Evaluation of neural tube defects from 2014 to 2019 in Turkey

Neural tube defects (NTDs) are among the common and serious congenital anomalies that cause hundreds of thousands of deaths, as well as lifelong disability in survivors [1, 2]. According to the March of Dimes estimates, in the year 2001, 323,904 cases of NTD were present globally (25 per 10,000 live births) [3]. A recent meta-analysis study showed that, for 2015, it was estimated that there were 260,100 (uncertainty range (UI): 213800, 322,000) NTD affected birth outcomes worldwide (prevalence 18.6; 15.3, 23.0/10000 live births) [4].

NTDs result from secondary to failure of the neural plate to close during embryonic development (postconceptional 21st to 28th days) [5]. Classically, NTDs are divided into two main groups: defects affecting brain structures (anencephaly and encephalocele) and structures of the spinal cord (meningocele, myelomeningocele, and other forms of spina bifida) [1, 6]. The etiology of NTDs is multifactorial; Nutritional deficiencies (folic acid, vitamin B12, etc.), genetic predisposition, and environmental factors play a role in the etiology [2, 7‐9]. Geography, race, maternal obesity, antiepileptic drug use, pesticide exposure, smoking, indoor air pollution from predominantly biomass heating, x-ray radiation exposure, family history, and previous history of stillbirth have been reported to contribute to the development of NTDs [10‐13]. Previous studies have shown that a significant proportion of NTDs can be prevented with pre-pregnancy folic acid supplementation (PFAS) [14‐16]. In Turkey, PFAS has been recommended by health professionals for women of childbearing age and included in the Ministry of Health (MoH) guidelines since 2014 [17, 18]. Counselling and training services promoting PFAS are provided through the Premarital Counselling Program and pregnancy preparation classes in Maternity Schools [19].

Hospital-based studies conducted in previous years indicate that NTDs are common in Turkey [7, 11, 20‐24]. However, there is no recent study evaluating NTD frequency with national data after the PFAS recommendation and there is no national study examining NTD mortality. Therefore, we designed this study to achieve the following objectives: a) To determine the frequency of patients with NTD and the NTD case fatality rate in a nationwide birth cohort in 2018, and b) To examine the epidemiological characteristics of NTD related deaths within the first 1 year of life using nationally collected data from 2014 to the end of 2019. The study is expected to be a reference study of preventive strategies.

During 2014–2019 total of 7,736,309 live births, 53,504 stillbirths, and 4018 ToPFA cases were registered (Table 1). Of the live births, 73,698 resulted in infant deaths. While overall stillbirth rate decreased from 74.3 in 2014 to 64.0 in 2019 (per 10,000 live births and fetal deaths), overall infant mortality rate (IMR) decreased from 101.5 in 2014 to 90.3 in 2019 (per 10,000 live births). In contrast, overall ToPFA cases rose from 4.8 in 2014 to 6.4 in 2019 (per 10,000 live births) (Table 1).

In the current study, NTDs were evaluated using available national data and the results showed that NTDs are still prevalent (27.5 per 10,000 births) in Turkey. In previous years, the epidemiology of NTDs have been studied in several studies, with varying results [7, 11, 20‐22, 24]. According to the results of studies conducted in various provinces before the 2000s, the frequency of NTD was reported to vary between 30 and 58 per 10,000 births [11, 20, 21, 23]. In a large-scale, nationally representative multicenter study of 21,907 children born between June 1993 and July 1994 in university clinics, the frequency of NTD was found to be 30.1 per 10,000 births [11]. A regional nested case-control study in İzmir province detected the incidence as 15.0 per 10,000 births in 2000 [24]. Another study evaluating all live births, stillbirths and therapeutic abortions, based on records of hospitals in Afyonkarahisar province in 2003–2004 reported the incidence of NTD as 35.8/10000 births [22]. The NTD rate in a tertiary care referral perinatology unit form low-income region of Eastern Turkey between 2016 and 2018 was 130.0 (151/11552) per 10,000 fetuses [7]. Differences in the results of these studies may be due to differences in time, geography, and population, as well as methodological differences such as data collection criteria, case definition, and study design. In a study estimating the burden of NTD in low- and middle-income countries showed that total NTD burden was 25.5 (IQR 15.6, 39.1) per 10,000 pregnancies [26]. A systematic review including 160 full text manuscripts and reports from 75 countries demonstrated that prevalence estimates vary widely by region: Africa; 11.70 per 10,000 birth (95% CI 5.20, 75.40); Eastern Mediterranean: 21.90 per 10,000 birth (95% CI 2.10, 124.10); European: 9.00 per 10,000 birth; (95% CI 1.30, 35.90), Americas: 11.50 per 10.000 birth (95% CI 3.30, 27.90), South-East Asia: 15.80 per 10,000 birth (95% CI 1.90, 66.20), and Western Pacific: 6.90 per 10,000 birth (95% CI 0.30, 199.40) [27]. In a meta-analysis study that included 19 studies from 1968 to 2013, the overall pooled prevalence of NTDs in India was 45.00 per 10,000 total births (95% CI 42.00, 49.00) [28]. In a recent study, which included a meta-analysis of 37 publications from the African region in 1990 and 2020, the prevalence of NTDs was reported as 50.71 (95% CI 48.03, 53.44) per 10,000 births [10].

NTD is a congenital anomaly with high mortality and morbidity. In the current study, the case fatality rate in live-born babies was 13.5% in the first year of life, and 15.6% at the end of March 2022. In a study from a tertiary care center in Konya, analyzing patients followed in with a diagnosis of NTD, the case fatality rate during the follow-up period was 7.5%. In another study from Samsun, analyzing patients followed in the neonatal intensive care unit with a diagnosis of NTD, the mortality rate during the follow-up period was 7.0% [29]. Since our study reflects the results of the whole country and all NTD types including anencephaly, higher mortality is expected compared to results from this well-equipped tertiary referral centre. In a systematic review conducted in high-income country settings including twenty studies, significant declines in spina bifida associated IMR (4.8% decrease in IMR per 100,000 live births) and case fatality (2.7% decrease in infant case fatality) were reported [30]. Possible reasons for this difference are reported as: primary prevention with mandatory folic acid fortification, early prenatal diagnosis with improved technology, termination of pregnancy, and advances in therapeutic medical and surgical interventions including improved ventilator support in neonatal intensive care and the use of antibiotics [30].

Our study showed that NTDs account for a significant proportion of infant deaths, stillbirths, and ToPFA. While overall IMR and stillbirth rate tend to decline, NTD-related IMR and ToPFA rates tend to increase over the years. NTD-specific stillbirth rates follow an irregular course. Although this result may seem contradictory, it was interpreted as a gradual improvement in the quality of the data entered on causes of death. There are also regional differences in NTD specific IMR, stillbirth and ToPFA rates. NTD-associated IMR and stillbirth are the highest, while NTD related ToPFA is the lowest in the Eastern region when compared to other regions. In the recently published report by the MoH, it was shown that both IMR and perinatal mortality rates are higher in the Eastern region, in line with our study results [31, 32]. In this study, we calculated NTD related stillbirths, ToPFA and infant death rates by some socio-demographic and obstetric characteristics. Higher NTD-related infant mortality rates were associated with low birth weight, prematurity, old maternal age, twin/triplet pregnancy, multiparity, and cesarean delivery whereas NTD-related stillbirth and ToPFA rates was higher in: low birth weight, prematurity, young maternal age, female infant, vaginal delivery, and multiparity. The highest rates for NTD specific mortality were in the prematurity and low birthweight variables. In a new meta-analysis study, similar to our study, prematurity and low birthweight are reported to be associated with increasing spina bifida infant case fatality [30].

In the current study, one out of 8 to 9 cases of all ToPFA cases were found to have a diagnosis of NTD. We showed that some socio-demographic characteristics of NTD related ToPFA cases differ from NTD related infant deaths and stillbirths. In ToPFA cases; mothers were younger, nulliparous, and had less history of miscarriage/stillbirth, parents were more educated, the house was less crowded, twin/triplet pregnancies and consanguineous marriages were less than those other death types. The regional distribution of NTD related ToPFA cases were also different. While 51.0% of stillbirth and infant death cases are seen in the Eastern region, 47.8% of NTD related ToPFA cases occurred in the Western region. However, the highest ToPFA rates were found in the Northern region and Western region respectively. In Turkey, abortion is legally allowed until the tenth week of pregnancy is completed. Termination of pregnancy due to serious diseases is done after the decision of the health board, regardless of the week of gestation [33]. In a study assessing ToPFA cases performed before the 16th week of gestation, cranial NTD and spina bifida accounted for 35.9% of all cases [34]. As a limitation of the current study, this study included only late ToPFA cases. While the gestational age at termination of pregnancy could be taken from the records, the gestational age at the diagnosis could not be obtained. Further studies that include both qualitative and quantitative components are needed to better analyze NTD-related termination cases.

Although the evidence is strong enough that PFAS can prevent a significant proportion of NTDs, it has been shown that the use of individual supplements is not effective enough to prevent NTD at the population level. Because unplanned pregnancies are common, and pre-pregnancy health check-up and use of folic acid supplementation before conception require a high level of awareness [35]. For this reason, mandatory folic acid fortification programs have launched to be implemented and a significant reduction in the prevalence of NTDs has been reported following mandatory fortification with folic acid in many countries [36‐40]. Long term surveillance data from the countries showed that the NTD birth prevalence can be reduced over time to as low as 5–6 per 100,000 pregnancies [9, 16, 41, 42]. However, legislative regulations mandating the fortification of staple foods with folic acid lag behind evidences, especially in Asian and European countries [43, 44]. Currently, in Turkey, a program regarding fortifying staple foods with folic acid is not implemented. Furthermore, according to Turkish Nutritional Guide-2015, > 30% of women of childbearing age were found to have folate intake below the estimated average requirement [45]. A recent study determined that 40.2% of women over the age of 15 had a folate deficiency or insufficiency (< 5.9 ng/mL) [46]. The results of our study and these supporting findings indicate the need for a public health intervention for the prevention of NTDs in Turkey.

The results of this study revealed that, despite the PFAS recommendation and promotion, NTD is still common in our country and has an important place among the causes of death. At this stage, primary prevention through mandatory folic acid supplementation seems to be the more rational solution in line with global progress. Initiation of a public health program to prevent NTD cases by fortifying staple foods with folic acid should be urgently addressed. A congenital anomaly surveillance system establishment should also be considered to monitor the progress.