羟氯喹在改善胎盘源性妊娠并发症中的应用及研究进展

doi:10.12280/gjfckx.20200867

摘要/Abstract

摘要：

羟氯喹（hydroxychloroquine,HCQ）是一种传统抗疟药,主要具有抑制细胞自噬的作用,因其母胎安全性,可用于计划妊娠的自身免疫性疾病患者,并被推荐孕前、孕期持续应用。近年来HCQ在妊娠中的应用愈发受到重视,由于其免疫调节和内皮保护作用,在自身免疫性疾病（如系统性红斑狼疮、抗磷脂综合征）合并妊娠的患者中有明确获益,但非自身免疫性疾病患者是否能够普遍受益仍不清楚。HCQ具有抗炎、调节免疫、抗凝、抗血栓、抗氧化和内皮保护作用,能够从多方面、多层次调节妊娠免疫,现就其在妊娠期应用以及改善胎盘源性妊娠并发症的机制和研究进展进行综述。

关键词: 羟氯喹, 妊娠, 免疫活性, 胎盘, 妊娠并发症, 妊娠结局, 流产,习惯性

Abstract:

Hydroxychloroquine (HCQ) is a widely used antimalarial drug that inhibits cellular autophagy. HCQ can be used in women with rheumatic diseases who planning pregnancy and is recommended for continued use during pregnancy. In recent years, the use of HCQ in pregnancy has received increasing attention due to its immunomodulatory and endothelial protection effects in autoimmune diseases. There is a clear benefit in pregnant patients with autoimmune diseases, such as systemic lupus erythematosus and antiphospholipid syndrome, but it remains unclear whether there is a general benefit for patients without autoimmune diseases. HCQ has anti-inflammatory, immune regulation, anticoagulant, antithrombotic, antioxidant and endothelial protection effects. The modulation of immunity in pregnancy can be multifaceted, multi-level. This paper discusses the mechanisms and advances in the use of HCQ in pregnancy and the improvement of placenta-derived pregnancy complications.

Key words: Hydroxychloroquine, Pregnancy, Immunocompetence, Placenta, Pregnancy complications, Pregnancy outcome, Abortion,habitual

李佳钋, 陈炳南, 张立阳, 李凡, 富月, 乔宠. 羟氯喹在改善胎盘源性妊娠并发症中的应用及研究进展[J]. 国际妇产科学杂志, 2021, 48(3): 241-246.

LI Jia-po, CHEN Bing-nan, ZHANG Li-yang, LI Fan, FU Yue, QIAO Chong. Advances in Research on Hydroxychloroquine in the Improvement of Placenta-Mediated Pregnancy Complication[J]. Journal of International Obstetrics and Gynecology, 2021, 48(3): 241-246.

参考文献 48

[1]	曾婵娟, 张卫社, 裴琛琳. 内分泌性血管内皮生长因子与胎盘源性妊娠并发症[J]. 中华围产医学杂志, 2019,22(10):735-739. doi: 10.3760/cma.j.issn.1007-9408.2019.10.009. doi: 10.3760/cma.j.issn.1007-9408.2019.10.009
[2]	Flint J, Panchal S, Hurrell A, et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding-Part I: standard and biologic disease modifying anti-rheumatic drugs and corticosteroids[J]. Rheumatology (Oxford), 2016,55(9):1693-1697. doi: 10.1093/rheumatology/kev404. doi: 10.1093/rheumatology/kev404
[3]	de Moreuil C, Alavi Z, Pasquier E. Hydroxychloroquine may be beneficial in preeclampsia and recurrent miscarriage[J]. Br J Clin Pharmacol, 2020,86(1):39-49. doi: 10.1111/bcp.14131. doi: 10.1111/bcp.14131 pmid: 31633823
[4]	Ponticelli C, Moroni G. Hydroxychloroquine in systemic lupus erythematosus (SLE)[J]. Expert Opin Drug Saf, 2017,16(3):411-419. doi: 10.1080/14740338.2017.1269168. doi: 10.1080/14740338.2017.1269168 pmid: 27927040
[5]	Balevic SJ, Green TP, Clowse M, et al. Pharmacokinetics of Hydroxychloroquine in Pregnancies with Rheumatic Diseases[J]. Clin Pharmacokinet, 2019,58(4):525-533. doi: 10.1007/s40262-018-0712-z. doi: 10.1007/s40262-018-0712-z
[6]	管桂雪, 颜磊. 免疫-凝血相关性复发性流产治疗进展[J]. 国际生殖健康/计划生育杂志, 2018,37(2):145-149. doi: 10.3969/j.issn.1674-1889.2018.02.014. doi: 10.3969/j.issn.1674-1889.2018.02.014
[7]	Scott RE, Greenwood SL, Hayes D, et al. Effects of hydroxychloroquine on the human placenta-Findings from in vitro experimental data and a systematic review[J]. Reprod Toxicol, 2019,87:50-59. doi: 10.1016/j.reprotox.2019.05.056. doi: 10.1016/j.reprotox.2019.05.056
[8]	Costedoat-Chalumeau N, Dunogué B, Morel N, et al. Hydroxychloroquine: a multifaceted treatment in lupus[J]. Presse Med, 2014,43(6 Pt 2):e167-180. doi: 10.1016/j.lpm.2014.03.007. doi: 10.1016/j.lpm.2014.03.007
[9]	Bertolaccini ML, Contento G, Lennen R, et al. Complement inhibition by hydroxychloroquine prevents placental and fetal brain abnormalities in antiphospholipid syndrome[J]. J Autoimmun, 2016,75:30-38. doi: 10.1016/j.jaut.2016.04.008. doi: 10.1016/j.jaut.2016.04.008
[10]	Xourgia E, Tektonidou MG. Type I interferon gene expression in antiphospholipid syndrome: Pathogenetic, clinical and therapeutic implications[J]. J Autoimmun, 2019,104:102311. doi: 10.1016/j.jaut. 2019.102311. doi: 10.1016/j.jaut. 2019.102311
[11]	Lisney AR, Szelinski F, Reiter K, et al. High maternal expression of SIGLEC1 on monocytes as a surrogate marker of a type I interferon signature is a risk factor for the development of autoimmune congenital heart block[J]. Ann Rheum Dis, 2017,76(8):1476-1480. doi: 10.1136/annrheumdis-2016-210927. doi: 10.1136/annrheumdis-2016-210927
[12]	Ghasemnejad-Berenji H, Ghaffari Novin M, Hajshafiha M, et al. Immunomodulatory effects of hydroxychloroquine on Th1/Th2 balance in women with repeated implantation failure[J]. Biomed Pharmacother, 2018,107:1277-1285. doi: 10.1016/j.biopha.2018. 08.027. doi: 10.1016/j.biopha.2018. 08.027
[13]	Tektonidou MG, Laskari K, Panagiotakos DB, et al. Risk factors for thrombosis and primary thrombosis prevention in patients with systemic lupus erythematosus with or without antiphospholipid antibodies[J]. Arthritis Rheum, 2009,61(1):29-36. doi: 10.1002/art.24232. doi: 10.1002/art.24232
[14]	Schreiber K, Breen K, Parmar K, et al. The effect of hydroxychloroquine on haemostasis, complement, inflammation and angiogenesis in patients with antiphospholipid antibodies[J]. Rheumatology (Oxford), 2018,57(1):120-124. doi: 10.1093/rheumatology/kex378. doi: 10.1093/rheumatology/kex378 pmid: 29045759
[15]	Rand JH, Wu XX, Quinn AS, et al. Hydroxychloroquine directly reduces the binding of antiphospholipid antibody-beta2-glycoprotein I complexes to phospholipid bilayers[J]. Blood, 2008,112(5):1687-1695. doi: 10.1182/blood-2008-03-144204. doi: 10.1182/blood-2008-03-144204
[16]	陈晓辉, 崔丽艳. 抗磷脂抗体谱与病理妊娠[J]. 中华检验医学杂志, 2018,41(12):922-927. doi: 10.3760/cma.j.issn.1009-9158. 2018.12.006. doi: 10.3760/cma.j.issn.1009-9158. 2018.12.006
[17]	Rahman R, Murthi P, Singh H, et al. The effects of hydroxychloroquine on endothelial dysfunction[J]. Pregnancy Hypertens, 2016,6(4):259-262. doi: 10.1016/j.preghy.2016.09.001. doi: 10.1016/j.preghy.2016.09.001
[18]	Rezabakhsh A, Montazersaheb S, Nabat E, et al. Effect of hydroxychloroquine on oxidative/nitrosative status and angiogenesis in endothelial cells under high glucose condition[J]. Bioimpacts, 2017,7(4):219-226. doi: 10.15171/bi.2017.26. doi: 10.15171/bi.2017.26 pmid: 29435429
[19]	Müller-Calleja N, Manukyan D, Canisius A, et al. Hydroxychloroquine inhibits proinflammatory signalling pathways by targeting endosomal NADPH oxidase[J]. Ann Rheum Dis, 2017,76(5):891-897. doi: 10.1136/annrheumdis-2016-210012. doi: 10.1136/annrheumdis-2016-210012
[20]	Rahman RA, Murthi P, Singh H, et al. Hydroxychloroquine Mitigates the Production of 8-Isoprostane and Improves Vascular Dysfunction: Implications for Treating Preeclampsia[J]. Int J Mol Sci, 2020,21(7):2504. doi: 10.3390/ijms21072504. doi: 10.3390/ijms21072504
[21]	Virdis A, Tani C, Duranti E, et al. Early treatment with hydroxychloroquine prevents the development of endothelial dysfunction in a murine model of systemic lupus erythematosus[J]. Arthritis Res Ther, 2015,17:277. doi: 10.1186/s13075-015-0790-3. doi: 10.1186/s13075-015-0790-3
[22]	Urbanski G, Caillon A, Poli C, et al. Hydroxychloroquine partially prevents endothelial dysfunction induced by anti-beta-2-GPI antibodies in an in vivo mouse model of antiphospholipid syndrome[J]. PLoS One, 2018,13(11):e0206814. doi: 10.1371/journal.pone.0206814. doi: 10.1371/journal.pone.0206814
[23]	Albert CR, Schlesinger WJ, Viall CA, et al. Effect of hydroxychloroquine on antiphospholipid antibody-induced changes in first trimester trophoblast function[J]. Am J Reprod Immunol, 2014,71(2):154-164. doi: 10.1111/aji.12184. doi: 10.1111/aji.12184
[24]	Wu XX, Guller S, Rand JH. Hydroxychloroquine reduces binding of antiphospholipid antibodies to syncytiotrophoblasts and restores annexin A5 expression[J]. Am J Obstet Gynecol, 2011,205(6):576.e7-e14. doi: 10.1016/j.ajog.2011.06.064. doi: 10.1016/j.ajog.2011.06.064
[25]	Eudy AM, Siega-Riz AM, Engel SM, et al. Effect of pregnancy on disease flares in patients with systemic lupus erythematosus[J]. Ann Rheum Dis, 2018,77(6):855-860. doi: 10.1136/annrheumdis-2017-212535. doi: 10.1136/annrheumdis-2017-212535
[26]	Levy RA, Vilela VS, Cataldo MJ, et al. Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-controlled study[J]. Lupus, 2001,10(6):401-404. doi: 10.1191/096120301678646137. doi: 10.1191/096120301678646137 pmid: 11434574
[27]	Balevic SJ, Cohen-Wolkowiez M, Eudy AM, et al. Hydroxychloroquine Levels throughout Pregnancies Complicated by Rheumatic Disease: Implications for Maternal and Neonatal Outcomes[J]. J Rheumatol, 2019,46(1):57-63. doi: 10.3899/jrheum. 180158. doi: 10.3899/jrheum. 180158
[28]	Schreiber K, Sciascia S, de Groot PG, et al. Antiphospholipid syndrome[J]. Nat Rev Dis Primers, 2018,4:17103. doi: 10.1038/nrdp.2017.103. doi: 10.1038/nrdp.2017.103 pmid: 29321641
[29]	Zhou Z, Teng J, Sun Y, et al. Characteristics of pregnancy complications and treatment in obstetric antiphospholipid syndrome in China[J]. Clin Rheumatol, 2019,38(11):3161-3168. doi: 10.1007/s10067-019-04670-7. doi: 10.1007/s10067-019-04670-7
[30]	Mekinian A, Vicaut E, Cohen J, et al. Hydroxychloroquine to obtain pregnancy without adverse obstetrical events in primary antiphospholipid syndrome: French phase II multicenter randomized trial, HYDROSAPL[J]. Gynecol Obstet Fertil Senol, 2018,46(7/8):598-604. doi: 10.1016/j.gofs.2018.06.008. doi: 10.1016/j.gofs.2018.06.008
[31]	Tektonidou MG, Andreoli L, Limper M, et al. EULAR recommendations for the management of antiphospholipid syndrome in adults[J]. Ann Rheum Dis, 2019,78(10):1296-1304. doi: 10.1136/annrheumdis-2019-215213. doi: 10.1136/annrheumdis-2019-215213
[32]	Ruffatti A, Tonello M, Hoxha A, et al. Effect of Additional Treatments Combined with Conventional Therapies in Pregnant Patients with High-Risk Antiphospholipid Syndrome: A Multicentre Study[J]. Thromb Haemost, 2018,118(4):639-646. doi: 10.1055/s-0038-1632388. doi: 10.1055/s-0038-1632388
[33]	Mekinian A, Lazzaroni MG, Kuzenko A, et al. The efficacy of hydroxychloroquine for obstetrical outcome in anti-phospholipid syndrome: Data from a European multicenter retrospective study[J]. Autoimmun Rev, 2015,14(6):498-502. doi: 10.1016/j.autrev.2015. 01.012. doi: 10.1016/j.autrev.2015.01.012 pmid: 25617818
[34]	Sciascia S, Hunt BJ, Talavera-Garcia E, et al. The impact of hydroxychloroquine treatment on pregnancy outcome in women with antiphospholipid antibodies[J]. Am J Obstet Gynecol, 2016,214(2):273.e1-e8. doi: 10.1016/j.ajog.2015.09.078. doi: 10.1016/j.ajog.2015.09.078
[35]	Izmirly PM, Costedoat-Chalumeau N, Pisoni CN, et al. Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSA/Ro-antibody-associated cardiac manifestations of neonatal lupus[J]. Circulation, 2012,126(1):76-82. doi: 10.1161/CIRCULATIONAHA.111.089268. doi: 10.1161/CIRCULATIONAHA.111.089268 pmid: 22626746
[36]	Carvalho JS. Fetal dysrhythmias[J]. Best Pract Res Clin Obstet Gynaecol, 2019,58:28-41.doi: 10.1016/j.bpobgyn.2019.01.002. doi: S1521-6934(18)30262-1 pmid: 30738635
[37]	Friedman D, Lovig L, Halushka M, et al. No histologic evidence of foetal cardiotoxicity following exposure to maternal hydroxychloroquine[J]. Clin Exp Rheumatol, 2017,35(5):857-859. pmid: 28598777
[38]	Izmirly P, Kim M, Friedman DM, et al. Hydroxychloroquine to Prevent Recurrent Congenital Heart Block in Fetuses of Anti-SSA/Ro-Positive Mothers[J]. J Am Coll Cardiol, 2020,76(3):292-302. doi: 10.1016/j.jacc.2020.05.045. doi: 10.1016/j.jacc.2020.05.045
[39]	Placais L, Carrat F, Carbillon L, et al. Obstetrical morbidity related to anti-SSA antibodies: Data from a French monocentric retrospective study[J]. Joint Bone Spine, 2019,86(4):523-524. doi: 10.1016/j.jbspin.2018.11.005. doi: S1297-319X(18)30428-7 pmid: 30528679
[40]	Do SC, Rizk NM, Druzin ML, et al. Does Hydroxychloroquine Protect against Preeclampsia and Preterm Delivery in Systemic Lupus Erythematosus Pregnancies?[J]. Am J Perinatol, 2020,37(9):873-880. doi: 10.1055/s-0039-3402752. doi: 10.1055/s-0039-3402752
[41]	Seo MR, Chae J, Kim YM, et al. Hydroxychloroquine treatment during pregnancy in lupus patients is associated with lower risk of preeclampsia[J]. Lupus, 2019,28(6):722-730. doi: 10.1177/0961203319843343. doi: 10.1177/0961203319843343 pmid: 30971164
[42]	Moroni G, Doria A, Giglio E, et al. Fetal outcome and recommendations of pregnancies in lupus nephritis in the 21st century. A prospective multicenter study[J]. J Autoimmun, 2016,74:6-12. doi: 10.1016/j.jaut.2016.07.010. doi: 10.1016/j.jaut.2016.07.010
[43]	Guillotin V, Bouhet A, Barnetche T, et al. Hydroxychloroquine for the prevention of fetal growth restriction and prematurity in lupus pregnancy: A systematic review and meta-analysis[J]. Joint Bone Spine, 2018,85(6):663-668. doi: 10.1016/j.jbspin.2018.03.006. doi: S1297-319X(18)30049-6 pmid: 29631068
[44]	Mekinian A, Cohen J, Alijotas-Reig J, et al. Unexplained Recurrent Miscarriage and Recurrent Implantation Failure: Is There a Place for Immunomodulation?[J]. Am J Reprod Immunol, 2016,76(1):8-28. doi: 10.1111/aji.12493. doi: 10.1111/aji.12493
[45]	Costedoat-Chalumeau N, Amoura Z, Aymard G, et al. Evidence of transplacental passage of hydroxychloroquine in humans[J]. Arthritis Rheum, 2002,46(4):1123-1124. doi: 10.1002/art.10150. doi: 10.1002/art.10150
[46]	Gaffar R, Pineau CA, Bernatsky S, et al. Risk of Ocular Anomalies in Children Exposed In Utero to Antimalarials: A Systematic Literature Review[J]. Arthritis Care Res (Hoboken), 2019,71(12):1606-1610. doi: 10.1002/acr.23808. doi: 10.1002/acr.23808 pmid: 30418703
[47]	Kaplan YC, Ozsarfati J, Nickel C, et al. Reproductive outcomes following hydroxychloroquine use for autoimmune diseases: a systematic review and meta-analysis[J]. Br J Clin Pharmacol, 2016,81(5):835-848. doi: 10.1111/bcp.12872. doi: 10.1111/bcp.12872 pmid: 26700396
[48]	Sciascia S, Branch DW, Levy RA, et al. The efficacy of hydroxychloroquine in altering pregnancy outcome in women with antiphospholipid antibodies. Evidence and clinical judgment[J]. Thromb Haemost, 2016,115(2):285-290. doi: 10.1160/TH15-06-0491. doi: 10.1160/TH15-06-0491