The annual prevalence rates for the 17 years of surveillance are shown in with a graphic representation of the rates of isolated NTDs, NTDs with other anomalies, and total NTDs for years 1–17 (). There were statistically significant declines in overall NTDs (p<0.0001) and in isolated NTDs (p<0.0001), but not for NTDs with associated anomalies (p=0.2803) from 1992 through 2009. also shows the rates of spina bifida, anencephaly, and encephalocele for 17 years of surveillance. The rates of spina bifida (p<0.0001) and anencephaly (p<0.0001) declined significantly during this period and the decrease in the rate of encephalocele (p=0.0586) was near significance. The number of NTD cases totalled 916 among the 945,685 livebirths and fetal deaths during the 17 year period.
Neural tube defect (NTD) numbers and rates1 per 1,000 live births and fetal deaths in South Carolina, by project year2 and type, 1992–2009
Figure 1 Rates of total NTDs (squares), isolated NTDs (circles), and NTDs with other anomalies (triangles) per 1000 live births and fetal deaths for 1992 through 2009. Project years run from October to September of the next year. Two-sided Cochrane-Armitage trend (more ...)
Ultrasonography was the most frequent means of NTD detection in all years of surveillance, accounting for 55% of identification of cases in the first five years and for 78% in the last five years (; available at www.jpeds.com
). Maternal serum screening for alpha fetoprotein became a progressively less frequent source of initial case identification. Only 13% of NTD cases reached delivery without prior detection. Three sources – medical records, genetics clinics/autopsy records, and obstetric offices/clinics – accounted for 76% of case notifications to the surveillance program (; available at www.jpeds.com
Table 2; online
Methods of detection of neural tube defects in South Carolina, 1992–2009
Table 3; online
Methods of notification for the surveillance program from 1992 through 2009
At the outset of this study, spina bifida was the most common of the NTDs, accounting for 52% of the total number. Anencephaly was intermediate in prevalence and encephalocele least common, accounting for 35% and 13%, respectively.
Prevalence rates for spina bifida and anencephaly decreased significantly during the 17 year period with the prevalence rate for anencephaly exceeding the rate for spina bifida in some years (). The prevalence rate for encephaloceles and for NTDs with associated anomalies did not decrease significantly. Among the 916 total NTDs identified, 728 (79%) were isolated defects.
A slight majority (106 of 188 – 56%) of NTDs with other structural anomalies constituted recognizable patterns of malformations (). Chromosome aberrations were found in 43 cases, with trisomy 18 (21 cases) being most common and triploidy (6 cases) being second most common. Other syndromes included amniotic bands (33 cases), Meckel syndrome (12 cases), OEIS (Omphalocele, Exstrophy of the bladder, Imperforate anus, and Sacral meningomyelocele; 7 cases), NTD-holoprosencephaly (6 cases), limb-body wall complex (2 cases), and Goldenhar syndrome (3 cases).
Neural tube defects (NTDs) with co-occurring anomalies
Eighty-two NTD cases with co-occurring anomalies did not appear to constitute recognizable syndromes or there was insufficient documentation to make a syndrome diagnosis (; available at www.jpeds.com
). The co-occurring anomalies ranged from mild and trivial (e.g. abnormal palmar creases, bifid scrotum) to severe and lethal (e.g. conjoined twinning, sirenomelia). Certain defects (e.g. diaphragmatic hernia, omphalocele) were placed in this category, although they might also have reasonably been classified as defects secondary to the NTDs.
Table 5; online
Eighty-two cases of co-occurring anomalies with neural tube defects that do not appear to constitute a recognizable syndrome
Maternal diabetes mellitus has long been recognized as a risk factor for NTDs.4
We had information on the diabetes status of mothers in 704 pregnancies that resulted in infants born with an NTD. Twenty-eight of these (4.0%) had preexisting diabetes and 27 (3.8%) had gestational diabetes. The percentage of NTD-associated pregnancies with preexisting diabetes (4.0%) was fourfold the background rate of preexisting diabetes in South Carolina (0.9%). The percentage of NTD-associated pregnancies with gestational diabetes (3.8%) was not significantly different from the background rate of gestational diabetes (4.0%).18
After fortification, the rates of NTDs among infants of mothers with preexisting diabetes decreased from 3.5 to 2.7 per 100,000 live births and fetal deaths. The rate of NTDs among infants of mothers with gestational diabetes decreased from 6.4 to 1.4 per 100,000 after fortification.
NTDs (66 spina bifida, 55 anencephaly, and 19 encephalocele) occurred in pregnancies in which the mother reported use of FA during the periconceptional period (; available at www.jpeds.com
). The dose of FA used by the mothers varied from 0.4 mg to 1.8 mg. A slightly higher, but non-significant (chi-square = 0.94, P
=0.3321), percentage (23.6%) of these NTD pregnancies had associated anomalies, as compared with the percentage of NTD-associated anomalies (20.0%) born to mothers not using FA.
Table 6; online
Neural tube defects (NTDs) occurring in pregnancies where mothers who took folic acid
Pregnancies (n=484) occurred to women with a prior NTD. Among 418 pregnancies in which the mother used periconceptional FA supplements, there was one recurrence (0.2%), a recurrent anencephaly with a 13q deletion. Among 66 pregnancies in which the mother did not use FA supplements, there were four (6.1%) recurrences (a recurrent Meckel/encephalocele, a recurrent anencephaly, a recurrent encephalocele, and a situation where the first child had spina bifida and the second had craniorachischisis). These proportions are significantly different (p=0.0014) using a two-tailed Fisher exact test. Two of the recurrences (1.2%) occurred in 173 pregnancies prior to fortification, and the other three (1.0%) occurred in 311 post-fortification pregnancies. These proportions are not significantly different (p=1.0000) using a two-tailed Fisher exact test.
Based on the 1992 prevalence rates of 1.87 cases per 1,000 live births and fetal deaths, approximately 1,738 NTD-affected pregnancies would have been expected over the subsequent 16 years; however, there were only 885 NTD-affected pregnancies during this time period. This represents a reduction of 853 NTD cases prevented by FA and other unknown factors ( and ; available at www.jpeds.com
). Since 1992–1993, there has been a decrease in the number of spontaneous abortions with NTDs (67% decrease), terminations of NTD-affected pregnancies (54% decrease), and live born infants with NTDs (54% decrease). Of the total 982 NTD-affected pregnancies over 17 years (), 124 (12.6%) were lost to spontaneous abortion and fetal death, 430 (43.8%) were prenatally diagnosed and the pregnancies interrupted, and 428 (43.6%) were live born NTD cases.
Figure 2 The combined impact of prenatal diagnosis and folic acid utilization on the number of NTDs. The top line of this figure gives an estimate of the neural tube defect cases that would have occurred without folic acid supplementation, fortification, and other (more ...)
The distribution among males and females with NTDs that had other associated anomalies was equal (87 males, 87 females, 14 with unknown sex), and the sex ratio of isolated NTDs showed significantly more females (47.5%) than males (39.7%, P-value = 0.003). There was a slightly higher prevalence rate of total NTDs among Hispanics (1.2 per 1,000 live births and fetal deaths) than any other racial group (non-Hispanic whites 1.1; non-Hispanic blacks 0.7). Although Hispanics had the highest rate of anencephaly, non-Hispanic whites had the highest rate of encephalocele as well as the highest rate of spina bifida. Hispanics had the highest rate of isolated NTDs, and all races had near equal rates of NTDs with other anomalies.
During the first year of this project (1992), 8% of the women of childbearing age knew of the health benefits of FA and 8% took FA. These percentages increased to 33% and 33% in year 5. These percentages were based on interviews of small numbers (Year 1=38, Year 5=60) of women of childbearing years who completed pregnancies not associated with an NTD infant. From 1997 to 2007, knowledge and use of FA was based on telephone interviews of approximately 1,000 women of childbearing age. The percentage of women having knowledge of FA increased from 32% to 65% and the percentage of women using FA four or more times a week increased from 25% to 35% during this period.