, . 17:13: 1201–1205 (1997)

EDITORIAL: DIAGNOSIS FOR MANAGEMENTAND TREATMENT

It has to be acknowledged that prenatal diagno-sis is a major component of modern obstetricpractice. The improvements in diagnostic andscreening procedures, especially earlier fetal ultra-sonography, fetoscopy, biochemical testing, DNAanalysis and molecular cytogenetics, mean that theobstetrician has increasingly powerful tools to helpin the management of pregnancies complicated byfetal abnormality. For those genetic defects andmalformations incompatible with handicap-freesurvival, termination proves to be the option takenby most women who have chosen prenatal diagno-sis. The hope has always been that prenatal diag-nosis will be used increasingly to direct theobstetrician to therapeutic measures which cancorrect the fetal abnormality and save the preg-nancy. The reviews included in this year’s SpecialIssue not only review important advances in diag-nostic technology in early pregnancy but also showhow these may have potential to lead to life-savingintervention.The advances in fetal medicine which have

reduced perinatal mortality and morbidity insingleton pregnancies during recent decades, havenot been matched by similar reductions in multiplepregnancies. Assisted conception techniquesincrease the prevalence of multiple pregnanciesincluding, surprisingly, monozygotic as well asdizygotic twinning. Monochorionic twin preg-nancies are at far greater risk of complicationsthan dichorionic pregnancies, and so chorionicitytesting by ultrasound in early pregnancy (describedby Bajoria and Kingdom, pp. 1207–1225) hasbecome important, as it provides essential infor-mation for management. Twin-twin transfusionsyndrome (TTTS), whose management is discussedby Duncan and Fisk (pp. 1227–1236) is one of themost serious complications and congenital heartdisease, discussed by Gembruch (pp. 1283–1298) isanother. A correct diagnosis of monochorionicitythus should prompt awareness of the possibledevelopment of TTTS, which may require serialamnioreduction or, in some advanced centres,laser coagulation of placental anastomoses.

CCC 0197–3851/97/131201–05 $17.50? 1997 by John Wiley & Sons, Ltd.

Successful miniaturisation of endoscopes andadvances in ultrasonography have combined in there-introduction of fetoscopy and the emergence ofembryoscopy for the diagnosis of fetal malforma-tion in the first trimester. The main indicationsare recurrent genetic disorders with characteristicexternal abnormalities. The successful appli-cation of this approach is reviewed by Ville et al.(pp. 1237–1246). Fetoscopy for fetal examinationand biopsy of skin and liver in the second andthird trimester was used in the early 1980s but,until recently, its main use was for fetal bloodsampling for cytogenetic analysis when the resultsof chorion villus sampling (CVS) and amniocente-sis were in doubt. The improved instrumentationof today has made operative fetoscopy a realityand the present state of this technology is discussedby Deprest et al. (pp. 1247–1260). Much of thiswork has been initiated in animal models, but anincreasing number of reports describe clinicalapplications in which fetal surgery has been usedto correct disorders such as urinary tract obstruc-tion, diaphragmatic hernia and cystic adeno-matoid malformation of the lung. For most ofthese disorders the fetal survival rates are atpresent disappointingly low but no doubt they willimprove. Premature rupture of membranes andpremature labour are common complications.There is currently much interest in the use of

ultrasound measurement of nuchal translucency inthe first trimester as a screening test for Downsyndrome. In trained hands, the method detectsover 70 per cent of affected pregnancies. However,as discussed by Jauniaux (pp. 1261–1268), nuchaltranslucency must be regarded as a measure offetal hydrops due to primary or secondary conges-tive cardiac failure from a variety of causes, espe-cially cardiac malformations and anaemia. Thelatter occurs in conditions as varied as alpha-thalassaemia and parvovirus B19 infection, par-ticularly in the second trimester. Those involved innuchal translucency screening at 10–14 weeks,should be aware of the possibility of cardiovascu-lar abnormalities as a cause in chromosomally

1202

normal fetuses, even if the sign is only transient. Amore detailed fetal cardiac scanning of such caseslater in pregnancy is indicated for their propermanagement.While the detection of chromosomal abnormali-

ties by screening in the first rather than the secondtrimester offers obvious advantages to the preg-nant woman, the review of ultrasound screening byChitty and Pandya (pp. 1269–1281) points to someof the disadvantages. The results show thatincreased nuchal translucency thickness in the firsttrimester identifies a substantial number of Downsyndrome pregnancies, perhaps over a third ofthose detected, that are destined to miscarry. Adetection rate of 80 per cent at 10–14 weeks istherefore not equivalent to a detection rate of80 per cent achieved by serum screening at 16–20weeks, unless adequate account is taken of Downsyndrome miscarriages between these two periods.Not all reports take proper account of pregnancyloss, or of maternal age distributions in comparingdifferent screening programmes. It is noticeablethat advocates of first trimester ultrasound screen-ing tend to compare their favourable results withthe least efficient second trimester maternal screen-ing programmes and vice versa. The results ofongoing observational studies of nuchal trans-lucency screening followed by maternal serumscreening should help to clarify which method is inthe best interests of those patients who opt forprenatal screening. In view of the problems associ-ated with CVS and the other disadvantages men-tioned, first trimester detection rates must be atleast as good as those currently demonstrated inthe most efficient second trimester serum screeningprogrammes.Experience with nuchal translucency screening

and fetal anomaly scanning draws attention to theneed for better detection of fetal congenital heartdisease by fetal echocardiography. Currently, it isestimated that 40–50 per cent of congenitalanomalies should be detectable using the fourchamber view, but in practice only 20 per cent ofthose detectable are being identified between 16–24weeks (Gembruch pp. 1283–1298). A major factorin low sensitivity appears to be the low level oftraining and experience of personnel involved inlevel I screening. This has led to the establishmentof centres of excellence run by experienced ultra-sonographers to whom high risk cases can bereferred. Experienced paediatric cardiologists andsurgeons are on hand to advise on diagnosis and toundertake appropriate therapy and management

. ., . 17: 1201–1205 (1997)

in the perinatal period. Indications for tertiaryreferral to these centres include pregnancies inwhich there is a family history and cases withnon-immune hydrops, cardiac arrhythmias, fetalgrowth retardation, monochorionic twinning andthose fetuses found to have extracardiac develop-mental anomalies such as exomphalos, congenitaldiaphragmatic hernia and single umbilical artery.Women with a high risk of fetal aneuploidy mayreduce the risk of CVS or amniocentesis-relatedfetal loss by detailed scanning including echocar-diography before having to decide on invasive fetalchromosome analysis. About 50 per cent of Downsyndrome fetuses have a detectable cardiac abnor-mality and the frequency is higher in the otherautosomal aneuploidies. Current experience sug-gests that fetal echocardiography earlier than 20weeks is unreliable and should be complementedby a second examination at 20–24 weeks. Relianceon centres of excellence is no substitute forimproved sensitivity in routine fetal anomalyscanning, and future efforts must be directed atimproving the training of those involved in level Iscreening.We have included in this year’s Special Issue a

review which was promised in the Editorial of lastyear’s Special Issue. It concerns the recent devel-opment of a DNA test for the rapid prenataldiagnosis of Down syndrome and other aneu-ploidies, which is particularly appropriate for usein conjunction with prenatal screening. The test isa quantitative fluorescent polymerase chain reac-ton (QF-PCR) assay which uses chromosome-specific short tandem repeat (STR) markers toprobe DNA extracted from uncultured CVS oramniotic fluid cells; the result is achieved in about6 hours from sampling and can be performed onsmall numbers of cells and even single cells.Adinolfi et al. (pp. 1299–1311) provide details ofthe STR markers that they have used successfullyto determine the copy number of chromosomes 21,18, 13, X and Y in fetal cells. Each marker consistsof a series of tetranucleotide repeats which arehighly polymorphic in populations, yet are suffi-ciently stable in individuals to be highly reproduc-ible. The PCR products of each marker areexamined by a DNA analyser. In normal hetero-zygotes, the ratio of the fluorescences in each alleleis 1:1, and in trisomy the ratio is either 1:1:1(trisomy triallelic) or 1:2 (trisomy diallelic). Severalmarkers are used for each chromosome (to exclude‘allele drop-out’) in a multiplex reaction and thefetal sample is always run alongside the maternal

? 1997 by John Wiley & Sons, Ltd.

1203

sample so that paternal and maternal alleles can bedistinguished. The method can also be applied tothe detection of mutations in single gene disordersfor which the fetus is known to be at risk. The testis robust and has wide application in the rapidprenatal diagnosis of genetic disease. It maywell replace chromosome analysis in high riskpregnancies identified by screening.Our final review paper assesses the connection

between early CVS and the occurrence of fetallimb reduction defects. This association was firstnoted in the late 1980s, but most attention wasaroused by a report of 4 cases of terminal trans-verse limb defects among 532 patients undergoingfirst trimester CVS; in all 4 cases, the CVS wasperformed between 8 and 9 weeks. Subsequent tothis report, two further cases were identified in thesame cohort of patients. Additional cases weresoon reported from other centres, but not at suchhigh frequency and this resulted in a prolongedcontroversy about the role of CVS in the causationof limb defects. Previous estimates suggested thatthe birth prevalence was in the order of 2·4/10 000,but the International Register of CVS comprising138 996 pregnancies gave a prevalence of 4·82/10 000. This comparatively low rate served toreassure those obstetricians who practised CVS,but Firth (pp. 1313–1330) points out that this dataset is misleading in a number of importantrespects; previable fetuses and terminations wereexcluded, single digital defects were excluded, thedata were collected after it was suspected that earlygestation was a factor (so that CVS was invariably

? 1997 by John Wiley & Sons, Ltd.

postponed beyond 9 weeks), and as data collectionwas voluntary it was biased towards incompleteascertainment. It has been shown by a number ofstudies that the risk of limb defects and the severityof the defect is increased with earlier gestationtimes at sampling. The most likely mechanism isplacental trauma leading to vascular disruption inthe developing limb bud at a critical stage ofembryogenesis, followed by necrosis and resorp-tion of recently formed structures. This hypothesisis supported by experiments in rodents wheresimilar defects can be produced by vascular insults.Whatever the pathogenesis, the causal associationbetween early CVS and limb reduction defectsmust be regarded as established. It is evident thatthe likelihood of this hazard can be greatly reducedby postponing CVS until at least 10 weeks ofgestation, by avoiding trauma to the placenta andby limiting the sample size to the minimumrequired for diagnosis.It is encouraging to observe the increasing role

of early prenatal diagnosis in the managementand treatment of fetal abnormality throughoutpregnancy and in the perinatal period. The Journalwill continue to welcome to its pages originalcontributions in obstetrics and neonatology whichadvance the application to fetal medicine ofimproved techniques in ultrasonography, bio-chemical screening, molecular cytogenetics andDNA analysis.

M. A. Ferguson-Smith

LIST OF REFEREES AND ADVISERS

We take this opportunity once again to express our thanks to those listed below who have generouslygiven their time to referee articles for the journal. Their constructive criticism has been greatlyappreciated by both the authors and the Editors.

J. AaseL. AbramskyM. AdinolfiD. A. AitkenE. AlbermanC. AlfordL. AndrewsS. AntonarakisP. AulaS. Ayme

R. BaehnerM. BamshadJ. BarbenB. BarshopM. BatshawA. BeaudetJ. R. BeekhuisR. BejarB. BenacerrafK. Benirschke

R. L. BerkowitzJ. BernsteinR. BernsteinG. BesleyE. BeutlerS. S. BhattacharyaD. W. BianchiB. BieseckerL. BirdF. Z. Bischoff

.

K. BlakemoreM. BlitzerB. BlumbergM. BocianM. BogartD. BorgoankarA. BoueJ. BowmanB. BrambatiW. Breg

., . 17: 1201–1205 (1997)

1204

R. BrendtP. BreyN. BrinkD. BrockB. BrownD. BrownT. BryndorfN. BudorickT-H. BuiB. BurtonJ. BusselP. Byers

D. CallenJ. CanickJ. CareyT. CaskeyS. CassidyJ. J. CassimanV. CatanzariteS. CederbaumG. V. P. ChamberlainT. ChardF. ChehabY. T. ChenF. ChervenakD. ChitayatL. ChittyD. ChuiR. ClarkJ. ClarkeM. CocalisA. CohenM. CohenL. ColeM. E. ConleyM. ConneallyA. CoppA. CoranL. CousinsJ. CowanD. CoxB. CrandallJ. CraneJ. A. CrollaH. A. CubieH. CuckleC. CunniffG. CunninghamC. Curry

W. DanknerK. E. Davies

. ., . 17: 1201–1205 (1

G. DavignonJ. DelhantyR. DesnickU. DesselbergerG. DevoreP. de WalsC. DezareuxH. DietzD. DonnaiG. Dunstan

D. EconomidesL. EichenfieldS. EliasB. EmmanuelR. EricksonN. EsterlyM. I. Evans

R. FalkA. H. FensomM. A. Ferguson-SmithR. FillyB. FineM. FinegoldH. FirthD. FisherA. FlakeA. FortunyN. FostB. FowlerJ. FriasS. FriedlanderJ. FriedmanU. FrosterA. FujimotoJ-P. Fryns

W. GahlA. GarberE. Gilbert-BarnessR. GilliesM. GolbusJ. GoldbergJ. GoldblattS. GoodburnS. GoodmanJ. GoodshipR. GorlinC. M. GosdenM. GottshalkS. GouldG. Grabowski

997)

J. GrahamR. GravelF. GreenbergR. GreensteinD. GriffinM. Grompe

R. HaasJ. HaddowB. HallJ. HallA. HallerJ. L. HamertonB. HardingJ. HarperM. HarrisonD. HarveyT. HassoldR. HawkinsH. HillR. HillmanR. HirschhornJ. HobbinsA. HoggeK. HolbrookW. HolzgreveE. B. HookW. HortonR. HowellL. HsuM. Hulten

L. JacksonP. A. JacobsD. JamesH. JamesE. JauniauxI. JohnstonM. JonesO. Jones

M. KabackD. K. KalousekY. W. KanH. KanhaiG. KaplanH. KazazianL. KellnerT. KellyT. KennedyR. KingJ. KingdomT. KiserudW. J. Kleijer

?

K. KlingerJ. KorenbergW. Kruger

R. LachmanE. LammerJ. LavineM. LaytonD. LedbetterK. Lee JonesC. LeonardF. LifshitzD. LinchS. LowdenD. LuthyF. LynchK. Lyons Jones

M. C. M. MacintoshJ. MacriE. MaherM. J. MahoneyT. M. MarteauR. MartinJ. MascarelloR. MatalonE. McCabeA. McDermottM. McGinnissI. McKenzieS. MelanconS. MendozaM. MenuttiS. MichieJ. MilesD. MilewiczW. MillerA. MilunskyB. ModellT. MohandasG. MooreT. MooreC. J. MorleyJ. MorrisonH. MuddR. MulivorJ. J. MulvihillA. Munnich

M. NatowiczM. NewU. NicoliniM. F. Niermeijer

1997 by John Wiley & Sons, Ltd.

1205

H. NitowskyB. Norgaard-PedersenD. NybergW. Nyhan

G. OakleyW. O’BrienR. OgleJ. M. OldS. OlsonJ. Opitz

M. PackerS. PackmanD. PaintinG. E. PalomakiP. PandyaA. PercyE. PergamentJ. PhilipG. PiluS. PiomelliL. D. PlattB. PopovichD. PretoriusH. PunnettR. Pyeritz

L. RaffelW. ReardonV. Reznik

? 1997 by John Wiley & Sons, Ltd.

C. RichardsD. L. RimoinN. RischA. RobinsonW. RobinsonC. H. RodeckA. RothmanJ. RotterP. RowleyD. RubinszteinG. Ryan

D. SahnD. SallerC. SandlinD. SartiM. SawyerA. SchinzelS. SchonbergC. SchranderR. SchrekI. SchulmanS. SchwartzA. SciosciaR. ScottC. ScriverM. SellarW. SepulvedaJ. SeverE. ShapiraL. Shapiro

G. SharlandT. ShepardL. ShulmanJ. SidburyE. SidranskyN. SiegelG. SimoniJ-L. SimpsonM. SklanskyW. SlyP. SoothillJ. SorensonR. SparkesS. SpectorK. SpencerH. SternR. StevensonL. Sweetman

D. TaylorA. TharapelJ. ThoeneG. ThomasP. ThorogoodG. Thorpe-BeestonN. TommerupB. Triggs-Raine

J. Uitto

D. ValleD. VanDyke

.

J. VaughanY. Ville

N. WaldS. WalkinshawD. K. WallerR. WapnerD. WarburtonJ. WatersM. WatsonK. WenstromC. WhitleyM. J. WhittleB. WilfondT. WilkinsonJ. WilliamsR. WilliamsonR. S. WilroyR. D. WilsonB. WinchesterJ. WinkelsteinR. WinterJ. W. WladimiroffJ. Wolstenholme

T. YamauchiJ. Yates

E. ZakaiH. ZakutJ. Zonana

., . 17: 1201–1205 (1997)