Advertisement
JOGC

Guideline No. 410: Prevention, Screening, Diagnosis, and Pregnancy Management for Fetal Neural Tube Defects

Published:November 16, 2020DOI:https://doi.org/10.1016/j.jogc.2020.11.003

      ABSTRACT

      Objective

      This revised guideline is intended to provide an update on the genetic aspects, prevention, screening, diagnosis, and management of fetal neural tube defects.

      Target population

      Women who are pregnant or may become pregnant. Neural tube defect screening should be offered to all pregnant women.

      Options

      For prevention: a folate-rich diet, and folic acid and vitamin B12 supplementation, with dosage depending on risk level. For screening: second-trimester anatomical sonography; first-trimester sonographic screening; maternal serum alpha fetoprotein; prenatal magnetic resonance imaging. For genetic testing: diagnostic amniocentesis with chromosomal microarray and amniotic fluid alpha fetoprotein and acetylcholinesterase; fetal exome sequencing. For pregnancy management: prenatal surgical repair; postnatal surgical repair; pregnancy termination with autopsy. For subsequent pregnancies: prevention and screening options and counselling.

      Outcomes

      The research on and implementation of fetal surgery for prenatally diagnosed myelomeningocele has added a significant treatment option to the previous options (postnatal repair or pregnancy termination), but this new option carries an increased risk of maternal morbidity. Significant improvements in health and quality of life, both for the mother and the infant, have been shown to result from the prevention, screening, diagnosis, and treatment of fetal neural tube defects.

      Benefits, harms, and costs

      The benefits for patient autonomy and decision-making are provided in the guideline. Harms include an unexpected fetal diagnosis and the subsequent management decisions. Harm can also result if the patient declines routine sonographic scans or if counselling and access to care for neural tube defects are delayed. Cost analysis (personal, family, health care) is not within the scope of this clinical practice guideline.

      Evidence

      A directed and focused literature review was conducted using the search terms spina bifida, neural tube defect, myelomeningocele, prenatal diagnosis, fetal surgery, neural tube defect prevention, neural tube defect screening, neural tube defect diagnosis, and neural tube defect management in order to update and revise this guideline. A peer review process was used for content validation and clarity, with appropriate ethical considerations.

      Validation Methods

      The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations).

      Intended Audience

      Maternity care professionals who provide any part of pre-conception, antenatal, delivery, and neonatal care. This guideline is also appropriate for patient education.

      RECOMMENDATIONS (GRADE ratings in parentheses)

      • Prevention
      • 1
        Women with a low risk for neural tube defects or other folic acid–sensitive congenital anomalies, whose male partner also has a low risk, require a diet of folate-rich foods and a daily oral multivitamin supplement containing 0.4 mg folic acid and vitamin B12 for at least 2 to 3 months before conception, throughout the pregnancy, and for 4 to 6 weeks postpartum or as long as breastfeeding continues (strong, moderate).
      • 2
        Women with a moderate risk for neural tube defects or other folic acid–sensitive congenital anomalies, or whose male partner has a moderate risk, require a diet of folate-rich foods and daily oral supplementation with a multivitamin containing 1.0 mg folic acid and vitamin B12, beginning at least 3 months before conception. Women should continue this regime until 12 weeks gestation (strong, high). From 12 weeks gestation, continued daily supplementation should consist of a multivitamin with 0.4 to 1.0 mg folic acid throughout the pregnancy and for 4 to 6 weeks postpartum or as long as breastfeeding continues (strong, moderate).
      • 3
        Women at high risk for neural tube defects or with a male partner with a neural tube defect affecting himself or his children require a diet of folate-rich foods and daily oral supplementation with 4.0 to 5.0 mg folic acid and vitamin B12 for at least 3 months before conception and until 12 weeks gestation. From 12 weeks gestation, continued daily supplementation should consist of a multivitamin with 0.4 to 1.0 mg of folic acid throughout the pregnancy and for 4 to 6 weeks postpartum or as long as breastfeeding continues (strong, high).
      • Screening
      • 4
        The primary screening technology used to detect fetal structural abnormalities, including open and closed neural tube defects (i.e., anencephaly, encephalocele, myelomeningocele, and other spina bifida malformations), is second-trimester anatomical sonography with detailed fetal intracranial and spinal imaging (strong, moderate).
      • 5
        First-trimester sonographic neural tube defect screening and diagnostic techniques are available and recommended, especially for women with moderate- or high-risk factors. Sonography providers and units providing this first-trimester service must demonstrate appropriate training, expertise, and evidence of follow-up and audit of first-trimester sonographic anomalies (strong, moderate).
      • 6
        Maternal serum alpha fetoprotein can be used as a primary screening tool for open/closed neural tube defects, in limited clinical indications, for pregnant women if their geographical location or their clinical factors (such as a pre-pregnant body mass index ≥35 kg/m2) limit timely and high-quality sonographic screening at 18 to 22 weeks gestation (strong, moderate).
      • 7
        As a complement to maternal serum cell-free placental DNA for aneuploidy screening, maternal serum alpha fetoprotein can be used as a secondary screening tool in the second trimester (strong, moderate).
      • 8
        Positive screening on imaging for an open or closed neural tube defect (sonography with or without maternal serum alpha fetoprotein) requires timely referral to experienced providers for confirmation, genetic/etiologic investigation and diagnosis, and pregnancy management counselling (strong, high).
      • 9
        Prenatal MRI can be considered if further detailed assessment of the fetal central nervous system is required for diagnostic or management counselling (strong, high).
      • Genetic Testing
      • 10
        Following the sonographic detection of fetal anomalies, including confirmed or suspected open or closed neural tube defects, if a diagnostic amniocentesis is performed, the amniotic fluid specimen should be evaluated for fetal genetic abnormalities. The evaluation should consist of chromosomal microarray and other genetic testing, as considered appropriate after assessment of fetal anomalies and family history, with amniotic fluid alpha fetoprotein and amniotic fluid acetylcholinesterase, if required by protocols for fetal surgery decisions (strong, high).
      • 11
        For fetuses with myelomeningocele or other spina bifida anomalies, fetal exome sequencing may be considered, but only after multidisciplinary counselling and after appropriate criteria for molecular genetic sequencing are met (strong, moderate).
      • Pregnancy Management if the Fetus Has Myelomeningocele
      • 12
        Once an isolated open or closed neural tube defect is detected, and diagnostic and genetic testing results (if applicable) are available, families should be offered a choice of 3 obstetrical care management options. In the absence of specific contraindications, families should be given information about the following options: prenatal surgical repair of myelomeningocele and prognosis, postnatal surgical repair of myelomeningocele and prognosis, and pregnancy termination with autopsy (strong, high).
      • 13
        Both cesarean and vaginal delivery are an option for a fetus with a myelomeningocele when the fetus is in a vertex presentation. A systematic review and meta-analysis did not identify any neurological benefits associated with cesarean delivery. Therefore, intrapartum care should be individualized based on head size, myelomeningocele lesion size, lower limb position, and mobility considerations (conditional, low).
      • 14
        If prenatal myelomeningocele surgical repair is conducted, a pre-labour cesarean delivery should be performed at 37 weeks at the latest, to prevent possible rupture of the hysterotomy scar during labour (strong, high).
      • 15
        Following either termination of pregnancy or prenatal/postnatal death, autopsy should be offered for all cases of myelomeningocele (isolated or complex) and other neural tube defects, to provide optimal counselling for the current pregnancy and future pregnancies, as well as neural tube defect risk assessment for future pregnancies (strong, high).
      • Subsequent Pregnancies
      • 16
        Daily oral supplementation with 4.0 to 5.0 mg of folic acid in a multivitamin supplement containing vitamin B12 should be recommended for the mother, starting at least 3 months before conception and throughout the first trimester, when either member of the couple has had an isolated neural tube defect or a previous pregnancy that involved a presumed folic acid–sensitive open or closed neural tube defect (i.e., no karyotype, chromosomal microarray, or identified single-gene disorder) (strong, high).
      • 17
        First-trimester sonographic neural tube defect screening can be offered when imaging expertise is available, to allow for early fetal anatomical assessment in subsequent moderate- or high-risk pregnancies (strong, moderate).
      • 18
        Subsequent pregnancy planning after prenatal surgical repair of a myelomeningocele requires (strong, high):
        • pre-conception counselling
        • appropriate daily oral supplementation with 4.0 to 5.0 mg folic acid daily starting 3 months before conception and continuing until 12 weeks gestation
        • sharing with the parents the risk of uterine rupture, estimated at 11%–14%, and the associated risk of fetal death of 2%–4%
        • first-trimester sonographic neural tube defect screening
        • a detailed second-trimester sonographic fetal, uterine, and placental location evaluation because of increased risk of placenta accreta
        • counselling that delivery will be by repeat cesarean delivery because of the risk of uterine rupture (either scheduled at 36 weeks gestation or on an emergency basis between 26 and 37 weeks gestation).

      Keywords

      Abbreviations:

      AF-AChE (amniotic fluid acetylcholinesterase), AFAFP (amniotic fluid alpha fetoprotein), MMC (myelomeningocele), MSAFP (maternal serum alpha fetoprotein), NTD (neural tube defect)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Obstetrics and Gynaecology Canada
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • AlRefai A
        • Drake J
        • Kulkarni AV
        • Connor KL
        • Shannon P
        • Toi A
        • et al.
        Fetal myelomeningocele surgery: Only treating the tip of the iceberg.
        Prenat Diagn. 2019; 39 (Available from:): 10-15
        • Copp AJ
        • Adzick NS
        • Chitty LS
        • Fletcher JM
        • Holmbeck GN
        • Shaw GM
        Spina bifida.
        Nat Rev Dis Primers. 2015; 1 (Available from:): 15007
        • Frey L
        • Hauser WA
        Epidemiology of neural tube defects.
        Epilepsia. 2003; 44 (Available from:): 4-13
        • Gucciardi E
        • Pietrusiak MA
        • Reynolds DL
        • Rouleau J
        Incidence of neural tube defects in Ontario, 1986-1999.
        CMAJ. 2002; 167 (Available from:): 237-240
        • Savvidou M
        • Jauniaux E
        Prenatal spina bifida: what has changed in diagnosis and management.
        BJOG. 2019; 126 (Available from:): 329
        • Ghi T
        • Pilu G
        • Falco P
        • Segata M
        • Carletti A
        • Cocchi G
        • et al.
        Prenatal diagnosis of open and closed spina bifida.
        Ultrasound Obstet Gynecol. 2006; 28 (Available from:): 899-903
        • Wilson RD
        • Sogc Genetics C
        • Special C
        Prenatal screening, diagnosis, and pregnancy management of fetal neural tube defects.
        J Obstet Gynaecol Can. 2014; 36 (Available from:): 927-939
        • Wilson RD
        • Genetics C
        • Wilson RD
        • Audibert F
        • Brock JA
        • Carroll J
        • et al.
        Pre-conception Folic Acid and Multivitamin Supplementation for the Primary and Secondary Prevention of Neural Tube Defects and Other Folic Acid-Sensitive Congenital Anomalies.
        J Obstet Gynaecol Can. 2015; 37 (Available from:): 534-552
      1. Prevalence of neural tube defects in 20 regions of Europe and the impact of prenatal diagnosis, 1980-1986. EUROCAT Working Group.
        J Epidemiol Community Health. 1991; 45 (Available from:): 52-58
        • Bamforth FJ
        Laboratory screening for genetic disorders and birth defects.
        Clin Biochem. 1994; 27 (Available from:): 333-342
        • Cameron M
        • Moran P
        Prenatal screening and diagnosis of neural tube defects.
        Prenat Diagn. 2009; 29 (Available from:): 402-411
        • Cuckle HS
        • Wald NJ
        • Cuckle PM
        Prenatal screening and diagnosis of neural tube defects in England and Wales in 1985.
        Prenat Diagn. 1989; 9 (Available from:): 393-400
        • Liu S
        • Evans J
        • MacFarlane AJ
        • Ananth CV
        • Little J
        • Kramer MS
        • et al.
        Association of maternal risk factors with the recent rise of neural tube defects in Canada.
        Paediatr Perinat Epidemiol. 2019; 33: 145-153
        • Lowry RB
        • Bedard T
        • MacFarlane AJ
        • Crawford S
        • Sibbald B
        • Agborsangaya BC
        Prevalence rates of spina bifida in Alberta, Canada: 2001-2015. Can we achieve more prevention?.
        Birth Defects Res. 2019; 111 (Available from:): 151-158
        • Kallen B
        • Cocchi G
        • Knudsen LB
        • Castilla EE
        • Robert E
        • Daltveit AK
        • et al.
        International study of sex ratio and twinning of neural tube defects.
        Teratology. 1994; 50 (Available from:): 322-331
        • Rittler M
        • Lopez-Camelo J
        • Castilla EE
        Sex ratio and associated risk factors for 50 congenital anomaly types: clues for causal heterogeneity.
        Birth Defects Res A Clin Mol Teratol. 2004; 70 (Available from:): 13-19
        • Drugan A
        • Johnson MP
        • Dvorin E
        • Moody J
        • Krivchenia EL
        • Schwartz D
        • 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 (Available from:): 88-92
        • Harmon JP
        • Hiett AK
        • Palmer CG
        • Golichowski AM
        Prenatal ultrasound detection of isolated neural tube defects: is cytogenetic evaluation warranted?.
        Obstet Gynecol. 1995; 86 (Available from:): 595-599
        • Hume Jr., RF
        • Drugan A
        • Reichler A
        • Lampinen J
        • Martin LS
        • Johnson MP
        • et al.
        Aneuploidy among prenatally detected neural tube defects.
        Am J Med Genet. 1996; 61 (Available from:): 171-173
        • Kanit H
        • Özkan AA
        • Öner SR
        • Ispahi C
        • Endrikat JS
        • Ertan K
        Chromosomal abnormalities in fetuses with ultrasonographically detected neural tube defects.
        Clin Dysmorphol. 2011; 20: 190-193
        • Kennedy D
        • Chitayat D
        • Winsor EJ
        • Silver M
        • Toi A
        Prenatally diagnosed neural tube defects: ultrasound, chromosome, and autopsy or postnatal findings in 212 cases.
        Am J Med Genet. 1998; 77 (Available from:): 317-321
        • Canda MT
        • Demir N
        • Bal FU
        • Doganay L
        • Sezer O
        Prenatal diagnosis of a 22q11 deletion in a second-trimester fetus with conotruncal anomaly, absent thymus and meningomyelocele: Kousseff syndrome.
        J Obstet Gynaecol Res. 2012; 38 (Available from:): 737-740
        • Chen CP
        Chromosomal abnormalities associated with neural tube defects (I): full aneuploidy.
        Taiwan J Obstet Gynecol. 2007; 46 (Available from:): 325-335
        • Chen CP
        Chromosomal abnormalities associated with neural tube defects (II): partial aneuploidy.
        Taiwan J Obstet Gynecol. 2007; 46 (Available from:): 336-351
        • Chen CP
        • Chen CY
        • Chern SR
        • Wu PS
        • Chen SW
        • Lai ST
        • et al.
        Molecular cytogenetic characterization of a duplication of 15q24.2-q26.2 associated with anencephaly and neural tube defect.
        Taiwan J Obstet Gynecol. 2017; 56 (Available from:): 550-553
        • Chen CP
        • Chen YJ
        • Chern SR
        • Tsai FJ
        • Lin HH
        • Lee CC
        • et al.
        Prenatal diagnosis of mosaic 1q31.3q32.1 trisomy associated with occipital encephalocele.
        Prenat Diagn. 2008; 28: 865-867
        • Ekin A
        • Gezer C
        • Taner CE
        • Ozeren M
        • Ozer O
        • Koc A
        • et al.
        Chromosomal and structural anomalies in fetuses with open neural tube defects.
        J Obstet Gynaecol. 2014; 34 (Available from:): 156-159
        • Lurie IW
        • Novikova IV
        • Tarletskaya OA
        • Lazarevich AA
        • Gromyko OA
        Distal 13q monosomy and neural tube defects.
        Genet Couns. 2016; 27 (Available from:): 177-186
        • Preiksaitiene E
        • Benusiene E
        • Ciuladaite Z
        • Sliuzas V
        • Mikstiene V
        • Kucinskas V
        Recurrent fetal syndromic spina bifida associated with 3q26.1-qter duplication and 5p13.33-pter deletion due to familial balanced rearrangement.
        Taiwan J Obstet Gynecol. 2016; 55 (Available from:): 410-414
        • Sepulveda W
        • Wong AE
        • Fauchon DE
        Fetal spinal anomalies in a first-trimester sonographic screening program for aneuploidy.
        Prenat Diagn. 2011; 31 (Available from:): 107-114
        • Yazici LE
        • Malatyalioglu E
        • Sakinci M
        • Tosun M
        • Bildircin FD
        • Ogur G
        • et al.
        Chromosomal anomalies and additional sonographic findings in fetuses with open neural tube defects.
        Arch Gynecol Obstet. 2012; 286 (Available from:): 1393-1398
        • Aguilera S
        • Soothill P
        • Denbow M
        • Pople I
        Prognosis of spina bifida in the era of prenatal diagnosis and termination of pregnancy.
        Fetal Diagn Ther. 2009; 26 (Available from:): 68-74
        • Alfarra HY
        • Alfarra SR
        • Sadiq MF
        Neural tube defects between folate metabolism and genetics.
        Indian J Hum Genet. 2011; 17 (Available from:): 126-131
        • Aneji CN
        • Northrup H
        • Au KS
        Deep sequencing study of the MTHFR gene to identify variants associated with myelomeningocele.
        Birth Defects Res A Clin Mol Teratol. 2012; 94 (Available from:): 84-90
        • De Marco P
        • Merello E
        • Cama A
        • Kibar Z
        • Capra V
        Human neural tube defects: genetic causes and prevention.
        Biofactors. 2011; 37 (Available from:): 261-268
        • De Marco P
        • Merello E
        • Rossi A
        • Piatelli G
        • Cama A
        • Kibar Z
        • et al.
        FZD6 is a novel gene for human neural tube defects.
        Hum Mutat. 2012; 33 (Available from:): 384-390
        • Lemay P
        • De Marco P
        • Traverso M
        • Merello E
        • Dionne-Laporte A
        • Spiegelman D
        • et al.
        Whole exome sequencing identifies novel predisposing genes in neural tube defects.
        Mol Genet Genomic Med. 2019; 7 (Available from:): e00467
        • Wang XW
        • Luo YL
        • Wang W
        • Zhang Y
        • Chen Q
        • Cheng YL
        Association between MTHFR A1298C polymorphism and neural tube defect susceptibility: a metaanalysis.
        Am J Obstet Gynecol. 2012; 206 (251 e1-7Available from:)
        • Chen CP
        Syndromes, disorders and maternal risk factors associated with neural tube defects (IV).
        Taiwan J Obstet Gynecol. 2008; 47 (Available from:): 141-150
        • Sarmah S
        • Muralidharan P
        • Marrs JA
        Common congenital anomalies: Environmental causes and prevention with folic acid containing multivitamins.
        Birth Defects Res C Embryo Today. 2016; 108 (Available from:): 274-286
        • Molloy AM
        Should vitamin B(12) status be considered in assessing risk of neural tube defects?.
        Annals of the New York Academy of Sciences. 2018; 1414 (Available from: https://pubmed.ncbi.nlm.nih.gov/29377209): 109-125
        • O'Malley EG
        • Reynolds CME
        • Cawley S
        • Woodside JV
        • Molloy AM
        • Turner MJ
        Folate and vitamin B12 levels in early pregnancy and maternal obesity.
        Eur J Obstet Gynecol Reprod Biol. 2018; 231 (Available from:): 80-84
        • Boulet SL
        • Yang Q
        • Mai C
        • Kirby RS
        • Collins JS
        • Robbins JM
        • et al.
        Trends in the postfortification prevalence of spina bifida and anencephaly in the United States.
        Birth Defects Res A Clin Mol Teratol. 2008; 82 (Available from:): 527-532
        • De Wals P
        • Tairou F
        • Van Allen MI
        • Uh SH
        • Lowry RB
        • Sibbald B
        • et al.
        Reduction in neural-tube defects after folic acid fortification in Canada.
        N Engl J Med. 2007; 357 (Available from:): 135-142
        • Van Allen MI
        • Boyle E
        • Thiessen P
        • McFadden D
        • Cochrane D
        • Chambers GK
        • et al.
        The impact of prenatal diagnosis on neural tube defect (NTD) pregnancy versus birth incidence in British Columbia.
        J Appl Genet. 2006; 47 (Available from:): 151-158
        • Roberts N
        • Bhide A
        Ultrasound prenatal diagnosis of structural abnormalities.
        Obstetrics, Gynaecology & Reproductive Medicine. 2007; 17 (Available from:): 1-8
        • Bergman JE
        • Otten E
        • Verheij JB
        • de Walle HE
        Folic acid supplementation influences the distribution of neural tube defect subtypes: A registry-based study.
        Reprod Toxicol. 2016; 59 (Available from:): 96-100
        • van Gool JD
        • Hirche H
        • Lax H
        • De Schaepdrijver L
        Folic acid and primary prevention of neural tube defects: A review.
        Reprod Toxicol. 2018; 80 (Available from:): 73-84
        • Shere M
        • Kapur BM
        • Koren G
        Folate status of women in Toronto: Implications of folate fortification and supplementation.
        Can J Public Health. 2016; 106 (Available from:): e509-e513
        • Wilson RD
        Woman's Pre-Conception Evaluation: Genetic and Fetal Risk Considerations for Counselling and Informed Choice.
        J Obstet Gynaecol Can. 2018; 40 (Available from:): 935-949
      2. Obstetric Care Consensus No. 8 Summary: Interpregnancy Care.
        Obstet Gynecol. 2019; 133 (Available from:): 220-225
        • Lamers Y
        • MacFarlane AJ
        • O'Connor DL
        • Fontaine-Bisson B
        Periconceptional intake of folic acid among low-risk women in Canada: summary of a workshop aiming to align prenatal folic acid supplement composition with current expert guidelines.
        Am J Clin Nutr. 2018; 108 (Available from:): 1357-1368
        • Cargill Y
        • Morin L
        No. 223-Content of a Complete Routine Second Trimester Obstetrical Ultrasound Examination and Report.
        J Obstet Gynaecol Can. 2017; 39 (e144-e9Available from:)
        • Coleman BG
        • Langer JE
        • Horii SC
        The diagnostic features of spina bifida: the role of ultrasound.
        Fetal Diagn Ther. 2015; 37 (Available from:): 179-196
        • Driscoll DA
        • Gross SJ
        • Professional Practice Guidelines C
        Screening for fetal aneuploidy and neural tube defects.
        Genet Med. 2009; 11 (Available from:): 818-821
        • Kokalj TS
        • Rejc B
        • Gersak K
        Incidence and prevention of neural tube defects in Slovenia.
        Eur J Obstet Gynecol Reprod Biol. 2011; 156 (Available from:): 119-120
        • Lu QB
        • Wang ZP
        • Gong R
        • Sun XH
        • Gao LJ
        • Zhao ZT
        Investigation of ultrasound screening efficiency for neural tube defects during pregnancy in rural areas of China.
        Public Health. 2011; 125 (Available from:): 639-644
        • Nevo O
        • Brown R
        • Glanc P
        • Lim K
        No. 352-Technical Update: The Role of Early Comprehensive Fetal Anatomy Ultrasound Examination.
        J Obstet Gynaecol Can. 2017; 39 (Available from:): 1203-1211
        • Norem CT
        • Schoen EJ
        • Walton DL
        • Krieger RC
        • O'Keefe J
        • To TT
        • et al.
        Routine ultrasonography compared with maternal serum alpha-fetoprotein for neural tube defect screening.
        Obstet Gynecol. 2005; 106 (Available from:): 747-752
        • Van den Hof MC
        • Smithies M
        • Nevo O
        • Oullet A
        No. 375-Clinical Practice Guideline on the Use of First Trimester Ultrasound.
        J Obstet Gynaecol Can. 2019; 41 (Available from:): 388-395
        • Salomon LJ
        • Alfirevic Z
        • Da Silva Costa F
        • Deter RL
        • Figueras F
        • Ghi T
        • et al.
        ISUOG Practice Guidelines: ultrasound assessment of fetal biometry and growth.
        Ultrasound Obstet Gynecol. 2019; 53 (Available from:): 715-723
        • Chaoui R
        • Benoit B
        • Mitkowska-Wozniak H
        • Heling KS
        • Nicolaides KH
        Assessment of intracranial translucency (IT) in the detection of spina bifida at the 11-13-week scan.
        Ultrasound Obstet Gynecol. 2009; 34: 249-252
        • Engels AC
        • Joyeux L
        • Brantner C
        • De Keersmaecker B
        • De Catte L
        • Baud D
        • et al.
        Sonographic detection of central nervous system defects in the first trimester of pregnancy.
        Prenat Diagn. 2016; 36 (Available from:): 266-273
        • Fong KW
        • Toi A
        • Okun N
        • Al-Shami E
        • Menezes RJ
        Retrospective review of diagnostic performance of intracranial translucency in detection of open spina bifida at the 11-13-week scan.
        Ultrasound Obstet Gynecol. 2011; 38 (Available from:): 630-634
        • Lachmann R
        • Chaoui R
        • Moratalla J
        • Picciarelli G
        • Nicolaides KH
        Posterior brain in fetuses with open spina bifida at 11 to 13 weeks.
        Prenat Diagn. 2011; 31: 103-106
        • Lachmann R
        • Picciarelli G
        • Moratalla J
        • Greene N
        • Nicolaides KH
        Frontomaxillary facial angle in fetuses with spina bifida at 11-13 weeks' gestation.
        Ultrasound Obstet Gynecol. 2010; 36: 268-271
        • Loureiro T
        • Ushakov F
        • Montenegro N
        • Gielchinsky Y
        • Nicolaides KH
        Cerebral ventricular system in fetuses with open spina bifida at 11-13 weeks' gestation.
        Ultrasound Obstet Gynecol. 2012; 39: 620-624
        • Scheier M
        • Lachmann R
        • Pětroš M
        • Nicolaides KH
        Three-dimensional sonography of the posterior fossa in fetuses with open spina bifida at 11-13 weeks' gestation.
        Ultrasound Obstet Gynecol. 2011; 38: 625-629
        • Al-Mukhtar A
        • Kasprian G
        • Schmook MT
        • Brugger PC
        • Prayer D
        Diagnostic pitfalls in fetal brain MRI.
        Semin Perinatol. 2009; 33: 251-258
        • Cannie M
        • Jani J
        • Dymarkowski S
        • Deprest J
        Fetal magnetic resonance imaging: luxury or necessity?.
        Ultrasound in Obstetrics & Gynecology. 2006; 27 (Available from:): 471-476
        • Coakley FV
        • Glenn OA
        • Qayyum A
        • Barkovich AJ
        • Goldstein R
        • Filly RA
        Fetal MRI: a developing technique for the developing patient.
        AJR Am J Roentgenol. 2004; 182: 243-252
        • Girard N
        • Chaumoitre K
        • Chapon F
        • Pineau S
        • Barberet M
        • Brunel H
        Fetal Magnetic Resonance Imaging of Acquired and Developmental Brain Anomalies.
        Seminars in Perinatology. 2009; 33 (Available from:): 234-250
        • Glenn OA
        • Cuneo AA
        • Barkovich AJ
        • Hashemi Z
        • Bartha AI
        • Xu D
        Malformations of cortical development: diagnostic accuracy of fetal MR imaging.
        Radiology. 2012; 263 (Available from: https://pubmed.ncbi.nlm.nih.gov/22495681): 843-855
        • Hosny IA
        • Elghawabi HS
        Ultrafast MRI of the fetus: an increasingly important tool in prenatal diagnosis of congenital anomalies.
        Magnetic Resonance Imaging. 2010; 28 (Available from:): 1431-1439
        • Ljubic A
        • Cetković A
        • Novakov Mikic A
        • Stamenkovic JD
        • Jovanovic I
        • Opincal T
        • et al.
        Ultrasound vs MRI in Diagnosis of Fetal and Maternal Complications.
        Donald School Journal of Ultrasound in Obstetrics and Gynecology. 2011; 5: 231-242
        • Pugash D
        • Brugger PC
        • Bettelheim D
        • Prayer D
        Prenatal ultrasound and fetal MRI: the comparative value of each modality in prenatal diagnosis.
        Eur J Radiol. 2008; 68: 214-226
        • Saleem SN
        • Said A-H
        • Abdel-Raouf M
        • Elkattan EA
        • Zaki MS
        • Madkour N
        • 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: 761-772
        • Sohn YS
        • Kim MJ
        • Kwon JY
        • Kim YH
        • Park YW
        The usefulness of fetal MRI for prenatal diagnosis.
        Yonsei Med J. 2007; 48: 671-677
        • Patenaude Y
        • Pugash D
        • Lim K
        • Morin L
        • Lim K
        • Bly S
        • et al.
        The use of magnetic resonance imaging in the obstetric patient.
        J Obstet Gynaecol Can. 2014; 36: 349-363
        • Ray JG
        • Vermeulen MJ
        • Bharatha A
        • Montanera WJ
        • Park AL
        Association Between MRI Exposure During Pregnancy and Fetal and Childhood Outcomes.
        Jama. 2016; 316: 952-961
        • Armour CM
        • Dougan SD
        • Brock JA
        • Chari R
        • Chodirker BN
        • DeBie I
        • et al.
        Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada.
        J Med Genet. 2018; 55 (Available from:): 215-221
        • Beulen L
        • Faas BHW
        • Feenstra I
        • van Vugt JMG
        • Bekker MN
        Clinical utility of non-invasive prenatal testing in pregnancies with ultrasound anomalies.
        Ultrasound Obstet Gynecol. 2017; 49: 721-728
        • Al Toukhi S
        • Chitayat D
        • Keunen J
        • Roifman M
        • Seaward G
        • Windrim R
        • et al.
        Impact of introduction of noninvasive prenatal testing on uptake of genetic testing in fetuses with central nervous system anomalies.
        Prenat Diagn. 2019; 39: 544-548
        • Charan P
        • Woodrow N
        • Walker SP
        • Ganesamoorthy D
        • McGillivray G
        • Palma-Dias R
        High-resolution microarray in the assessment of fetal anomalies detected by ultrasound.
        Aust N Z J Obstet Gynaecol. 2014; 54: 46-52
        • Reddy UM
        • Page GP
        • Saade GR
        • Silver RM
        • Thorsten VR
        • Parker CB
        • et al.
        Karyotype versus microarray testing for genetic abnormalities after stillbirth.
        N Engl J Med. 2012; 367: 2185-2193
        • Sun L
        • Wu Q
        • Jiang SW
        • Yan Y
        • Wang X
        • Zhang J
        • et al.
        Prenatal Diagnosis of Central Nervous System Anomalies by High-Resolution Chromosomal Microarray Analysis.
        Biomed Res Int. 2015; 2015426379
        • Tonni G
        • Palmisano M
        • Perez Zamarian AC
        • Rabachini Caetano AC
        • Santana EFM
        • Peixoto AB
        • et al.
        Phenotype to genotype characterization by array-comparative genomic hydridization (a-CGH) in case of fetal malformations: A systematic review.
        Taiwan J Obstet Gynecol. 2019; 58: 15-28
        • Wapner RJ
        • Martin CL
        • Levy B
        • Ballif BC
        • Eng CM
        • Zachary JM
        • et al.
        Chromosomal microarray versus karyotyping for prenatal diagnosis.
        N Engl J Med. 2012; 367: 2175-2184
        • Best S
        • Wou K
        • Vora N
        • Van der Veyver IB
        • Wapner R
        • Chitty LS
        Promises, pitfalls and practicalities of prenatal whole exome sequencing.
        Prenat Diagn. 2018; 38: 10-19
        • Wou K
        • DeBie I
        • Carroll J
        • Brock JA
        • Douglas Wilson R
        Fetal Exome Sequencing on the Horizon.
        J Obstet Gynaecol Can. 2019; 41: 64-67
      3. Joint Position Statement from the International Society for Prenatal Diagnosis (ISPD), the Society for Maternal Fetal Medicine (SMFM), and the Perinatal Quality Foundation (PQF) on the use of genome-wide sequencing for fetal diagnosis.
        Prenat Diagn. 2018; 38: 6-9
        • Nizard J
        Amniocentesis: technique and education.
        Curr Opin Obstet Gynecol. 2010; 22: 152-154
        • Wilson RD
        • Gagnon A
        • Audibert F
        • Campagnolo C
        • Carroll J
        Prenatal Diagnosis Procedures and Techniques to Obtain a Diagnostic Fetal Specimen or Tissue: Maternal and Fetal Risks and Benefits.
        J Obstet Gynaecol Can. 2015; 37: 656-668
        • Alfirevic Z
        • Navaratnam K
        • Mujezinovic F
        Amniocentesis and chorionic villus sampling for prenatal diagnosis.
        Cochrane Database Syst Rev. 2017; 9Cd003252
        • Bakker M
        • Birnie E
        • Robles de Medina P
        • Sollie KM
        • Pajkrt E
        • Bilardo CM
        Total pregnancy loss after chorionic villus sampling and amniocentesis: a cohort study.
        Ultrasound Obstet Gynecol. 2017; 49: 599-606
        • Beta J
        • Zhang W
        • Geris S
        • Kostiv V
        • Akolekar R
        Procedure-related risk of miscarriage following chorionic villus sampling and amniocentesis.
        Ultrasound Obstet Gynecol. 2019; 54: 452-457
        • Obeidi N
        • Russell N
        • Higgins JR
        • O'Donoghue K
        The natural history of anencephaly.
        Prenat Diagn. 2010; 30: 357-360
        • Al-Obaidly S
        • Thomas J
        • Abu Jubara M
        • Al Ibrahim A
        • Al-Belushi M
        • Saleh N
        • et al.
        Anencephaly and obstetric outcome beyond the age of viability.
        J Perinat Med. 2018; 46: 885-888
        • Bowman RM
        • McLone DG
        • Grant JA
        • Tomita T
        • Ito JA
        Spina bifida outcome: a 25-year prospective.
        Pediatr Neurosurg. 2001; 34: 114-120
        • Bensen JT
        • Dillard RG
        • Burton BK
        Open spina bifida: does cesarean section delivery improve prognosis?.
        Obstet Gynecol. 1988; 71: 532-534
        • Cochrane D
        • Aronyk K
        • Sawatzky B
        • Wilson D
        • Steinbok P
        The effects of labor and delivery on spinal cord function and ambulation in patients with meningomyelocele.
        Childs Nerv Syst. 1991; 7: 312-315
        • Hill AE
        • Beattie F
        Does caesarean section delivery improve neurological outcome in open spina bifida?.
        Eur J Pediatr Surg. 1994; 4 (Available from:): 32-34
        • Luthy DA
        • Wardinsky T
        • Shurtleff DB
        • Hollenbach KA
        • Hickok DE
        • Nyberg DA
        • 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 (Available from:): 662-666
        • Merrill DC
        • Goodwin P
        • Burson JM
        • Sato Y
        • Williamson R
        • Weiner CP
        The optimal route of delivery for fetal meningomyelocele.
        Am J Obstet Gynecol. 1998; 179 (Available from:): 235-240
        • Sakala EP
        • Andree I
        Optimal route of delivery for meningomyelocele.
        Obstet Gynecol Surv. 1990; 45: 209-212
        • Tolcher MC
        • Shazly SA
        • Shamshirsaz AA
        • Whitehead WE
        • Espinoza J
        • Vidaeff AC
        • et al.
        Neurological outcomes by mode of delivery for fetuses with open neural tube defects: a systematic review and meta-analysis.
        BJOG. 2019; 126 (Available from:): 322-327
        • Sileo FG
        • Pateisky P
        • Curado J
        • Evans K
        • Hettige S
        • Thilaganathan B
        Long-term neuroimaging and neurological outcome of fetal spina bifida aperta after postnatal surgical repair.
        Ultrasound Obstet Gynecol. 2019; 53 (Available from:): 309-313
        • Masini L
        • De Luca C
        • Noia G
        • Caruso A
        • Lanzone A
        • Rendeli C
        • et al.
        Prenatal diagnosis, natural history, postnatal treatment and outcome of 222 cases of spina bifida: experience of a tertiary center.
        Ultrasound Obstet Gynecol. 2019; 53 (Available from:): 302-308
        • Adzick NS
        • Thom EA
        • Spong CY
        • Brock 3rd, JW
        • Burrows PK
        • Johnson MP
        • et al.
        A randomized trial of prenatal versus postnatal repair of myelomeningocele.
        N Engl J Med. 2011; 364 (Available from:): 993-1004
        • Liu T
        • Ouyang L
        • Thibadeau J
        • Wiener JS
        • Routh JC
        • Castillo H
        • et al.
        Longitudinal Study of Bladder Continence in Patients with Spina Bifida in the National Spina Bifida Patient Registry.
        J Urol. 2018; 199 (Available from:): 837-843
        • Choi EK
        • Ji Y
        • Han SW
        Sexual Function and Quality of Life in Young Men With Spina Bifida: Could It Be Neglected Aspects in Clinical Practice?.
        Urology. 2017; 108 (Available from:): 225-232
        • Choi EK
        • Kim SW
        • Ji Y
        • Lim SW
        • Han SW
        Sexual function and qualify of life in women with spina bifida: Are the women with spina bifida satisfied with their sexual activity?.
        Neurourol Urodyn. 2018; 37 (Available from:): 1785-1793
        • Matuszewski L
        • Perdriolle-Galet E
        • Clerc-Urmes I
        • Bach-Segura P
        • Klein O
        • Masutti JP
        • et al.
        [Prenatal diagnosis of neural tube defects: Correlation between prenatal and postnatal data].
        J Gynecol Obstet Hum Reprod. 2017; 46 (Available from:): 291-296
        • Dicianno BE
        • Karmarkar A
        • Houtrow A
        • Crytzer TM
        • Cushanick KM
        • McCoy A
        • et al.
        Factors Associated with Mobility Outcomes in a National Spina Bifida Patient Registry.
        Am J Phys Med Rehabil. 2015; 94 (Available from:): 1015-1025
        • Krol M
        • Sibinski M
        • Stefanski M
        • Synder M
        [Assessment of life quality in children with spina bifida].
        Chir Narzadow Ruchu Ortop Pol. 2011; 76 (Available from:): 52-55
        • Barf HA
        • Post MW
        • Verhoef M
        • Jennekens-Schinkel A
        • Gooskens RH
        • Prevo AJ
        Life satisfaction of young adults with spina bifida.
        Dev Med Child Neurol. 2007; 49 (Available from:): 458-463
        • Fischer N
        • Church P
        • Lyons J
        • McPherson AC
        A qualitative exploration of the experiences of children with spina bifida and their parents around incontinence and social participation.
        Child Care Health Dev. 2015; 41 (Available from:): 954-962
        • Heller MK
        • Gambino S
        • Church P
        • Lindsay S
        • Kaufman M
        • McPherson AC
        Sexuality and Relationships in Young People With Spina Bifida and Their Partners.
        J Adolesc Health. 2016; 59 (Available from:): 182-188
        • McPherson AC
        • Leo J
        • Church P
        • Lyons J
        • Chen L
        • Swift J
        An environmental scan of weight assessment and management practices in paediatric spina bifida clinics across Canada.
        J Pediatr Rehabil Med. 2014; 7 (Available from:): 207-217
        • McPherson AC
        • Swift JA
        • Peters M
        • Lyons J
        • Joy Knibbe T
        • Church P
        • et al.
        Communicating about obesity and weight-related topics with children with a physical disability and their families: spina bifida as an example.
        Disabil Rehabil. 2017; 39 (Available from:): 791-797
        • McPherson AC
        • Swift JA
        • Yung E
        • Lyons J
        • Church P
        The assessment of weight status in children and young people attending a spina bifida outpatient clinic: a retrospective medical record review.
        Disabil Rehabil. 2013; 35 (Available from:): 2123-2131
        • Shepard CL
        • Doerge EJ
        • Eickmeyer AB
        • Kraft KH
        • Wan J
        • Stoffel JT
        Ambulatory Care Use among Patients with Spina Bifida: Change in Care from Childhood to Adulthood.
        J Urol. 2018; 199 (Available from:): 1050-1055
        • Tulipan N
        • Wellons 3rd, JC
        • Thom EA
        • Gupta N
        • Sutton LN
        • Burrows PK
        • et al.
        Prenatal surgery for myelomeningocele and the need for cerebrospinal fluid shunt placement.
        J Neurosurg Pediatr. 2015; 16 (Available from:): 613-620
        • Clayton DB
        • Tanaka ST
        • Trusler L
        • Thomas JC
        • JCt Pope
        • Adams MC
        • et al.
        Long-term urological impact of fetal myelomeningocele closure.
        J Urol. 2011; 186 (Available from:): 1581-1585
        • Johnson MP
        • Bennett KA
        • Rand L
        • Burrows PK
        • Thom EA
        • Howell LJ
        • et al.
        The Management of Myelomeningocele Study: obstetrical outcomes and risk factors for obstetrical complications following prenatal surgery.
        Am J Obstet Gynecol. 2016; 215 (778 e1- e9Available from:)
        • Inversetti A
        • Van der Veeken L
        • Thompson D
        • Jansen K
        • Van Calenbergh F
        • Joyeux L
        • et al.
        Neurodevelopmental outcome of children with spina bifida aperta repaired prenatally vs postnatally: systematic review and meta-analysis.
        Ultrasound Obstet Gynecol. 2019; 53 (Available from:): 293-301
        • Goodnight WH
        • Bahtiyar O
        • Bennett KA
        • Emery SP
        • Lillegard JB
        • Fisher A
        • et al.
        Subsequent pregnancy outcomes after open maternal-fetal surgery for myelomeningocele.
        Am J Obstet Gynecol. 2019; 220 (494 e1- e7Available from:)
        • Wilson RD
        • Lemerand K
        • Johnson MP
        • Flake AW
        • Bebbington M
        • Hedrick HL
        • et al.
        Reproductive outcomes in subsequent pregnancies after a pregnancy complicated by open maternal-fetal surgery (1996-2007).
        Am J Obstet Gynecol. 2010; 203 (209 e1-6Available from:)
        • Sacco A
        • Van der Veeken L
        • Bagshaw E
        • Ferguson C
        • Van Mieghem T
        • David AL
        • et al.
        Maternal complications following open and fetoscopic fetal surgery: A systematic review and meta-analysis.
        Prenat Diagn. 2019; 39 (Available from:): 251-268
        • Dickens BM
        • Cook RJ
        Legal and ethical issues in fetal surgery.
        Int J Gynaecol Obstet. 2011; 115 (Available from:): 80-83
        • Moldenhauer JS
        • Bahtiyar O
        • Benett KA
        • Emery SP
        • Lillegard JB
        • Fischer A
        • et al.
        213: Fetal myelomeningocele closure: outcomes from the fMMC consortium registry sponsored by NAFTNet.
        Am J Obstet Gynecol. 2019; : S154
        • Belfort MA
        • Whitehead WE
        • Shamshirsaz AA
        • Bateni ZH
        • Olutoye OO
        • Olutoye OA
        • et al.
        Fetoscopic Open Neural Tube Defect Repair: Development and Refinement of a Two-Port, Carbon Dioxide Insufflation Technique.
        Obstet Gynecol. 2017; 129 (Available from:): 734-743
        • Blumenfeld YJ
        • Belfort MA
        Updates in fetal spina bifida repair.
        Curr Opin Obstet Gynecol. 2018; 30 (Available from:): 123-129
        • Degenhardt J
        • Schurg R
        • Winarno A
        • Oehmke F
        • Khaleeva A
        • Kawecki A
        • et al.
        Percutaneous minimal-access fetoscopic surgery for spina bifida aperta. Part II: maternal management and outcome.
        Ultrasound Obstet Gynecol. 2014; 44 (Available from:): 525-531
        • Kohl T
        Percutaneous minimally invasive fetoscopic surgery for spina bifida aperta. Part I: surgical technique and perioperative outcome.
        Ultrasound Obstet Gynecol. 2014; 44 (Available from:): 515-524
        • Pedreira DA
        • Zanon N
        • Nishikuni K
        • Moreira de Sa RA
        • Acacio GL
        • Chmait RH
        • et al.
        Endoscopic surgery for the antenatal treatment of myelomeningocele: the CECAM trial.
        Am J Obstet Gynecol. 2016; 214 (111 e1- e11Available from:)
        • Lapa DA
        Endoscopic fetal surgery for neural tube defects.
        Best Pract Res Clin Obstet Gynaecol. 2019; 58 (Available from:): 133-141
        • Licci M
        • Guzman R
        • Soleman J
        Maternal and obstetric complications in fetal surgery for prenatal myelomeningocele repair: a systematic review.
        Neurosurg Focus. 2019; 47 (Available from:): E11
        • Riddle S
        • Huddle R
        • Lim FY
        • Stevenson C
        • Dean K
        • Sparling K
        • et al.
        Morbidity and cost burden of prenatal myelomeningocele repair.
        J Matern Fetal Neonatal Med. 2019; (Available from:): 1-7
        • Radic JAE
        • Illes J
        • McDonald PJ
        Fetal Repair of Open Neural Tube Defects: Ethical, Legal, and Social Issues.
        Camb Q Healthc Ethics. 2019; 28 (Available from:): 476-487
        • Barry S
        Quality of life and myelomeningocele: an ethical and evidence-based analysis of the Groningen Protocol.
        Pediatr Neurosurg. 2010; 46 (Available from:): 409-414
        • Boyd PA
        • Devigan C
        • Khoshnood B
        • Loane M
        • Garne E
        • Dolk H
        • 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 (Available from:): 689-696