry out some genomic studies in order to identify potential genetic variants associated with the risk of NTDs among patients affected by SB despite FA supplementation.

In this context, the most studied gene at the global level is methylenetetrahydrofolate reductase gene (MTHFR), in which the polymorphism c.C677T generates a thermolabile enzyme that could be associated with alterations of the metabolism of folates. In Chile the first study regarding this gene was conducted by Nitsche et al., in 2003 [15], who compared 58 mothers of children with SB, with 184 mothers of healthy children, with no evidence of any association ( p = 0.35). A subsequent study that analyzed the polymorphisms c.C677T and A1298C in blood samples from 105 patients with myelomeningocele and their parents, also found no association with SB [16].

Considering the postulated association of maternal obesity and gestational diabetes with SB, further studies were carried out on three genes related to energy homeostasis (SLC2A1, LEPR and HK1) in 105 patients with myelomeningocele (MM) and their parents, finding a protective polymorphism in the gene SLC2A1 (haplotype T-A rs710218-rs2229682; P = 0.04), and a variation in the gene LEPR associated to an increased risk of MM in patients who inherited the G Allele of the SNP rs1137100 from the mother (OR: 2.43; 95% Cl:1.01–5.86 ), an effect maintained even by only considering lower MM (OR: 3.2; 95% Cl:1.17–9.33) [17]. Currently, Chile participates in an international genome-wide association study of NTDs, and results are expected for in 2018.

4. Health care and associations of individuals and families affected by spina bifida

In 1978 a non-profit foundation to help disabled children was created in Chile (TELETON). It was originally intended for the rehabilitation of children affected by polio and also for children with SB, in order to provide comprehensive care and rehabilitation services. In addition, in 2005, the Chilean Ministry of Health implemented a program for the diagnosis and treatment of children with SB. The program guarantees neurosurgical management before discharge from the maternity unit. In addition, it provides follow-up for patients with occult SB, to define the need and/or the best time for its surgical correction. This program is part of the national program of explicit health guarantees, and covers both the beneficiaries of the public health system and the private sector.

Concurrently, SB clinics in some public hospitals in the metropolitan region, that have been historically associated with pediatric services, have implemented new programs. These programs have been concerned not only with the medical aspects of SB care (e.g., neurosurgery, gastroenterology, nephrology, urology, orthopedics, pediatrics, and nursing), but also with aspects of physical rehabilitation (physiatry), children’s activities in school and community participation supported by other professionals (e.g., psychology, social workers, and psychopedagogues).

On the other hand, given the outcomes reported by the Management of Myelomeningocele Study [18], which showed improved results related to in utero closure of SB, surgical procedures for this condition in utero have been in conducted in three Chilean centers since 2011 (one private and two public). There have been limitations to their execution given the strict criteria for inclusion for this type of procedures, along with the lack of agreement on whether it is better to perform surgery before or after birth. Additionally, there has been limited coverage of these surgeries by the health insurance companies, arguing that the fetus is not “a real patient”. This situation is being appealed to national government by groups seeking the right to this type of intervention for families.

Patients in turn have organized themselves into an association, the Corporación de Espina Bífida Chile (CORPEB), whose objective is to provide tools to individuals living with SB in order to improve their quality of life and independence, strengthen rehabilitation activities, promote inclusion and socialization of individuals with SB in the country, as well as with institutions in other countries in order to ensure better outcomes

5. Challenges to be addressed about spina bifida in Chile

Given the advances in the development of medical management of the SB, Chile now has new challenges: 1) to implement a laboratory for the measurement of folate with a microbiological technique that facilitates population measurements and the monitoring of the program, 2) to conduct studies on SB etiology among patients, 3) to support the recognition of unborn patients as legal subjects deserving of health benefits separate from their mothers, 4) to strengthen the Chilean National Registry for Congenital Anomalies (RENACH) in order to have data about the rate of prevalence of SB, and 5) to generate guidelines and clinical follow-up for all patients with SB entering adulthood, which must necessarily be accompanied by employment and social inclusion..

6. Conclusion

In conclusion, Chile as a country has made great strides in SB care by mobilizing medical teams and health authorities and reforming the milling industry. In addition work has been completed to revamp academic, national, and international communities to contribute in areas such as research for SB etiology, prevention, treatment, rehabilitation, and inclusion into the Chilean society. However, there are still some tasks to be completed to improve SB management. These should include developing better registries to estimate national prevalence, identifying genetic risk factors specific to the Chilean population, patient follow-up plans, and social and employment inclusion opportunities. Worldwide efforts should continue to work in these areas to ensure improvements in the care that is provided to individuals living with SB.