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中华妇幼临床医学杂志(电子版)

Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition) ›› 2018, Vol. 14 ›› Issue (06): 621 -628. doi: 10.3877/cma.j.issn.1673-5250.2018.06.001

Special Issue: ；

Editorial

Effects of preventive vaccination of human papillomavirus vaccines on pregnancy outcomes

Ting Lai1, Yanping Wang1, Xiaohong Li1, Jing Tao1, Jun Zhu1,†()   

  1. 1. National Center for Birth Defects Monitoring, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
  • Received:2018-05-09 Revised:2018-09-12 Published:2018-12-01
  • Corresponding author: Jun Zhu
  • About author:
    Corresponding author: Zhu Jun, Email:
  • Supported by:
    National Key Research and Development Program of Ministry of Science and Technology(2016YFC1000102)
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Persistent high-risk human papillomavirus (HPV) infection can lead to cervical cancer. Nowadays, millions of women in childbearing age around the world have been vaccinated with preventive HPV vaccines. Studies which mainly discussed the effects of HPV vaccines on adverse pregnancy outcomes including spontaneous miscarriage, major birth defects in the latest 10 years showed that the risks of spontaneous miscarriage and major birth defects of pregnant women with preventive vaccination of HPV vaccines during pregnancy were not significantly higher than those with preventive vaccination of hepatitis A vaccination (HAV) or without vaccination of HPV vaccines (P>0.05). In this article, we review the status of preventive vaccination of HPV vaccines, and summarize the latest research progresses of the effects of preventive vaccination of HPV vaccines on pregnancy outcomes during peri-conception or pregnancy.

Key words: Human papillomavirus, Papillomavirus vaccines, Hepatitis A vaccines, Comparative study, Pregnancy outcome, Adverse reaction, Mass vaccination, Pregnant women
表1 3种人乳头瘤病毒疫苗一般特征比较
一般特征 2价疫苗 4价疫苗 9价疫苗
生产厂家 英国葛兰素史克公司 美国默沙东公司 美国默沙东公司
全球上市时间(年) 2009 2006 2014
接种3针疫苗时间(月) 0、1、6 0、2、6 0、2、6
适用人群(岁，性别) 9～25，女性 9～26，女性/男性(美国)20～45，女性(中国) 9～15，男性；9～26，女性
有效预防HPV亚型 HPV-16、-18 HPV-6、-11、-16、-18 HPV-6、-11、-16、-18、-31、-33、-45、-52、-58
宫颈癌预防率(%) 70 70 90
尖锐湿疣预防率(%) － 90 90
阴道癌/肛门癌预防率(%) － － 85～95
佐剂 ASO4：500 μg Al(OH)3、50 μg 3-氧-脱酰-4′单磷酰脂质A AAHS：225 μg非晶形羟基磷酸铝硫酸盐 AAHS：500 μg非晶形羟基磷酸铝硫酸盐
每剂容量(mL) 0.5 0.5 0.5
注射方式 肌内注射 肌内注射 肌内注射
储存温度(°C，勿冻结) 2～8 2～8 2～8
表2 13篇有关孕期意外暴露于人2价与4价人乳头瘤病毒疫苗孕妇与妊娠结局方面的最新研究文献
疫苗类型 文献作者(发表年) 研究类型/数据来源地 孕期接种HPV疫苗时的年龄 暴露组(n/n′) 对照组(n/n′) 主要不良妊娠结局
2价HPV疫苗(Cervarix?) Wacholder等[24](2010) 2项多中心、Ⅲ期临床试验(双盲随机对照试验汇总分析)/哥斯达黎加 15～25岁(PATRICIA)或18～25岁(CVT)，均为接种HPV疫苗后发现妊娠者 2 346/13 075 2 364/13 055 胎儿胎龄<20周时自然流产
? Panagiotou等[25](2015) 双盲、随机对照试验及长期随访试验/哥斯达黎加 18～25岁(妊娠90 d内接种疫苗者) 2 279/3 727 2 225/3 739、720/2 836 c 胎儿胎龄<20周时自然流产
? Baril等[26](2015) 观察性队列研究/英国 15～25岁(末次月经前30 d至末次月经后45 d内接种疫苗者) 207/839 632/839 胎儿胎龄<23周时自然流产
? Angelo等[27](2014) 42个已完成或正在进行的临床试验汇总分析/比利时及美国 超过90%为15～25岁(末次月经前60 d至早孕期内接种疫苗者) 465/27 353 449/20 504 自然流产、选择性终止妊娠术
? Lópezfauqued等[28](2017) 妊娠暴露登记，前瞻性评估/英国及美国 14～31岁(孕期和分娩前60 d接种疫苗者) 181 a － 胎儿胎龄<22周时自然流产、胎儿先天畸形
? Descamps等[29](2009) 11个临床研究汇总分析/30个国家 超过95%为15～25岁(至少接种1针HPV疫苗者) 870/16 142 867/13 811 自然流产、早产、选择性终止妊娠术
4价HPV疫苗(Gardasil?) Garland等[30](2009) 5项Ⅲ期临床试验(随机对照临床试验汇总分析)/澳大利亚 15～45岁(孕期第1天、2个月、6个月接种疫苗者) 1 796/10 126 1 824/10 425 胎儿先天畸形、自然流产
? Dana等[31](2009) 原始研究/美国 约90%为12～26岁(孕期或末次月经前1个月接种疫苗者) 517 a － 自然流产、选择性终止妊娠术
? Moro等[32](2014) 疫苗不良事件报告系统/美国 平均年龄为17岁(孕期接种疫苗者) 147 a － 自然流产、选择性终止妊娠术、分娩重大出生缺陷新生儿
? Goss等[33](2015) 疫苗上市后产前疫苗暴露登记/美国、法国及加拿大 平均年龄为20岁(孕期或末次月经前1个月接种疫苗者) 1 752 a － 胎儿死亡、自然流产、选择性终止妊娠术、分娩重大出生缺陷新生儿
? Lipkind等[34](2017) 回顾性观察队列研究/美国 13～27岁(末次月经前2周至后2周接种疫苗的单胎、活产者) 9 554 a － 早产、重大出生缺陷新生儿
? Scheller等[35](2017) 国家登记数据，匹配分析/丹麦 20～30岁(孕期接种疫苗者) 463 b 1 852 b 自然流产
? 501 2 004 死产
? 1 665 6 660 重大出生缺陷新生儿
? Sy等[36] (2018) 疫苗上市后安全监测描述性研究/美国 9～26岁(孕期或末次月经前1个月接种疫苗者) 2 678/189 269 － 胎儿先天畸形、自然流产
表4 7篇有关孕期意外暴露于4价人乳头瘤病毒疫苗孕妇的活产率、自然流产率、重大出生缺陷/先天畸形胎儿或新生儿发生率的文献回顾分析[%(n/n′)]
文献作者 已知妊娠结局例数 活产 自然流产 重大出生缺陷/先天畸形胎儿或新生儿a
Garland等[30] 2 008 72.1(1 447/2 008) 18.2(366/2 008) 1.6(33/2 008)
Dana等[31] 517 87.2(451/517) 6.6(34/517) 2.2(10/454)
Moro等[32] 147 70.1(103/147) 10.2(15/147) 1.4(2/147)
Goss等[33] 1 752 86.6(1 518/1 752) 6.3(111/1 752) 2.4(37/1 527)
Lipkind等[34] 638 85.0(542/638) － 2.0(11/542)
Scheller等[35] － － 4.3(20/463) 3.9(65/1 665)
Sy等[36] 1 740 38.2(665/1 740) － 3.6(24/665)
表3 2价人乳头瘤病毒疫苗接种与自然流产率的关系
文献作者 HPV疫苗组[%(n/n′)] HAV疫苗组[%(n/n′)] 安慰剂组或空白对照组[%(n/n′)] RR/ P值
Wacholder等[24] 11.5(197/1 708) 10.2(176/1 727) － P＝0.16
Panagiotou等[25] 13.3(451/3 394) 12.6(316/2 507) 13.6(98/720) RR＝1.02(95%CI：0.78～1.34) /P＝0.436 a
3.5(119/3 394) 2.3(58/2 507) 3.6(26/720) RR＝1.35(95%CI：1.02～1.77) /P＝0.017 b
Baril等[26] 11.6(24/207) － 9.0(57/632) RR＝1.30(95%CI：0.79～2.12) /P＝0.30
接种2针：20.7(6/29) RR＝2.55(95%CI：1.09～5.93) /P＝0.03
接种1针：10.1(18/178) RR＝1.11(95%CI：0.64～1.91) /P＝0.71
Angelo等[27] 15.3(71/465) － 11.1(50/449) RR＝1.37(95%CI：0.94～2.01)
Lópezfauqued等[28] 7.7(14/181) － － －
Descamps等[29] 9.5(79/833) 7.6(52/683) 11.8(18/152) －
合计 12.3(836/6 788) 11.1(544/4 917) 11.4(223/1 953) －
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