Analysis of Mortality among Neonates and Children with Spina Bifida: An International Registry‐Based Study, 2001‐2012

Abstract Background Medical advancements have resulted in better survival and life expectancy among those with spina bifida, but a significantly increased risk of perinatal and postnatal mortality for individuals with spina bifida remains. Objectives To examine stillbirth and infant and child mortality among those affected by spina bifida using data from multiple countries. Methods We conducted an observational study, using data from 24 population‐ and hospital‐based surveillance registries in 18 countries contributing as members of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). Cases of spina bifida that resulted in livebirths or stillbirths from 20 weeks' gestation or elective termination of pregnancy for fetal anomaly (ETOPFA) were included. Among liveborn spina bifida cases, we calculated mortality at different ages as number of deaths among liveborn cases divided by total number of liveborn cases with spina bifida. As a secondary outcome measure, we estimated the prevalence of spina bifida per 10 000 total births. The 95% confidence interval for the prevalence estimate was estimated using the Poisson approximation of binomial distribution. Results Between years 2001 and 2012, the overall first‐week mortality proportion was 6.9% (95% CI 6.3, 7.7) and was lower in programmes operating in countries with policies that allowed ETOPFA compared with their counterparts (5.9% vs. 8.4%). The majority of first‐week mortality occurred on the first day of life. In programmes where information on long‐term mortality was available through linkage to administrative databases, survival at 5 years of age was 90%‐96% in Europe, and 86%‐96% in North America. Conclusions Our multi‐country study showed a high proportion of stillbirth and infant and child deaths among those with spina bifida. Effective folic acid interventions could prevent many cases of spina bifida, thereby preventing associated childhood morbidity and mortality.


Methods:
We conducted an observational study, using data from 24 population-and hospital-based surveillance registries in 18 countries contributing as members of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR).
Cases of spina bifida that resulted in livebirths or stillbirths from 20 weeks' gestation or elective termination of pregnancy for fetal anomaly (ETOPFA) were included.
Among liveborn spina bifida cases, we calculated mortality at different ages as number of deaths among liveborn cases divided by total number of liveborn cases with spina bifida. As a secondary outcome measure, we estimated the prevalence of spina bifida per 10 000 total births. The 95% confidence interval for the prevalence estimate was estimated using the Poisson approximation of binomial distribution.
Results: Between years 2001 and 2012, the overall first-week mortality proportion was 6.9% (95% CI 6.3, 7.7) and was lower in programmes operating in countries with policies that allowed ETOPFA compared with their counterparts (5.9% vs. 8.4%). The majority of first-week mortality occurred on the first day of life. In programmes where information on long-term mortality was available through linkage to administrative databases, survival at 5 years of age was 90%-96% in Europe, and 86%-96% in North America.

Conclusions:
Our multi-country study showed a high proportion of stillbirth and infant and child deaths among those with spina bifida. Effective folic acid interventions could prevent many cases of spina bifida, thereby preventing associated childhood morbidity and mortality.

K E Y W O R D S
epidemiology, mortality, registry-based study, spina bifida

| BACKG ROU N D
Spina bifida is a common and major congenital disorder of the central nervous system characterised by incomplete or incorrect closure of the neural tube during the embryonic development. 1 Spina bifida affects over 150 000 births worldwide and contributes to significant disability and child mortality. 2 The observed prevalence of spina bifida varies globally and is largely influenced by differences in surveillance methods, prenatal diagnosis and elective termination policies, and folic acid fortification of staple foods in a given country or region. [3][4][5] Evidence from both randomised clinical trials and observational studies shows that many cases of spina bifida can be prevented by women taking 400-800 mcg/day of folic acid during preconception and early pregnancy. [6][7][8][9] The United States Preventive Services Task Force (USPSTF) recommends that all women planning or capable of pregnancy take a daily supplement containing 0.4-0.8 mg (400-800 mcg) of folic acid. 10 Medical advancements since the 1960s, especially in developed countries, have resulted in better survival and life expectancy among those with spina bifida. 11 But even with improved medical care, studies show a significantly increased risk of perinatal and postnatal mortality for individuals with spina bifida compared to those without. 1,[12][13][14][15][16][17][18] Mortality associated with spina bifida is more frequent in countries with fewer resources and less health care access compared with their counterparts in high-income regions of the world. 1,2,4,5 Few studies have been conducted that examined mortality associated with spina bifida, and most of them were conducted in developed countries. 15,16,19,20 Wang  two studies from the United States and Canada showed an improvement in survival among cohorts born in later years compared with those born during the late 1970s and the early 1980s. 17,20,21 There are opportunities to study mortality among infants born with spina bifida utilising pooled data from large networks of established birth defects surveillance systems, which have a potential to link to death certificates or other administrative health data sets.
The primary objective of our study was to examine perinatal and infant and child mortality for those affected by spina bifida using data from multiple birth defects registries affiliated with the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR) and examine temporal trends in mortality. As a secondary objective, we examined the total prevalence of spina bifida using data from participating programmes. We were also able to stratify by the availability of elective termination for fetal anomalies (ETOPFA) on perinatal and infant and child mortality.

| Study design and setting
International Clearinghouse for Birth Defects Surveillance and Research was established in 1974 and is a voluntary non-profit organisation affiliated with the World Health Organization (http:// www.icbdsr.org/). As a consortium of birth defects surveillance and research programmes from around the world, ICBDSR investigates and aims to prevent birth defects and minimise any negative consequences associated with them. As of 2018, there are 42 birth defects surveillance programmes in ICBDSR, either population-based or hospital-based, of which 27 contribute data on an annual basis.
These registries provide aggregated data on children and fetuses affected with at least one of 39 different birth defects to ICBDSR for surveillance purposes (a list of all monitoring programmes and their surveillance attributes can be found at http://www.icbdsr.org/ wp-conte nt/annual_repor t/Repor t2014.pdf). Each programme also collects data on the total annual number of livebirths and stillbirths in their source population for each of the surveillance years to aid in prevalence estimation.
For the current analysis, each programme contributed data for the longest period available, and in general, this period included the year the surveillance programme started until year 2015 or last year of the surveillance (Figure 1). We used data from 24 ICBDSR member registries or programmes, representing 18 countries in Asia, Europe, North America, and South America. Programmes were eligible to participate in the study if they collected data on both spina bifida prevalence and mortality among infants born with spina bifida. For each programme in our study, we examined indicators describing the type of registry (population-based vs. hospital-based systems), coverage, ascertainment period, stillbirth definition, ETOPFA allowed and availability of prenatal screening services (Table 1). Each programme has local procedures for ethics approval, and because this study was done using aggregated data, no additional ethics committee approval was required.

Study question
To examine perinatal and infant and child mortality and its trends for those affected with spina bifida.

What is already known
Medical advancements have resulted in better survival and life expectancy among those with spina bifida, but a significantly increased risk of perinatal and infant and child mortality remains.

What this study adds
Our multi-country study showed perinatal and infant and child mortality is a major concern for those with spina bifida. The overall first-week mortality proportion was lower in programmes with policies that allowed elective terminations of pregnancy for fetal anomalies compared with those that did not. The proportion of perinatal and infant and child deaths were higher among spina bifida cases with co-occurring unrelated major anomalies or genetic syndromes compared with those with isolated spina bifida. co-occurring unrelated major birth defects. The definition of MCA included spina bifida co-occurring with one or more unrelated major anomalies. A case was defined as 'syndromic' when the spina bifida was part of a genetic disorder or a recognised syndrome.

| Mortality
Information on mortality was based on several follow-up methods as applied by the surveillance programmes, including follow-up until discharge from the hospital after birth, active or passive follow-up of the children by clinicians or registry staff, or follow-up by linking to administrative databases such as death records or other health care databases. Programmes could use more than one follow-up method.
In Table 2, we present the method of follow-up that was applied in each programme. In our analysis, we examined mortality at different ages, including up to the first day of life, day 2-6 (early neonatal), day 7-27 (late neonatal), day 28-1 year (infant), 1-4 years (under five), and ≥5 years of age.

| Statistical analysis
We report results primarily per individual programme, and not as a pooled analysis, because some programmes contributed considerably more cases than others, and because our main goal was to examine variations across individual programmes and countries.
For each programme, we calculated total prevalence of spina bifida as the total number of cases with spina bifida (livebirths + stillbirths +ETOPFA for spina bifida) divided by the total number of births (livebirths + stillbirths) in a specified time period. We estimated prevalence and 95% confidence interval for the prevalence estimate using the Poisson approximation of binomial distribution.
We did not include ETOPFA in the denominator of the prevalence formula because of lack of data on the total number of terminations for each programme. We estimated the proportion of spina bifida-affected pregnancies resulting in livebirths, stillbirths, and ETOPFA.
We did not report results by single years or for programmes that had fewer than 5 cases.

| Programme characteristics
A total of 24 ICBDSR member programmes with birth defects registries representing 18 countries contributed data for a part or entire time period between years 1974 and 2015 examined in our analysis ( Figure 1). Sixteen of the 24 registries were population-based, with regional (n = 10), statewide (n = 3), or national (n = 3) coverage.
The maximum age of ascertainment for birth defects varied by programme; however, most cases of spina bifida can be easily identified at birth. Criteria to define stillbirths also varied. ETOPFA was not TA B L E 3 Total number of births, total number of spina bifida cases and prevalence per 10 000 births, proportion of livebirth among total cases of spina bifida, proportion of stillbirths among total cases of spina bifida, and proportion of ETOPFA allowed in the surveillance region for 5 of the 24 programmes. In all regions covered by the ICBDSR programmes included in our analysis, prenatal screening services were offered in recent years (Table 1).
Mortality analysis was mostly restricted to a short postnatal follow-up (Table 2)   and UK-Wales, 72.7%). Overall, the proportion of stillbirths ranged between 0% and 10%, and the proportion of stillbirths was highest in programmes from countries that do not allow termination of pregnancy.

| Prevalence and pregnancy outcome
The overall results on prevalence of spina bifida, examined as a secondary objective of the study, for the complete surveillance period , are presented in Table S1. The total number of births covered by all programmes was 28 213 327 (including livebirths and stillbirths), and the total number of spina bifida cases equalled to 14 159. Thus, the prevalence of spina bifida in our study was estimated to be 5.0 per 10 000 total births (95% CI 4.9, 5.1).
When taking isolated and complex cases together, the majority of A total of 17 programmes provided data on additional birth defects co-occurring with spina bifida. Since the number of spina bifida cases with a syndromic aetiology was very small, we pooled them with the MCA cases in the analyses. On average, 68% presented as isolated and 32% as MCA or as part of a genetic syndrome ( Table 5). The distribution varied by programme; in Israel and Mexico-RYVEMCE, more than 90% of spina bifida cases were described as isolated, whereas in Italy-Lombardy and in South America-ECLAMC, 53% and 51% were described as isolated, respectively. In Europe, where ETOPFA is allowed and common, ETOPFA proportion was similar between isolated and MCA/syndromic cases.
Among all programmes, the proportion of first-day and first-week mortality was higher in MCA/syndromic cases compared with isolated cases (Table 5).

| Principal findings
This is the first multi-country, multi-registry study that provides estimates of prevalence, perinatal and infant and child mortality, and mortality trends among those born with spina bifida using data from 24 birth defects programmes in 18 countries affiliated with the ICBDSR. Our findings confirm that a substantial propor-

| Strengths of the study
Our study was the first to examine perinatal and infant child mortality among those born with spina bifida in a diverse set of populations using multi-registry, multi-country data.

| Interpretation
The average prevalence of spina bifida (including all cases) in our analysis, using data from 24 programmes reporting to ICBDSR,

| CON CLUS IONS
Data from 24 programmes provided a first summary of spina bifida-associated perinatal and infant and child mortality and their trends. In the many countries that contributed data for our analysis, mortality among those affected with spina bifida is a major concern, especially during the first day and first week of life.

ACK N OWLED G EM ENTS
We thank each ICBDSR member programme's staff for providing information on the characteristics of their programme and data on spina bifida case status, and for conducting linkages between birth defects registries and administrative databases to assess mortality outcomes.
Disclaimer The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.