懷孕期間類風濕性關節炎疾病對懷孕結果的影響

妊娠期間有 RA 診斷但沒有使用 NSAIDs，Steroids 和非生物性 DMARD 藥物者，除在 LBW 有極小機率外，在早產和 SGA 上與對照組無不同，過去 亦有研究顯示控制良好的類風濕性關節炎在懷孕結果上與一般孕產婦無不同 (de Man et al., 2009)。因此需進一步探討當 RA 疾病持續並以藥物治療時是否 對懷孕結果有所影響，並於第三節討論。

第三節 懷孕期間抗類風濕性關節炎藥物對懷孕結果的影響

較一般孕產婦，妊娠期間使用抗類風濕關節炎藥物的確有相對較高的機 會引起早產、低出生體重和 SGA，隨著藥物不同勝算比亦不同。

NSAIDs 本身除具有止痛效用外，另具有抗發炎作用，是類風性性關節 炎病人長期使用的藥品之一。RA婦女於妊娠期間使用NSAIDs 較對照組在 LBW，早產和SGA上有較高的機率，勝算比分別為 2.00 倍(95%CI 1.44-2.80)，

1.61 倍(95%CI 1.18-2.21)，1.38 倍(95% CI 1.07-1.78)，其結果與Gunnar Lauge Nielsen及Ostensen等人研究結果有所不同，不論是早產、低出生體重或SGA較 一般孕產婦有較高機率發生此不良反應，雖然目前引發機轉並不清楚，但許 多NSAIDs容易穿過胎盤，進入胎兒血液循環，並可能改變胎兒的發育，尤其 是發展的腎臟，繼而造成子宮內發展遲緩和腎臟不良反應，這些反應包括羊水 減少甚至腎臟衰竭( Boubred F, Vendemmia M, Garcia-Meric P, Buffat C, Millet V, & Simeoni U.,2006)。羊水是胎兒正常生長的重要因素之一，當羊水量過 低，則胎兒生長便受限，懷孕初期羊水減少的原因目前仍不清楚，然第二期 顯示RA婦女於妊娠期間使用Steroids較對照組在SGA上風險倍數增為 2.37 倍 (95%CI 1.26-4.44)。類固醇同樣會穿過胎盤對胎兒產生影響。長期投與外生性 類固醇後，人體下視丘–腦下垂體–腎上腺（Hypothalamic-Pituitary-Adrenal

axis，HPA）軸會受到抑制，當突然停止投與類固醇後，可能產生腎上腺皮質 功能不全症，而腎上腺與胎兒生長發育有很大的關係。由過去的動物研究及 臨床觀察，顯示類固醇具有子宮內胎兒生長遲滯及增加低出生體重機率的風 險(Scott JR.,1977)(Lockwood C.J., Radunovic N., Nastic D., Petkovic S., Aigner S., &Berkowitz GS.,1996)。

於早產方面，本研究Steroids 發生此風險機率較對照組來得高，。這可能 與 Steroids 降低細胞外基質(extracellular matrix，ECM)合成，而低 ECM 濃度 與早期破水有關(Guller S., Kong L.,Wozniak R., Lockwood C.J.,1995)。

妊娠期間使用一種以上藥物的組別在LBW，早產和 SGA 的機率較單一藥 治療，而 Steroid 同時具有抗發炎和免疫抑制的效果。本研究發現合併 NSAIDs 和 Steroid 治療者，不論在低出生體重、早產和 SGA 上相較對照組其風險性明 顯增加，除 SGA 外均具加成性結果。同時由統計分析結果發現合併 NSAIDs 和Steroid 治療者相較於單一 Steroid 使用者，SGA 的風險有減少的傾向。Steroid 具有多重副作用，且副作用發生及嚴重性與劑量有相依關係，故常會盡量以 低劑量方式投與治療。合併 NSAIDs 治療，可減少 Steroid 的使用劑量，間接 降低 Steroid 對胎兒的影響。

非生物性DMARs 方面，在本次研究上並無統計差異，可能與納入研究中 之樣本數少有關，顯示醫師在懷孕婦女上，非生物性DMARs 的使用仍非普遍

性處方，故不在此次研究中進行討論。

第四節 研究限制

1. 類風濕性關節炎本身是一自體免疫疾病，會攻擊身體各個器官當然也包括 子宮及胎盤，抗類風濕性藥物使用乃依疾病嚴重程度選擇藥物進行治療，

因此也間接說明藥物的選用相對應也代表了類風濕性關節炎發炎的程 度。本研究結果無納入妊娠期間疾病症狀之嚴重程度，故無法排除疾病嚴 重度對妊娠結果的影響及風險。

2. 本研究無進一步討論藥物使用累計劑量或時間對懷孕結果的影響，無法說 明這些風險是否與劑量或使用時間的長短有關。

3. 本研究非前瞻性研究，無法確實控制孕產婦實際服藥配合度，僅就處方進 行藥物與懷孕結果之分析。

4. 本研究為回溯性資料且懷孕間即併進程和藥品使用狀況無法進一步控 制，故無將藥物廓清期（washout period）納入考量。

第六章 結論與建議

第一節 結論

基於本研究結果發現，在藥物選用上我國使用 NSAIDs 和 Steroid 使用頻 率與國外研究結果相反，NSAIDs 在我國使用頻率較高，而 Steroid 則較低，

顯示抗類風濕性關節炎藥物的選擇在國內外並無完全一致的藥物使用之風險 利益評估。

過往研究著重於藥物對懷孕初期的影響，本研究則以探討藥物對懷孕結 果是否有影響為主軸，探討妊娠婦女於懷孕期間使用各類抗類風濕性藥物對 胎兒的影響如早產，低出生體重和 SGA。由研究結果發現，相較於一般孕產 婦，類風濕性關節炎患者妊娠期間使用抗類風濕性關節炎藥物對胎兒有影 響，其中以 NSAIDs 及 Steroids 有明顯的統計上的意義，Steroids 影響性較 NSAIDs 大。NSAIDs 可能會經由間接的方式影響胎兒的發育，而 Steroids 則 會透過抑制調控生長激素之作用來限制胎兒於子宮內的生長。

當病患無法以單一藥物來控制自身的疾病時，就必須要同時使用超過一 種以上的藥物來治療，本研究結果使用一種藥物以上的組別較單一使用組之 良懷孕結果風險機率來得高，而併用 NSAIDs 及 Steroids 是使用頻率較高的型 態。妊娠期間併用此二藥物，在早產和低出生體重之風險上有加成性，但在 產出 SGA 胎兒的風險則降低，是否與 Steroids 劑量和使用期間有關並無法由 此次的研究中得到結果。

第二節 建議

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附錄

附錄一、妊娠期間，抗發炎藥物治療使用準則

疾病活動程度 治療

無活動 不需要

輕微活動 acetaminophen

妊娠第二期，需要時使用NASID 低劑量prednisone (<10mg/day) hydroxychloroquine

中度活動 中劑量prednisone(10 至 20 mg/day) hydroxychloroquine

sulfasalazine

嚴重活動 高劑量prednisone (20 至 60mg/day) sulfasalazine

TNFα抑制劑

資料來源：“The management of rheumatic disease in pregnancy”,Mitchell, k.,Kaul, M., Clowse M.E.B., 2010, Scand J Rheumatol, 39,104.

附錄二、懷孕用藥分級

分級 定義

A 針對孕婦所做的研究中，有足夠的證據證明用於懷孕初期及後期 皆不會造成胎兒之危害。

B

動物實驗證實對胎兒無害但缺乏足夠的孕婦實驗；或動物實驗有 副作用報告，但孕婦實驗無法證明對懷孕初期及後期之胎兒有 害。

C 動物實驗顯示對胎兒有害但缺乏控制良好的孕婦實驗；或缺乏動 物實驗或孕婦實驗數據。

D 已有實驗證實對人類胎兒之危害；但緊急或必要時權衡利害之使

D 已有實驗證實對人類胎兒之危害；但緊急或必要時權衡利害之使