Hormone Replacement Therapy and Cognitive Function

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From the 1

Department of Neurology, Taipei Medical University, Wan Fang Hospital, Taipei, Taiwan; 2

Department of Obstetrics and Gynecology, Taipei City Hospital, Branch for Women and Children, Taipei, Taiwan.

Received November 9, 2005. Revised December 9, 2005.

Reprint requests and correspondence to: Chi-Tzong Hong, MD. Department of Neurology, Taipei Medical University, Wan Fang Hospital, No. 111, Sec. 3, Hsing-Long Road, Taipei, Taiwan.

E-mail: jayhuang1976@yahoo.com.tw

Chun-Ping Huang

1

, Chi-Tzong Hong

1

, and I-Tsan Huang

2

Abstract- Observational studies have suggested that postmenopausal hormone replacement therapy (HRT)

may improve cognitive function, but data from randomized clinical trials have been sparse and inconclusive. The effects of HRT on dementia and mild cognitive impairment were assessed in a subgroup of participants in the Women’s Health Initiative Memory Study (WHIMS) (a multicenter, randomized, double-blind, place-bo-controlled clinical trial). There were two study arms, one involved 4,532 postmenopausal women who received continuous combined estrogen (conjugated equine estrogens [CEE] plus medroxyprogesterone acetate [MPA]) or placebo, and the other involved 2,947 hysterectomized women randomized to continuous unopposed CEE or placebo. All participants were aged 65 years or older. CEE with or without MPA did not protect against (but substantially increased the risk of) dementia of any cause or cognitive decline. Incidence of probable dementia in the estrogen-alone trial was statistically similar to that in the estrogen plus progestin trial. When data from both trials were pooled, the overall risk for probable dementia was increased by 76% (HR, 1.76; 95% CI, 1.19 to 2.60; P = 0.005). A second report from WHIMS suggested that cognitive decline in women aged 65 years and older was greater in those receiving hormone therapy than in those receiving placebo (HR, 1.25; 95% CI, 0.97-1.60).

The WHIMS results clearly indicate that CEE with or without MPA should not be used to prevent demen-tia or enhance cognition in women older than 65 years.

Key Words: Hormone replacement therapy, Women’s Health Initiative, Women’s Health Initiative Memory

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ѣᙯෲႬᄋྃ·ᒚڱ۞ᗁጯಡӘѭͱ·ഏĂҭ ௢᎕ᇴ˩ѐ۞៍၅ᙋፂĂ̂ౌ޽Ш˘࣎͞ШĈྃ· ෲႬᄋΪѣр఍ĄдЧᘽᇄ̂˧ҖዚĂᗁर׶૎̃ ࠧ˵ሤ̷ଳϡ˭ĂࣧώෲႬᄋᒚڱўдѣड़නቤՀ

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1

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1

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2 1_{ᄂΔᗁጯ̂ጯąξϲ༱۾ᗁੰৠགྷ̰ࡊĂ}2_{έΔξϲᓑЪᗁ} ੰ૎ρੰડ૎யొĄ צ͛͟ഇĈ2005 ѐ 11 ͡9 ͟Ą࣒Լ͟ഇĈ2005 ѐ 12 ͡9 ͟Ą ତצ͟ഇĈ2006 ѐ 4 ͡ 17 ͟Ą ఼ੈү۰Ĉ߸ୁ؟ᗁरĂ༱۾ᗁੰৠགྷ̰ࡊĄέΔξᎸษ ྮˬ߱ 111 ཱིĄ E-mail: jayhuang1976@yahoo.com.tw ៍၅ّࡁտ޽΍ෲႬᄋྃ·ᒚڱΞͽԼචᄮۢΑਕĂҭߏᐌ፟ᓜԖྏរಡӘݒ̙к˫଀̙ זඕኢĄWHIMS (Women’s Health Initiative Memory Study) ߏк͕̚ăᐌ፟ᗕ۠ᓜԖྏរĂ࡚ ઼઼छ኎Ϡࡁտੰ͹ጱ̝૎̃ઉ૵ᙯᘃ WHI (Women’s Health Initiative hormone therapy trials) ۞˘ొЊࡁտࢍထĂ͹ࢋͧྵ׶ෞҤઃགྷ૎̃ಏ፾ֹϡᅬ፬৵ٕඕЪᅬ፬৵׶เវ৵ڼᒚߏӎ ਕࢫҲٙѣࣧЯ۞εംা׶ᅅޘᄮۢΑਕᅪᘣྏរĄࡁտͽ 65 ໐ͽ˯ઃགྷ૎̃ࠎ၆෪Ă̶ࠎ ˟̶͚Ĉ׎̚˘͚ߏѣ̄झ۞ઃགྷ૎̃В 4,532 ЩĂֹϡඕЪᅬ፬৵׶เវ৵ڼᒚٕග̟щᇐ ጗ćΩγ˘͚ߏ൑̄झ۞ઃགྷ૎̃В 2,947 ЩĂಏ፾ֹϡᅬ፬৵ڼᒚٕග̟щᇐ጗Ąඕڍព ϯĂᅬ፬৵ಏ፾ٕЪ׀ֹϡเវ৵̙ҭ̙ਕ࿰֨εംাٕࢫҲᄮۢΑਕĄ҃̂ͅវ˯ົᆧΐε ംা׶ᄮۢΑਕࢫҲ۞ПᐍĄ૟ᅬ፬৵ಏ፾ٕЪ׀ֹϡเវ৵̝ྤफ़˘੓̶ژॡĂΞਕεംা ᓁПᐍّᆧ੼ 76%ĞПᐍͧĂ1.76ć95% ܫᏥડมĂ1.19-2.60ćP = .005ğĄ ෲႬᄋྃ·ᒚڱ̙ᑕ఍͞ග̟ 65 ໐ͽ˯Հѐഇ૎̃ĂֽԼචᄮۢΑਕٕ࿰֨εംাĄ WHIMS ̝ඕڍߏӎΞؼҩዋϡٺ 65 ໐ͽ˭ઃགྷ૎̃إ̙୻຾ĂЯѩԧࣇޙᛉ૟ WHIMS ̝ඕ ڍᛋӘྵѐܦ۞ઃགྷ૎̃Ąҭߏࢋᄮۢд఺ֱྵѐܦ۞ઃགྷ૎̃εംা۞඗၆ПᐍّޝҲĂТ ॡෲႬᄋྃ·ᒚڱᓜԖӀ̂ٺၑĄ

ෲႬᄋྃ·ᒚڱĂWomen’s Health Initiative, Women’s Health Initiative Memory Study, εംাĂᅅޘᄮۢΑਕᅪᘣĂܠਬঔᐵা

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΍ధк࿅ޘྒ̂ᒚड़ĂּтΞͽ࿰͕֨ҕგ়ঽă ̚ࢲᄃεംাඈĄώ͛ўд̶ژෲႬᄋྃ·ᒚڱ౵ າ൴णĂপҾߏ၆̂ཝΑਕĞεംাĂᄮۢΑਕğ ̝ड़ৈĄ Ϥٺέ៉ҁѐˠ˾۞ԣిᆧΐĂεംা˵ᐌ̝ ᆧΐĄϫ݈Ч჌εംাౌు႙൴ण΍পளّ۞ڼᒚ ͞ёĂѝഇ෧ᕝಶ˩̶ࢦࢋĄέ៉εംা۞஽Җ தĂд 65 ໐ͽ˯ҁˠࡗࠎ 2~4%Ă80 ໐ͽ˯ҁˠε ംা۞஽Җதᆧΐז 15~20%Ą έ៉εംা۞஽ҖதᅈҲٺ̏ฟ൴઼छĂΞਕ ۞ࣧЯѣĈҁѐˠ˾ඕၹͽ 65~75 ໐ྵҲ᛬̝ҁˠ ࠎ͹ĂٕߏεംҁˠѪ˸தྵ੼ĂЯ҃෧ᕝྵ̙ट ٽ ҃ జ Ҳ Ҥ Ă ͽ ̈́ έ ៉ ˠ ѣ ਌ క Ϩ E4 ૄ Я (Apolipoprotein E4) ̝ᐛதྵҲ̝୉ཏ۞পّඈĄֶ ፂ 1998 ѐ੼ฯ̂ጯڒᗁरඈˠдݑᄂ៉۞አߤಡ ӘĂεംা̝ᙷݭͽܠਬঔᐵͩঽ (Alzheimer’s dis-ease, AD) ࠎ͹ĂࡗҫΗᇴć׎Ѩࠎҕგݭεംা (Vascular dementia, VaD) ࡗҫ 20~25%Ă஄Ъݭεം া (Mixed dementia, mixed AD and VaD) ࡗҫ 5-10%Ă׎΁ᙷݭ݋ࡗҫ 15~20%ĞΒ߁׎΁ੜّ̼ε ംাĂּтĈ͐ܛ഑ͩাĂ͐ܛ഑ͩা࣏ཏඈć׎ ΁ΞڼᒚّεംাĂּтĈͪཝাĂϥېཛྷҲ˭ ඈćͽ̈́׎΁ࣧЯĂּтĈγ๋ඈࣧЯğĄ1998 ѐ੼ ฯ̂ጯڒᗁरඈˠ̝ࡁտ˵ពϯĂέ៉ 65 ໐ͽ˯ҁ ˠĂՏѐεംা൴Ϡதࠎ 3.7%Ĉ65-69 ໐εംা൴Ϡ தࠎ 1.3 %Ă85 ໐ͽ˯εംা൴Ϡதᆧ੼Ҍ 16.5%(1)_Ą າ൴Ϡ۞εംঽˠĂ̪ͽܠਬঔᐵাاкĂࡗҫ 4 0 %ćҕგݭεംা۰ᔵ̪اѨĂҭͧத೩੼ࠎ 35%ć஄Ъّ۞ͧத˵ҫ˞ 15%ĄϤٺҕგݭεം াᄃ஄Ъݭεംা̝Ѫ˸தځព੼ٺܠਬঔᐵাĂ ٙͽд஽Җதአߤ݈̚׌۰̝ͧத࠹၆ྵҲ(2)_Ą 1975 ѐ Naftolin ඈ൴ன˭ෛ͸ਕ૟༝˱৵ᖼ̼ ඈѣᙯĂ߇Ⴭ఺ֱϤৠགྷր௚Ъј̶ٕοдৠགྷր ௚۞ᙷ׽ዔ፬৵Ⴭࠎৠགྷᙷ׽ዔĄᅬ፬৵ତצጡΒ ߁ ɗ ׶ ɘ ତצጡҜٺፋ࣎̂ཝĂপҾߏጯ௫׶੃ ጸડĂтঔ੺׶Ճ̥ડĂ఺ֱડા̰൴னّ፬৵Ъ јυᅮ۞֥ՏĂ೩ϯᅬ፬৵дᇶॡ੃ጸ̚۞үϡĂᅬ ፬৵၆̂ཝ᜕ܲүϡᔘΒ߁ܳซᓙែ፬৵۞߿ّĂ ഴ͌ৠགྷ۞ϴεĂו፬คࡎܜ܂׶ፘېࡎ۞ԛјĂ Լචཝҕ߹ͽഴ͌ཝ৿ҕ׶ᓙ׽ዔ۞ͪπĂአ༼ྶ ਌కϨ E ૄЯ۞ܑ྿ĂᒉዳৠགྷĂഴ͌ ɘ ᙷ፥ৰ۞ Օ᎕Ă၆ৠགྷ็ᅍۏኳ׶ৠགྷాତѣአ༼үϡĄᆧ ΐৠགྷ็ᅍۏኳ۞ᛖٸĂ֨ͤউ̼۞ຫ๋(3,4)_Ą ᙯٺเវ৵၆ᄮۢΑਕ۞үϡĂ̙ٙۢкćϠ நጯ˯Ăเវ৵ѣᆧૻăአ༼׶޻ԩᅬ፬৵۞ү ϡĄд͌ᇴဂ׶൚۞௟ࡪૈዳ၁រ̚ĂТॡֹϡᅬ ፬৵׶เវ৵ົ̚׶ᄃਗ਼ᖼᅬ፬৵۞р఍Ą ઃགྷޢᅬ፬৵˭ࢫߏӎ׶εംাѣᙯĂ͚޺ᅬ ፬৵৿ͻߏεംাঽЯ̝˘۞ᙋፂт˭Ĉ(1) Ϗଈε ംাҁ૎ֹ̃ϡᅬ፬৵ΞͽԼචᄮۢΑਕĄ(2) ঽּ ၆໰ࡁտă៍၅ّࡁտٕ݈ᖀّࡁտౌಡӘઃགྷᅬ ፬৵ڼᒚົࢫҲεംা൴ϠதĄ14 ࣎߹Җঽአߤಡ Ә̚ĂҤࢍֹϡᅬ፬৵ޢ۞ܠਬঔᐵাᓁПᐍͧࠎ 0.56Ăҭ˵ѣೀ݈࣎ᖀّ៍၅ࡁտ൴னᅬ፬৵՟ѣܲ ᜕εംাٕᄮۢΑਕĄࡁտ˯΍னϒ̝ͅϬ࠼ĂΞ ਕࡁտ੠ᖸॡม͉ൺĂٕᇹώᇴઐҲĄ

WHI

Ϥ઼छ኎Ϡࡁտੰ͹ጱ̝૎̃ઉ૵ᙯᘃWHI (Women’s Health Initiative hormone therapy trials) ߏͧ ྵ׶ෞҤಏ፾ᅬ፬৵ٕඕЪᅬ፬৵׶เវ৵ڼᒚઃ གྷ૎̃ᒚड़۞̂ݭᗕ۠ăᐌ፟၆໰ᓜԖྏរĄЯࠎ ྍࡁտ۞ࢍထ׹БĂ֭Ϥ 40 छᗁጯ͕̚ВТଯҖĂ ׎ܫᏥޘ੼Ăͷߏ۩݈ĞΞਕ˵ߏ඗ޢğ۞̂ݭࡁ տĄВѣ 27,347 Щצྏ۰Ă׎̚੫၆ѐ᛬̬ٺ 50-79

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໐֭ܲѣ˘࣎Ԇፋ̄झ۞Հѐഇ૎̃ 16,608 ҜĂᐌ ̶፟ࠁ 8,506 ЩֹϡඕЪᅬ፬৵ premarin 0.625mg ΐ ˯เវ৵ provera 2.5mg Ą၆໰௡ 8,102 Щֹϡщᇐ ጗Ą੠ᖸ 5.2 ѐҌ 2002 ѐ 4 ͡ 30 ٙ͟ү۞ࡁտ൴ னĂܜഇྃ·ᅬ፬৵׶เវ৵ 7,968 ЩĂົᆧΐͽ˭ ়ঽ۞Пᐍّ Ĉ݄͕ঽПᐍͧ 1.29 (௖ 95% ܫᏥડ ม 1.02-1.63) ѣ 286 ּĂ֯ᒛ 1.26 (1.00-1.59) 290 ּĂ̚ࢲ 1.41 (1.07-1.85) 212 ּĂ۱ং๫ 2.13 (1.39-3.25) 101 ּć࠹၆гĂ̄झ̰ቯᒛ 0.83 (0.47-1.47) 47 ּĂ̂བۡབᒛ 0.63 (0.43-0.92) 112 ּĂ̂ჿ੻ ੻Զ 0.66 (0.45-0.98) 106 ּĂ׎΁ࣧЯѪ˸ 0.92 (0.74-1.14) 331 ּѪ˸Ą༊ॡ၆໰௡ 7,608 Щ߿඾֭ ೩ֻྤफ़Ą ඗ ၆ П ᐍ ّ Ξ ᕩ Я ٺ ᅬ ፬ ৵ ׶ เ វ ৵ ۰ Տ 10,000 ˠ˘ѐᆧΐ 7 Ҝ݄͕ঽĂ̚ࢲᆧΐ 8 Ҝă۱ ং๫ᆧΐ 8 Ҝă֯ᒛᆧΐ 8 ҜĂҭ඗၆ПᐍّՏ 10,000 ˠ˘ѐ̂བۡབᒛഴ͌ 6 ҜĂ̂ჿ੻੻Զഴ ͌ 5 ҜĄࣧώ࿰ࢍ੠ᖸҌ 2005 ѐ 3 ͡ĂҭߏЯᎮଈ ֯ᒛˠᇴ੼΍࿰ഇ྿ 290 ּĂᑭؠ௚ࢍ࿀ܕᓜࠧᕇ Ğ௖ 95% ܫᏥડม 1.00-1.59ğĂٺߏՙؠღާ಄ઃĄ ܲѣ˘࣎Ԇፋ̄झ۞Հѐഇ૎̃ĂܜഇෲႬᄋྃ· ᒚڱ̙ਕ࿰݄͕֨ঽĂͷົᆧΐ֯ᒛă͕҉ୟ๫ă ̚ࢲ̈́۱ং๫۞ПᐍّĂᔵ൒̂ჿ੻੻Զ̈́̂བۡ བᒛഴ͌Ăҭࢲᐍ׶ӀৈෞҤ੓ֽ̪ၑ̂ٺӀ(5)_ĄΩ γĂ̄झ̷ੵ۞ઃགྷ૎̃ 10,793 Щᐌ̶፟ࠁĂ5,310 Щಏ৷ֹϡᅬ፬৵ 0.625mg Ą၆໰௡ 5,429 Щֹϡщ ᇐ጗Ąಏ৷ֹϡᅬ፬৵Ăົᆧΐ̚ࢲПᐍĂഴ͌۵ ੻੻ԶПᐍĂ֯ᒛ۞൴Ϡதഴ͌ĂТॡ̙ົᇆᜩ݄ ͕ঽ൴ϠதĄЯѩ੠ᖸ 6.8 ѐॡĂд 2004 ѐ 2 ͡ 29 ͟೩݈ඕՁ(6)_Ą WHI ࡁտߏܕֽ౵ၔغăΞያ۞ࡁտࢍထĂҭ ˵ϏҺѣֱ໰ᜪ̙ז۞ְีĈтણᄃ૎̃ѐ᛬ઐ੼ ĞπӮ 63.3 ໐ğćΪෞҤ˘჌ᘽ۞ಏ˘጗ณć̚ዄˠ ᇴ к Ğ ఈ Ⴌ ᄋ ௡ 42%ć щ ᇐ ጗ ௡ 10.7% Լ ఈ Ⴌ ᄋğćѣ 30% ૎̃дણΐࡁտࢍထ݈അགྷֹϡ 5 ѐ ͽ˯۞ఈႬᄋྃ·ᒚڱඈඈĄ၆έ៉૎̃҃֏Ăྍ ࢍထֲ͉̚୉ཱྀΪѣ 194 ˠĂέ៉૎̃֯ٗᒛᎮଈ தࠎ઼࡚૎̃۞̶̣̝˘Ă၁ᅫПᐍّᑕᐌ׎ͧத ҃ഴ͌Ąྍࡁտזڼᒚ۞ௐ̣ѐ̖࠻ז֯ᒛᆧΐ۞ ன෪ĂϺӈᐝαѐ֭൑֯ᒛ۞ᆧΐĄ

WHIMS

WHIMS (the Women’s Health Initiative Memory

Study) ߏ WHI ۞˘ొЊĂϤ 39 छᗁጯ͕̚ВТଯ Җ۞̂ݭࡁտĄ͹ࢋͧྵ׶ෞҤઃགྷ૎̃ಏ፾ֹϡ ᅬ፬৵ٕඕЪᅬ፬৵׶เវ৵ڼᒚߏӎਕࢫҲ 65 ໐ ͽ˯૎̃ٙѣࣧЯ۞εംাٕᅅޘᄮۢΑਕᅪᘣྏ រĄι೩ֻ˞צྏ۰Ğ7,510 Щğ౵ྎႽ۞ྤफ़Ă੠ ᖸॡม౵ܜĂ၆ᄮۢΑਕෞҤ۞޽ᇾ౵БࢬĂ੃ᐂ ّ˵౵ԆፋĂኳณଠט˯˩̶ᚑॾĄWHIMS ࡁտА Ϥགྷ૞ຽ੊ቚ̝ԫఙࣶАͽ 3MSE (modified mini-Mental state examination) ֽෞҤᄮۢΑਕ׶εംাĂ ྍෞ̶͞ёΒ߁ 15 ొ̶Ă46 ีϫĂ̶ᇴ 0~100Ăπ Ӯ෱ॡ 10~12 ̶ᛗĂڇᘽ݈ޢՏѐซҖෞҤĄ ≤ 8 ѐ ିֈ඀ޘĈcut point ≤ 72ć≥ 9 ѐିֈ඀ޘĈcut point ≤ 76Ą੠ᖸ 16 ࣎͡ޢĂԼࠎ ≤ 8 ѐିֈ඀ޘĈcut point ≤ 80ć≥ 9 ѐିֈ඀ޘĈcut point ≤ 88Ą൒ޢϤ

ৠགྷ̰ࡊٕჟৠࡊ૞ࡊᗁरઇ෧ᕝ(7)_Ą WHIMS צྏ۰׎̚ѣ̄झ۞ 4,532 ЩĂᐌ̶፟ ࠁ 2,229 Щֹϡᅬ፬৵ premarin 0.625mg ΐ˯เវ৵ provera 2.5mgĄ၆໰௡ֹϡщᇐ጗ѣ 2,303 ЩĄགྷ࿅ 4 ѐ۞੠ᖸĂдྏរ௡ 2,229 ּ̚ѣ 40 ּĞ1.8%ğ ࠎεംাĂ၆໰௡ 2,303 ּ̚ѣ 21 ּĞ0.9 %ğࠎε ംাĄ׌௡൴Ϡத̶ҾࠎՏ˘༱ˠѐ 45 ׶Տ˘༱ˠ ѐ 22ĂПᐍͧࠎ 2.05 (95% CI 1.21-3.48, p = 0.01)Ă ඕڍពϯඕЪᅬ፬৵׶เវ৵ڼᒚົᆧΐ 2 ࢺ۞ε ംাПᐍّĄПᐍّᆧΐдֹϡᘽޢ 1 ѐӈܑன΍ ֽĂЯѩ஄Ъֹϡᅬ፬৵׶เវ৵่̙̙ਕؼޢ় ঽ۞ೋ̼Ă҃ͅΐిঽଐซणĂдᐌޢ੠ᖸ 5 ѐ มĂ఺჌Пᐍّमள޺ᜈхдĄᒣϒ׎΁׶εംা ѣᙯЯ৵ޢĂ఺჌Пᐍّमள̪൒ᆧΐĂ҃ͷ၆ٙ ѣࣧЯ͔੓۞εംা۞ඕڍӮ˘࡭Ă஄Ъֹϡᅬ፬ ৵׶เវ৵ᆧΐܠਬঔᐵা̝ࣧЯ̙ځĂϤٺෲႬ ᄋྃ·ᒚڱֹ̚ࢲПᐍّᆧΐĂ߇ܠਬঔᐵা۞П ᐍّᆧΐΞਕ׶̈۞ăϏ൴ன۞ཝҕგঽត׶ටᅩ

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0.74-1.55, p = .72) Ą 1995 ѐ 6 ͡၆൑̄झ۞ 65 Ҍ 79 ໐ 2,947 Щ૎ ̃ซҖ WHIMSĈಏ፾ֹϡՏ͟ᅬ፬৵ѣ 1,387 ЩĂ ၆໰௡ѣ 1,421 ЩĄҌ 2004 ѐ 2 ͡ࡁտࢍထͤ̚Ă πӮ੠ᖸ 5.4 ѐĄֹϡՏ͟ᅬ፬৵۰ͧϏڇϡ۰πӮ 3MSE ̶ᇴҲ 0.26 (0.13; p = .04)Ă62% צྏ۰׎ 3MSE ≥ 95Ă3MSE ҲٺᎡᑭࣃҫצྏ۰ 9.6%Ą૟ྤ फ़׶஄Ъᅬ፬৵׶เវ৵۰˘੓̶ژॡĂπӮ 3MSE ̶ᇴҲ 0.21 (0.08; p = .006)Ą дྏរ௡ 1,464 ּ̚ѣ 28 ּĞ1.9 %ğࠎεം াĂ၆໰௡ 1,483 ּ̚ѣ 19 ּĞ1.3 %ğࠎεംাĄ ׌௡൴Ϡத̶ҾࠎՏ˘༱ˠѐ 37 ׶Տ˘༱ˠѐ 25Ă Пᐍͧࠎ 1.49 (95% CI 0.83-2.66, p = 0.18)Ăඕڍពϯ ಏ፾ֹϡᅬ፬৵ෲႬᄋྃ·ᒚڱ̙ົᆧΐεംা۞ ПᐍّĄ˵̙ົᆧΐᅅޘᄮۢΑਕᅪᘣĄ׎Пᐍͧ ࠎ 1.34 (95% CI 0.95-1.89 )Ąтڍ૟ྤफ़׶஄Ъᅬ፬ ৵׶เវ৵۰˘੓̶ژॡĂᅅޘᄮۢΑਕᅪᘣПᐍ ͧࠎ 1.25 (95% CI 0.97-1.60)ĂεംাПᐍͧ݋ࠎ 1.76 (95% CI, 1.19-2.60; P = .005)(10,11)_Ą ˵ಶߏᄲෲႬᄋᒚڱ̙͚޺ѣ᜕ܲҁѐ૎̃ᄮ ۢΑਕ۞үϡĂ̂кᇴ૎̃ڇᘽޢ՟ѣ̙р۞ᇆ ᜩĂ͌ᇴ૎̃݋ЯڇᘽົֹᄮۢΑਕѣࢫҲ۞П ᐍć˵ΞͽᄲӎؠෲႬᄋྃ·ᒚڱĂਕ֨ͤεംা ׶᜕ܲᄮۢΑਕ۞ኢᕇĄтڍֹϡ̙Тᇄൕ۞ᅬ፬ ৵׶เវ৵ߏӎົТᇹ۞ඕڍĂ૟ޞซ˘ՎࡁտĄ ෲႬᄋྃ·ᒚڱ۞ड़ৈдྋੵՀѐഇাېĂ࿰ ֨ౚ྽෇ᒺĂ࿰֨੻ኳ߹εĂ֭ਕࢫҲ̂བᒛ۞Ꭾ ଈதĄՀѐഇ૎̃ᑕྍΞͽֹϡෲႬᄋྃ·ᒚڱĂ ͍׎ߏѣՀѐഇাې۞૎̃ĂෲႬᄋ۞ֹϡυᅮ׶ ᗁरથ੅ෞҤӀၑ҃ޢ၁ҖĄ̙ޙᛉܜഇֹϡෲႬ ᄋᒚڱֽ࿰֨εംা׶ԼචҁѐˠᄮۢΑਕĄ

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