后代中运动发育迟缓与产前替比夫定暴露有关

StephenW

Medicine (Baltimore). 2018 Mar;97(9):e0053. doi: 10.1097/MD.0000000000010053.
Motor development delay in offspring is associated with prenatal telbivudine exposure.Zhou C1,2,3, Yu Y1, Yang Q4,3, Wang H4,3, Hou M4,3, Jin L4,3, Zhang F1, Sheng J5, Miao M1, Yang X1, Huang HF1,4,2,3.
Author information
1Woman's Hospital, School of Medicine, Zhejiang University.2Key Laboratory of Reproductive Genetics, Ministry of Education.3Institute of Embryo-Fetal Original Adult Disease, School of Medicine, Shanghai Jiao Tong University, China.4International Peace Maternal and Child Health Hospital, Shanghai Jiao Tong University.5Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University.

AbstractTelbivudine is an orally nucleoside analog with potent and specific antihepatitis B virus (HBV) activity, and it has been reported to block mother-to-infant transmission. However, few studies have focused on the safety of prenatal exposure for offspring development.This is a prospective noninterventional study. Participants were enrolled during delivery through the Women's Hospital of Zhejiang University School of Medicine between January 2012 and September 2013. Neonate's umbilical cord arterial blood (UCAB) was collected after delivery. Hepatitis B virus DNA copy, HBV serology, alanine aminotransferase (ALT), creatine kinase (CK), creatinine (CRE), and blood urea nitrogen (BUN) were measured. The development of the offspring was evaluated by the Chinese Revision of Bayley Scales of Child Development (BSCD-CR) at 12 to 24 months old.Around 30 and 31 chronic hepatitis B mothers were recruited in untreated group (non-LdT group) and telbivudine-treatment group (LdT group), respectively, and 2 children (one in non-LdT group and 1 in LdT group) were lost in follow-up. Sixty-one normal women and their children were recruited as a normal control (control group). Compared with non-LdT group, telbivudine treatment effectively blocks HBV transmission from mother to infant. However, CK in UCAB was significantly increased in the LdT group. Moreover, children with prenatal telbivudine exposure showed lower level of serum creatinine than non-LdT group, reduction of psychomotor developmental index and increased risk of motor development delay.Prenatal telbivudine exposure is correlated with motor development delay in offspring.


PMID:29489662DOI:10.1097/MD.0000000000010053

StephenW

医学（巴尔的摩）。 2018年3月; 97（9）：e0053。 doi：10.1097 / MD.0000000000010053。
后代中运动发育迟缓与产前替比夫定暴露有关。
周C1,2,3，余Y1，杨Q4,3，王H4,3，侯M4,3，金L4,3，张F1，盛J5，苗M1，杨X1，黄HF1,4,2,3 。
作者信息

1
    浙江大学医学院女子医院。
2
    教育部生殖遗传重点实验室。
3
    上海交通大学医学院胚胎 - 胎儿原始成人疾病研究所，中国。
4
    上海交通大学国际和平妇幼保健院。
五
    浙江大学医学院病理与病理生理学系。

抽象

替比夫定是口服核苷类似物，具有强效和特异性的抗乙型肝炎病毒（HBV）活性，据报道可阻止母婴传播。然而，很少有研究关注产前暴露对后代发育的安全性。这是一项前瞻性非介入性研究。参加者于2012年1月至2013年9月期间通过浙江大学医学院妇产医院分娩。分娩后收集新生儿的脐带动脉血（UCAB）。测量乙型肝炎病毒DNA拷贝，HBV血清学，丙氨酸氨基转移酶（ALT），肌酸激酶（CK），肌酸酐（CRE）和血尿素氮（BUN）。在12至24个月大时，通过中国修订的Bayley儿童发育量表（BSCD-CR）评估后代的发育。在未治疗组（非LdT组）和替比夫定组中招募了约30和31名慢性乙型肝炎母亲治疗组（LdT组），2例患儿（非LdT组1例，LdT组1例）随访失访。 61名正常妇女及其子女被招募为正常对照组（对照组）。与非LdT组相比，替比夫定治疗有效阻断HBV从母婴传播到婴儿。然而，UCAB中的CK在LdT组中显着增加。此外，产前替比夫定暴露的儿童血清肌酐水平低于非LdT组，降低了精神运动发育指数，增加了运动发育迟缓的风险。产前替比夫定暴露与后代运动发育迟缓相关。

结论：
    29489662
DOI：
    10.1097 / MD.0000000000010053

StephenW

https://journals.lww.com/md-jour ... _associated.23.aspx

StephenW

回复 brad2309 的帖子

我不是这方面的专家，对此知之甚少. 我只想说说有关该研究的更多细节.

"替比夫定是2006年，被美国食品和药物管理局分配给妊娠类别B; 因此，它可以在怀孕期间使用。"
"LdT治疗即使在高病毒载量下也能显示阻断MTCT(垂直传输)的有效性，无论是在妊娠晚期开始，还是在整个妊娠期开始。[9-12]此外，一些CHB妇女在抗病毒治疗过程中可能会怀孕."

"The Chinese Revision of the Bayley Scales of Child Development (BSCD-CR) was used to evaluate motor and mental development. The test is a revision of Bayley Scales of Child Development-Second Edition (BSCD-II) and provides 2 subscales, a motor scale providing a psychomotor developmental index (PDI) and a mental scale yielding a mental developmental index (MDI). The mean score (± standard deviation) for both indexes for a normal population is 100 ± 15, and a score of less than 85 indicates developmental delay.[16]
中国修订的贝利儿童发展量表（BSCD-CR）被用于评估运动和智力发育。 该测试是对贝利儿童发育量表第二版（BSCD-II）的修订，并提供2个分量表，一个提供心理运动发育指数（PDI）的运动量表和一个产生心智发育指数（MDI）的心理量表。 正常人群的两项指标的平均得分（±标准差）为100±15，小于85的得分表示发育迟缓[16]。"

Our results showed that prenatal LdT exposure group showed increased CK in fetal UCAB, reduced serum Cre, PDI score and thus appears to increase the risk of delayed motor development.
我们的结果显示，产前LdT暴露组显示胎儿UCAB中CK增加，血清Cre，PDI评分降低，因此似乎增加了延迟运动发育的风险。

There are limitations in the present study. Some parental information was not obtained, such as social class, income and smoking history, which could be confounding factors in this study. In addition, children in 12 to 24 months old were in the rapid development stage and the follow-up period was too short to document long-term motor development disorders. As mentioned above, long-term follow-up with more samples is necessary to validate our findings.
目前的研究存在局限性。 没有获得一些父母的信息，如社会阶层，收入和吸烟史，这可能是本研究中混杂因素。 此外，12至24个月大的儿童处于快速发展阶段，随访时间太短，无法记录长期运动发育障碍。 如上所述，需要更多样本的长期随访来验证我们的发现。

希望这可以帮助你.

一个额外的个人观察:
许多研究表明替比夫定可以改善肾功能. 这与血清肌酐降低有关吗？这是替比夫定一个副作用或发育迟缓？

StephenW

回复 brad2309 的帖子

1. 疫苗和HBIG注射不能100％消除母播到儿童hbv感染, 特别是在HBeAg阳性和高病毒载量的母亲中. 经过多次临床研究，所有指南现在推荐病毒载量高的母亲在怀孕第三期接受替诺福韦或替比夫定治疗.就是高病毒载量的母亲孕期应该吃替比或替诺提高阻断率.
母亲孕期服药导致发育迟缓没有被显示, 上述研究是第一个替比夫定与发育迟缓可能有关的研究.

问题应该是确切的.

为什么高病毒载量的母亲孕期应该吃替比或替诺提高阻断率? 吃替比或替诺可以显着降低出生时母亲的病毒载量, 因此可以提高阻断率.

2.替比是说也有一定肾毒性吗？相反, 临床研究表明替比可以改善肾脏功能.

3.暴露组 - 治疗组 - 30名乙型肝炎母亲治疗组（LdT组）
                               31名乙型肝炎母亲未治疗组 (非LdT组)
                               61名正常妇女(对照组）

StephenW

回复 brad2309 的帖子

你不懂，我也不懂. 只能依靠医生和研究文献.

1.大三阳携带者孕期抗病毒是为了降低宫内感染吗，宫内感染概率高吗？是和不是.
有三种可能的传播途径：宫内传播HBV（子宫内传播），(产时传播）和产后传播期间的护理或通过母乳（产后传播）.
2.1. Intrauterine transmission

Intrauterine transmission of HBV is considered to be the most important reason for the failure of passive-active immunoprophylaxis in preventing MTCT [7,9]. Different diagnostic criteria [12–20] had been applied for the diagnosis of HBV intrauterine infection. Since there is no consensus on the diagnosis criteria of HBV intrauterine infection, different proofs that could identify the existence of HBV components in serum of newborns had been used (Table 1). The exact mechanism of intrauterine transmission of HBV remains to be illuminated. The most frequently mentioned hypotheses involve: (a) serum/body fluid transmission, which usually occurs in conditions of placenta damage caused by contraction of the uterine muscle such as threatened abortion [21], invasive procedures into the uterus like amniocentesis during pregnancy [22] or specific infections like TORCH (Toxoplasma, Rubella, Cytomegalovirus and Herpes Simplex) infection; (b) cellular transmission, which refers to transmission of HBV from the maternal side to the fetal side through placenta cells and transfer of infected peripheral blood mononuclear cell (PBMC) [15] from the maternal circulation system into the fetal circulation system; and (c) genetic transmission, germ cells like sperm and oocytes could be infected by HBV and transferred the virus to the embryo [23,24].
2.1。宫内传播

HBV宫内传播被认为是被动免疫预防预防MTCT失败的最重要原因[7,9]。不同的诊断标准[12-20]已应用于HBV宫内感染的诊断。由于对乙型肝炎病毒宫内感染的诊断标准尚未达成共识，因此已经使用了不同的证据来确定新生儿血清中HBV成分的存在（表1）。宫内传播HBV的确切机制仍有待阐明。最经常提及的假设包括：（a）血清/体液传播，通常发生在子宫肌肉收缩导致的胎盘损伤的情况下，如先兆流产[21]，怀孕期间羊水穿刺入侵子宫等[22] ]或TORCH（弓形虫，风疹，巨细胞病毒和单纯疱疹）感染等特定感染; （b）细胞传播，即通过胎盘细胞将HBV从母体一侧传递到胎儿一侧，并将受感染的外周血单核细胞（PBMC）[15]从母体循环系统转移到胎儿循环系统中;和（c）遗传传播，生殖细胞如精子和卵母细胞可能被HBV感染并将病毒转移到胚胎[23,24]。

Accumulated proofs have identified that high serum HBV DNA levels and HBeAg positive status in pregnant mothers are key factors for indicating the increased risk of MTCT of HBV, especially in intrauterine transmission of HBV through villous capillary endothelial cells [25–27]. Wiseman et al. [28] have shown a transmission rate of 9% for newborns born from mothers with virus load > 8 log10 copies/ml (7.3 log10 IU/ml) despite standard passive-active immunoprophylaxis administration and no transmission below this cut-off. Recent studies even proposed a lower level of 6 log10 copies/ml (5.3 log10 IU/ml) of maternal viremia as the cut-off [29,30] and the reported rate [15,31] of MTCT of HBV to newborns ranged from 8% to nearly 30% if maternal HBV DNA levels are higher than 6 log10 copies/ml (5.3 log10 IU/ml).
已有证据表明孕妇高血清HBV DNA水平和HBeAg阳性状态是指示HBV MTCT风险增加的关键因素，尤其是通过绒毛毛细血管内皮细胞发生HBV的宫内传播[25-27]。 Wiseman等人 [28]尽管采用标准的被动主动免疫预防给药，但病毒载量> 8log10拷贝/ ml（7.3log10IU / ml）的母亲新生儿的传播率为9％，并且在该截止值以下没有传播。 最近的研究甚至提出较低的6 log10拷贝/ ml（5.3 log10 IU / ml）为HBV的MTCT对新生儿的截止[29,30]. 如果母亲HBV DNA水平高于6log10拷贝/ ml（5.3log10IU / ml），HBV MTCT报告给新生儿的比例[15,31]介于8％至近30％.