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1 종 설 online ML Comm 대한간질학회지 2007;11(2):85-90 항간질약물과선천성기형및임신중발작조절 허 경 연세대학교의과대학신경과학교실 Antiepileptic Drugs and Congenital Malformations, and Seizure Control during Pregnancy Kyoung Heo, M.D. Department of Neurology, Yonsei University College of Medicine, Seoul, Korea Epilepsy is one of the most common neurological problems in pregnancy. For the majority of women, pregnancy proceeds without any apparent difficulties but there is growing evidence of an increased risk of major malformations and later cognitive problems in children exposed to antiepileptic drugs in utero. Updated evidence from several prospective pregnancy registries suggests an increased risk of major malformations with valproic acid compared with other antiepileptic drugs, becoming more evident as doses exceed 1,000 mg/day. The effects of polytherapy appear to carry greater risks compared with monotherapy. Limited data exist for the newer AEDs except for lamotrigine. Although most women with epilepsy have no change in seizure frequency, seizures, especially generalized tonic-clonic seizures can produce adverse effects on mother and fetus. Data about the risk associated with seizures in pregnancy are limited. The pregnancy registry will be performed in Korea to assess the relative risk of major congenital malformation from in utero exposure to antiepileptic drug and to analyze seizure control and treatment in pregnant women with epilepsy. (J Korean Epilep Soc 2007;11(2):85-90) KEY WORDS: Epilepsy Antiepileptic drugs Congenital malformation Pregnancy. 서론 간질환자의다수는장기간의치료를필요로한다. 따라서임신중에서도약물치료를하게된다. 낮은결혼률과출산기피로인해우리나라에서는이보다낮을것이라추정되지만외국통계에의하면임신여성의 0.3~0.6% 가항간질약물에노출된다고한다. 1,2 항간질약물이태아에미치는영향을조사하는것은매우중요하다. 그러나무작위로통제된연구는실제임상에서시행되기매우어렵고윤리적인문제가있어시행될수없기때문에관찰연구가시행될수밖에없다. 이러한연구들은환자모집방법및시기, 기형의정의및판단시점, 환자수, 정상대조군, 사 산자료의확인등의차이가결과의차이를가져올수있다. 또한기형의발생에영향을가져올수있는발작의정도, 간질유형 ( 약물의선택에영향을줄수있는 ), 기형의가족력, 사회및경제요인등의변수의기여정도에대한조사가미약하다. 새로운여러항간질약물이발매되면서이에발맞추어기형발생에미치는위험도를대규모의임신등록을통해조사한여러연구결과들이 2000년대에들어발표되었다. 2008년에시작될우리나라에서의임신등록연구에즈음하여최근연구들을중심으로각각의약물에따른중대기형발생및신경발달지연, 덧붙여임신중발작의조절에대한문제를고찰해보고자한다. 기형발생과항간질약물 Received 6 November 2007 Accepted 27 December 2007 Corresponding author: Kyoung Heo, M.D., Department of Neurology, Yonsei University College of Medicine, 134 Sinchon-dong, Seodaemoon-gu, Seoul , Korea kheo@yuhs.ac 대부분의연구는일반인구에비해중대기형발생빈도가 2~3 배증가한다는결과를제시하였다. 간질을가진아버지와기형발생과는관계가없다. 발작자체, 특히전신강직-간대성발작및간질중첩증이환자및태아에악 대한간질학회지 2007;11(2):

2 Antiepileptic Drugs and Congenital Malformations 영향 ( 태아심박동수의감소, 태아뇌출혈, 조기분만, 태아및환자사망등 ) 을줄수있다는사실은확실하나, 중대기형발생에미치는영향에대해서는오래전에임신첫 1/3 분기에발작이있었던환자에서기형발생률이높았다는보고가있고, 3 임신중 5회가넘는전신발작이있었던경우환자에서태어난소아에서언어성지능의감소가관찰되었다는연구결과가있으나, 4 연구대상자의숫자가적지만전향적인임신등록연구에서는전신발작과중대기형발생과의의미있는연관성이발견되지않았다. 5-8 간질자체가미치는영향에대해서는최근 meta-analysis 에서정상대조군에비해치료받지않은간질에서기형발생이증가하였지만통계학적으로는의미가없어간질자체가기형의위험을증가시킬것이라는일반적인통념을뒷받침하지못했다. 9 덧붙여간질을가진남성환자는기형발생에영향을주지못한다. 또한기형이외에일반인구에비해간질환자에서 2배정도의자연유산, 사산, 주산기태아사망의위험도가있다는일관성있는증거가있고, 10 자궁내성장지연 ( 체중, 신장, 머리둘레등의감소 ) 이보고되고있으나, 11,12 특정약물과의연관성이나 동반된기형에대한연구에대한정보는미약하다. 기형발생위험증가에는항간질약물의역할이가장중요할것으로생각된다. 중대기형은주로수술치료가필요한구조적결손을의미하는데임신첫 1/3 분기에항간질약물에의노출, 단독요법보다는다약물요법에서, 특히 valproic acid가포함된경우에중대기형발생의증가와연관되어있다 (Table 1). 항간질약물복용과관련된중대기형으로는선천성심장결손, 신경관결손, 요생식기결손, 구안면파열등이있다. 특정약물과의관계에있어서는 valproic acid 복용과신경관결손 (1~6%) 과의연관성이일관되게제시되었고, carbamazepine 도신경관결손 (1%) 과의관련성이오래전부터제시되었으나, 22 최근연구결과에서는신경관결손의위험이매우낮다. 14,20 북미임신등록연구에서 lamotrigine 과구안면파열의증가와의연관성이제시되었으나, 23 다른임신등록연구에서는확인되지않았다. Table 2는최근연구결과에서나타난각각의항간질약물의단독요법과연관된중대기형발생률을기술한것이다. Phenobarbital 은북미임신등록연구에서단독요 Table 1. Risk of major malformations with monotherapy and polytherapy from recent pregnancy registries Pregnancy registry Monotherapy Polytherapy Comments US (Boston) % 8.6% 1.8% of controls without epilepsy (n=223) (n=93) UK % (n=2,468) 6.0% (n=718) Odds ratio=2.49 in +VPA Compared with -VPA Italy % (n=313) 5.3% (n=114) Finland % (n=1,231) 7.2% (n=180) -VPA: no increased risk Lamotrigine % (n=707) 11.8% +VPA 2.7% -VPA Oxcarbazepine % (n=248) 6.6% (n=61) Table 2. Comparison of recent registries for major malformations with antiepileptic drug in pregnancy with monotherapy exposures AED North America 24,25 UK 14 Australia 26 Finland 16 NEAD 27 (US & UK) Sweden 20 Italy 15 VPA 10.7% 6.2% 16.8% 10.6% 17.4% 9.7% 13.6% PB 6.5% N/A N/A N/A N/A N/A 2.4% CBZ N/A 2.2% 3.8% 2.7% 4.5% 4.0% 6.2% PHT N/A 3.7% 5.9% 2.6% 7.1% 6.8% 0% LTG N/A 3.2% 0% N/A 1.0% 4.4% N/A GBP N/A 3.2% N/A N/A N/A N/A N/A TPM N/A 7.1% N/A N/A N/A N/A N/A OXC N/A N/A N/A 1.0% N/A N/A N/A LEV N/A 0% N/A N/A N/A N/A N/A No AED 1.62% 3.5% N/A 2.8% N/A N/A N/A AED, antiepileptic drug; VPA, valproic acid; PB, phenobarbital; CBZ, carbamazepine; PHT, phenytoin; LTG, lamotrigine; GBP, gabapentin; TPM, topiramate; OXC, oxcarbazepine; LEV, levetiracetam; NEAD, the neurodevelopmental effects of antiepileptic drugs study; N/A, not available. Reference 24: data of each AEDs except for VPA and PB are not available but the prevalence of major malformations among in all other AED monotherapies was 2.9% 86 대한간질학회지 2007;11(2):85-90

3 허경 법으로노출된 77 임신중 5(6.5%) 에서, 이태리임신등록연구 ( 단일센터 ) 에서 83 중 2(2.4%; 경도의기형을포함하면 4.8%) 에서중대기형이발생되었다. 다른연구에서는노출숫자가적어의미있는결과를산출할수없었다. 인지, 지능, 언어발달등의행동장애의위험도가임신중 phenobarbital 에노출된경우에높았다. 28,29 Phenytoin 단독요법의경우 0%( 이태리임신등록연구에서경도의기형을제외하였을때 ) 에서 7.1% 까지보고되었으나각각 31과 56으로적은숫자이었고, 비교적많은숫자의영국임신등록연구에서의 82의노출에서는 3.7% 이었고핀란드임신등록연구에서의적어도 124 명 ( 이전연구자료에서인용 30 ) 이넘는노출에서 2.6% 이었다 년에발표된일본, 이태리, 캐나다합동연구에서는 132 노출에서 9.1% 라는높은기형발생빈도가보고되었다. 8 Carbamazepine 단독요법의경우에서는 110 에서 900 의노출수에서 2.2%(900 의노출수에서조사된영국임신등록연구 ) 에서 6.2% 의중대기형이발생되었다. Carbamazepine 에노출된소아의지능을조사한핀란드연구에서지능지수가대조군과차이가없었다. 31 이전의연구결과들과함께최근의임신등록연구들은일관되게 valproic acid의항간질약물중가장높은기형발생위험도의증가와의연관성을제시하고있다. Valproic acid 단독요법의경우 69에서 715의노출수에서조사되었는데 6.2%(715 의노출수에서조사된영국임신등록연구 ) 에서 17.4%{(69의노출수에서조사된 NEAD (Neurodevelopmental Effects of Antiepileptic Drugs) 연구 ) 까지중대기형이발생되었다. 또한가장많은노출수의영국임신등록연구에서는통계학적으로의미있는용량반응을보이지않았지만호주임신등록연구에서는하루용량 1,400 mg 32 혹은 1,100 mg, 핀란드임신등록연구에서는 1,500 mg, 네덜란드임신등록연구에서는 1,000 mg, 33 일본, 이태리, 캐나다합동임신등록연구에서는 1,000 mg과혈중농도 70 μg/ml 이상이높은기형발생과관련되어있다고보고하였다. 또한 phenobarbital 에서도제시된것처럼 valproic acid에서도자궁속에서노출된소아의발달에악영향을준다는여러연구결과들이발표되었다 언어발달지연, 언어성지능지수의감소, 행동장애등이관찰되었다. 편견의가능성, 적은환자수로인해확실한결론을내기위해서는대규모의전향적인연구가필요한데현재진행중인전향적으로항간질약물의단독요법에노출된소아의발달을조사한미국과영국합동 NEAD 연구의중간발표에서 2세된 166 명 (carbamazepine=43, lamotrigine=57, phenytoin=38, vaproic acid=28) 대상으로유아발달의 Bayley Scales 중 Mental Scale 을분석하였다. 다른세약물과비교하여 valproic acid 에노출되었던소아에서가장낮은점수가관찰되었고 lamotrigine 군과통계학적으로유의미한차이를, carbamazepine 군과는차이가있는경향을보였다. 38 Valproic acid 와관련된기형형성기전은확실치않으나엽산대사의이상, 39 신경관성장중세포증식의억제, 40 내재되어있는유전적감수성이나 41 이러한요인들의조합이관여된다고알려져있다. 현시점에서이러한발달과정의악영향과더불어기형발생의높은위험도의연구결과는임신을원하거나, 임신잠재성의여성간질환자에서의 valproic acid 는반드시심각하게유익과불이익이고려된후사용되어야한다는점을강력하게제시하고있다. Lamotrigine 은새로이개발된항간질약물중충분한숫자로연구된유일한약물이라할수있다. Lamotrigine 단독요법의경우 61에서 647 의노출수에서조사되었는데 0%(61의노출수에서조사된호주임신등록연구 ) 에서 4.4%(90의노출수에서조사된스웨덴연구 ) 까지중대기형이발생되었다. 제조회사후원국제임신등록연구에서 lamotrigine 단독요법은기형발생을증가시키지않는약물로생각되었다. 1992년부터 2005년임신등록을통해조사된결과가 2006년미국간질학회에서발표되었는데단독요법 707 노출수에 2.8% 의중대기형발생빈도가관찰되었다. 17 그러나영국임신등록연구에서 647 노출수에서비교적낮은빈도의 3.2% 에서기형이발생되었고, 용량반응을보여하루 200 mg 이하의용량에서는 1.6% 에서 200 mg이넘는용량에서는 5.4% 로증가하였다. 이수치는이연구에서관찰된 1,000 mg 이하의 valproic acid의 5.1% 와필적할만하다. 따라서 lamotrigine 이임신가능연령의여성환자에대한적합성에대한의문이제기되었다. 앞서기술한국제임신등록연구에서는중대기형유무에따른 lamotrigine 의용량차이가발견되지않았다. 다른약물중에는비교적많은단독요법의경험이축적된 oxcarbazepine 의경우 248 노출수에 2.4% 이었다. 18 그러나다른약물의경우숫자가적어신뢰성있는결과라생각되기어려우나, 영국임신등록연구에서 gabapentin 의경우 37 노출수에 3.2%, levetiracetam 은 39 노출수에 0%, 42 topiramate는 28 노출수에 7.1% 이었다. 여러임신등록연구들에서 valproic acid와다약물치료가상대적으로기형발생의위험도를높인다는결과가공통적으로발견되지만임신등록연구에따라중대기형의발생률은다르다. 적은등록숫자는신뢰성있는결과 대한간질학회지 2007;11(2):

4 Antiepileptic Drugs and Congenital Malformations 를줄수없다. 등록시점의차이가영향을줄수있다. 등록전산전검사를받지않거나산전검사에서음성이나온환자만이등록기준이되고임신초기가지나서등록되는것이허용된다면조기에일어나는중대기형이배제되기때문에기형발생률을감소시킬가능성이있다. 북미나호주임신등록처럼환자자신이등록하는방법을취한다면기형의가족력이나과거력이있는환자가더참여할가능성이있다. 기형판단시점도영향을줄수있다. 영국임신등록에서는탄생시혹은 6주내에일어나는중대기형으로정의한반면에호주임신등록에서는탄생후 1년시점에기형에대한정보가얻어졌다. 몇몇중대기형은탄생시발견되지못하는경우가있기때문에탄생시보다 1년시점에파악되는정보는기형발생률을높일가능성이있다. 또한유산이나사산의경우중대기형발생에대한정보의정도가영향을줄수있다. 사회경제적인위치, 환자의연령, 간질증후군, 항간질약물의용량및복용순응도등의기형발생영향을줄수있는다른인자에대한정보정도도항간질약물과기형발생의연관성의결과에영향을미칠수있다. 임신가능간질환자의치료는항간질약물과관련된기형의위험성을고려해야하지만발작의조절및삶의질과관련된여러문제들이고려되어야한다. 부분발작을가진환자들은 valproic acid 이외선택할수있는항간질약물이상대적으로많아처음약물의선택이비교적용이하다. 또한장기간발작관해상태라면발작재발의인자들을고려하여임신전에약물중단, 감량, 다약물에서단독약물치료등을시도해볼수있다. 특발성전신성간질, 특히청소년근간대경련간질 (juvenile myoclonic epilepsy) 의경우해결방안이쉽지않다. 장기간발작관해가이루어졌다고하더라도약물중단시도에재발의위험성이매우높다. 또한현재까지효과면에서다른광범위약물들이 valproic acid에비해못미치고있다고생각되고, 43 대체약물인 lamotrigine 의경우영국연구에서 200 mg 이상의용량과관련된비교적높은기형발생빈도가발견되고다른대체약물인 topiramate, zonisamide, levetiracetam 은임신연구결과가미약해서어떤결론을내릴수없다. 새로운항간질약물의기형발생위험도, 항간질약물의용량과의관련성, valproic acid 이외의특정한조합의다약물치료에따른위험도, 자궁에서노출된소아의발달에미치는영향, 최근에제기되고있는기형에기여하는약물유전적요인, 엽산치료의예방효과, 항간질약물의기형기전등의문제에대한더많은연구가필요하다. 임신중의발작조절 대다수의환자는임신중발작빈도에있어서변화를보이지않는다. 15% 에서 33% 의환자에서만더많은발작빈도를가지게된다. 44,45 최근에발표된 1,956 의임신을대상으로한 EURAP 연구 46 결과에따르면임신첫 1/3 주기에비교할때 64% 의환자에서임신중간 1/3 주기나마지막 1/3 주기에서발작빈도의변화가나타나지않았고 17% 의환자는발작의빈도가증가하였고 16% 의환자는발작빈도의감소가관찰되었고 3% 의환자에서는중간 1/3 주기나마지막 1/3 주기에서반대방향의발작조절이일어났고, 3.5% 의환자에서발작이해산중에일어났다. 발작빈도의악화가능성은모든발작과경련성발작에서부분간질과다약물치료, 경련성발작에서 oxcarbazepine 단독요법과연관성이있었다. 또한흥미로운결과로과거에문헌에서예상되는중첩발작과높은임신사고의연관성은적어, 36명의환자에서중첩발작 (12 증례의경우경련성 ) 이일어났는데한증례에서사산을초래하였고유산이나산모의사망은일어나지않았다. 이러한결과는과거에비해임신중간질처치의발전을반영하거나과거의적은숫자의증례보고가가질수있는편견에기인될수있다. 임신중발작의악화는약물복용의순응도의감소, 약물대사및배설의증가, 흡수감소, 분포의증가등에따른약물농도의감소, 스트레스나불안의증가, 수면박탈, 호르몬의변화등으로설명된다. 새로운항간질약물중 lamotrigine 과 oxcarbazepine (MHD) 은대사증가로말미암아용량대혈중농도가임신전의 50~60% 로감소하게된다. 47,48 이러한 oxcarbazepine (MHD) 의혈중농도의감소는 oxcarbazepine 단독요법과발작빈도의악화가능성과의연관성이있다는 EURAP 연구결과를설명할지모른다. 우리나라인구를대상으로체계적이고전향적인임신등록연구가시행된적이없다. 우리나라간질환자에서항간질약물과기형발생의관계, 임신중발작의조절상태및영향등에관한연구가필요하다고생각된다. 이에대한간질학회에서는임신가능여성간질환자를치료하는대한간질학회정회원의사가참여하는전국적인임신환자등록을통하여이에대한연구를진행할것이다. REFERENCES 1. Fairgrieve SD, Jackson M, Jonas P, et al. Population based, prospective study of the care of women with epilepsy in pregnancy. Br Med J 2000;321: 대한간질학회지 2007;11(2):85-90

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R