Antenatal diagnosis of neural tube defects in Canada:extension of a collaborative studyNANCY E. SIMPsoN,* PH D, FCCMG; L. DALLAIRE,t MD, PH D, FCCMG; J.R. MILLER4 PH D, FCCMG;L. SIMINovIrcII,§ PH D. JANET MILLER,* MA; J.L. HAMERTON,¶ D SC, FCCMG

Experience with the diagnosis of neuraltube defects from a1.fetoprotein (AFP)concentrations in amniotic fluid isreported from a prospective study offive laboratories testing for 13 Canadiangenetic centres. The results of thestudy indicate that antenatal diagnosisof open neural tube defects is beingcarried out effectively in Canada (in99.20/0 of cases the AFP measurementswere interpreted correctly). Amnio-centesis should be recommended towomen at high risk for having a childwith a neural tube defect (i.e., thosewho have a child, a parent or a siblingwith a neural tube defect). The rateof neural tube defects in 182 high.riskpregnancies was 2.20/c for an opendefect and 1.10/o for a closed defect,whereas the rate in 673 pregnancies Inwhich amniocentesis was beingperformed for other reasons was0.3"/o. This suggests that the AFPconcentration should be measured Inany sample of amniotic fluid collectedfor other reasons (usually fetalkaryotyping).There were three instances of false.

negative results, for a rate of 0A0/o.Two closed neural tube defects werenot detected; this limitation of thetest has also been found by others.

*Division of medical genetics, Queen'sUniversity, Kingston, Ont.tSection of medical genetics, h6pitalSainte-Justine, MontrealWepartment of medical genetics,University of British Columbia, Vancouver§Department of medical genetics,University of Toronto¶Division of genetics, University ofManitoba, WinnipegReprint requests to: Dr. Nancy E.Simpson, Department of pediatrics,Queen's University, Kingston, Oat.K7L 3N6

One of the six fetuses with an openneural tube defect, who died in utero,had a large myelocele in the neckthat was not recognized.There were also four instances of

false-positive results, for a rate ofO.50/o. The findings suggest that AFPvalues that are more than 2 but lessthan 7 standard deviations (SDs) abovethe mean may indicate a neural tubedefect, and that values 7 or moreSDs above the mean very likelyindicate such a defect, although otherreasons for such high values (e.g.,fetal erythrocytes in the amniotic fluid,Intrauterine death and mistakengestational age) must be ruled out byother methods.

On rapporte l'exp6rience accumui6edans le diagnostic des anomalies dutube neural par Ia mesure des con*centrations d'c11.foetoprot6ine (AFP) dansle liqulde amniotique, au cours d'une6tude prospective impliquant les cinqlaboratoires de d6plstage de 13 centrescanadiens de g6n6tique. Les resultatsde cette etude indiquent que lediagnostic pr6natal des anomaliesouvertes du tube neural est 6tabliefficacement au Canada (chez 99.0/odes cas, les interpr6tatlons des mesuresde l'AFP ont 6t6 correctes). L'amnio-centese devrait 6tre recommand6e chezles femmes presentant un risque61ev6 de d6fauts du tube neural(c'est.&.dire, celles qui ont un enfant,un parent ou un fr&re ou une soeurporteur d.un d6faut du tube neural).Le taux de d6fauts du tube neuraldans 182 grossesses & risque .lev6a .t6 de 2.2/o pour les anomaliesouvertes et de l.l0/c pour les anomaliesferm6es, alors que le taux a 6t6 deO.30/o dans 673 grossesses au cours

desquelles on a pratiqu6 une amnio.centese pour une autre raison. CeciIndique que Ia concentration d'AFPdevrait .tre mesuree dans tous lesechantillons de liquide amniotiquepreleves pour d'autres raisons (habi.tuellement pour une karyotypie foetale).

II y eut trois cas de faux resultatsnegatifs, pour un taux de O.40/o. Deuxanomalies fermees du tube neuraln'ont pas 6te d6tectees; cette limitedu test a deja et6 observee par d'autresUn des six foetus porteurs d'uneanomalie ouverte du tube neural,qui sont mort in utero, avait un grosmyelocele au niveau du cou, qui n'avaitpas ete reconnu.

II y eut 6galement quatre cas defaux r6sultats positlfs, pour un tauxde 0.50/c. Ces r6sultats suggerent queles valeurs d'AFP qui repr6sentent plusde 2 mais moms de 7 ecarts typesau dessus de Ia moyenne peuventindiquer un defaut du tube neural, etque les valeurs qul sont 7 6cartstypes ou plus au dessus de Ia moyenneindiquent tres fortement un tel d6faut,bien que d'autres causes de tellesvaleurs 6levees (pr6sence d'6rythrocytesfoetaux dans le liquide amniotique,mortalite intraut6rine et erreur dansl'appreciation de l'&ge de gestation)doivent itre 6cart6es par d'autresmethodes.

The results of a prospective study onantenatal diagnosis in Canada werepublished in 19761 and 19772 by aworking group established by theMedical Research Council of Can-ada. Thirteen centres that were pro-viding antenatal diagnostic servicescontributed their data, and the re-

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T,ble WI-Frequency of nural tuib difects In Muses of hIgla'.snd low-risk pregnancies

No1 of fetuses with a neursi tuhe defectRlsk Opus Closed TotalHlgh(n-I62) 4 2 6Low(o-613) 2 0 2Tb.rlsk was hlghiAu thewuasa bed a child oraifret-degree relative with a neuraltuWdefect. It*as le.ip all ollaerolrcumstances.'

tal 3.3%) than in fetuses carriedby women at low risk (those inwhom the indication for amniocent-esis was other than a neural tubedefect) (2 of 673 [0.3%]). The dif-ference is significant (X . = 4.9, P <0.05), although the small numeratorsmake statistical analysis question-able. Details of the eight pregnanciesin which the fetus had either an open

or a closed neural tube defect aregiven in Tables III and IV.The overall efficacy of interpreta-

tion of the AFP values is summar-ized in Table V from reports of thecollaborating centres. The interpreta-tion was correct in 848 (99.2%) ofthe 855 cases, 5 in which there wasa neural tube defect and 843 inwhich there was no such defect. The

AFP values in the instances of cor-rect diagnosis of an open neural tubedefect ranged from 9 to 121 SDsabove the mean.

There were four false-positivediagnoses of a neural tube defect(Table IV). In two cases (nos. 1 and2) the AFP values were clearly high,at 15 or more SDs above the mean.In case 1 elective abortion was done;the fetus was hydropic and presum-ably would have been abnormal, butthere was no evidence of a neuraltube defect. In case 2 the motherelected to carry the fetus to term,and the child was apparently normalat birth. In case 3 the AFP valuesreported by two laboratories for thesame sample were 5 and 3 SDs abovethe mean. In case 4 the AFP valueswere 2, 3 and 5 SDs above the meanat 17, 18 and 19 weeks' gestationrespectively. The existence of aneural tube defect was thought to bepossible and fetography was sug-gested, but the woman elected tohave a therapeutic abortion beforefetography could be done. This caseoccurred early in the experience ofthe laboratory that measured theAFP concentration.

There were three false-negativeinterpretations (Table IV). In case 5the AFP value was high (79 SDsabove the mean), but because thefluid was brown a diagnosis of fetal

CMA JOURNAL/MARCH 17, 1979/VOL. 120 655

Table Y-Efflcaey i, Intr.rint$.pi. iV.P f.adbg In flul. taken at 12 b 21 w.sks.gstatlon

Naomipregnam. ti.*fott Mab.dotwt Total

4 647I S S2 A

Total 116 9 655

ral tube defects from AFP values inamniotic fluid is bound to increaseas screening for AFP in the serumof pregnant women becomes wide-spread, and especially if such screen-ing becomes routine. Obstetriciansand geneticists involved should there-fore be aware of the pitfalls. Thenumber of open neural tube defectsdiagnosed antenatally is also boundto increase. The United Kingdom col-laborative study8 has shown that10% of women whose serum AFPvalue is 2.5 times the median forlow-risk singleton pregnancies arecarrying a fetus with an open neuraltube defect. This proportion is con-siderably higher than that for womenwho have a family history of a neuraltube defect (2.2% in our study). Al-though the prevalence of neural tubedefects in the population varies geo-graphically, the risk for womenwhose serum is screened likely doesnot vary, and in the future the AFPconcentration in amniotic fluid islikely to be measured in fluid fromwomen whose serum has beenscreened and who therefore have arisk of about 10% of carrying a fetuswith an open neural tube defect.

We gratefully acknowledge the sup-port of the Medical Research Councilof Canada, which made this studypossible, and the cooperation and con-tinued flow of data from the coordin-ators in each of the centres. Thecentres and their directors were: Dr.S. Styles, Victoria; Dr. R. Lowry,Vancouver; Dr. P. Bowen, Edmonton;Dr. C.C. Lin, Calgary; Drs. M.H.K.Shokeir and K.L. Ying, Saskatoon;Dr. A.G.W. Hunter, Winnipeg; Dr. I.lJchida, Hamilton; Drs. T.A. Doranand N.L. Rudd, Toronto; Dr. M.H.Roberts, Ottawa; Drs. H. Goldman andL. Dallaire, Montreal; Dr. J.P. Welch,Halifax; and Dr. N.E. Simpson, King-ston.

References1. SIMPsoN NE, DALLAIRE L, MILLER

FR, et al: Prenatal diagnosis of geneticdisease in Canada: report of a colla-borative study. Can Med Assoc J 115:739, 1976

2. HAMERTON JL, DALLAIRE L, MILLERJR, et al: Diagnosis of genetic diseaseby amniocentesis during the secondtrimester of pregnancy. A Canadianstudy. MRC Rep 5: 1977

3. MILUNSKY A, ALPERT E: Prenataldiagnosis of neural tube defects. I.Problems and pitfalls: analysis of 2495

cases using the aipha-fetoprotein as-say. Obstet Gynecol 48: 1, 1976

4. Idem: Prenatal diagnosis of neuraltube defects. II. Analysis of falsepositive and false negative aipha-feto-protein results. Ibid, p 6

5. BROCK DJH: Antenatal misdiagnosisof neural-tube defects. Lancet 2: 495,1975

6. BROCK DJH, GOSDEN C: Are second-trimester amniotic fluids being prop-

erly examined? Lancei' 2: 1168, 1977

7. LAURENCE KM: Fetal malformationsand abnormalities. Lancet 2: 939,1974

8. Maternal serum-alpha-fetoprotein meas-urement in antenatal screening foranencephaly and spina bifida in earlypregnancy. Report of U.K. Collabora-tive Study on Alpha-fetoprotein inRelation to Neural-tube defects. La,z-cet 1: 1323, 1977

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