medlink.fetal anticonvulsant syndrome

8/12/2019 Medlink.fetal Anticonvulsant Syndrome

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Fetalni antikonvulzantno sindrom SuradniciYu-T ze Ng MD , autor. Dr. Ng sa Sveučilišta u Arizoni i St. Joseph bolnica i Me ical !enter u"hoeni#u, Arizona, obila honorariu$s iz !%beronics, Novartisa, &vation 'ar$aceuti(a i )!*"har$a za govoren+e anga $ane. arve% * Sarnat MD , e itor. Dr. Sarnat sa Sveučilišta u !algar%+u ne$a relevantne inanci+s(eo nose ot(riti.

Bivši autor (i)Marcio Sotero e Menezes MD /izvorni autor0, John *o ensteiner MD, i 1aura 'lores-Sarnat MD

Datuma objave,2zvorno ob+avl+en 34. stu eni 35556 za n+i put 33. ru+na 78856 ist+eč e 33. ru+na 7837 Napomena: &va+ 9linič(a Sa eta( +e iste(ao i stoga ni+e ostupan za pru an+e !M: (re it.

Sinonimi:$br%o oetal valproic sin ro$ (iseline6 i antoino$-barbiturat-(arba$azepin e$br%o oetopath%

Povijesna napomena i nomenklatura

;o ine 35<=, M>llers-9>ppersa izvi+estio i+ete s rasc+epo$ nepca, $i(roce ali+a , $alrotationcri+eva, govornih proble$a, i blaga $entalna retar aci+a na(on što +e u $aternici izlo enosti$ephen%toin /Mullers-9>ppersa 35<=0 . Janz i 'uchs +e retrospe(tivna analiza ?7< tru no@aepileptič(ih $a+(i6 ia(o su $a+(e po(azala pove@anu pobača+ i $rtvoro enče stopu, učestalost$al or$aci+a ni+e bio znača+no različit o lo(alnog z rave populaci+e /Janz i 'uchs 35<?0 . Na(ontoga +e 35<4, !enta i Basore-Cuartino pri+avio sluča+ u (o+e$u su priro ene srčane bolestirazvila na(on što +e u $aternici izlo enosti enitoin i enobarbiton /!enta i Basore-Cuartino 35<40. Melchior i (olege na(on što +e opisao oro-lica cle ts u $aternici izlo enosti pri$i ona ienobarbiton /Melchior et al 35< 0 . 1iva a izvi+estio < +ece (o+i su bili izlo eni Antiepilepticili+e(ovi u $aternici po(azu+e oro-lica cle ts, (o+i +e u ? sluča+a su u pratn+i rugih %s$orphic

crta$a lica i priro ene bolesti srca /Mea oE 35<F0 . &n +e pri$i+etio a $nogi antiepilepticii$a+u olne (iseline - svo+stva antagonista. T a(o er +e pri$i+etio a antiepileptič(i$ li+e(ovi$a-in ucirane uzora( $al or$aci+a +e sličan ono$e vi i na(on neusp+elih po(uša+a a in ucira+upobača+a s antagonisti$a olne (iseline. Na(on toga, pri+avl+eno +e speci ični obrasci et alne $al or$ac i+e povezane s po+e inačni$antiepileptič(ih izlo enosti roge. ;o ine 35 8, n+e$ač(i i (olege izvi+estio teratogeni učina( otri$eta ion, a (asni+e Gac(ai i (olege s(ovao ter$in H etalni tri$eta ion sin ro$H /Gac(ai et al35 40 . Ne(oli(o rugih izv+eš@a etalnih anti(onvulzivnih sin ro$a izlagan+a su izvi+estili, ali

+e an o na+poznat i+i +e v+ero+atno etusa hi antoino$ sin ro$ /1oughnan et al 35 =0 . S vre$eno$, post alo +e +asno a +e raz va+an+e različitih sin ro$a e$brio- etalni izlo enostiantiepilepti(a ni+e bio +asan (ao što se pri+e $islilo /Spei el i 1iva a 35 76 9ell% 35F?a6 Aicar i35570 . Ne avna ispitivan+a o at no elaborirat i o (ronologi+i izv+ešta+i$a za teratogenih učina(aantiepilepti(a /"ennell 788=6 Yerb% 788=a6 788=b0 .

lini!ke mani"estacije Fetusa #ntiepileptici sindrom$ Mnogi su po(uša+i a se obil+e ava+u različite obrasce



$al or$aci+a (o+i su tipični ili i+agnostič(i +er u $aternici antiepileptično izlo enosti li+e(u. 2pa(,anas +e op@enito prihva@eno a su $nogi o (onvencionalnih anti(onvulzive, uz $ogu@uizni$(u valproična (iselina , $o e proizvesti Slično $al or$aci+a /9ell% 35F?a6 Aicar i 35576 Yerb%i !ollins 355 0 . 2a(o posto+i aneg ota uv+eren+e a novi+e antiepilepti(e $ogu biti $an+eteratogeni, više stu i+a $ora+u potvr iti ni e$antirati ovu teori+u. ) ovo$ poglavl+u @e$oopisati počet(u uzora( (o+i +e na+češ@i način antiepileptično izlo enosti li+e(u u $aternici. Gbogpovre$ene paci+ent po(azu+e više i erencirane uzora(a /t+. etusa (arba$azepin sin ro$0, $i@e$o t a(o er opisati više spec i ičnih sin ro$a. 2zraz etusa anti(onvulzantno sin ro$ u(l+uču+erazličite (o$binaci+e nalaza, u(l+uču+u@i intrauterino zaosta+an+e u rastu, $inor ano$ali+a, veli(ihuro enih $al or$ac i+a, $i(roce ali+a i (ognitivna is un(ci+a (o +ece ena s epilepsi+e , te +eopisana u uporabi gotovo svih antiepilepti(a /Arpino 78886 "ennell 788=0 . Točni+e, etalniant i(onvulzivno sin ro$ u(l+uču+e (o$binaci+u $entalna retar ac i+a , s$an+io opseg glave, a(ranio-lica %s$orphis$s, (ao i igitalne ano$ali+e /Aicar i 35570 . ) (ranio-lica $al or$aci+eu(l+uču+u h%perteloris$ , stan nosni hrbat, nis(o usa ene uši, $i(roce ali+a, trigonocephal% i(rat(i vrat. Mogu se +aviti i te e $al or$aci+e lica ili rasc+ep nepca. ;lavni ano$ali+a prsti+uvi +eti u ovo+ populaci+i +e h%poplasia o istalne alange ili no(ti$a /Ieselo i r., 35FF0 . 2a(o suučinci na rast i velič ini glave su reverzibilni u ve@ini sluča+eva, ugotra+ne proble$i u ponašan+ui (ognitivni e iciti $ogu se vi +eti u ovo+ populaci+i /;al i Sharplcss 35F?6 ol$es i 'lanner%35FF6 Aicar i 35570 . Tren zabil+e en +e za izlagan+e (arba$azepina izazvati izra eni+i učina(na opseg glave /Jones et al, 35F50 . Digitalni ano$ali+e $ogu biti više za+e nič(og s enitoin

izlo enosti /Ieselo i r., 35FF6 Aicar i 35570 . "oprečni pal$arnog nabori, priro ene srčanegreš(e, i $eningo$%elocele se ta(o er $ogu vi +eti u ovi$ sin ro$o$ /Desnica i ie e$ann355 0 . De e(ata neuralne ci+evi $o e se vi +eti, osobito u sura n+i s valproična(iselina /Ar inger i r., 35FF6 A%$e 35586 &$tzigt et al 35570 i (arba$azepin izlo enosti u$aternici /Bosa i 1in hout 35580 . Fetalna izlo%enost &idantoinom i sindrom$ "očetne opisi entoin teratogenosti u l+u i subili ob+avl+eni u 35<8-ih i ranih 35 8-ih /"antarotto 35<46 1iva a 35<F6 ill i sur 35 =6 1oughnanet al 35 =0 . ;o ine 35<<, izvi+estio Masse% teratogeni učina( u $iševa enitoina /Masse% 35<<0. anson i S$ith s(ovao ter$in H etalni hi antoino$ sin ro$H / anson i S$ith 35 40 . Mnogi otih ranih izv+eš@a / ill i sur 35 =6 1oughnan sur 35 =6 anson i S$ith 35 40 su uv+etovaniizlo enosti u $aternici na ruge antiepilepti(a. ;lavni i stalan ano$ali+a (o bolesni(a izlo enihhi antoine ti+e(o$ tru no@e su h%poplasia o istalne alange ili no(te i ne ostata( rasta / ill i

sur 35 =6 anson i sur, 35 <6 Ieselo i r., 35FF6 *uehler i anson 35580 . Basc+ep usne inepca, razvo+no zaosta+an+e, $entalna retar aci+a, a sre ino$ lice h%poplasia su i potpore zai+agnozu / ill i sur 35 =6 *uehler i anson 35580 . Je na stu i+a po(azala +e a 33K +eceizlo ene enitoina u $aternici razvi+e puni sin ro$a, a =8K ih i$a sa$o su ne(e označa+(i / anson i sur 35 <0 . ) stu i+i poto$stva o 5F ena (o+e su enitoin ti+e(o$ tru no@e,sa$o =8K +e utvr eno a i$a+u is(l+učivo igitalni hipoplazi+u /9ell% *o i@ni( 35F?b0 . Digitalni i no(ti+u h%poplasia se često opisu+e (ao t ipičan et usa hi antoins(og sin ro$a, aliova+ uzora( +e ta(o er vi en s izlagan+e$ phenobarbital /Siep 35 <0 , pri$i ona /Bu i Slobo a35 50 , a (arba$azepin /Jones et al, 35F50 . ) ipoplastični no(ti $ogu pobol+šati ili ri+ešititi+e(o$ vre$ena / ill i sur 35 =0 . "ol% act%l% bez igitalnog no(ti+u hipoplazi+e +e pri+avl+en (obolesni(a izlo eni enitoina u $aternici /Yalcin(a%a et al 355 0 . Sluča+a etalnog hi antoins(ogsin ro$a s +e nostrani$ atipično$ rasc+epo$ ruci +e in i(ativno za re o$ vas(ularne pre(i /DeS$et i Debeer 78870 . Basc +ep usne i nepca +e povezan s gestaci+s(i izlo enost i enitoina +er rano / ill i sur 35 =0 . )

+e no+ norveš(o+ stu i+i, učestalost rasc+epo$ usne i nepca (o novoro enča i i $a+(i sepilepsi+o$ pala +e u izravno$ o$+eru sa s$an+en+e$ enobarbitonu i entoin uporabu /9ing i sur355<0 . &stali (ranio-lica ano$ali+e u(l+uču+u širo( pre n+i ontanelle, očni h%perteloris$, stannosni $ost, (rat(i nos, i na(lonio gorn+u usnu /Jones 355 0 . Do+enča izlo eni enitoina u $aternici $o e o go ili psiho$otorni razvo+ ili $entalno$retar aci+o$ / ill i sur 35 =0 . Mentalna retar aci+a +e često blaga, ili inteligenci+a $o e bitigranica /Jones 355 0 . "ovezanost iz$e u $entalne retar aci+e i in utero izlo enosti entoin +eove ena u pitan+e. ) stu i+i prove eno+ na 38= +ece i $a+(i s epilepsi+o$ izlo eni enitoino$ti+e(o$ tru no@e, sa$o 3,?K i$ao ta+ proble$, re(venci+u sličnu ono+ u op@o+ populaci+i /Ieselo

i r., 35FF0 . )čen+u $o e biti prisutan (o +ece (o+a nisu is(reno retar irana / einer et al355F0 . Neusp+eh a bi se usp+ešno i zapa eno +e u o+enča i izlo ene enitoina u $aternici / ill i sur35 =0 . "roble$i rasta u tih bolesni(a su prenatalni i postnatalni / anson i S$ith 35 46 *uehler ianson 35580 . &stale $al or$aci+e povre$eno vi +eti na(on gestac i+s(a izlo enost i enitoina u(l+uču+eL



h%pospa ias, priro ene srčane greš(e /tetralogi+a o 'allot, septalni$ ne ostaci (oar(taci+e oaorte, it .0, iščašen+a (u(a, uralne i erenci+a+ci+u cista, pilorusa stenoza, i+a rag$alna iingvinalne herni+e, hirzutiza$, (rat(i vrat i colobo$ata / ill i sur 35 =6 1iva a 35536 Jones355 0 . Bi+et(a $aligna bolest povezana s in utero izlo enosti entoin +e li$ oblastičneli$ o$a /Murra% et al 355<0 . $ Fetalna izlo%enost karbamazepin i sindrom ;o ine 35F3, iiles$aa izvi+est io +e statistič(iznača+no s$an+en+e veličine glave u +ece i $a+(i s epilepsi+o$ izlo eni (arba$azepina u$aternici6 &va razli(a u veličini +e +oš uporan na 3F $+eseci starosti / iiles$aa et al 35F30 . &virezultati su po r ani o strane rugog $onoterapi+o$ stu i+e /*ertollini i r., 35F 0 . 2a(o +eopseg glave bolesni(a izlo enih (arba$azepina u $aternici +e $an+a u (ontrola$a, veličine glaveu ve@ini sluča+eva su u granica$a nor$ale i i$a+u ten enci+u a rastu HuH nor$alno$ rasponu svre$eno$ /Yerb% 355<0 . Ma+čins(a izlagan+e (arba$azepin +e u(l+učen u nast an(u spina bi i a u +ece i $a+(i sepilepsi+o$. Spina bi i a +e spo$enuto u F o 78 ob+avl+enih i neob+avl+enih stu i+a(arba$azepina izlo enosti $a+(i /Bosa i 1in hout 35580 . "oton+i an(ete ot(rili 33 sluča+eva spinebi i e u 3?4 $a+čins(ih izlo enosti (arba$azepina /bez izlagan+a valproat0, što po razu$i+evapo+avnost 3 u 3=7 sluča+eva. Da +e o(o 38 puta oče(ivani o$+er u op@o+ populaci+i. Jones opisu+e sin ro$ (ara(terizira %s$orphic lica, Mi(roce ali+a, igitalne ano$ali+e i(ašn+en+a u razvo+u /Jones et al, 35F50 . 1ica %s$orphic znača+(e u(l+uču+u upslantingpalpebralni$ pu(otina, epicanthal nabora, (rat(i nos i ugo philtru$. 2stra ivan+e ot(riva a

78K +ece izlo ene i$ao (ašn+en+a u razvo+u. &ve $otorič(ih i (ognitivnih e icita suispitivali /Yerb% 355<6 Yerb% i !ollins 355 0 . Jasno +e sličnost iz$e u $al or$aci+a etusa(arba$azepin sin ro$a i one izlo enosti rugi$ Antiepileptici li+e(ovi (ao što su enitoin ienobarbital bi (orisnost i+agnoze ograničen. "ovezanost iz$e u encephalocele a u $aternici izlo enosti (arba$azepin +e izvi+estio i sa$i i u(o$binaci+i s valproične (iseline izlo enosti /Bosa i 1in hout 35580 . Fetalni barbiturat izlo%enost i u!inak$ 2a(o enobarbiton i$ao reputaci+u siguran za(orišten+e ti+e(o$ tru no@e, Siep opisao +ece s pre-i postnatalne zaosta+an+e u rastu,(ašn+en+a u razvo+u, %s$orphic aci+esu, i $an+e abnor$alnosti u sura n+i s enobarbitonu(orišten+e ti+e(o$ tru no@e /Siep 35 <0 . Ano$ali+e lica u(l+učene (rat(i nos, širo(i nosni $ost,h%perteloris$, epicanthal nabora, ptozu, loE-set uši, i širo(a usta s istureni$ usna$a."reporučl+ivo +e a +e novi etalnog barbiturat sin ro$ ne stvorena zbog sličnosti iz$e u

učina(a enobarbital, enitoin, ili al(ohol izlo enost i u $aternici. 'enobarbiton, enitoin, i al(ohol$o e uzro(ovat i ne ostata( olata i č est i su $ehaniz$i za tih $al or$aci+a /Siep 35 <0 . A(tualni po ac i (ontroverzna o pravog opsegu teratogene e e(te enobarbitala u l+u i. )stu i+a$a na ivotin+a$a, pove@ana učestalost rasc+epo$ usne i nepca, priro ene srčanegreš(e, i ruge $an+e priro eni$ ano$ali+a$a su prona ena u poto$stvu tru nih $iševa išta(ora enobarbitalo$ /'rie $an i "oli (a 355?0 . ) $+eri u (o+o+ ta ispitivan+a $ogu biti uo nosu na l+u s(e situac i+e, +er +e nepoznata enobarbital oza (oristi u $iševa bila +e ne(oli(oputa ve@a /u o nosu na t+elesne te ine0 o one (o+a se nor$alno (oristi u l+u i /'ritz et al,35 <6 Nishi$ura et al 35 56 'innell Dans(% i 35530 . )čest alost priro eni$ ano$ali+a$a u(l+uču+u@i glavnih i spore nih $al or$ac i+a ni+e po(azalo sea +e ve@a u 3?34 ena li+ečenih enobarbitalo$ /ne nu no za napa a+a0 u prva ? $+esecatru no@e u National !ollaborative perinatalnu "ro+e(ta / einonen i sur 35 0 . Druge su stu i+epo(azale pove@ anu učestalost priro enih ano$ali+a u +ece $a+(i (o+e enobarbital ti+e(o$tru no@e za napa a+e /Shapiro et al 35 <0 . Slični rezultati su vi +eli u rugo+ seri+i (o+apri+avl+en pove@an bro+ rasc+epo$ nepca i priro enih srčanih bolesti u etusa ro ene epileptični$ena (o+e su uzi$ale enobarbital u o nosu na (ontrolnu s(upinu /;reenberg i sur 35 6 Both$ani sur 35 56 Na(ane et al 35F80 . 'etusi (ronično izlo ene enobarbitala u $aternici su po(azalia i$a+u učestalost o 38K o 78K o $al or$aci+a, u(l+uču+u@i ozbil+ne proble$e (ao što subolesti srca priro ene /Spei el i 1iva a 35 76 Annegers et al 35 ?0 . 2nci enci+a etalnog$al or$aci+a $o e biti pove@ana u bolesni(a (o+i uzi$a+u enobarbital u (o$binaci+i s rugi$ant iepilept ič(i$ li+e(ovi$a /Bosa i 'r%ns 35580 . 2zni$(a tog pravilu sni avan+e rizi(a spina bi i au bolesni(a izlo enih valproins(e (iseline u (o$binaci+i s enobarbitalo$. &va+ učina( ni+eneoče(ivano +er enobarbital i$a ubrzan+a +elu+e na (ataboliza$ valproins(e (iseline, a

Antiepileptič(i ni e razine li+e(a su povezane s $an+i$ rizi(o$ o etusa $al or$aci+a /Dans(% ir., 35F86 Bosa i 'r%ns 35580 . Je no izv+eš@e spo$in+e povezanost sa su en+e$ aorte u$aternici izlo enosti viso(i$ oza$a barbiturati$a /se(obarbital i a$obarbital0 /Bosa 35F<0 . ) Nac ionalno$ !ollaborative perinatalnu "ro+e(ta, (oe ici+ent inteligenci+e +ece izlo ene ineosvi+etl+eni a phenobarbital u $aternici +e u uspore bi /Shapiro et al 35 <0 . Ne$a statistič(iznača+nih razli(a $o e se o(azati u to+ stu i+i.



"henobarbital izlo enost u $aternici bila povezana s prolazni$ neonatalna se ira+u@i$ ipovlačen+a si$pto$a u novoro enča i /Des$on i sur 35 76 9och i sur 35F40 . Si$pto$ao vi(avan+a su slični oni$a (o+i se susre@u (o rugih ovisnosti izlo enosti li+e(a u $aternici (aošto su (o(ain i opi+ati. Novoro enča i$a+u ten enci+u a se raz ra l+ivo, pro$i+enili su obrascespavan+a, teš(o hraniti, i$a+u pove@an uplašiti re le(s, i i$a+u hiperre le(si+u. Ta+$ingpovlačen+e si$pto$a, (a(o se čini rugači+e, sa sre n+o$ počet(a o(o se $og ana i pros+ečno=-$+esečnog tra+an+a /Des$on i sur 35 70 . Sličan sin ro$, ali s počet(o$ počet(araz ra l+ivost u prvi$ sat i$a ivota, na(on št o +e opisao $e obarbital izlo enosti u $aternici / illi sur 35 =0 . Baz ra l+ivost i al+e sve o četvrtog $+eseca ivota. e$oragi+s(a bolest novoro enčeta zbog ne ostat (a vita$ina 9 +e opisano na(onenobarbitonu izlo enosti ti+e(o$ tru no@e /Davis 35 86 ill i sur 35 =0 . Iita$in 9 treba se atina sve novoro enča i izlo ene barbiturata u $aternici /Morrell 355F0 . 'zlo%enost primidona i embr opat& $ Gnan+e o učinci$a izlo enosti pri$i ona u $aternicise te$el+i uglavno$ na sluča+u izv+eš@a. "ri$i on izlagan+e u $aternici +e u(l+učen u razvo+speci ične %s$orpholog% lica. "oton+e u(l+uču+e pove@anu la(e na licu /osobito na čelu0,abnor$alne nos s anteverte nosnice, uge philtru$s i ebeli$ nosni (ori+eni$a /Bu i slobo a35 56 ;ustavson i !hen 35F40 . Basc+ep usne i nepca su ta(o er izvi+estili /Bosa 35580 . Ne(i otih paci+enata čini se a su znača+(e slične ;ol enhar sin ro$o$ /!hen i ;ustavson 35F40 .*olesnici s pri$i on e$br%opath% uzora( $o e i$ati (ognitivnih i $otorič(ih (ašn+en+a,usporavan+a i (ongenitalnih bolesti srca. &ni su često $ale za gestaci+s(u ob pri ro en+u /Bu

i slobo a 35 56 ;ustavson i !hen 35F40 . Ta su izv+eš@a ta(o er spo$enuti prst i no(atabnor$alnosti slične oni$a (o+i se susre@u (o izlagan+a entoin. 9ongenitalne bolesti srcata(o er +e izvi+est ila u sluča+evi$a izlo enost i pri$i ona, u(l+uču+u@i aorte (oar(tac i+c ie#trocar ia /Bosa 35580 . &stale ri+et(e u ruge obuhva@a+u anence ali+a i oculo-auriculo-vertebralnih ano$ali+a /Bosa 35580 . Dva sluča+a spine bi i e zabil+e eni su, +e an za izlagan+epri$i ona $onoterapi+o$ i rugi u politerapi+i valproične (iseline i (arba$azepina /Bosa 35580 .e$oragični bolest novoro enčeta, zbog ne ostat(a vita$ina 9 +e opisano na(on izlagan+apri$i ona u $aternici. Iita$in 9 treba se ati na sve novoro enča i izlo ene pri$i ono$ u$aternici. Fetalni trimetadion sindrom ("etalni dion sindrom)$ &va+ sin ro$ +e sa a ri+et(ost zbogs$an+ene upotrebe o(sazoli ino$ erivata (ao što su tri$eta ion i para$etha ione. N+e$ač(i isura nici izvi+estili sluča+ epileptič(i ena li+ečenih tri$eta ion (o+i +e i$ao četiri neusp+ešne

tru no@e, na(on čega se ostave 7 z rave +ece na(on što +e prestao uzi$ati roge /N+e$ač(iet al 35 80 . Gac(ai i (olege opisao (linič(i enotip etalno$ tri$eta ion sin ro$o$ /Gac(ai et al35 40 . &va+ sin ro$ se sasto+i o intrauterino zaosta+an+e u rast u, $i(roce ali+o$, $al or$ac i+a$alica, priro ene srčane greš(e, i urogenitalnog ano$ali+a. 1ica $al or$aci+e su u obli(u slova Iobrve, epicanthal nabora, loE-set uši i nepravilne zube. Sre išn+i ivčani sustav $al or$aci+e$ogu se vi +eti. Mentalna retar aci+a +e prisutna u o 75K bolesni(a, govora (ašn+en+e u ? K,a zaosta+an+a u razvo+u 4=K /Bosen i 1ightner 35 F0 . )ro enih srčanih bolesti u(l+uču+u hipoplastičnu sin ro$ li+evog srca, t et ralogi+u o 'allot iprenošen+e veli(ih ila /Bosen i 1ightner 35 F0 . Mal or$aci+e $ogu se vi +eti u bubrezi$a,ušni(, gr(l+an, i +e n+a(a. Iiso(a stopa $al or$aci+a, $nogi o n+ih teš(i, +e povezana sviso(o$ stopo$ s$rtnosti neonatalnog a $o e i@i blizu ?8K. ) stu i+i o 4= tru no@a u (o+i$atri$eta ion se (oriste, zabil+e eno +e ?< sluča+eva gubit(a etusa ili priro eni$ano$ali+a$a /'el $an et al 35 0 . Je an olloE- up stu i+a o paci+enti$a (o+i su bili izlo eni tri$eta ion u $aternici po(azao stopu75K o $entalne retar aci+e, Mi(roce ali+a u 48K sluča+eva, i nis(og rasta u 4=K /Bosen i1ightner 35 F0 . Fetalni valproat sindrom$ prva izv+eš@a na teratogeni učina( valproins(e (iseline po+avio urani$ 35F8-ih /Dalens i r., 35F86 !la% i sur 35F36 ;o$ez 35F30 . Na(on toga, Bobert i ;uibanopisao povezanost valproične (iseline i ošte@en+e neuralne ci+evi /Bobert i ;uiban 35F70 .Di1iberti i (olege (onsoli irana i e+u o speci ično+ (onstelaci+i $al or$aci+a etusa valproatnisin ro$o$ /Di1iberti et al, 35F?0 . ) $al or$aci+e s$atra+u obil+e +e ovog sin ro$a su tipičniis$or iza$ lica i ošte@en+e neuralne c i+evi /A%$e 35586 Jones 355 0 . &ve $al or$aci+e

po+avl+u+u se o ozi, +er $a+(e (o+e (oriste više o 3888 $g valproins(u (iseline nevno bili suviše v+ero+atno a @e i$ati ispravan novoro enča i u o nosu na one (o+e su <88 $g ili $an+e poanu /Sa$ren et al 355 0 . )čestalost lica i $an+e e or$aci+e na(on izlagan+a valproične(iseline u $aternici se proc+en+u+e na iz$e u 48K o 4K /A%$e 35586 Desnica i ie e$ann355 0 . ) ošte@en+e neuralne ci+evi (o+e se često naziva+u labavo (ao Hspina bi i aH su v+ero+atno



na+više napa an $al or$aci+e povezane s valproins(u izlo enosti (iseline u $aternici. Ar inger in+egovi (olege ot(rili su ob+e lu$bosacral $eningo$%elocele i zgrčeno stopalo e uinovarus /sneta(nuto$ (ral+e nice0 biti tipičan za etalne valproatni sin ro$o$ /Ar inger i r., 35FF0 .Neuralne ci+evi su ta(o er izvi+estili u bolesni(a izlo enih (arba$azepina u $aternici /Bosa i1in hout 35580 , te va bolesni(a /bolesni( 5 i paci+ent 3<0 s lu$bosacral $eningo$%elocelesta(o er bili izlo eni (arba$azepina /Ar inger i r., 35FF0 . "revalenci+a neuralne ci+evi +e 38 o78 puta ve@a u etusa izlo enih valproične (iseline u $aternici, u uspore bi s op@o$populaci+o$ /&$tzigt et al 35570 . Bizi( neuralne c i+evi e e(t u $aternici na(on izlagan+avalproins(e (iseline se proc+en+u+e na 3K o 4K /A%$e 35580 . 2zgle lica tih paci+enata +e prilično tipično, s epicanthal torove or$iran+u nabor po orbita,telecanthus, i širo( i niza( nosni $ost s (rat(i$ nos i anteverte nosnice /Di1iberti et al, 35F?6Ar inger i r., 35FF6 A%$e 35586 Jones 355 0 . 1ong philtru$, t an(a cinober granice, sre ino$lice h%poplasia, a $ala usta /$icrosto$ia0 često su ta(o er prisutne u sin ro$o$ /Di1iberti etal, 35F?6 Ar inger i r., 35FF0 . Basc+ep usne i nepca su ta(o er izvi+estili /Ar inger i r., 35FF6Jones, 355 6 Desnica i ie e$ann 355 0 , ali su ri+et(i, +avl+a+u u 3 o 35 paci+enata /Ar inger ir., 35FF0 . Ar inger i n+egovi (olege ot(rili su van+s(i orbitalna ne ostata( greben i bi rontalsu avan+e biti tipičan izgle lica bolesni(a s etalno$ valproatni sin ro$o$. "rsti$a et alnih valproat sin ro$o$ su tan(i i pre(lapa+u, a no(ti su h%perconve# a $o e bit i ihipoplastična /Di1iberti et al, 35F?6 A%$e 35580 . "osta#ial pol% act%l%, triphalangeal palac,palac aplazi+a, s%n act%l% i ra i+alni aplazi+a $o e se vi +eti /Jones, 355 6 Desnica i ie e$ann

355 0 . Mentalna retar ac i+a +e obično blage o u$+erene /Desnica i ie e$ann 355 0 . 9ognitivnie iciti sa ili bez rugih neurološ(ih abnor$alnosti su prisutni u 3K o $onoterapi+e u $aterniciizlo enosti iu 58K politerapi+i izlo enosti /Ar inger i r., 35FF0 . Ar inger i (olege oc+en+u+u 35 +ece izlo ene valproične (iseline u $aternici, u po(uša+u a seprov+eri enotip etalno$ valproatni sin ro$o$ /Ar inger i r., 35FF0 . )natoč o sustvuprenatalno$ ili postnatalno$ ne ostata( rasta u +ece izlo ene Ialproic (iselina $onoterapi+e u$aternici, vi+e tre@ine +ece ta(o er izlo ene rugi$ antiepilepti(a i$ao postnatalnene ostata( rasta i Mi(roce ali+a. Gna(ovi novoro enog ence alopati+e po+avl+u+u se češ@e nego što se oče(ivalo u +ece $a+(i(o+e valproičnu (iselinu za napa a+e /Jager-ri$s(i et al 35F<0 . &va+ proble$ +e bio opisan snis(o$ Apgar rezultat /7FK sluča+eva0 i perinatalni t+es(oba (o+e su često pra@ene i postnatalne

proble$a rast a i s$an+en opseg glave. Jeavons izv+eš@a a +e 35,FK o poro a bila abnor$alnona(on valproins(u izlo enosti (iseline u $aternici, ali ne$a o(aza o učin(u oza o govorposto+i /Jeavons 35F?0 . Jeavons i Jager-ri$s(i i po at(e (olega treba tu$ačiti s oprezo$ zbogteš(o@a u i+agnosticiran+u natalna epresi+a tegobe ili novoro enče ence alopati+u na(on što +eu $aternici izlo enosti valproične (iseline. Ta izv+eš@a /Jeavons 35F?6 Jager-Bo$an i sur 35F<0 ,u stvari $o e o raziti, bare$ +elo$ično, se at ivni i teratogeni učina( valproične (iseline uetusa. &va+ st av po r an +e gotovo univerzalni h%pera$$one$ia i se iran+e +e opa eno (oIalproična (iselina $o e se upotri+ebiti u li+ečen+u neonatalne (onvulzi+e /;al i r., 35FF0 . Iiso(e oze valproičnu (iselinu u $aternici +e povezana s o vi(avan+e o roga i h%potonia uneonatalnog perio a i zati$ $otora i +ezi(a (ašn+en+a /Jager-ri$s(i et al 35F<0 . 9ar iovas(ularni ošte@en+a u(l+uču+u aorte (oar(taci+c ili valvularna stenoza, hipoplast ičnuli+evu srce, ibrilaci+a ili ventri(ularne septalno $ana, patent uctus arteriosus, i tetralogi+u o'allot /Ar inger i r., 35FF6 A%$e 35586 Jones 355 0 . &stale r+e e povezane $al or$ac i+e su pore$e@a+a rasta , h%pospa ias, (riptorhiza$, vovrherebro, širo(a prsa, ingvinalne i pupčanu (ilu, pre(obro+ne bra avice i plu@a hipoplazi+u /Jones,355 6 Desnica i ie e$ann 355 6 Janas et al 355F0 . Ne avne stu i+e su izvi+estiliasoci+aci+e cranios%nostosis , autiz$a , te očnih ot(ri@a u(l+uču+u@i suhe oči, (rat(ovi nosti inovoro enče potil+ačni e e$a /1a+eunie sur 78836 illia$s i sur 78836 ;lover i r. 78876 itterset al 78870 . &si$ toga, = obitel+i su opisani u (o+i$a po+ava etalnog valproat sin ro$a ošlo usvi$ bra@e, sna no u(azu+e nasl+e nu s(lonost valproična (iselina-in ucirana isho /Mal$ et al78870 . erato*enesis od noviji& antiepileptika$ po ata(a (o+i se o nose na rizi( za (ongenitalne$al or$aci+e povezane s novi+ih antiepilepti(a / gabapentin , elba$at, la$otrigin , levetiraceta$

,o(s(arbazepin , tiagabin , topira$at , zonisa$i , i vigabatrin 0 i al+e su ograničeni. ) osvrtu nateratogenih učina(a novi+ih ant iepilepti(a u stu i+a$a na ivotin+a$a, elba$at, gabapentin,la$otrigin, o(s(arbazepin, topira$at, t iagabina i vigabat rin $o e izazvat i zast o+ rasta /Morrell355<0 . ' elba$ate, gabapentin, la$otrigine, an topira$ate c ause s(eletal $al or$at ions, butonl% high oses o topira$ate can cause li$b agenesis. Iigabatrin can cause cle t lip anpalate in ani$als. Teratogenic e ects o vigabatrin Eere oun in $ouse etuses6 the



e#encephal% , $an ibular an $a#illar% h%poplasia, arche palate, cle t palate, li$b e ects,o$phalocele, an e#o$phalos Eere observe in the etuses e#pose to vigabatrin in utero/Ab ulrazza et al 355 0 . "rospective ata ro$ the )nite 9ing o$ :pileps% an "regnanc%Begistr% Begister Eere anal%ze . The etal anticonvulsant s%n ro$e rate or pol%therap%e#posure Eas greater than $onotherap% e#posure an signi icantl% higher in regi$enscontaining valproate. 'or $onotherap% e#posures, carba$azepine Eas associate Eith theloEest ris( o etal anticonvulsant s%n ro$e /MorroE 788<0 . An ongoing, prospective,observational stu % across 74 epileps% centers enrolling pregnant Eo$en in the )nite Statesan )nite 9ing o$ oun that valproate re$ains the highest ris( to the etus /78.=K0 ansuggeste that la$otrigine $a% have the loEest etal anticonvulsant s%n ro$e rate /3.8K,hoEever, see beloE0 in a co$parison involving $onotherap% e#posures to carba$azepine,la$otrigine, phen%toin, an valproate /Mea or 788<0 . ;abapentin . A large post$ar(eting surveillance stu % o =,388 :nglish patients receiving therug i enti ie onl% 33 pregnancies Eithout an% congenital ano$alies / ilton an Sha(ir 78870 .2n another stu % o =5 Eo$en an 43 pregnancies receiving gabapentin, the rate o $a+or$al or$ations Eas ?.4K. :ight%-seven percent o the pregnancies resulte in live births,33.=K in $iscarriages, an 7K in therapeutic abortions /Montouris 78870 . 1a$otrigine . 'ro$ a registr% o ==? pregnancies, there Eere i erent rates o $a+or structuralbirth e ects epen ing on Ehether la$otrigine Eas use in $onotherap% or pol%therap%. Therate Eith la$otrigine $onotherap% Eas 3.FK6 the rate Eith pol%therap% Eith valproic aci Eas

38K6 an pol%therap% Eithout valproic aci Eas ?.=K /Tennis an :l ri ge 78870 . The $ostrecent 2nternational 1a$otrigine "regnanc% Begistr% shoEe that a$ong ?3? irst-tri$estere#posures to la$otrigine $onotherap%, there Eere 37 outco$es Eith $a+or birth e ectsreporte , ie, 7.5K, si$ilar to that in the general population /!unnington 78840 . Although therehave been suggestions that la$otrigine $a% be less teratogenic than ol er antiepileptic rugs,recentl% publishe ata ro$ the North A$erican Antiepileptic Drug "regnanc% Begistr% report =cases o isolate , non s%n ro$ic c le t palate an 7 cases o isolate , non s%n ro$ic c le t lipEithout cle t palate in in ants ro$ 4<? irst-tri$ester la$otrigine $onotherap% e#posures,giving a rate o F.5 per 3,888 / ol$es 788<0 . &#carbazepine . 2n 7 stu ies o a total o ?? cases o pregnanc% Eith e#posure too#carbazepine, both as $onotherap% an pol%therap%, there Eere = spontaneous abortions an3 chil Eith ventricular septal e ec t Eho Eas also e#pose to phenobarbital /'riis et al 355=6BabinoEicz et al 78870 . The $anu acturer has been noti ie o 4 cases o etal $al or$ationinclu ing 3 car iac e ect, = cle t palates, an 3 ac ial %s$orphis$. Three o these etusesEere e#pose to pol%therap% /Yerb% 788=a0 . Topira$ate . 1i$ite in or$ation is available regar ing topira$ate. 2n clinical trials, there Eere7F reporte pregnancies, all pol%therap% cases, Eith 3 resultant $al or$ation an 7 chil renEith ano$alies /Yerb% 788=a0 . Gonisa$i e. There have been 7< reporte pregnancies in assoc iation Eith zonisa$i ee#posure. There Eere 7 cases / . K0 o congenital $al or$ations, but both o these casesEere pol%therap% cases /phen%toin also in one an phen%toin an valproic aci in the other0/9on o et al 355<0 .

+linical vi*nette A neurologic consultation Eas re ueste or a - a%- ol in ant Eho ha neonatal seizures .The patient Eas born to a =?-%ear-ol $other Eith a histor% o generalize tonic-c lonicseizures since a olescence that ha been treate Eith phenobarbital 58 $g per a%. Thetreat$ent alloEe the $other to be seizure- ree, although she occasionall% co$plaine o eeling sa . The pregnanc% Eas otherEise unco$plicate , an the $other Eas seizure- reethrough the gestation. A $ale bab% Eas elivere Eithout proble$s a ter a =5 Eee( gestation6the birth Eeight Eas 7,788 g$ /s$all or gestational age0, an the Apgar scores Eere /3$inute0 an F /4 $inutes0. Di icult% ee ing an se ation Eere notice ro$ a% 3. Theee ing i iculties i$prove sloEl%, but or$ula an breast $il( ha to be given throughgavage. A pe iatric neurolog% consultat ion Eas re ueste on the seventh a% o li e ue topoor ee ing an spontaneous sha(ing $ove$ents involving the upper $ore than the loEere#tre$ities, lasting a eE secon s, an occurring inter$ittentl%. The patient s ph%sical e#a$shoEe short nose, broa nasal bri ge, h%perteloris$ , epicanthal ol s, an Ei e $outh. As$all palate cle t coul be seen but no cle t lip Eas note . The neurologic e#a$ Easre$ar(able or irritabilit% alternating Eith sleepiness. The patient Eas al$ost never in the uiet



alert stat e. Mil to $o erate a#ial h%potonia Eas not ice . A eE episo es o spontaneous ast/several c%cles per secon 0 sha(ing o the e#tre$ities Eere seen, Ehich coul be suppresseb% restraining. &therEise, the neurologic e#a$ Eas nor$al or the patient s chronological angestat ional age. A lu$bar puncture Eas one, an the patient Eas st arte on a$picillin an genta$icin ue topresu$e sepsis . The cerebrospinal lui Eas clear an ha zero re cells an one Ehite cell6protein an glucose Eere Eithin the nor$al range or the patient s age. An ::; Eas $il l%abnor$al ue to %s$ature eatures, but no electroencephalographic seizures Eere seen. The hospital course Eas charac terize b% sloE i$prove$ent o the patient irritabilit%. Theee ing i$prove Eith upright positioning an special nipple use or bottle- ee ing. The patientEas ischarge on a% 73 o li e, ee ing b% $outh an gaining Eeight /38 to 78 g per a%0.The patient Eas re erre to the cranio- acial clinic or $anage$ent o the cle t palate. Thepatient Eas seen on olloE-up / ro$ = to 37 $onths ol 0, an the neurologic e#a$ Easco$pletel% nor$al.

tiolo* 'et al anticonvulsant s%n ro$e has been lin(e to e#posure to antiepileptic rugs, an e ec tin epen ent o epileps% /Yerb% 78830 . &ther actors $a% also be at Eor( in the genesis o $al or$ations in chil ren e#pose to the antiepileptic $e ications in utero, such as genetics ,socioecono$ic, nutritional in luences, an e#posure to other teratogens. ;enetic variabilit% inthe ree-ra ical scavenging, epo#i e eto#i ication, an environ$ental actors have beeni$plicate in the Ei e phenot%pe variation in these patients. The e#act $echanis$s o antiepileptic rug teratogenesis are not clearl% (noEn.

Pat&o*enesis and pat&op& siolo* The biological basis o the etal anticonvulsant s%n ro$e re$ains largel% speculative,although so$e evi ence points to epo#i e an ree-ra ical to#icit% pla%ing a role in theteratogenesis associate Eith these rugs. Man% rugs are pri$aril% $etabolize into epo#i es/Jerina an Dal% 35 ?0 . A$ong the epo#i es, the arene o#i es have been associate Eith acarcinogenic an $utagenic e ec t ue to their electrophilic properties an c ovalent bin ing to$acro$olecules /Jerina an Dal% 35 ?6 Nebert an Jensen 35 56 Shu$ et al 35 50 . &ne o thepathEa%s o epo#i e eto#i ication /epo#i e h% rolase enz%$e0 is $uch less active in etusesEhen co$pare to a ults /"aci ic i et al 35F=0 . Another contributing actor $a% be the actthat at least one t hir o the etal circulation b%passes the liver, Ehich is one o the $ain siteso rug eto#i ication /"aci ici an Bane 35F70 . "hen%toin or$s a trans ih% ro iol $etabolite that $a% be etec te in the hu$an neEborne#pose to that rug in utero / orning et al 35 ?0 . "hen%toin bin s irreversibl% in vitro to ratliver, an this bin ing is increase b% inhibition o the epo#i e h% rolase but ecrease b%glutathione /Martz et al 35 0 . Spielberg an colleagues e$onstrate that phen%toin to#icit%in vitro is increase b% inhibition o epo#i e h% rolase /Spielberg et al 35F30 . 'eE hu$an stu ies have been one that e#plore the role o epo#i es in the etalanticonvulsant s%n ro$e. Stric(ler an colleagues incubate hu$an l%$phoc%tes anphen%toin Eith the $icroso$al s%ste$ o $ice /Stric(ler et al 35F40 . An increase eath rate inthe cells o the s%ste$ Eas notice Ehen the l%$phoc%tes ca$e ro$ chil ren Eith $a+or$al or$ations. The l%$phoc%tes ro$ a$il% $e$bers o these chil ren o ten %iel a si$ilarresponse. Stric(ler an colleagues suspecte that a loE arene o#i e eto#i ication capabilit%Eas responsible or the increase ris( o $al or$ations a ter phen%toin e#posure /Stric(ler et al35F40 . &ne ele$ent that Eas $issing in the latter stu % Eas the lac( o $easure$ent o theepo#i e h% rolase activit% in these patients. 2n 35F4, *uehler oun that a higher epo#i eh% rolase activit% correlate Eith an increase nu$ber o eatures o etal h% antoin s%n ro$ein a pair o iz%gotic tEins /*uehler 35F40 . 2n another stu %, the activit% o the epo#i eh% rolase Eas $easure b% thin-la%er chro$atograph% in a$niotic cells o 388 pregnant Eo$en

to establish nor$al levels6 a tri$o al istribution Eas oun , suggesting that the enz%$e isregulate b% a single gene Eith 7 allelic or$s /*uehler et al 35580 . 'etuses ho$oz%gous orthe recessive allele have loE epo#i e h% rolase activit% an , there ore, Eoul be at high ris( i e#pose to phen%toin or other epo#i e pro ucing rugs uring gestation. 2n 35 cases o pregnant $others receiving phen%toin $onotherap%, in Ehich the pregnancies Eere $onitoreb% a$niocentesis, the 34 $others at loE ris( or etal h% antoin s%n ro$e on the basis o



nor$al epo#i e h% rolase activit% elivere in ants lac(ing the phenot%pe o the etalphen%toin s%n ro$e, but ? etuses consi ere at high ris( on this basis all shoEe eatures o the s%n ro$e at birth /*uehler et al 35580 . These in ings alloE or so$e prenatal pre iction o the ris( o etal $al or$ation in $others ta(ing phen%toin. :ven though all the evi ence orpero#i e teratogenicit% above is i$pressive, ethotoin, $ephen%toin, an tri$etha ione havebeen shoEn to have teratogenic e ects but o not have arene o#i e $etabolites /Yerb%355<0 . ;eneticall% eter$ine patterns o eto#i ication an $etabolization o anticonvulsantshave an i$pact on teratogenic ris( /1in hout 35570 . ells an colleagues revieEe the role o o#i ative a$age in che$ical teratogenesis / ells et al 355 0 . Stu ies in pregnant $ice thate$onstrate sensitivit% to phen%toin-in uce $al or$ations an that involve chronicphen%toin e#posure have shoEn signi icantl% altere e#pression o several genes at i erentti$es o $orphogenesis6 in particular, retinoic aci receptors alpha, beta, an ga$$a Eeresigni icantl% increase /;elineau-Ian aes et al 35550 . Man% antiepileptic rugs have olic aci antagonistic properties, an si$ilar patterns o $al or$ations can be seen a ter in utero e#posure to olic aci antagonists /unsuccess ulatt e$pts to in uce abortion0 /Mea oE 35<F0 . ill an colleagues notice that so$e $othersta(ing phen%toin Eho elivere $al or$e etuses ha bor erline or loE olate levels / ill et al35 =0 . Although the utilit% o olic aci supple$entation or the general e$ale repro uctivepopulation is clearl% establishe , Ehether or not it re uces teratogenic ris( or Eo$en Eithepileps% ta(ing antiepileptic rugs is unclear. There have been = case reports o Eo$en Eho

too( goo oses /=.4 to 4 $g0 o olic aci supple$entation $onths be ore conception anthroughout pregnanc% Eho Eere also on valproic aci Eith resultant neural tube e ects /oneEith other $al or$ations also0 /!raig et al 35556 Duncan et al 78830 . These cases are not thatsurprising as there has been e$onstrate ailure o olate to re uce valproic aci -in uceneural tube e ects an e$br%oto#icit% both in vitro an in vivo ro ent $o els / ansen an;ra ton 35536 ansen et al 35540 . &ther actors have been i$plicate in the genesis o etal anticonvulsant s%n ro$e,especiall% in association Eith phen%toin e#posure. Acet%lsalic%lic aci inhibits prostaglan ins%nthase that o#i ates phen%toin /9uenssberg an 9no# 35 =0 . The or$er reaction pro ucesree ra icals that $a% bin to proteins /9uenssberg an 9no# 35 =0 . "retreat$ent o pregnant$ice ta(ing phen%toin Eith acet%lsalic%lic aci re uces the ris( o cle t lip an palate in theiro spring / ells et al 35F?0 . The sa$e authors oun a si$ilar e ect Eith pretreat$ent Eithca eic aci , an antio#i ant agent. A recent SEe ish stu % in rats shoEe goo correlation betEeen phar$aco(inetic ata anpregnanc% outco$e ata, ie, t he egree o evelop$ental to#icit% Eas relate to ree $aternalplas$a phen%toin levels. The results suggest that the evelop$ent o to#icit% o phen%toin iscause b% concentration- epen ent in uction o e$br%onic %srh%th$ia an h%po#ia-relatea$age uring a restricte sensitive perio /Danielsson et al 78880 .

pidemiolo* The rates o $al or$at ion in in ant s o $others Eith epileps% ranges ro$ 7.=K /Janz an'uchs 35<?0 to 3F.<K /Me%er 35 =0 . The rate o $al or$ations o the general population in

various reports ranges ro$ as loE as 3.?K to as high as 48K. The $ost co$$onl% acceptevalues are 3.4K to =K /9alter an ar(an% 35F=6 9ell% 35F?a6 Yerb% an !ollins 355 0 . ThisEi e range is cause b% i erences in the threshol or iagnosing $inor acial or ore ingerano$alies an the variabilit% in $etho olog%. 2n one revieE, =5 stu ies o $al or$ation rates inthe o spring o epileptic an control $others Eere anal%ze /Yerb% an !ollins 355 0 . Theanal%sis e$onstrate a c o$bine est i$ate o $al or$ation o ?K to <K or an in ivi ualepileptic pregnanc%. The sa$e authors point out that $ost stu ies shoE that in ants o $others Eith epileps% have about 7.4 to 38.4 ti$es $ore $al or$ations than the generalcontrol populations. A group stu ie the relative ris(s o particular $a+or $al or$ations Eithetal e#posure to antiepileptic rugs. The% oun the relative ris( or car iovascular e ectsEas 7.7, oral cle ts 7.4, an urinar% tract e ects 7.4 / ernan ez-Diaz et al 78880 . 'etal$ortalit% is another ris( or Eo$en Eith epileps%. Beporte rates o stillbirth / e ine as greaterthan 78 Eee(s gestational age0 var% betEeen 3.=K an 3?K co$pare Eith rates o 3.7K to.FK or Eo$en Eithout epileps%. "erinatal eath rates are also up to 7 ti$es higher orEo$en Eith epileps% /3.=K to .FK0 co$pare to controls /3.8K to =.5K0 /Yerb% 78880 .Spontaneous abortions /less than 78 Eee(s gestation0 $a% also occur $ore re uentl%although the igures var% consi erabl% betEeen i erent stu ies /"ennell 788=0 .



Several ac tors re$ain i icult to e#plainL Eo$en Eith epileps% o ten Eill have a loEer socialecono$ic status an ecrease abilit% to hol high pro ile +obs, an the% are $ore prone toacci ents, alls, an serious in+uries relate to seizures. :pileptic patients are also less li(el% tobe riving an $a% have $ore i icult% having access to prenatal care in areas Ehere publictransportat ion is not e icient. These ac tors $a% contribute in part to intrinsic i erences inthese populations, Ehich are i icult to control. ;enetic in luences probabl% also pla% a role inthe genesis o $al or$ations in in ants o $others Eith epileps%. The rate o $al or$ations inthe relatives o t he a ec te chil ren is higher than in the relatives o the ones Eithoutano$alies /Dans(% an 'innell 35530 . Mal or$ation rates appear to be higher in in ants o untreate Eo$en Eith epileps% than in those born o $others Eithout epileps% /Shapiro et al35 <6 9och et al 35570 . A a$il% histor% o spina bi i a Eas present in 74K o the chil ren Ehoevelope neural tube e ects a ter antiepileptic rug e#posure in utero /1in hout et al 3557a63557b0 . Spina bi i a occulta is $ore co$$on in the genetic epilepsies than in the s%$pto$aticones /9lepel an 'reitag 35570 . :pileps% is also $ore co$$on a$ong the irst an secon -egree relatives o pat ients Eith c le t lip an palate /Drona$ra+u 35 80 . Nonetheless, theauthors still believe that $al or$ations in in ants o $others Eith epileps% are cause $ostl%b% teratogenic e ects o the antiepileptic rugs /Janz an 'uchs 35<?6 Spei el an Mea oE35 76 Annegers et al 35 F6 Na(ane 35 50 . hen a chil has etal h% antoin s%n ro$e, a 58Kris( e#ists that the ne#t sibling Eill be a ecte , in contrast to a 7K o ris( i the irst chil isnor$al /Ian D%(e et al 35FF0 .

The rate o so$e spec i ic $al or$ations is espec iall% increase in in ants o $others Eithepileps%. 'or e#a$ple, the rate o cle t lip an palate is ?. ti$es higher Ehen co$pare Eiththe general population /'riis 35F50 . The re uenc% o neural tube e ects is 38 to 78 ti$eshigher in chil ren e#pose to valproic ac i in utero /&$tzigt et al 35570 an about 38 ti$eshigher Eith carba$azepine e#posure /Bosa an 1in hout 35580 . Most st u ies o cognitive outc o$es o in ants e#pose to antiepileptic rugs in utero reportan increase ris( o $ental e icienc% , a ecting betEeen 3.?K an <K o chil ren o Eo$enEith epileps% co$pare Eith 3K o controls /1eavitt et al 35576 9och et al 35550 . TEo recentstu ies ro$ the )nite 9ing o$ involving a total o =48 chil ren have shoEn that prenatalantiepileptic rug e#posure in the setting o $aternal epileps% is associate Eith evelop$entalela%, particularl% speech ela%, an later chil hoo $orbi it%, in a ition to congenital$al or$ation /Moore et al 78886 Dean et al 78870 . The plas$a concentrations o antiepileptic rugs appear to be higher in the $others o in ants Eith epileps% Ehen co$pare to epileptic $others Eho gave birth to nor$al chil ren/Dans(% et al 35F80 . A $other using $ore than 3888 $g o valproic aci per a% is $ore li(el%to have $al or$e o spring than a $other ta(ing <88 $g or less per a% /Sa$ren et al 355 0 .The epileptic $other treate Eith antiepileptic rug pol%therap% is $ore li(el% to give birth toan in ant Eith $al or$ations Ehen co$pare to the one treate Eith $onotherap% /Na(ane35 50 . The e ec t o $aternal seizures in the inc i ence o $al or$ation is unclear at t his point.Annegers an colleagues an Na(ane an associates oun no i$pact o seizures in the ris( o etal $al or$ations /Annegers et al 35 F6 Na(ane et al 35F80 . 1in hout an collaborators ouna =- ol increase in $al or$ations in the etuses e#pose to seizures uring the irst tri$ester/1in hout et al 3557a6 3557b0 .

Prevention 2n $an% cases, the e#posure to anticonvulsant $e ication is unavoi able uring pregnanc%.TEo $ain consensus articles Eere publishe that outline so$e gui elines or antiepileptic ruguse uring pregnanc% /Delga o-:scueta an Janz 35576 Morrell 355F0 . There has also been arecent practice para$eter su$$ar% state$ent ro$ the A$erican Aca e$% o Neurolog%/Cualit% Stan ar s Subco$$ittee o the A$erican Aca e$% o Neurolog% 355F0 .The $ain eatures o these gui elines inclu eL /30 ean patients o their $e ication i the% have been seizure- ree or $ore than 7 %ears. /70 hen necessar%, use the antiepileptic $e ication o irst choice or the patient s epileps%s%n ro$e in $onotherap% at the loEest e ective ose. /=0 Alert patients Eho use valproic ac i an carba$azepine that i a a$il% $e$ber has neuraltube e ect , his or her o spring is at a higher ris( or this t%pe o $al or$ation. /?0 "atients ta(ing valproic ac i or carba$azepine shoul have an alpha- etoproteineter$ination one b% a$niocentesis at 3< Eee(s an ultrasoun visualization o the etus at



3F to 77 Eee(s, loo(ing or $al or$ations - especiall% neural tube e ects. /40 Monitor antiepileptic rug levels re uentl% / ree levels i possible0. !hange to re uentail% oses - or e#a$ple, valproic ac i in ? ivi e oses. T his st rateg% is ue to the ac t thathigher oses an bloo levels o antiepileptic rugs have been associate Eith a higherinci ence o etal $al or$ations. /<0 "rescribe ail% olate supple$entation. The ail% olate ose reco$$en e is 8.? $g pera%, but perhaps oses o 8.4 or 8.< $g per a% $ight be $ore e ective, an patients at ris(or neural tube e ects have been recentl% reco$$en e to ta(e up to ? $g per a%. 2 eall%,olate nee s to be ta(en be ore conception. / 0 A $inister vita$in 9 or the neEborns o $others ta(ing antiepileptic rugs. To i$ple$ent these gui elines, epileptic pregnant Eo$en nee to have care ul prenatal care.The obstet ric ian shoul eci e ahea o ti$e i a Eo$an nee s to be sent to ac ilities prepareor high-ris( eliveries. e$orrhagic isease o the neEborn ue to vita$in 9 e icienc% has been esc ribe a tergestational use o anticonvulsant rugs, especiall% phenobarbital an phen%toin /Davis 35 86ill et al 35 =0 . Iita$in 9 shoul be a $inistrate to all neEborns e#pose to antiepilepticrugs in utero to prevent he$orrhagic isease o the neEborn /Morrell 355F0 . So$e neonatalunits in the )nite States have been reco$$en ing an aggressive regi$en or the Eo$en onantiepileptic rugs /especiall% phen%toin, pri$i one , $ethsu#i$i e, or phenobarbital0, Ehichinclu es intra$uscular a $inistration o 38 $g o vita$in 9 to the $other 7? hours prior to the

eliver% /;oorin an !lohert% 35F40 olloEe b% intra$uscular a $inistration o 3 $g to theneEborn in ant. !urrent prenatal test ing reco$$en ations are as olloEs /Yerb% 788=a0 L /30 Anato$ic ultrasonograph% at 33 to 3= Eee(s. This can i enti % the $ost severe e ects,such as anencephal% . /70 Maternal seru$ alpha protein. /=0 Bepeate anato$ic ultrasonograph% at 3< Eee(s. This can help i enti % abnor$alitiessuch as oro acial cle ts, heart e ects, an cau al neural tube e ects. &bviousl%, therapeutic abortion can be per or$e , although not all patients $a% Eant toacc ept this option.

Di""erential dia*nosis *oth the ac ial appearance an the histor% o antiepileptic rug e#posure uring earl%pregnanc% help $a(e the iagnosis o etal anticonvulsant s%n ro$e. So$e o the acialeatures are si$ilar to the ones seen in etal alcohol s%n ro$e . A$ong the or$er are$icrocephal% , groEth retar ation, upturne nostrils, h%poplastic philtru$, an irritabilit%/!hiriboga an 'erriero 355<0 . Micro- or retrognathia an h%poplastic $a#illa are not co$$ona ter etal anticonvulsant e#posure but are co$$on in etal alcohol s%n ro$e /!hiriboga an'erriero 355<0 . &ne o the eatures that t en s to be help ul in supporting the iagnosis o et alanticonvulsant s%n ro$e is the h%poplasia o the nails an istal phalanges. Accurate ph%sicaliagnosis $a% be i$portant because $others Eho su er ro$ che$ical epen enc% $a% notalEa%s volunteer the in or$ation about the rugs an alcohol uring earl% pregnanc%. &n the

other han , phen%toin an other antiepileptic rugs are co$$onl% prescribe or patients Eithalcohol Eith raEal seizures .

Dia*nostic -orkup The iagnosis o the etal anticonvulsant s%n ro$es, e ects, an e#posures is one b%ph%sical e#a$ination an observation o the patients. "at ients Eith suspecte $al or$at ions o spec i ic organs $a% re uire spec ialize ra iologicalstu ies. hen the neurologic e#a$ination o the loEer e#tre$ities is abnor$al, a spinal MB2 isre uire to elineate neural tube e ects. "atients e#pose to antiepileptic rugs in uteropresenting Eith a heart $ur$ur, c%anosis, an heart ailure nee to be evaluate Eith an

echocar iogra$.

Pro*nosis and complications The true prognosis o etal anticonvulsant s%n ro$e is largel% un(noEn6 hoEever, it epen s



greatl% on the egree o involve$ent an the t%pe o $al or$ation seen /*uehler an anson35586 Bosa an 'r%ns 35586 Bosa an 1in hout 35580 . The loE hea circu$ erence e ect o carba$azepine ten s to isappear over ti$e. 'et al tri$etha ione s%n ro$e has a ba prognosis ue to the high rate o serious$al or$ations an neonatal eath /Bosen an 1ightner 35 F0 . The sa$e is true or the etalvalproate s%n ro$e ue to its association Eith neural tube e ec ts. "at ients Eith neural tubee ec ts $a% evelop h% rocephalus an tethere cor as co$plications6 both re uireneurosurgical treat$ent.

.ana*ement No speci ic treat$ents e#ist or $an% o the antiepileptic rug-spec i ic e ec ts ot her than thes%$pto$atic e ects. &bviousl%, etaile neurologic assess$ent is re uire . "h%sical,occupational, an speech t herap% are in icate or patients Eith $otor, cognitive, anlanguage e icits. "atients Eith cle t lip an palate an hea %s$orphis$s / trigonocephal% 0shoul un ergo $ulti isc iplinar% evaluation an surgical treat$ent in centers a$iliarize Eithcranio acial patholog%. !ar iac an other a ec te s%ste$s nee to be evaluate an repaireaccor ingl%. )nco$$onl%, neEborns $a% have Eith raEal s%$pto$s, particularl% i the $otherEas on large oses o barbiturates. This can be treate Eith phenobarbital, $orphine, or otheropiates.

Pre*nanc The paucit% o ata on the neEer antiepileptic rugs has le to the evelop$ent o severalpregnanc% registries. "roble$s Eith such registries are that $ost Eo$en Eill not be enrolle 6a itionall%, there $a% be so$e egree o selection bias a$ongst the enrolle population ueto the nature o the Eo$en Eho are $otivate to participate an the possibl% better care thatsuch Eo$en $ight receive ro$ their ph%sicians. Nevertheless, pregnanc% registries are ause ul source o in or$ation, an all Eo$en shoul be encourage to enroll. National or regionalpregnanc% registries or antiepileptic rugs can be oun in :urope, North A$erica, Australia,2n ia, an the )nite 9ing o$ /Yerb% 788=a0 . 2n a ition, $an% o the phar$aceuticalco$panies the$selves have establishe or are establishing pregnanc% registries, possibl% thebest (noEn being the 2nternational 1a$otrigine "regnanc% Begistr%.

#nest&esia No in or$at ion Eas provi e b% the author.

'+D codes2!D-5L

!ongenital ano$aliesL ?8- ?5No#ious in luences a ec ting etus via placenta, anticonvulsantsL <8. 2!D-38L!ongenital $al or$ations, e or$ations an chro$oso$al abnor$alitiesL C88-C55'etal h% antoin s%n ro$eL CF<.3

#ssociated disordersNone i enti ie

/elated summaries!arba$azepine!entral neurologic co$plications o pregnanc%Microcephal%"hen%toin"osttrau$atic epileps%Topira$ate



Ialproic aciIigabatrin

Di""erential dia*nosisetal alcohol s%n ro$ealcohol Eith raEal seizures

Demo*rap&ics'or $ore speci ic e$ographic in or$ation, see the :pi e$iolog%, :tiolog%, an "athogenesisan pathoph%siolog% sections o this clinical su$$ar%.

#*e8-83 $onth83-7= $onths

PopulationNone selectivel% a ecte .

0ccupation

None selectivel% a ecte . Se1$aleO e$ale

Famil &istora$il% histor% t%pical

2eredithere it% $a% be a actor

/e"erences citedAb ulrazza YM, *asta(i SM, "a $anabhan B. Teratogenic e ects o vigabatrin in T& $ouseetuses. Teratolog% 355 644/=0L3<4- <. Aicar i J. The e ec ts o ant iepileptic rugs. 2nL Aicar i J, e itor. Disease o t he central nervouss%ste$ in chil hoo . 1on onL Mac 9eith "ress, 3557L75-?<. Annegers J', :lvebac( 1B, auser A, et al. Do anticonvulsants have a t eratogenic e ec tPArch Neurol 35 ?6=3L=<?- =. Annegers J', auser A, :lvebac( 1B, An erson I:, 9urlan 12. !ongenital $al or$ations anseizure isor ers in the o spring o parents Eith epileps%. 2nt J :pi e$iol 35 F6 L7?3- . Ar inger , At(in J', *lac(ston BD, et al. Ieri ication o etal valproate s%n ro$e phenot%pe.A$ J Me ;enet 35FF675L3 3-F4. Arpino !, *rescianini S, Bobert :, et al. Teratogenic e ects o antiepileptic rugsL use o aninternational atabase on $al or$ations an rug e#posure /MADB:0. :pilepsia 78886?3L3?=<-?=. A%$e S. 'etal valproate s%n ro$e. 2nL *u%se M1, e itor. *irth e ects enc%clope ia.!a$bri geL *lac (Eell Sc ienti ic "ublications, 3558L =8. *ertollini B, 9allen *, Mastroiacovo ", Bobert :. Anticonvulsant rugs in $onotherap%. : ect onthe et us. :ur J :pi e$iol 35F 6=L3<?- 3. *uehler *A. :po#i e h% rolase activit% an the Q etal h% antoin s%n ro$eR. !lin Bes35F46==L375.



*uehler *A, Deli$ont D, van aes M, 'innell B . "renatal pre iction o ris( o the etalh% antoin s%n ro$e. N :ngl J Me 35586=77L34< - 7. *uehler *A, anson J . 'etal h% antoin s%n ro$e. 2nL *u%se M1, e itor. *irth e ectsenc%clope ia. !a$bri geL *lac(Eell Scienti ic "ublications, 3558L 3?-4. !enta :, Basore-Cuartino A. 1a sin ro$e $al or$atine igitocar iaca or$e genetsche eenocopie. "robabile Azione Tertogena ei 'ar$aci Antiepileptici "athologica 35<464 L77 -=7. !hiriboga !A, 'erriero DM. Neurological co$plications o $aternal rug abuse. 2nL *erg *&,e itor. "rinciples o chil neurolog%. NeE Yor(L Mc ;raE- ill, 355<L3=<=- ?. !la% SA, McIie B, !hen . "ossible teratogenic e ect o valproic aci . J "e iatr 35F3655LF7F. !raig J, Morrison ", MorroE J, "atterson I. 'ailure o periconceptual olic aci to prevent aneural tube e ect in the o spring o a $other ta(ing so iu$ valproate. Seizure 35556FL74=-?. !unnington M, Tennis "6 2nternational 1a$otrigine "regnanc% Begistr% Scienti ic A visor%!o$$ittee. 1a$otrigine an the ris( o $al or$ations in pregnanc%. Neurolog% 78846<?L544-<8.

Dalens *, Ba%nau :J, ;aul$e J. Teratogenicit% o valproic aci . J "e iatr 35F865 L==7-=. Danielsson *, S(ol A!, Azarba%+ani ', &h$an 2, ebster . "har$aco(inetic ata supportphar$acologicall% in uce e$br%onic %srh%th$ia as e#planation to et al h% antoin s%n ro$ein rats. T o#ic Appl "har$acol 788863<=L3<?- 4. Dans(% 1I, An er$ann :, SherEin A1, An er$ann ', 9inch BA. Maternal epileps% ancongenital $al or$ationsL a prospective stu % Eith $onitoring o plas$a anticonvulsant levelsuring pregnanc%. Neurolog% 35F86=L34. Dans(% 1I, 'innell B . "arental epileps%, anticonvulsant rugs, an repro uctive outco$eLepi e$iologic an e#peri$ental in ings spanning three eca es6 7L u$an stu ies. Bepro

To#icol 355364L=83-=4. Davis "". !oagulation e ec t ue to anticonvulsant rug treat$ent in pregnanc%. 1ancet35 863L?3=. De S$et 1, Debeer ". 'etal h% antoin s%n ro$e Eith unilateral at%pical cle t han L a itionalevi ence or vascular isruption. ;enet !ouns 788763=L34 -<3. Dean J!, aile% , Moore SJ, 1lo% DJ, Turnpenn% "D, 1ittle J. 1ong ter$ health anneuro evelop$ent in chil ren e#pose to antiepileptic rugs be ore birth. J Me ;enet78876=5L743-5. Delga o-:scueta AI, Janz D. !onsensus gui elinesL preconception counseling, $anage$entan care o the pregnant Eo$an Eith epileps%. Neurolog% 35576?7L3?5-<8. Des$on MM, SchEanec(e B", ilson ;S, Yasunaga S, *urg or 2. Maternal barbiturateutilization an neonatal Eith raEal s%$pto$atolog%. J "e iatr 35 76F8L358- . Di1iberti J , 'arn on "A, Dennis NB, !urr% !J. The etal valproate s%n ro$e. A$ J Me ;enet35F?635L? =-F3. Drona$ra+u 9B. :pileps% an c le t lip an palate. 1ancet 35 867LF <- .

Duncan S, Mercho S, 1opes-!en es 2, et al. Bepeate neural tube e ec ts an valproate$onotherap% suggest a phar$acogenetic abnor$alit%. :pilepsia 78836?7L 48-=. 'el $an ;1, eaver DD, 1ovrien : . T he etal tri$etha ione s%n ro$eL report o an a itionala$il% an urther elineation o this s%n ro$e. A$ J Dis !hil 35 63=3LF5-57.



'innell B , Dans(% 1I. "arental epileps%, anticonvulsant rugs, an repro uctive outco$eLepi e$iologic an e#peri$ental in ings spanning three eca es6 3L Ani$al stu ies. BeproTo#icol 355364L7F3-55. 'rie $an JM, "oli (a J:. "henobarbital. 2nL 'rie $an JM, "oli (a J:, e itors. Teratogenic e ectso rugsL a resource or c linic ians. *alti$oreL Johns op(ins )niversit% "ress, 355?L?58-?. 'riis M1. 'acial cle ts an congenital heart isease in chil ren o parents Eith epileps%L genetican environ$ental etiologic actors. Acta Neurol Scan 35F56 5L?==-45. 'riis M1, 9ristensen &, *oas J, et al. Therapeutic a vances Eith 5? epileptic outpatients ino#carbazepine treat$ent. Acta Neurol Scan 355=6F L77?- . 'ritz , Muller D, ess B. !o$parative stu % o the teratogenicit% o phenobarbitone,iphen%lh% antoin an carba$azepine in $ice. To#icolog% 35 <6<L=7=-=8. ;ail% :, ;ranstro$ M1, iiles$aa I, *ar % A. Minor ano$alies in o spring o epileptic $others. J"e iatr 35FF6337L478-5. ;al ", &les 9S, ;il$an JT, eaver B. Ialproic aci e icac%, to#icit%, an phar$aco(inetics in

neonates Eith intractable seizures. Neurolog% 35FF6=FL?< - 3. ;al ", Sharpless M9. ' etal rug e#posure-behavioral teratogenesis. Drug 2ntell !lin "har$35F?63F/=0L3F<-783. ;elineau-Ian aes J, *ennett ;D, 'innell B . "hen%toin-in uce alterations in cranio acialgene e#pression. Teratolog% 3555645L7=-=?. ;er$an J, 9oEal A, :hlers 9 . Tri$etha ione an hu$an teratogenesis. Teratolog%35 86=L=?5-<7. ;lover SJ, Cuinn A;, *arter ", et al. &phthal$ic in ings in etal anticonvulsant s%n ro$e/s0.

&phthal$olog% 78876385L5?7- . ;o$ez MB. "ossible teratogenicit% o valproic aci . J "e iatr 35F365FL48F-5. ;oorin AM, !lohert% J". *lee ing. 2nL !lohert% J", Star( AB, e itors. Manual o neonatal care.7n e . *oston TorontoL 1ittle, *roEn, an !o$pan%, 35F4L7<5- ?. ;reenberg ;, 2n$an , eatherall JA, et al. Maternal rug histories an congenitalabnor$alities. *r Me J 35 67LF4=-<. ;ustavson ::, !hen . ;ol enhar s%n ro$e, anterior encephalocele, an a ue uctal stenosisolloEing etal pri$i one e#posure. Teratolog% 35F46=7L3=- . ansen D9, ;ra ton T' . 1ac( o att enuation o valproic aci -in uce e ects b% olinic ac i inrat e$br%os in vitro. Teratolog% 35536?=/<0L4 4-F7. ansen D9, ;ra ton T', Dial S1, ;ehring TA, Siitonen " . : ect o supple$ental olic aci onvalproic aci -in uce e$br%oto#icit% an tissue zinc levels in vivo. Teratolog% 3554647/40L7 -F4. anson J , M%rianthopoulos N!, arve% MA, S$ith D . Bis(s to the o spring o Eo$entreate Eith h% antoin anticonvulsants, Eith e$phasis on the etal h% antoin s%n ro$e. J"e iatr 35 <6F5L<<7-F.

anson J , S$ith D . The etal h% antoin s%n ro$e. J "e iatr 35 46F L7F4-58. einonen &", Slone D, Shapiro S. *irth e ects an rugs in pregnanc%. 1ittletonL John right-"S;, 35 L=?=.



ernan ez-Diaz S, erler M, al(er A. 'olic aci antagonists uring pregnanc% an the ris( o birth e ects. N :ngl J Me 78886=?=L3<8F-3?. iiles$aa I9, Tera$o 9, ;ranstro$ M1, *ar % A . 'etal hea groEth retar ation associateEith $aternal antiepileptic rugs. 1ancet 35F367L3<4- . ill BM, orning M;, orning :!. Antiepileptic rugs an etal Eell-being. 2nL *oreus 1&, e itor.'etal phar$acolog%. NeE Yor(L Baven "ress, 35 =L= 4-F8. ol$es ;1, 'lanner% D*. The e ect o $aternal seizures an anticonvulsants on etal brainevelop$ent. 2nt J "e iatr Nephrol 35FF6F<-5?. ol$es 1*, %sz%ns(i D', *al Ein :J, abec(er :, ;lass$an 1 , S$ith !B. 2ncrease ris( ornon-s%n ro$ic cle t palate a$ong in ants e#pose to la$otrigine uring pregnanc% /abstract0.*irth De ects Bes A !lin Mol Teratol 788<6 </40L=3F. orning M;, Stratton !, ilson A, orning :!, ill BM. Detection o 4- /=,?- iphen%lh% antoin0in the neEborn hu$an. Bes !o$$un !he$ "athol "har$acol 35 ?6?L4= -F7. Jager-Bo$an :, Deichl A, Ja(ob S, et al. 'etal groEth, $a+or $al or$ations, an $inor

ano$alies in in ants born to Eo$en receiving valproic ac i . J "e iatr 35F<638FL55 -388?. Janas MS, Arroe M, ansen S , ;rae$ N. 1ung h%poplasia--a possible teratogenic e ect o valproate. !ase report. A"M2S 355F638<L=88-?. Janz D, 'uchs ). Are antiepileptic rugs har$ ul Ehen given uring pregnanc%P ;er Me Mon35<?65L78-7. Jeavons "M. Non- ose relate si e-e ects o valproate. :pilepsia 35F?674LS48-4. Jerina DM, Dal% J . Arene o#i esL a neE aspect o rug $etabolis$. Science 35 ?63F4L4 =-F7.

Jones 91. 'etal h% antoin s%n ro$e, etal tri$etha ione s%n ro$e an etal valproates%n ro$e. 2nL Jones 91, e itor. Becognizable patt erns o hu$an $al or$at ion. 4th e ."hila elphiaL * Saun ers, 355 L445-< . Jones 91, 1acro BI, Johnson 9A, A a$s J. "attern o $al or$ations in the chil ren o Eo$entreate Eith carba$azepine uring pregnanc%. N :ngl J Me 35F56=78L3<<3-<. 9alter , ar(an% J. !ongenital $al or$ations. N :ngl J Me 35F=6=8FL?53- . 9ell% T:. Teratogenicit% o anticonvulsant rugs 2L revieE o literature. A$ J Me ;enet35F?a635L?3=-=?. 9ell% T:. Teratogenicit% o anticonvulsant rugs 222L ra iographic han anal%sis o chil rene#pose in utero to iphen%lh% antoin. A$ J Me ;enet 35F?b,35L??4-48. 9ing "*, 1ie BT, 2rgens 1M. Spina bi i a an cle t lip a$ong neEborns o NorEegian Eo$en Eithepileps%L changes relate to the use o anticonvulsants. A$ J "ublic ealth 355<6F<L3?4?-<. 9lepel , 'reitag ;. Spina bi i a occulta in epileps% s%n ro$es. Neurolog% 35576?7L37<- . 9och S, ;oep ert-;e%er 2, aeuser 2, et al. Neonatal behaviour isturbances in in ants o epileptic Eo$en treate uring pregnanc%. "rog !lin *iol Bes 35F463<=*L?4=-<3.

9och S, 1osche ;, Jager-Bo$an :, et al. Ma+or an $inor birth $al or$ations an antiepilepticrugs. Neurolog% 35576?7LF=-F. 9och S, Titze 9, Gi$$er$ann B*, Schro er M, 1eh$(uhl ), Bauh . 1ong-ter$neurops%chological conse uences o $aternal epileps% an anticonvulsant treat$ent uring



pregnanc% or school age chil ren an a olescents. :pilepsia 35556?8L37= -?=. 9on o T, 9ane(o S, A$ano Y, :gaEa 2. "reli$inar% report on teratogenic e ects o zonisa$i ein the o spring o treate Eo$en Eith epileps%. :pilepsia 355<6= L37?7-?. 9uenssberg :I, 9no# JD. Teratogenic e ects o anticonvulsants. 1ancet 35 =63L35F. 9unze J, ie e$ann B. % antoin-barbiturate-carba$azepine e$br%o oetopath% ane$br%o oetal valproic aci s%n ro$e. 2nL ie e$ann B, 9unze J, e itors. !linical s%n ro$es.?th ;er$an an =r :nglish e . 1on onL Ti$es Mirror 2nternational "ublishers 1i$ite ,355 L47?- . 1a+eunie :, *arci( ), T horne JA, ;houzzi I:, *ourgeois M, Benier D. !ranios%nostosis an etale#posure to so iu$ valproate. J Neurosurg 7883654L F-F7. 1eavitt AM, Yerb% MS, Bobinson N, Sells !J, :ric(son DM. :pileps% in pregnanc%L evelop$entaloutc o$e o o spring at 37 $onths. Neurolog% 35576?7/Suppl 40L3?3-=. 1in hout D. "har$acogenetics an rug interactionsL role in antiepileptic- rug-in uceteratogenesis. Neurolog% 35576?7L?=- .

1in hout D, Meinar i , Mei+er J , Nau . Antiepileptic rugs an teratogenesis in tEoconsecut ive cohortsL changes in prescription polic% parallele b% changes in patt ern o $al or$ations. Neurolog% 3557a6?7L5?-338. 1in hout D, &$tzigt J;, !ornel M!. Spectru$ o neural-tube e ects in =? in ants prenatall%e#pose to antiepileptic rugs. Neurolog% 3557b6?7L333-F. 1oughnan "M, ;ol , Iance J!. "hen%toin teratogenicit% in $an. 1ancet 35 =63L 8-7. Mal$ , 9a+antie :, 9iviri((o S, 9aariainen , "eippo M, So$er M. Ialproate e$br%opath% inthree sets o siblingsL urther proo o here itar% susceptibilit%. Neurolog% 7887645L<=8-=.

Martz ', 'ailinger !, *la(e DA. "hen%toin teratogenesisL correlation betEeen e$br%opathice ec t an covalent bin ing o putat ive arene o#i e $etabolite to gestational tissue. J"har$acol :#p Ther 35 678=L7=3-5. Masse% 9M. Teratogenic e ects o iphen%lh% antoin so iu$. J &ral Ther "har$acol35<<67L=F8-4. Mea or 9J, *a(er ;A, 'innell B , et al6 N:AD Stu % ;roup. 2n utero antiepileptic rug e#posureLetal eath an $al or$ations. Neurolog% 788<6< L?8 -37. Mea oE B. Anticonvulsants in pregnanc%. Arch Dis !hil 35536<<L<7-4. Mea oE SB. Anticonvulsant rugs an congenital abnor$alities. 1ancet 35<F67L375<. Melchior 2!, SvensEar( &, Trolle D. "lacental trans er to phenobarbitone in Eo$en aneli$inat ion in neEborns. 1anc et 35< 67LF<8-3. Me%er J;. The teratological e ects o anticonvulsants an the e ects o pregnanc% an birth.:ur Neurol 35 =638L3 5-F8. Montouris ;. Sa et% o gabapentin treat$ent uring pregnanc% UAbstractV. :pilepsia78876?=/Suppl 0L7=?.

Moore SJ, Turnpenn% ", Cuinn A, et al. A clinical stu % o 4 chil ren Eith etal anticonvulsants%n ro$es. J Me ;enet 78886= L?F5-5 . Morrell MJ. The neE antiepileptic rugs an Eo$enL e icac%, repro uctive health, pregnanc%,an etal outco$e. :pilepsia 355<6= LS=?-??.



Morrell MJ. ;ui elines or the care o Eo$en Eith epileps%. Neurolog% 355F643LS73- . MorroE J, Bussell A, ;uthrie :, et al. Mal or$ation ris(s o antiepileptic rugs in pregnanc%L aprospective stu % ro$ the )9 :pileps% an "regnanc% Begister. J Neurol Neurosurg "s%chiatr%788<6 L35=-F. Mullers-9uppers von M. :$br%opath% uring pregnanc% cause b% ta(ing anticonvulsants. Acta"ae ops%chiatr 35<=6=8L?83-4. Murra% J!, ill BM, ege$ier S, urEitz B1. 1%$phoblastic l%$pho$a olloEing prenatale#posure to phen%toin. J "e iatr e$atol &ncol 355<63FL7?3-=. Na(ane Y. !ongenital $al or$at ions a$ong in ants o epileptic $others treate uringpregnanc%. 'olia "s%chiatr Neurol Jpn 35 56==L=<=-5. Na(ane Y, &(u$a T, Ta(ahashi B, et al. Multi-institutional stu % on the teratogenicit% an etalto#icit% o antiepileptic rugsL a report o a collaborative stu % group in Japan. :pilepsia35F8673L<<=-F8.

Nebert D , Jensen NM. The Ah locusL genetic regulation o the $etabolis$ o carcinogens,rugs, an other environ$ental che$icals b% c%tochro$e "-?48 $e iate $ono-o#%genases.!B! !rit Bev *ioche$ 35 56<L?83-= . Nishi$ura 9Y, Tera a Y, Mu(u$oto 9, et al. Teratogenic e ects o phenobarbital in etal rats.Teratolog% 35 5678L34<- . &$tzigt J;, 1os 'J, ;robee D:, et al. The ris( o spina bi i a aperta a ter irst-tri$estere#posure to valproate in a prenatal cohort. Neurolog% 35576?7L335-74. Cualit% Stan ar s Subco$$ittee o the A$erican Aca e$% o Neurolog%. "ractice para$eterL$anage$ent issues or Eo$en Eith epileps% /su$$ar% state$ent0. Beport o the Cualit%

Stan ar s Subco$$ittee o the A$erican Aca e$% o Neurolog%. Neurolog% 355F643/?0L5??-F. "ac i ici ;M, !olizzi !, ;iuliani 1, Bane A. !%tosolic epo#i e h% rolase in etal an a ult hu$anliver. Arch To#icol 35F=64?L==3-?3. "aci ici ;M, Bane A. Metabolis$ o st%rene o#i e in i erent hu$an etal tissues. Drug MetabDispos 35F7638L=87-4. "antarotto M'. A case o bone $arroE aplasia in a neEborn attributable to anticonvulsantrugs use b% the $other uring pregnanc%. Cua !lin &stet ;inecol 35<46< L=?=-F. "ennell "*. T he i$portance o $onotherap% in pregnanc%. Neurolog% 788=6<8/Suppl ?0LS=3-F. BabinoEicz A, Meischenguiser B, 'erraro SM, et al. Single center, -%ear e#perience o o#carbazepine e#posure uring pregnanc%. :pilepsia 78876?=/Suppl 0L78F-5. Bobert :, ;uiban :. Maternal valproic aci an congenital neural tube e ects. 1ancet35F767L5=?. Bosa ' . u$an barbiturate teratolog%. Teratolog% 35F<6==L7 A. Bosa ' . "ri$i one e$br%opath%. 2nL *u%se M1, e itor. *irth e ects enc%clope ia. !a$bri geL*lac(Eell Scienti ic "ublications, 3558L<58-3.

Bosa ' , 'r%ns J". 'etal barbiturate e ec ts. 2nL *u%se M1, e itor. *irth e ects enc%c lope ia.!a$bri geL *lac(Eell Sc ienti ic "ublications, 3558L<F -F. Bosa ' , 1in hout D. 'etal carba$azepine e#posure. 2nL *u%se M1, e itor. *irth e ectsenc%clope ia. !a$bri geL *lac(Eell Scienti ic "ublications, 3558L<58-3.



Bosen B!, 1ightner : . "henot%pic $al or$ations in assoc iation Eith $aternal tri$etha ionetherap%. J "e iatr 35 F657L7?8. Both$an 9J, '%ler D!, ;ol blatt A, 9re berg M*. :#ogenous hor$ones an other ruge#posures o chil ren Eith c ongenital heart isease. A$ J :pi e$iol 35 56385L?==-5. Bu N1, 'ree o$ BM. A possible pri$i one e$br%opath%. J "e iatr 35 565?LF=4- . Sa$ren :*, van Dui+n !M, 9och S, et al. Maternal use o antiepileptic rugs an the ris( o $a+or congenital $al or$ationsL a +oint :uropean prospective stu % o hu$an teratogenesisassociate Eith $aternal epileps%. :pilepsia 355 6=FL5F3-58. Shapiro S, artz S!, Sis(in I, et al. Anticonvulsants an parental epileps% in the evelop$ento birth e ects. 1ancet 35 <63L7 7-4. Shu$ S, Jensen NM, Nebert D . The $urine Ah locusL in utero to#icit% an teratogenesisassociate Eith genetic i erences in benzo/a0p%rene $etabolis$. Teratolog% 35 5678L=<4-<.

Siep M. ;roEth retar ation, %s$orphic acies an $inor $al or$ations olloEing $assivee#posure to phenobarbital in utero. Acta "ae iatr Scan 35 <6<4L<3 -73. Spei el *D, Mea oE SB. Maternal epileps% an abnor$alities o the etus an neEborn. 1ancet35 767LF=5-?=. Spielberg S", ;or on ;*, *la e DA, Mellits :D, *ross DS. Anticonvulsant to#icit% in vitroLpossible role o arene o#i es. J "har$acol :#p Ther 35F3673 L=F<-5. Stric(ler SM, Dans(% 1I, Miller MA, Seni M , An er$ann :, Spielberg S". ;enetic pre ispositionto phen%toin in uce birth e ects. 1ancet 35F463L ?<-5.

Tennis ", :l ri ge BB6 2nternational 1a$otrigine "regnanc% Begistr% Sc ienti ic A visor%!o$$ittee. "reli$inar% results on pregnanc% outco$es in Eo$en using la$otrigine. :pilepsia78876?=L33<3- . Ian D%(e D!, o ge S:, ei e ', ill 1B. 'a$il% stu ies in etal phen%toin e#posure. J "e iatr35FF633=L=83-<. einer TS, Bo$ancz%( B;, Donovic( "J. Speci icit% o treat$ent e ects or learning isabilitiesin a bo% prenatall% e#pose t o Dilantin. "e iatr Behabil 355F67L?3-4. ells ";, 9i$ "M, 1aposa BB, Nicol !J, "ar$an T, inn 1M. &#i ative a$age in che$icalteratogenesis. Mutat Bes 355 6=5<L<4- F. ells ";, Gubovits JT, ong ST, Malinaro 1M, Ali S. Mo ulation o "hen%toin teratogenicit% ane$br%onic covalent bin ing b% acet%lsalic%lic aci , ca eic aci an alpha-phen%l-N-:-but%lnitroneL i$plications or bioactivation o prostaglan in s%nthase. To#icol Appl "har$acol35F?65 L357-787. illia$s ;, 9ing J, !unningha$ M, Stephan M, 9err *, ersh J . 'etal valproate s%n ro$e anautis$L a itional evi ence o an association. Dev Me !hil Neurol 78836?=L787-<. ilton 1I, Sha(ir S. A post$ar(eting surveillance stu % o gabapentin as a -on therap% or=,388 patients in :nglan . :pilepsia 78876?=L5F=-57.

itters 2, Ian Assche ', 'r%ns J". Nuchal e e$a as the irst sign o etal valproate s%n ro$e."renat Diagn 7887677LF=?-4. Yalcin(a%a !, Tu%suz *, So$a% ;, !enani A. "ol% act%l% an etal h% antoin s%n ro$eL ana itional co$ponent o the s%n ro$eP !lin ;enet 355 643L=?=-4.

medlink.fetal anticonvulsant syndrome

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