PEDIATRICS Vol. 106 No. 4 October 2000, pp. 677-683

Decline in Prevalence of Neural Tube Defects in a High-Risk Region of the United States

Roger E. Stevenson, MD^*, William P. Allen, MD^*, , G. Shashidhar Pai, MD^§, Robert Best, PhD, Laurie H. Seaver, MD^*, Jane Dean, RN^*, and Shirley Thompson, PhD^¶

From the ^* Greenwood Genetic Center, Greenwood, South Carolina;  Fullerton Genetics, Asheville, North Carolina; ^§ Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina;  Department of Obstetrics and Gynecology, University of South Carolina School of Medicine, Columbia, South Carolina; and ^¶ Department of Epidemiology and Biostatistics, University of South Carolina School of Public Health, Columbia, South Carolina.

	ABSTRACT

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Objectives.  To conduct surveillance for neural tube defects (NTDs) in a high-risk region of the United States and to prevent occurrence and recurrence of NTDs through the periconceptional use of folic acid supplements.

Design.  Active and passive methods were used for surveillance of NTD-affected pregnancies and births during a 6-year period (October 1992-September 1998). Individual genetic counseling was used to prevent NTD recurrences and a public awareness campaign was used to reduce NTD occurrences.

Setting.  State of South Carolina.

Patients.  All cases of spina bifida, anencephaly, and encephalocele identified among 278 122 live births and fetal deaths to South Carolina residents during 1992-1998 were included.

Main Outcome Measure.  Changes in occurrence and recurrence rates during a 6-year period.

Results.  Over the 6 years of surveillance, the prevalence rates for NTDs decreased from 1.89 to .95 cases per 1000 live births and fetal deaths. The prevalence decrease is explained primarily by a decrease in cases of spina bifida. Isolated NTDs accounted for 297/360 (82%) NTDs and 63/360 (18%) had at least 1 other structural anomaly. Females predominated among isolated NTDs but the sex distribution was equal among NTD cases with other anomalies. Prevalence rates for whites (1.48 cases per 1000 live births and fetal deaths) were higher than rates for blacks (.87 cases per 1000 live births and fetal deaths). There were no NTD recurrences in 113 subsequent pregnancies to mothers of infants with isolated NTDs who took periconceptional folic acid. The rate of periconceptional folic acid use among women of childbearing years increased from 8% to 35% during the 6-year project period.

Conclusion.  The prevalence of NTDs in a high-risk region has declined coincident with the increased periconceptional use of folic acid supplements among women of childbearing age.neural tube defects, high-risk region, birth defects, folic acid, spina bifida, anencephaly, encephalocele.

Birth defects have emerged as the leading cause of infant death in developed countries and contribute significantly to pregnancy loss and chronic disability.^1,2 Three of the most serious birth defects, spina bifida, anencephaly, and encephalocele, result from failure of neural tube closure during the first month of embryogenesis.³ The use of folic acid supplements in the periconceptional period has been shown to substantially reduce the risk of occurrence and recurrence of these defects.^4-6

South Carolina has been identified as a region with high prevalence of neural tube defects (NTDs).^7-9 The high prevalence was first noted in a study of birth certificate data for 1973 to 1977 by the National Center for Health Statistics.⁷ The magnitude of the increased prevalence, about twice the national prevalence, was not known until recently, and the reason(s) for the high prevalence has not been determined.^8-11

As part of an initiative to prevent recurrence of NTDs among high-risk mothers with the use of folic acid during the periconceptional period, a statewide surveillance system to detect pregnancies and deliveries with NTDs was started in October 1992.^9,12,13 Through this system, the high prevalence of NTDs was confirmed and the epidemiology of the defects in South Carolina characterized. During the first 6 years of surveillance (1992-1998) a reduction in the prevalence rate of >40%, a shift in the types of NTDs, and an increase in the periconceptional use of folic acid have been observed.

	METHODS

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Case Definition

NTDs were defined as cases of anencephaly, spina bifida, and encephalocele (International Classification of Diseases, Ninth Revision codes 740.0, 741.0, and 742.0) among infants of any gestational age born to residents of South Carolina. Both live births and fetal deaths were included. Surveillance included isolated and syndromic types of NTDs. Infants conceived in South Carolina and delivered out-of-state were included. Infants born to women who conceived out-of-state were excluded.

Prevention rates were expressed as NTD cases per 1000 live births and fetal deaths (calculated using the formula: total NTD cases with estimated date of confinement October 1 through September 30  total live births and fetal deaths October 1 through September 30 × 1000).

Surveillance

Each project year began October 1 and concluded September 30 of the subsequent year. Active and passive surveillance measures were used throughout the study period. Active surveillance methods included monitoring results of maternal serum -fetoprotein (MSAFP) laboratories, amniocentesis testing, and pregnancy ultrasonography programs. Passive methods included monthly reporting from medical records of delivery hospitals and biannual reporting from state birth certificates and death certificates. Except during year one (October 1992-September 1993) when surveillance was conducted in a pilot 14-county region of upstate South Carolina, surveillance activities were conducted statewide. Annually, there are 50 000 to 55 000 deliveries, comprised of approximately 99% live births and 1% fetal deaths. No surveillance of elective abortions was possible. It is assumed that NTDs in pregnancies of women who elect pregnancy termination would occur at the same rate as in all pregnancies. The major components of surveillance were:

1. MSAFP program monitoring. MSAFP screening is performed throughout the state and an estimated 30% to 40% of all pregnancies are screened. The MSAFP programs were continuously monitored for possible NTD-affected pregnancies;
2. Prenatal diagnosis (amniocentesis) program monitoring. Three prenatal diagnosis programs are in operation in South Carolina and approximately 2500 pregnancies are tested by amniocentesis annually. The prenatal diagnosis programs were continuously monitored for potential NTD-affected pregnancies;
3. Physician offices and prenatal centers reporting. All medical practitioners and perinatal centers that provide care for pregnant women were requested to report cases of NTD-affected pregnancies to the surveillance project. Cooperation was requested through initial direct communication and followed-up with periodic newsletters and telephone contacts;
4. Medical records reporting. Medical record departments of hospitals with delivery and newborn units were surveyed monthly by the project case workers for NTD cases recorded on medical records. Only 1 of the delivery hospitals in South Carolina did not participate in this surveillance system;
5. Vital records review. Birth and death certificates were reviewed twice annually and possible NTD cases were matched to cases ascertained by other means. Possible NTD cases that had not been previously ascertained were verified by the surveillance team;
6. Centers for Disease Control and Prevention (CDC) confirmation. Epidemiology officers from the CDC were invited to verify the completeness of case ascertainment at the end of years 1 and 4.

In addition to identifying the method by which the Surveillance Team was notified, the initial method of NTD detection was also determined. The methods of detection included ultrasonography, MSAFP testing, amniotic fluid -fetoprotein testing and examination at delivery.

All participating units adhered to informed consent procedures approved by their respective institutional review boards. Case mothers were contacted after delivery and presented with information regarding prevention of recurrence by using folic acid during the periconceptional period. Recommendations for recurrence prevention were those issued by the CDC.¹²

Coincident with the surveillance and recurrence prevention effort, the project team also promoted the population-wide supplementation of folic acid through communications with health care workers and a public awareness campaign. The educational efforts promoted folic acid supplementation for all women of childbearing age as recommended by the CDC. Initially, a statewide conference on NTD prevention was held for health care workers and health alerts were distributed to physicians and nurses who provide care for women. Thereafter, the physicians and nurses received a series of fact sheets, brochures, and annual newsletters. Materials used to inform the general public about folic acid prevention included public service announcements for television and radio, a television documentary film, billboards, advertisements, payroll envelope inserts for businesses, a calendar, and a series of brochures and posters. The First Lady of South Carolina served as spokesperson for the public campaign, which was directed not only to women who were planning a pregnancy but to all women of childbearing age.

A cohort of control mothers, randomly selected from among all registrants at delivery hospitals in South Carolina, was used to determine the frequency of folic acid utilization during the periconceptional period. In addition, telephone surveys of women in childbearing years were used to estimate changes in folic acid use in South Carolina during the last 3 years of the project.

	RESULTS

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Prevalence

The annual prevalence for all types of NTDs during the 6 years of surveillance was 1.89 (95% confidence interval [CI]: 1.31, 2.72), 1.54 (95% CI: 1.23, 1.92), 1.26 (95% CI: .98, 1.61), 1.24 (95% CI: .97, 1.60), 1.30 (95% CI: 1.02, 1.66) and .95 (95% CI: .72, 1.26) NTD cases per 1000 live births and fetal deaths (Fig 1). The observed decline in NTD prevalence rates over the most recent 5 years (pilot year excluded) was statistically significant (Mantel Haenszel ² test for trend; P = .02). The total NTDs numbered 360 and the total live births and fetal deaths were 278 122 (rate = 1.29 cases per 1000 live births/fetal deaths). Cases excluded from these numbers were 4 cases born of mothers who conceived out-of-state. Two cases born out-of-state to South Carolina residents (year 3) were included.

View larger version (16K): [in this window] [in a new window]   Fig. 1.   Rates of NTDs in South Carolina 1992-1998. Rates for anencephaly, spina bifida, and encephalocele are shown as separate curves below the curve for all NTDs. The annual periods extend from October 1 of the first year indicated through September 30 of the next year.

Types of NTDs

Of the 360 total NTDs, 297 (82.5%) were isolated NTDs: 108 (30%) with isolated anencephaly, 10 (3%) with anencephaly and spina bifida (tabulated elsewhere in this report as anencephaly), 142 (39%) with isolated spina bifida, 2 (1%) with spina bifida and encephalocele (tabulated elsewhere in this report as spina bifida), and 35 (10%) with isolated encephalocele. Two cases without overt NTDs (1 with cranial cutis aplasia, 1 with multiple vertebral anomalies) were considered to be formes frustes of isolated anencephaly and spina bifida, respectively. NTDs with at least 1 other anomaly accounted for 63 (17.5%) of the cases including 7 with Meckel syndrome, 6 with spina bifida and holoprosencephaly, 5 with chromosome aberrations, 4 with cranial defects and amniotic bands, and 41 with other anomalies listed in Table 1. One case of Meckel syndrome had hydrocephaly without an overt NTD.

During the 6 years of surveillance, the percentage of NTD cases represented by spina bifida varied from 40% to 58%, anencephaly varied from 29% to 48%, and encephaloceles varied between 7% and 16% of the total NTD cases. During years 3 to 6 the number of anencephaly cases equaled or exceeded the number of spina bifida cases (Fig 1). Among the 141 total cases of anencephaly, 118 (84%) were isolated and 23 (16%) were associated with 1 or more other anomalies. One hundred forty-four (88%) of 163 total cases of spina bifida were isolated and 19 (12%) were associated with at least 1 other anomaly. Thirty-five (62%) of 56 cases of encephalocele were isolated and 21 (38%) were associated with at least 1 other anomaly (Table 1).

Distribution

NTD cases were distributed throughout the state without any apparent prevalence gradient (Fig 2). The generally lower prevalence in the central counties of the state currently is not explained. The overall rates in various counties during the 6-year period ranged from a low of 0 cases/1000 live births and fetal deaths (McCormick, Edgefield, Saluda, Union, Lee, Calhoun, and Bamberg counties) to a high of 4.1 cases/1000 live births and fetal deaths (Clarendon County). There appeared to be no concentration of cases in the proximity of the Savannah River Nuclear Site or known hazardous waste sites.

View larger version (52K): [in this window] [in a new window]   Fig. 2.   Rates for NTDs in South Carolina by mother's county of residence, 1992-1998. Stars indicate the location of the 3 surveillance centers. Counties with rates of <1.30 cases per 1000 live births and fetal deaths are shown in white, counties with rates between 1.30 and 2.0 are lightly shaded, and counties with rates >2.0 are darkly shaded. No cases of NTDs occurred in the 8 counties with no prevalence rates indicated.

Parental Ages

Among parents of infants with isolated NTDs, the mean maternal age was 25 years (range: 14-42 years; n = 291) and mean paternal age was 28 years (range: 14-58 years; n = 224). Mean maternal age among parents of infants with NTDs and other anomalies was 25 years (range: 14-41 years; n = 63) and mean paternal age 28 years (range: 16-45 years; n = 42). The mean maternal age among controls was 26 years (range: 14-40 years; n = 288).

Predisposing Factors

In 6 instances, the mother took anticonvulsants during the periconceptional period. Depakote was used in 4 instances in which infants had spina bifida (3 cases) or spina bifida and agenesis of the corpus callosum (1 case). Depakote and Tegretol were used in 1 instance and the infant had spina bifida. One mother used phenobarbital and the infant had an encephalocele. Seventeen mothers had gestational diabetes mellitus and 9 mothers had insulin-dependent diabetes mellitus.

All except 4 cases were first occurrences in the nuclear family. One case of spina bifida was born of a mother with spina bifida, 1 twin with spina bifida had a co-twin with spina bifida, 1 case of anencephaly had a prior sibling with anencephaly, and 1 case of Meckel syndrome had a prior sibling with Meckel syndrome.

Sex Distribution and Racial Distribution

Although the sex distribution among NTD cases with other anomalies was equal (31 males, 30 females, 2 unknown), females predominated among isolated NTDs (119 males, 151 females, 27 unknown; Table 1). The rates for isolated NTDs and for NTDs with other anomalies were higher among whites (1.24 and .24 cases per 1000 live births and fetal deaths, respectively) than among blacks (.70 and .17 cases per 1000 live births and fetal deaths, respectively). The number of cases among other racial groups was insufficient for meaningful rate calculations.

Methods of NTD Detection

Ultrasonography was the leading means of initial identification of NTD cases, followed by MSAFP screening (Table 2). Only 61 cases (17%) came to delivery before detection of an NTD. Initial detection was by amniotic fluid -fetoprotein in 10 (3%) cases.

Reporting of NTDs to Surveillance System

Of the numerous sources that reported NTD cases to the surveillance project, obstetrics offices and clinics, MSAFP screening programs, genetic clinics, and hospital medical records were most important, reporting 304 (85%) of the NTD-affected pregnancies/deliveries. Other sources are shown in Table 3.

Outcome of Index Pregnancies

Of the 360 conceptions in 359 pregnancies, 4 (1%) spontaneously aborted between 13 and 21 weeks, 179 (50%) were medically aborted between 13 and 26 weeks, 24 (7%) had spontaneous fetal death after week 21, and 153 (42%) continued to live birth. Of the 153 infants born alive, 28 (18%) died within the first month of life.

Subsequent Pregnancies

During the 6-year follow-up period, 132 subsequent pregnancies are known to have occurred among 108 women who had infants with isolated NTDs. Periconceptional folic acid was used in 113 pregnancies (daily intake of .4 mg in 19, .8 mg in 10, 2 mg in 1, and 4 mg in 83 pregnancies). The outcomes of the pregnancies included 20 spontaneous abortions including 3 with blighted ova, 3 ectopic pregnancies, 3 fetal demises, 1 elective termination for trisomy 9, 80 live-born normal infants, and no NTD-affected infants. Six pregnancies are still in progress. Among 19 pregnancies to mothers who did not take periconceptional folic acid, 1 mother of an infant with isolated anencephaly moved out-of-state, failed to take folic acid, and had a subsequent pregnancy with anencephaly.

During this same period, 31 pregnancies occurred among 23 mothers of infants with syndromic NTDs. One mother of an infant with Meckel syndrome had a subsequent pregnancy with an affected infant.

Use of Folic Acid

The use of folic acid among control women before conception was reported by 8%, 16%, 17%, 17% and 30% during years 1 through 5, respectively. Most vitamin users (90%) took 400 µg of folic acid daily as part of an over-the-counter multivitamin preparation. Ten percent of vitamin users took prescription prenatal vitamins containing 800 µg of folic acid. Telephone surveys during years 4 (1996), 5 (1997) and 6 (1998) indicated that 25.2% (n = 178) and 34.4% (n = 501) and 35% (n = 603) of women of childbearing age were taking folic acid 4 or more times weekly.

	DISCUSSION

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Our surveillance findings confirm previous reports of high prevalence of NTDs in South Carolina.^7,8 Prevalence of spina bifida during years 1 to 6 of the study was .58 cases per 1000 live births and fetal deaths, which is high compared with the rate of .33 cases per 1000 live births and fetal deaths reported by the Metropolitan Atlanta Congenital Defects Program for the years 1990-1996. It also exceeds the rates of .46 and .44 cases per 1000 live births reported by the 16 state-based birth defects surveillance systems in the United States and the Birth Defects Monitoring Program for the period 1983-1990.¹¹ The overall prevalence for anencephaly during the study period was .51 cases per 1000 live births and fetal deaths. This rate greatly exceeds the rate of .18 cases per 1000 live births and fetal deaths reported by the Metropolitan Atlanta Congenital Defects Program for the period 1990-1996.¹⁴

The reduction in NTD prevalence over the 6 years may be attributed primarily to a reduction in the rate for spina bifida (Fig 1). During years 1 to 3, the rates of spina bifida (.98, .80, and .60/1000 live births and fetal deaths) exceeded the rates of anencephaly (.67, .53, and .41/1000 live births and fetal deaths) by >40%. During years 4 to 6, the rate of anencephaly was equal to or greater than the rate of spina bifida. In this series, there were consistently more encephaloceles than in most other NTD series, accounting for 16% of the 1992-1998 NTDs.^3,14,15

The frequency with which other structural anomalies have been associated with NTDs varies considerably from study to study, but overall averages about 20%.^3,15-17 In this study, isolated defects accounted for 62% of encephaloceles, 84% of anencephaly cases, and 88% of spina bifida cases (Table 1). Among the 63 NTDs with other structural anomalies, several recognized syndromes were documented. These included chromosome aberrations (5 cases), single gene defects (Meckel syndrome: 7 cases), and environmentally caused defects (amniotic bands: 4 cases). In 30 cases there were other midline defects: holoprosencephaly/aprosencephaly: 7 cases; cleft lip/cleft palate: 8 cases; diaphragmatic hernia: 4 cases; cardiac defects: 6 cases; and abdominal wall defects: 5 cases. The higher rate of associated defects with encephalocele has been documented in other studies.³

Prenatal diagnosis through ultrasonography, MSAFP screening, and amniocentesis may influence NTD surveillance substantially^9,18,19 NTD-affected pregnancies so identified may be electively terminated and not recorded as NTD cases in hospital medical records or vital records. Of the 1992-1998 NTD cases reported here, 44% were prenatally diagnosed and the pregnancies terminated before the end of the 20th week. Failure to include these cases in surveillance will result in inaccurate lower rates for NTDs.

The literature reports an expected recurrence rate for isolated NTDs of 2% to 5%. Therefore, out of the 113 subsequent pregnancies among women who used folic acid in the periconceptional period, perhaps 2 to 6 cases of NTDs would be expected. None have occurred thus far, suggesting that periconceptional folic acid use had a protective effect against recurrence of NTDs.

Although there was no recurrence of isolated NTDs among women who took periconceptional folic acid, there was an apparently high rate of spontaneous fetus loss. Twenty-five percent of repeat pregnancies among case mothers taking folic acid resulted in spontaneous abortion, fetal demise, or ectopic implantation. This rate of spontaneous fetal loss is higher than the generally accepted rate in the United States (10%-15%), and higher than the rates in folic acid exposed pregnancies (11.2%-13%) reported by Hook and Czeizel.^2,20,21 Although our findings may appear to support the previous suggestion of terathanasia as a mechanism for folic acid's preventive effects on NTDs, we believe our findings may be more indicative of the intensity of monitoring of subsequent pregnancies.²¹ In the absence of a group of unexposed controls comparably monitored for fetal loss, we cannot directly address the role that terathanasia might play in NTD prevention in our patient population.

Both the reporting of folic acid use in population-based telephone surveys and by control subjects enrolled in this project suggest a steady increase in awareness of the protective effect of periconceptional folic acid use against NTDs. As of the last 2 years of this project, only about one third of women of childbearing years use folic acid daily as recommended by the US Public Health Service and by the South Carolina Task Force on Folic Acid. This number is reminiscent of the March of Dimes surveys of 1995, 1997, and 1998 showing that 28%, 32%, and 32%, respectively, of women in childbearing years reported folic acid supplementation on a daily basis.²²

Specific reasons for the high rate of NTDs in South Carolina and for the decrease in rates during the surveillance period are not yet identified. The decline may be a temporary phenomenon reflecting one valley in an oscillating prevalence curve. It may be a part of the worldwide decrease in these defects, a phenomenon likewise not explained. It may reflect the impact of the nominal population-wide increase in folic acid intake from dietary sources, vitamin supplements, and food fortification. In the absence of a clear understanding of the cause(s) of NTDs, there may be unrecognized variables associated with the changes in rates. These uncertainties aside, the temporal relationship between the reduction in NTD rates and the increased utilization of folic acid supplements by women of childbearing years in South Carolina is in agreement with the known protective effect of folic acid against these malformations.^5,6

	ACKNOWLEDGMENTS

The project was supported through a cooperative agreement with the Centers for Disease Control and Prevention (U85/CCU 408774), and through grants from the South Carolina Department of Disabilities and Special Needs, the South Carolina Developmental Disabilities Council, the Duke Endowment, the South Carolina Department of Health and Environmental Control, and the South Carolina Chapter of the March of Dimes.

The contributions and cooperation of the obstetricians, perinatologists, and delivery hospitals in South Carolina were essential to the surveillance of NTDs in South Carolina. Sylvia Stidham, RN, Rene Betros, RN, Beth Allen, MS, and Kim Stewart assisted in the surveillance, verification, specimen collection, and prevention activities of the project. Joe Mulinare, MD, Marcia Kelly, and Karen Buchanan provided assistance and advice.

	FOOTNOTES

Received for publication Oct 21, 1999; accepted Jan 25, 2000.

Reprint requests to (R.E.S.) Greenwood Genetic Center, 1 Gregor Mendel Circle, Greenwood, SC 29646. E-mail: res{at}ggc.org

	ABBREVIATIONS

NTD, neural tube defects; MSAFP, maternal serum -fetoprotein; CDC, Centers for Disease Control and Prevention; CI, 95% confidence interval.

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