妊娠前中断核苷（酸）类药物治疗对慢性乙型肝炎女性妊娠结局的影响

Effect of interruption of nucleos（t）ide analogues before pregnancy in women with chronic hepatitis B on the pregnancy outcomes

目的 探讨慢性乙型肝炎（CHB）患者妊娠前中断核苷（酸）类药物治疗对妊娠结局的影响. 方法 收集2008年11月1日至2016年11月30日在首都医科大学附属北京地坛医院生育的CHB患者的病历资料进行回顾性分析.将中断核苷（酸）类药物治疗至少1个月后妊娠者纳入观察组,妊娠期持续替比夫定治疗者纳入对照组.比较2组患者妊娠期肝病进展情况、孕产期并发症发生情况和胎儿结局,并记录替比夫定相关不良反应发生情况. 结果 纳入分析的患者共265例.观察组94例,年龄21~45岁,平均（29 ± 4）岁;对照组171例,年龄20~43岁,平均（31 ± 4）岁.首次孕检时观察组患者中HBeAg阳性、ALT异常、HBV DNA〉1×10^5IU/ml者占比和全组患者ALT中位水平均明显高于对照组[81.9%（77/94）比70.2%（120/171）,P=0.036;40.4%（38/94）比9.4%（16/171）,P〈0.001;83.0%（78/94）比3.5%（6/171）,P〈0.001;78 U/L比15 U/L,P〈0.001].妊娠期间,观察组94例患者中有26例出现肝病进展,25例入院治疗,1例发生肝衰竭致胎儿早产后死亡,1例发展为肝癌,60例在妊娠12~33周再次开始拉米夫定或替比夫定治疗.对照组171例患中仅1例因替比夫定耐药出现肝病加重而入院,改用替诺福韦酯治疗后好转.2组患者孕产期糖尿病、妊娠胆汁淤积症、中/重度贫血、妊娠期高血压等并发症发生率差异均无统计学意义（均P〉0.05）.2组患者的胎儿结局除了观察组新生儿胎龄小于对照组[（38.4 ± 1.7）周比（38.8 ± 1.2）周,t =2.352,P=0.019]外,出生缺陷发生率、新生儿出生体重和早产儿/低体重儿占比差异均无统计学意义（均P〉0.05）.2组患者中各有1例发生替比夫定相关不良反应,分别为血清CK水平升高和周围神经病.结论 接受核苷（酸）类药物治疗的CHB患者在未达到停药标准时中断治疗,妊娠期间有肝病进展的风险.未发现妊娠期应用替比夫定或拉米夫定导致孕产期并发症增加或胎儿异常.

Objective To explore the effect of interruption of nucleos（t）ide analogues before pregnancy in women with chronic hepatitis B on the pregnancy outcome. Methods The medical records of pregnant patients in Beijing Ditan Hospital,Capital Medical University from November 1st,2008 to November 30th,2016 were analyzed retrospectively. These patients had chronic hepatitis B and accepted anti-hepatitis B virus（HBV）treatment with nucleos（t）ide analogues before pregnancy. They were divided into the obser-vation group and the control group. In the observation group anti-HBV treatment was interrupted for 1 month at least before pregnancy. The control group maintained anti-HBV treatment with telbivudine till pregnancy occurred. Two groups of patients with liver disease progression,pregnant complication,fetal results,and adverse drug reactions were analyzed. Results A total of 265 patients were enrolled into the analysis. There were 94 cases in observation group aged from 21 to 45 years with average age of（29 ± 4）years. There were 171 cases in control group aged from 20 to 43 years with average age of（31 ± 4）years. The proportions of HBeAg positive,elevated alanine aminotransferase level and the proportion of cases with HBV DNA 〉1 ×105IU/ml and median level of alanine aminotransferase in the observation group in the first pregnancy examination were significantly higher than those of the control group [81.9%（77/94）vs. 70.2%（120/171）,P=0.036;40.4%（38/94）vs. 9.4%（16/171）,P〈0.001;83.0%（78/94）vs. 3.5%（6/171）,P〈0.001;78 U/L vs. 15 U/L,P〈0.001]. Twenty-six cases in the observation group had liver disease progression and 25 cases were hospitalized,and one case had liver failure which led to death of the neonate because of preterm birth,one case developed liver cancer. Sixty cases were treated again with lamivudine or telbivudine at 12-33 weeks of gestation. In the control group, only one case was hospitalized for aggravation of the liver disease caused by telbivudine resistance,and recovered after treatment with tenofovir. The difference in adverse pregnant complications including gestational diabetes mellitus,intrahepatic cholestasis of pregnancy,moderate and severe anemia and pregnancy induced hypertension in both groups were not statistically significant（all P〉0.05）. Gestational age of newborns in the observation group was different from that of the control group[（38.4 ± 1.7）weeks vs.（38.8 ± 1.2）weeks,t =2.352,P =0.019]. The proportion of birth defects,birth weight,the proportion of preterm infants or low birth weight infants in both groups were not significantly different（all P〉0.05）. One case in every group had adverse reaction related to telbivudine,they were elevated level of creatine kinase and peripheral neuropathy,respectively. Conclusions Patients with chronic hepatitis B had the risk of hepatitis B progression once they interrupted anti-HBV treatment before meeting the criteria for termination of the treatment. No evidence showed that telbivudine or lamivudine caused relevant adverse pregnant complication or inborn abnormality of infants during pregnancy.