Neural tube defects

Neural tube defects (NTD) are major structural birth defects, largely comprising of spina bifida and anencephaly, and are characterised by incomplete closure of the neural tube around the 28^th day of gestation^{(Reference Botto, Moore and Khoury1)}. Anencephaly is not compatible with life, while infants born with spina bifida have a high risk of perinatal and neonatal mortality^{(Reference Botto, Moore and Khoury1)}. Most infants that survive with spina bifida require multidisciplinary expertise, including neurosurgeons, urologists, orthopaedics, orthotics, radiologists, stoma therapists, physio- and occupational therapists and social workers^{(Reference Gandy, Castillo and Kelly2–Reference Alabi, Thibadeau and Wiener6)}.

The most common cause of NTD is maternal folate insufficiency before and during early pregnancy^{(Reference Kancherla and Black7)}. Folic acid or folate is vitamin B₉, an essential micronutrient required in early pregnancy for proper neurulation. Folate is a natural form of B₉ available through dietary sources (e.g. lentils, beans and green leafy vegetables), while folic acid is a synthetic form of folate, available as tablets and in folic acid-fortified foods (e.g. enriched wheat and maize flour).

According to the WHO, folic acid intake is a Category 1 intervention, recommending that all women of reproductive age take 400 mcg/d folic acid (ideally before conception) to prevent NTD⁽⁸⁾. In May 2023, World Health Assembly resolution 76·19 was passed – ‘Accelerating efforts for preventing micronutrient deficiencies and their consequences, including spina bifida and other neural tube defects, through safe and effective food fortification’⁽⁹⁾. All World Health Assembly member nations were urged to invest in sustainable folic acid interventions, including food fortification, and to monitor periodically for effectiveness⁽⁹⁾.

Birth prevalence of neural tube defect

Globally on average, there are twenty cases of NTD per every 10 000 live births^{(Reference Blencowe, Kancherla and Moorthie10)}. In Sub-Saharan Africa and North-West Africa, the rate is approximately 14·2 and 17·5 per 10 000 live births, respectively^{(Reference Blencowe, Kancherla and Moorthie10)}. The NTD birth prevalence varies widely globally due to different folic acid-interventions implemented, that is, supplement programmes and mandatory or voluntary food fortification policies^{(Reference Atta, Fiest and Frolkis11)}. In South Africa (SA), which implements mandatory fortification of wheat flour with folic acid, the latest NTD birth prevalence is estimated as 8–12 per 10 000 live births^{(12,Reference Krzesinski, Geerts and Urban13)} .

Neural tube defect birth prevalence in South Africa

SA is an upper-middle income country located at the southern tip of Africa with a population of just over 63·2 million people, spread over 1·2 million km²⁽¹⁴⁾. The NTD birth prevalence in SA was first examined in the 1990s using hospital-based studies. A study undertaken in the rural province of Limpopo reported that most infants born with an NTD died before the age of 2 years^{(Reference Christianson, Zwane and Manga15)}. In 2006, Christianson et al. estimated the SA birth prevalence of non-syndromic NTD as 25 per 10 000 births^{(Reference Christianson, Howson and Modell16)}. Subsequently in 2019, Krzesinski et al. ^{(Reference Krzesinski, Geerts and Urban13)} reported 8–12 cases per 10 000 births. Further modelled NTD birth prevalence rates published in 2018 by Blencowe et al., using 2015 births data, indicated 10 cases per 10 000 live births in SA, equating to about 1000 cases per year^{(Reference Blencowe, Kancherla and Moorthie10)}. Blencowe et al. (2018) estimated that of the annual NTD-affected births in the SA, about 165 result in elective terminations of pregnancies, 270 result in stillbirths, and 575 result in live births^{(Reference Blencowe, Kancherla and Moorthie10)}. Spina bifida alone impacts 350 live born infants per year in SA^{(Reference Blencowe, Kancherla and Moorthie10)}. Many of those surviving with NTD in SA can experience premature mortality or are expected to live with lifelong health complications and associated disability^{(Reference Blencowe, Kancherla and Moorthie10)}.

Neural tube defect-related services and support in South Africa

Rates of prenatal diagnosis of NTD through ultrasonography vary provincially and between facilities. All pregnant women in SA should receive an ultrasound before 20 weeks gestation, with those screening positive for NTD (and other identifiable, priority birth defects) referred for invasive diagnostic interventions to confirm diagnosis. However, in practice, this does not routinely occur due to limited infrastructure and lack of staff trained in ultrasound screening^{(17–Reference Mashamba, Eyo and Towobola20)}.

In SA, NTD are one of the priority birth defects notified through the Birth Defect Collection Tool, a paper-based population-based surveillance programme administered by the South African National Department of Health. The current system has been implemented since 2006, with the sole emanating publication indicating gross underreporting of all priority birth defects, including NTD^{(Reference Lebese, Aldous and Malherbe21)}. An ongoing health system strengthening project, Ubomi Buhle (https://ubomibuhle.org.za/), is implanted at 16 primary healthcare sites across three provinces. While primarily focused on an improved understanding of the effects of medicine and vaccine exposure during pregnancy, the project also monitors and reports birth outcomes, including NTD. Ubomi Buhle is piloting an SA-adapted, surveillance version of the Global birth defects app, and if successful, implementation could be expanded elsewhere in the country^{(Reference Dolk, Leke and Whitfield22)}.

Pregnant women attending state antenatal care are prescribed and dispensed folic acid tablets (5 mg daily) as recommended by the Guidelines for Maternity Care in South Africa⁽¹⁷⁾. The South African Clinical Guidelines for Genetic Services specifically recommend folic acid supplementation as an NTD-preventative measure as part of pre-conception and pre-pregnancy care to prevent birth defects and to use staple foods fortified with folic acid⁽¹⁸⁾. While these and other relevant guidelines exist^(17,18,23) , their practical implementation remains limited, fragmented and under-resourced.

Health education and awareness of NTD is an essential part of family planning and ante-natal care, highlighting the importance of folic acid supplementation and use of folic acid fortified staple foods, throughout the life cycle and particularly preconception. This is particularly important when planning subsequent children following the birth of an NTD-affected child. Education and psychosocial support for affected families is offered by the Association for Spina Bifida and Hydrocephalus South Africa, founded in 2014. Association for Spina Bifida and Hydrocephalus South Africa (www.asbah-sa.org/) aims to protect and promote the interests of those impacted; support measures to prevent or reduce NTD and advocate for accessible and equitable medical, educational, vocational, social, and rehabilitation services.

Folic acid food fortification in South Africa

South Africa first implemented a nation-wide food fortification programme in October 2003, after rural black women of childbearing age were found to have insufficient folic acid intake^{(24,Reference Robertson, Steyn and Venter25)} . The fortification regulation required the milling industry to add specific formulations of vitamins and minerals, including folic acid, to certain wheat flours and maize meals. Regulations were subsequently amended in 2008⁽²⁶⁾ and are currently implemented as detailed in Table 1. The associated cost of fortification and the amount passed onto the consumer were found to be nominal, translating to only a ZAR0·01 (one cent) increase per loaf of bread and ZAR0·02 per kilogram of maize meal⁽²⁷⁾.

Table 1

Current (2008) South African regulations relating to folic acid fortification⁽²⁶⁾

Currently, maize flour fortification occurs in both domestically produced and imported products, including flour that is used in the household and processed foods. The fortification concentration is 2 mg of folic acid per 1 kilogram of maize flour⁽²⁸⁾. Wheat (bread) flour is also fortified, including domestically produced and imported products, used in household and processed foods. The concentration of folic acid added to wheat flour is 1·4 mg per 1 kilogram of flour⁽²⁸⁾. Current regulations exclude the fortification of cake flour⁽²⁶⁾. While this exclusion of cake flour is addressed in additional regulatory amendments proposed in 2016⁽²⁹⁾, 8 years later these remain unfinalised, despite cake flours accounting for almost 30 % of wheaten products manufactured in SA⁽³⁰⁾.

Effectiveness of folic acid fortification in South Africa

In 2007, Modjadji et al. ^{(Reference Modjadji, Alberts and Mamabolo31)} used serum and red blood cell folate levels among non-pregnant women of childbearing age in Dikgale Health and Demographic Surveillance System in a rural district of Limpopo Province, SA. These blood markers are commonly used biomarkers to study the effectiveness of folic acid fortification. In the study, median serum folate concentration increased from 3·58 to 10·51 ng/ml following fortification, while the median red blood cell (RBC) folate concentration rose from 227·01 to 429·29 ng/ml. The proportion of women with low serum folate levels (<3 ng/ml) decreased from 16·3 % to 0 % post-fortification, while those with low RBC folate (<164 ng/ml) decreased from 26·4 % to 1·9 %^{(Reference Modjadji, Alberts and Mamabolo31)}. This study showed the benefits of folate fortification in improving serum and RBC folate concentrations in SA target populations.

In 2008, Sayed et al. ^{(Reference Sayed, Bourne and Pattinson32)} compared the birth prevalence of NTD pre-folic acid fortification to post-fortification using data from twelve hospitals in SA. The study showed a 11 % reduction in anencephaly and a 42 % reduction in spina bifida birth prevalence. The perinatal mortality rate associated with NTD also declined by 65·9 % in the post-fortification period, with the total national infant mortality rate declining by 38·8 %. The cost–benefit ratio of food fortification was estimated to be 46:1, showing the great benefit of this intervention in SA^{(Reference Sayed, Bourne and Pattinson32)}.

Status of food fortification monitoring for adequacy of folic acid

While previous studies demonstrate the effectiveness of folic acid fortification in SA, continuous monitoring is needed to ensure implementation and full compliance as per national policy. To encourage this, WHO has published a guidance manual for millers, regulators and for program managers monitoring fortification⁽⁸⁾. These regulations require suppliers of micronutrient premix to register with the Department of Health and to submit analysis reports on their premixes at 6-monthly intervals undertaken by an independent laboratory accredited with the South African National Accreditation System^(26,33) .

Additionally, Food Control Sections within both National and Provincial Department of Health have trained ±2000 inspectors to conduct onsite checks at mills countrywide. While the original regulations⁽²⁴⁾ specified that samples should be taken at the ‘point of manufacturing, importation or sale’, this was later amended to exclude the point of sale for legal reasons related to traceability, counterfeiting, etc⁽²⁶⁾.

While the South African government intended premix suppliers to provide Department of Health with data related to sales volumes (kg) of each premix type, this met with resistance from suppliers due to confidentiality and competition issues. Information relating to the internal stability of micronutrients is required from premix suppliers with annual registration, although compliance levels are not publicly available.

Whilst SA does not publish fortification data, it is believed that compliance by the large millers, who dominate circa 75 % of the maize market and almost all the wheat market, is now at 80 %⁽²⁸⁾. This is marred by the exclusion of cake flour that remains unfortified.