寧莉 王健 趙穎 姚琴 溫華英
[關(guān)鍵詞] 緩解期;狼瘡性腎炎;小劑量激素;羥氯喹;計劃妊娠結(jié)局;腎臟損害
[中圖分類號] R692.3? ? ? ? ? [文獻(xiàn)標(biāo)識碼] B? ? ? ? ? [文章編號] 1673-9701(2021)18-0054-03
Effects of low-dose hormone and hydroxychloroquine on planned pregnancy outcome and renal injury in patients with lupus nephritis in remission
NING Li1? ?WANG Jian2? ?ZHAO Ying3? ?YAO Qin1? ?WEN Huaying1
1.Department of Obstetrics and Gynecology, the First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China; 2.Department of Nephrology, the First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China; 3.Department of Reproductive Medicine, the First Affiliated Hospital of Gannan Medical University,Ganzhou? ?341000, China
[Abstract] Objective To observe the influence of planned pregnancy on maternal safety and pregnancy outcome of patients with lupus nephritis (LN) in remission under the maintenance treatment of low-dose hormone and hydroxychloroquine, and to investigate the pregnancy time and drug use of LN patients. Methods A total of 23 patients with LN in remission were treated with low-dose prednisone (10 mg/day) and hydroxychloroquine (400 mg/ day) in our hospital from January 2013 to December 2018, and their pregnancy was planned under the guidance of obstetricians, reproductive medicine doctors and nephrologists. The general condition during pregnancy, blood and urine test results, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, fetal development and delivery were recorded. Results 1.There were 29 pregnancies and 6 spontaneous abortions in 23 patients,and 2 patients terminated their pregnancy due to severe lupus activity and preeclampsia in the second trimester of pregnancy. The abortion rate was 20.69%. The pregnancy success rate was 91.30% and the premature birth rate was 19.05%. There was no stillbirth, and the fetus developed well. 2.Before delivery,SLEDAI score and urine total protein of all patients were higher than those before pregnancy, with statistically significant difference(P<0.05). And the plasma albumin was lower than that before pregnancy, without statistically significant difference(P>0.05). The recurrence rate of nephritis was 43.47%, and the incidence of nephrotic syndrome was 21.74%. Conclusion LN patients in remission planning pregnancy with low dose of hormone and hydroxychloroquine can have a good control of the lupus activity and nephritis, and obtain satisfactory pregnancy outcome.
[Key words] Remission; Lupus nephritis; Low dose hormone; Hydroxychloroquine; Planned pregnancy outcome; Renal injury
系統(tǒng)性紅斑狼瘡(Systemic lupus erythematosus,SLE)是一種多系統(tǒng)受累的自身免疫性疾病,常見于年輕女性,其病程具有周期性緩解和復(fù)發(fā)的特點。狼瘡性腎炎(Lupus nephritis,LN)是SLE的常見并發(fā)癥,其發(fā)生率為50.7%[1],表現(xiàn)為蛋白尿、血清肌酐升高、高血壓、血小板減少、貧血等。隨著對疾病認(rèn)識的深入和越來越多的青年狼瘡性腎炎患者對于生育的渴望,提高狼瘡性腎炎患者的安全妊娠成功率是近年來備受關(guān)注的研究內(nèi)容。研究表明妊娠會增加SLE加重的風(fēng)險,尤其是妊娠前病情未控或孕期病情活動者[2-3]。對于狼瘡性腎炎穩(wěn)定期患者在維持小劑量激素及羥氯喹治療下,計劃妊娠的安全性及妊娠結(jié)局報道較少。基于此,本研究選取我院2013年1月至2018年12月診斷為狼瘡性腎炎且治療后處于緩解期的計劃妊娠婦女,在產(chǎn)科、生殖醫(yī)學(xué)科及腎內(nèi)科指導(dǎo)下用藥及密切監(jiān)測,研究妊娠結(jié)局及藥物的安全性,為LN患者妊娠提供臨床證據(jù),現(xiàn)報道如下。
1 資料與方法
1.1 一般資料
選取2013年1月至2018年12月經(jīng)我院診斷為狼瘡性腎炎的青年女性患者23例,年齡21~32歲,平均(26.43±2.97)歲;病程2.82~7.15年,平均(4.41±1.19)年。納入標(biāo)準(zhǔn):①妊娠前病情穩(wěn)定,無明顯狼瘡活動,系統(tǒng)性紅斑狼瘡的活動指數(shù)(SLEDAI)積分≤4分,且停用免疫抑制劑或胎兒致畸藥物6個月以上;②24 h尿蛋白<1 g以下,血清肌酐<100 μmol/L;③糖皮質(zhì)激素劑量≤10 mg/d,羥氯喹片劑量≤400 mg/d;④血壓控制良好,<140/90 mmHg。排除標(biāo)準(zhǔn):①狼瘡性腎炎非計劃懷孕者;②抗磷脂抗體陽性者;③合并其他系統(tǒng)疾病可威脅妊娠安全,如精神疾病、心臟疾病、凝血功能障礙、腫瘤、合并感染等。
1.2 方法
所有患者繼續(xù)服用潑尼松片和羥氯喹片。潑尼松(上海信誼藥廠有限公司,國藥準(zhǔn)字H31020675,規(guī)格:5 mg/片)1次/d,10 mg/次;羥氯喹片(上海上藥中西制藥有限公司,國藥準(zhǔn)字H19990263,規(guī)格:100 mg/片)2次/d,200 mg/次。有高血壓者繼續(xù)服用無致畸作用的降壓藥物,同時在生殖科醫(yī)生指導(dǎo)下助孕,孕后需完成產(chǎn)科常規(guī)檢查,每月定期檢查尿分析、尿總蛋白、血液常規(guī)、肝腎功能電解質(zhì)血糖、補(bǔ)體、血沉等檢查。
1.3 觀察指標(biāo)及評價標(biāo)準(zhǔn)
觀察患者妊娠、胎兒分娩及發(fā)育情況(流產(chǎn)率、妊娠成功率、早產(chǎn)率、出生孕周及嬰兒發(fā)育情況),及狼瘡活動和腎臟損害程度。①狼瘡活動:根據(jù)患者臨床表現(xiàn)及相關(guān)輔助檢查結(jié)果計算妊娠前后系統(tǒng)性紅斑狼瘡的活動指數(shù)(SLEDAI)積分,0~4分基本無活動、5~9分輕度活動、10~14分中度活動、≥15分重度活動[4]。②腎臟損害程度評估:觀察孕前及分娩前24 h尿總蛋白、血漿白蛋白、血清肌酐值變化,計算腎炎的復(fù)發(fā)率(尿總蛋白量>2 g)、腎病綜合征發(fā)生率。留取24 h尿液,混勻后取尿液5 mL,并測量總尿量,送檢我院檢驗科尿液分析儀檢測計算尿總蛋白。抽取清晨空腹外周血5 mL送我院檢驗科,使用全自動生化分析儀(Cobas 8000-701)檢測血漿白蛋白、血清肌酐,血液分析儀(SYSMEX XN-2000)檢測血常規(guī)。
1.4 病情變化及處理
1.4.1 根據(jù)SLEDAI積分處理? ?①狼瘡輕度活動者:觀察或據(jù)病情加大激素用量或酌情加用環(huán)孢素控制病情;②狼瘡中度活動者:增加激素用量并加用環(huán)孢素,必要時終止妊娠;③狼瘡重度活動者:增加激素用量并加用環(huán)孢素治療,必要時激素或丙種球蛋白沖擊治療,據(jù)病情終止妊娠。
1.4.2 其他并發(fā)癥處理? 妊娠期常見并發(fā)癥,如合并高血壓、妊娠期糖尿病、先兆流產(chǎn)、妊娠晚期出血、多胎妊娠、巨大胎兒、羊水量異常、胎兒的發(fā)育異常及死胎、胎兒窘迫及胎膜早破等,由產(chǎn)科醫(yī)師按診療常規(guī)處理。妊娠期若合并其他內(nèi)科及外科疾病,請相關(guān)科室會診后按診療規(guī)范積極處理。
1.5 統(tǒng)計學(xué)方法
采用SPSS 24.0統(tǒng)計學(xué)軟件處理數(shù)據(jù)。計量資料以(x±s)表示,采用t檢驗。P<0.05為差異有統(tǒng)計學(xué)意義。
2 結(jié)果
2.1 妊娠、胎兒分娩及發(fā)育情況
共23例患者妊娠29次,其中6次自然流產(chǎn),流產(chǎn)率為20.69%(6/29)。2例患者妊娠中期出現(xiàn)狼瘡活動,表現(xiàn)為腎病綜合征、肌酐升高,伴有高血壓、頭痛先兆子癇而中途終止妊娠。完成妊娠的21例患者中,3例中晚期出現(xiàn)狼瘡活動及腎病綜合征,給予增加激素劑量、加用環(huán)孢素、補(bǔ)充白蛋白及對癥治療,后病情控制,其中早產(chǎn)結(jié)束妊娠2例,無畸形及重大疾病。其余18例中早產(chǎn)2例,足月妊娠16例,胎兒均存活,無畸形及重大疾病。23例患者中成功妊娠21例,妊娠成功率為91.30%,早產(chǎn)率為19.05%(4/21),成功分娩孕齡為(37.81±1.72)周。
2.2 孕前及分娩前狼瘡活動及腎臟損害程度比較
分娩前SLEDAI積分、尿總蛋白高于孕前,血漿白蛋白低于孕前,差異有統(tǒng)計學(xué)意義(P<0.05);分娩前血清肌酐均值略低于孕前,但差異無統(tǒng)計學(xué)意義(P>0.05)。見表1。10例患者因尿總蛋白量增加>2 g,增加了激素用量或加用了環(huán)孢素治療,腎炎的復(fù)發(fā)率(尿總蛋白量>2 g)43.47%(10/23);5例患者表現(xiàn)為腎病綜合征,發(fā)生率為21.74%(5/23)。
3 討論
有研究發(fā)現(xiàn),SLE活動期患者血清中大量免疫復(fù)合物及補(bǔ)體在胎盤沉積,血管內(nèi)皮細(xì)胞受損,并激發(fā)凝血系統(tǒng)形成局部微血栓,導(dǎo)致管壁增厚,管腔狹窄,造成胎盤絨毛發(fā)育不良,影響交換功能,使胎兒供養(yǎng)減少,發(fā)生胎兒宮內(nèi)生長受限甚至胎死宮內(nèi)[5]。狼瘡性腎炎為SLE患者妊娠SLE活動進(jìn)展的獨立危險因素[6-7],薈萃分析顯示,SLE患者中狼瘡性腎炎明顯增加了不良妊娠結(jié)局和增加藥物使用的風(fēng)險[8]。狼瘡性腎炎患者的藥物治療對于妊娠減少狼瘡活動及并發(fā)癥十分重要,但需考慮對胎兒的安全性[9]。鈣神經(jīng)素拮抗劑(環(huán)孢素、他克莫司)、抗代謝藥物(硫唑嘌呤)是目前認(rèn)為是相對安全的免疫抑制劑,而核苷酸合成抑制劑(環(huán)磷酰胺、甲氨蝶呤、環(huán)孢素、來氟米特等)在妊娠患者中被列為禁忌用藥,已有臨床研究顯示該類藥物有潛在的致畸作用[10-11]。羥氯喹在SLE合并妊娠患者中的宮內(nèi)暴露效應(yīng),胎兒畸形率與普通人群無明顯差異,且SLE孕期時間更長、復(fù)發(fā)率更低,糖皮質(zhì)激素用量降低趨勢[12]。妊娠期大劑量應(yīng)用糖皮質(zhì)激素可增加子癇前期、子宮胎盤功能減退、胎膜早破及糖耐量減低和感染的風(fēng)險,同時可能導(dǎo)致新生兒腎上腺功能不全,而小劑量應(yīng)用(5~10 mg/d)相對安全。
本研究選擇狼瘡性腎炎緩解期患者且繼續(xù)服用小劑量激素和羥氯喹妊娠觀察,結(jié)果顯示胎兒的自然流產(chǎn)率為20.69%、早產(chǎn)率為19.05%及不成功妊娠率為8.70%,且無死胎及畸形等情況,低于Smyth等[13]研究報道,提示狼瘡性腎炎緩解期患者使用小劑量激素和羥氯喹治療下計劃妊娠可提高妊娠成功率和妊娠質(zhì)量。本研究結(jié)果顯示,分娩前SLEDAI積分、尿總蛋白高于孕前,血漿白蛋白低于孕前,差異有統(tǒng)計學(xué)意義(P<0.05);分娩前血清肌酐略低于孕前,但差異無統(tǒng)計學(xué)意義(P>0.05);其中10例患者因尿總蛋白量增加>2 g,增加了激素用量或加用了環(huán)孢素治療,腎炎的復(fù)發(fā)率(尿總蛋白量>2 g)43.47%,低于報道的復(fù)發(fā)率(50.7%)[1];5例患者表現(xiàn)為腎病綜合征,發(fā)生率為21.74%。雖孕后患者整體上SLEDAI積分增加至輕度活動,43.47%的患者的尿總蛋白量明顯增加,但表現(xiàn)為腎病綜合征的發(fā)生率并不高,提示小劑量激素及羥氯喹方案下妊娠,狼瘡活動及腎炎控制情況良好,為成功妊娠奠定了基礎(chǔ)。Raimbourg等[14]認(rèn)為,盡管妊娠可誘發(fā)狼瘡活動,但如果將妊娠安排在最低風(fēng)險期間且在治療前后過程進(jìn)行多學(xué)科密切監(jiān)測,妊娠一般是成功和安全的。本研究結(jié)果顯示,雖然妊娠增加狼瘡活動,但在狼瘡緩解期妊娠是可以獲得活動良好的妊娠結(jié)局,與Raimbourg等[14]觀點是一致的。
結(jié)合Bramham[15]及Naseri等[2]研究報道,狼瘡性腎炎患者妊娠時機(jī)應(yīng)為計劃妊娠,狼瘡性腎炎穩(wěn)定緩解期,且停用免疫抑制及其他可能致畸藥物至少半年,肌酐<100 μmol/L,尿蛋白<0.5 g/24 h,血壓≤140/90 mmHg。LN患者除了妊娠時機(jī)的選擇及妊娠期的維持治療外,妊娠期應(yīng)密切進(jìn)行定期產(chǎn)前檢查,觀察孕婦血壓、體重指數(shù)、宮高、腹圍的變化[16];還要定期監(jiān)測各項血生化指標(biāo)及相關(guān)免疫學(xué)指標(biāo)的動態(tài)變化,評估SLE的活動程度,及時調(diào)整治療方案。同時加強(qiáng)胎兒監(jiān)護(hù),如胎兒B超、胎兒心電圖和超聲心動圖檢查。若出現(xiàn)嚴(yán)重并發(fā)癥危及母體健康,應(yīng)及時終止妊娠。
綜上所述,緩解期狼瘡性腎炎患者維持小劑量激素和羥氯喹治療下計劃妊娠,狼瘡活動及腎炎控制情況良好,可以獲得較滿意妊娠結(jié)局。本研究也存在不足,如樣本量少、無嬰幼兒長期隨訪情況等。
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(收稿日期:2020-09-17)