UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Open neural tube defects: Risk factors, prenatal screening and diagnosis, and pregnancy management

Authors
Stephanie Dukhovny, MD
Louise Wilkins-Haug, MD, PhD
Section Editors
Deborah Levine, MD
Lynn L Simpson, MD
Deputy Editor
Vanessa A Barss, MD, FACOG

INTRODUCTION

Open neural tube defects (NTDs) are relatively common congenital anomalies that develop when a portion of the neural tube fails to close normally during the third and fourth weeks after conception (the fifth and sixth weeks of gestation). The resulting defect may involve the vertebrae, spinal cord, cranium, and/or brain. (See "Pathophysiology and clinical manifestations of myelomeningocele (spina bifida)", section on 'Embryology of the neural tube'.)

Two key advances related to open NTDs have occurred in recent decades:

Folic acid fortification of commonly consumed foods (eg, bread, flour, cornmeal, rice, pasta) and administration of folic acid supplements have been shown to prevent occurrence/recurrence of most open NTDs

Maternal serum and sonographic screening programs have led to identification of most affected pregnancies, allowing parents to make decisions about pregnancy management

This topic will review prenatal screening and diagnosis of open NTDs and other information of interest to obstetrical providers. Folic acid supplementation for prevention of open NTDs is discussed separately. (See "Folic acid supplementation in pregnancy".)

                                         
To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Sep 2017. | This topic last updated: Aug 29, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
References
Top
  1. Zaganjor I, Sekkarie A, Tsang BL, et al. Describing the Prevalence of Neural Tube Defects Worldwide: A Systematic Literature Review. PLoS One 2016; 11:e0151586.
  2. Johnson CY, Honein MA, Dana Flanders W, et al. Pregnancy termination following prenatal diagnosis of anencephaly or spina bifida: a systematic review of the literature. Birth Defects Res A Clin Mol Teratol 2012; 94:857.
  3. Copp AJ, Stanier P, Greene ND. Neural tube defects: recent advances, unsolved questions, and controversies. Lancet Neurol 2013; 12:799.
  4. Wen SW, Walker M. Risk of fetal exposure to folic acid antagonists. J Obstet Gynaecol Can 2004; 26:475.
  5. Hernández-Díaz S, Werler MM, Walker AM, Mitchell AA. Neural tube defects in relation to use of folic acid antagonists during pregnancy. Am J Epidemiol 2001; 153:961.
  6. Ornoy A. Neuroteratogens in man: an overview with special emphasis on the teratogenicity of antiepileptic drugs in pregnancy. Reprod Toxicol 2006; 22:214.
  7. Hernández-Díaz S, Werler MM, Walker AM, Mitchell AA. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med 2000; 343:1608.
  8. Wald NJ, Hackshaw AD, Stone R, Sourial NA. Blood folic acid and vitamin B12 in relation to neural tube defects. Br J Obstet Gynaecol 1996; 103:319.
  9. van der Put NM, van Straaten HW, Trijbels FJ, Blom HJ. Folate, homocysteine and neural tube defects: an overview. Exp Biol Med (Maywood) 2001; 226:243.
  10. Steegers-Theunissen RP, Boers GH, Blom HJ, et al. Neural tube defects and elevated homocysteine levels in amniotic fluid. Am J Obstet Gynecol 1995; 172:1436.
  11. Yang Y, Chen J, Wang B, et al. Association between MTHFR C677T polymorphism and neural tube defect risks: A comprehensive evaluation in three groups of NTD patients, mothers, and fathers. Birth Defects Res A Clin Mol Teratol 2015; 103:488.
  12. Windham GC, Bjerkedal T, Sever LE. The association of twinning and neural tube defects: studies in Los Angeles, California, and Norway. Acta Genet Med Gemellol (Roma) 1982; 31:165.
  13. Ross ME, Mason CE, Finnell RH. Genomic approaches to the assessment of human spina bifida risk. Birth Defects Res 2017; 109:120.
  14. Deak KL, Siegel DG, George TM, et al. Further evidence for a maternal genetic effect and a sex-influenced effect contributing to risk for human neural tube defects. Birth Defects Res A Clin Mol Teratol 2008; 82:662.
  15. Li DK, Janevic T, Odouli R, Liu L. Hot tub use during pregnancy and the risk of miscarriage. Am J Epidemiol 2003; 158:931.
  16. Edwards MJ. Review: Hyperthermia and fever during pregnancy. Birth Defects Res A Clin Mol Teratol 2006; 76:507.
  17. Dreier JW, Andersen AM, Berg-Beckhoff G. Systematic review and meta-analyses: fever in pregnancy and health impacts in the offspring. Pediatrics 2014; 133:e674.
  18. Edwards MJ. Hyperthermia as a teratogen: a review of experimental studies and their clinical significance. Teratog Carcinog Mutagen 1986; 6:563.
  19. Graham JM Jr, Edwards MJ, Edwards MJ. Teratogen update: gestational effects of maternal hyperthermia due to febrile illnesses and resultant patterns of defects in humans. Teratology 1998; 58:209.
  20. Feldkamp ML, Meyer RE, Krikov S, Botto LD. Acetaminophen use in pregnancy and risk of birth defects: findings from the National Birth Defects Prevention Study. Obstet Gynecol 2010; 115:109.
  21. Sukanya S, Bay BH, Tay SS, Dheen ST. Frontiers in research on maternal diabetes-induced neural tube defects: Past, present and future. World J Diabetes 2012; 3:196.
  22. Gabbay-Benziv R, Reece EA, Wang F, Yang P. Birth defects in pregestational diabetes: Defect range, glycemic threshold and pathogenesis. World J Diabetes 2015; 6:481.
  23. Garne E, Loane M, Dolk H, et al. Spectrum of congenital anomalies in pregnancies with pregestational diabetes. Birth Defects Res A Clin Mol Teratol 2012; 94:134.
  24. Loeken MR. Current perspectives on the causes of neural tube defects resulting from diabetic pregnancy. Am J Med Genet C Semin Med Genet 2005; 135C:77.
  25. Makelarski JA, Romitti PA, Rocheleau CM, et al. Maternal periconceptional occupational pesticide exposure and neural tube defects. Birth Defects Res A Clin Mol Teratol 2014; 100:877.
  26. Pettigrew SM, Bell EM, Van Zutphen AR, et al. Paternal and joint parental occupational pesticide exposure and spina bifida in the National Birth Defects Prevention Study, 1997 to 2002. Birth Defects Res A Clin Mol Teratol 2016; 106:963.
  27. Benedum CM, Yazdy MM, Mitchell AA, Werler MM. Impact of Periconceptional Use of Nitrosatable Drugs on the Risk of Neural Tube Defects. Am J Epidemiol 2015; 182:675.
  28. Reefhuis J, Honein MA, Schieve LA, et al. Use of clomiphene citrate and birth defects, National Birth Defects Prevention Study, 1997-2005. Hum Reprod 2011; 26:451.
  29. Benedum CM, Yazdy MM, Parker SE, et al. Association of Clomiphene and Assisted Reproductive Technologies With the Risk of Neural Tube Defects. Am J Epidemiol 2016; 183:977.
  30. Wu YW, Croen LA, Henning L, et al. Potential association between infertility and spinal neural tube defects in offspring. Birth Defects Res A Clin Mol Teratol 2006; 76:718.
  31. Greenland S, Ackerman DL. Clomiphene citrate and neural tube defects: a pooled analysis of controlled epidemiologic studies and recommendations for future studies. Fertil Steril 1995; 64:936.
  32. Boyd PA, Devigan C, Khoshnood B, et al. Survey of prenatal screening policies in Europe for structural malformations and chromosome anomalies, and their impact on detection and termination rates for neural tube defects and Down's syndrome. BJOG 2008; 115:689.
  33. Wang ZP, Li H, Hao LZ, Zhao ZT. The effectiveness of prenatal serum biomarker screening for neural tube defects in second trimester pregnant women: a meta-analysis. Prenat Diagn 2009; 29:960.
  34. Jorde LB, Carey JC, Bamshad MJ. Genetic testing and gene therapy. In: Medical Genetics, 5th ed, Elsevier, Philadelphia 2015.
  35. ACOG Committee on Practice Bulletins. ACOG practice bulletin. Clinical management guidelines for obstetrician-gynecologists. Number 44, July 2003. (Replaces Committee Opinion Number 252, March 2001). Obstet Gynecol 2003; 102:203.
  36. Driscoll DA, Gross SJ, Professional Practice Guidelines Committee. Screening for fetal aneuploidy and neural tube defects. Genet Med 2009; 11:818.
  37. Bartkute K, Balsyte D, Wisser J, Kurmanavicius J. Pregnancy outcomes regarding maternal serum AFP value in second trimester screening. J Perinat Med 2016.
  38. Gagnon A, Wilson RD, Audibert F, et al. Obstetrical complications associated with abnormal maternal serum markers analytes. J Obstet Gynaecol Can 2008; 30:918.
  39. Norem CT, Schoen EJ, Walton DL, et al. Routine ultrasonography compared with maternal serum alpha-fetoprotein for neural tube defect screening. Obstet Gynecol 2005; 106:747.
  40. Practice Bulletin No. 163 Summary: Screening for Fetal Aneuploidy. Obstet Gynecol 2016; 127:979.
  41. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 101: Ultrasonography in pregnancy. Obstet Gynecol 2009; 113:451.
  42. Cameron M, Moran P. Prenatal screening and diagnosis of neural tube defects. Prenat Diagn 2009; 29:402.
  43. Racusin D, Stevens B, Campbell G, Aagaard KM. Obesity and the risk and detection of fetal malformations. Semin Perinatol 2012; 36:213.
  44. Gitlin D, Perricelli A, Gitlin GM. Synthesis of -fetoprotein by liver, yolk sac, and gastrointestinal tract of the human conceptus. Cancer Res 1972; 32:979.
  45. Bredaki FE, Poon LC, Birdir C, et al. First-trimester screening for neural tube defects using alpha-fetoprotein. Fetal Diagn Ther 2012; 31:109.
  46. Aitken DA, McCaw G, Crossley JA, et al. First-trimester biochemical screening for fetal chromosome abnormalities and neural tube defects. Prenat Diagn 1993; 13:681.
  47. Bernard JP, Cuckle HS, Bernard MA, et al. Combined screening for open spina bifida at 11-13 weeks using fetal biparietal diameter and maternal serum markers. Am J Obstet Gynecol 2013; 209:223.e1.
  48. Sebire NJ, Spencer K, Noble PL, et al. Maternal serum alpha-fetoprotein in fetal neural tube and abdominal wall defects at 10 to 14 weeks of gestation. Br J Obstet Gynaecol 1997; 104:849.
  49. Spencer K, Khalil A, Brown L, et al. First trimester maternal serum alpha-fetoprotein is not raised in pregnancies with open spina bifida. Prenat Diagn 2014; 34:168.
  50. Wald N, Cuckle H, Boreham J, et al. The effect of maternal weight on maternal serum alpha-fetoprotein levels. Br J Obstet Gynaecol 1981; 88:1094.
  51. Thornburg LL, Knight KM, Peterson CJ, et al. Maternal serum alpha-fetoprotein values in type 1 and type 2 diabetic patients. Am J Obstet Gynecol 2008; 199:135.e1.
  52. Reichler A, Hume RF Jr, Drugan A, et al. Risk of anomalies as a function of level of elevated maternal serum alpha-fetoprotein. Am J Obstet Gynecol 1994; 171:1052.
  53. Morrow RJ, Whittle MJ, McNay MB, et al. Prenatal diagnosis and management of anterior abdominal wall defects in the west of Scotland. Prenat Diagn 1993; 13:111.
  54. http://www.acmg.net/pages/acmg_activities/stds-2002/ontd.htm (Accessed on January 18, 2017).
  55. Flick A, Krakow D, Martirosian A, et al. Routine measurement of amniotic fluid alpha-fetoprotein and acetylcholinesterase: the need for a reevaluation. Am J Obstet Gynecol 2014; 211:139.e1.
  56. Sepulveda W, Donaldson A, Johnson RD, et al. Are routine alpha-fetoprotein and acetylcholinesterase determinations still necessary at second-trimester amniocentesis? Impact of high-resolution ultrasonography. Obstet Gynecol 1995; 85:107.
  57. Wald N, Cuckle H, Nanchahal K. Amniotic fluid acetylcholinesterase measurement in the prenatal diagnosis of open neural tube defects. Second report of the Collaborative Acetylcholinesterase Study. Prenat Diagn 1989; 9:813.
  58. Loft AG, Høgdall E, Larsen SO, Nørgaard-Pedersen B. A comparison of amniotic fluid alpha-fetoprotein and acetylcholinesterase in the prenatal diagnosis of open neural tube defects and anterior abdominal wall defects. Prenat Diagn 1993; 13:93.
  59. Huerta-Enochian G, Katz V, Erfurth S. The association of abnormal alpha-fetoprotein and adverse pregnancy outcome: does increased fetal surveillance affect pregnancy outcome? Am J Obstet Gynecol 2001; 184:1549.
  60. Stoll C, Dott B, Alembik Y, Roth MP. Associated malformations among infants with neural tube defects. Am J Med Genet A 2011; 155A:565.
  61. Kennedy D, Chitayat D, Winsor EJ, et al. Prenatally diagnosed neural tube defects: ultrasound, chromosome, and autopsy or postnatal findings in 212 cases. Am J Med Genet 1998; 77:317.
  62. Hume RF Jr, Drugan A, Reichler A, et al. Aneuploidy among prenatally detected neural tube defects. Am J Med Genet 1996; 61:171.
  63. Sepulveda W, Corral E, Ayala C, et al. Chromosomal abnormalities in fetuses with open neural tube defects: prenatal identification with ultrasound. Ultrasound Obstet Gynecol 2004; 23:352.
  64. Drugan A, Johnson MP, Dvorin E, et al. Aneuploidy with neural tube defects: another reason for complete evaluation in patients with suspected ultrasound anomalies or elevated maternal serum alpha-fetoprotein. Fetal Ther 1989; 4:88.
  65. Warner AA, Pettenati MJ, Burton BK. Risk of fetal chromosomal anomalies in patients with elevated maternal serum alpha-fetoprotein. Obstet Gynecol 1990; 75:64.
  66. Ekin A, Gezer C, Taner CE, et al. Chromosomal and structural anomalies in fetuses with open neural tube defects. J Obstet Gynaecol 2014; 34:156.
  67. Kanit H, Özkan AA, Öner SR, et al. Chromosomal abnormalities in fetuses with ultrasonographically detected neural tube defects. Clin Dysmorphol 2011; 20:190.
  68. Rossi AC, Prefumo F. Additional value of fetal magnetic resonance imaging in the prenatal diagnosis of central nervous system anomalies: a systematic review of the literature. Ultrasound Obstet Gynecol 2014; 44:388.
  69. Saleem SN, Said AH, Abdel-Raouf M, et al. Fetal MRI in the evaluation of fetuses referred for sonographically suspected neural tube defects (NTDs): impact on diagnosis and management decision. Neuroradiology 2009; 51:761.
  70. Committee on Obstetric Practice, Society for Maternal–Fetal Medicine. Committee Opinion No. 720: Maternal-Fetal Surgery for Myelomeningocele. Obstet Gynecol 2017; 130:e164.
  71. Practice bulletin no. 145: antepartum fetal surveillance. Obstet Gynecol 2014; 124:182.
  72. Frey HA, Odibo AO, Dicke JM, et al. Stillbirth risk among fetuses with ultrasound-detected isolated congenital anomalies. Obstet Gynecol 2014; 124:91.
  73. Wilson RD, SOGC GENETICS COMMITTEE, SPECIAL CONTRIBUTOR. Prenatal screening, diagnosis, and pregnancy management of fetal neural tube defects. J Obstet Gynaecol Can 2014; 36:927.
  74. Rendeli C, Nucera E, Ausili E, et al. Latex sensitisation and allergy in children with myelomeningocele. Childs Nerv Syst 2006; 22:28.
  75. Cremer R, Kleine-Diepenbruck U, Hoppe A, Bläker F. Latex allergy in spina bifida patients--prevention by primary prophylaxis. Allergy 1998; 53:709.
  76. Luthy DA, Wardinsky T, Shurtleff DB, et al. Cesarean section before the onset of labor and subsequent motor function in infants with meningomyelocele diagnosed antenatally. N Engl J Med 1991; 324:662.
  77. Obeidi N, Russell N, Higgins JR, O'Donoghue K. The natural history of anencephaly. Prenat Diagn 2010; 30:357.
  78. Jaquier M, Klein A, Boltshauser E. Spontaneous pregnancy outcome after prenatal diagnosis of anencephaly. BJOG 2006; 113:951.
  79. Osathanondh R, Donnenfeld AE, Frigoletto FD Jr, et al. Induction of labor with anencephalic fetus. Obstet Gynecol 1980; 56:655.
  80. Thiery M, Parewijck W, Decoster JM. Prostaglandins for the management of anencephalic pregnancy. Prostaglandins 1981; 21:207.
  81. Milic AB, Adamsons K. The relationship between anencephaly and prolonged pregnancy. J Obstet Gynaecol Br Commonw 1969; 76:102.
  82. Cowchock S, Ainbender E, Prescott G, et al. The recurrence risk for neural tube defects in the United States: a collaborative study. Am J Med Genet 1980; 5:309.
  83. Toriello HV, Higgins JV. Occurrence of neural tube defects among first-, second-, and third-degree relatives of probands: results of a United States study. Am J Med Genet 1983; 15:601.
  84. Seller MJ. Recurrence risks for neural tube defects in a genetic counseling clinic population. J Med Genet 1981; 18:245.
  85. Czeizel A, Métneki J. Recurrence risk after neural tube defects in a genetic counselling clinic. J Med Genet 1984; 21:413.
  86. Koch M, Fuhrmann W. Sibs of probands with neural tube defects--a study in the Federal Republic of Germany. Hum Genet 1985; 70:74.
  87. Nussbaum R, McInnes RR, Willard, HF. Genetics of disorders with complex inheritance. In: Thompson & Thompson Genetics in Medicine, 6th ed, WB Saunders Co, Philadelphia 2001. p.289.
  88. MacCarthy PA, Dalrymple IJ, Duignan NM, et al. Recurrence rates of neural tube defects in Dublin maternity hospitals. Ir Med J 1983; 76:78.
  89. Medical Task Force on Anencephaly. The infant with anencephaly. N Engl J Med 1990; 322:669.