怀孕早期使用地屈孕酮是否与出生缺陷有关？

欧洲人类生殖与胚胎学学会（ESHRE）年会是生殖医学领域规模最大、最具影响力的年度国际学术会议之一，覆盖生殖医学领域所有专业。2023年ESHRE年会已经召开，生殖医学论坛精选了众多会议精华内容进行了翻译，希望给大家带来最新鲜、最前沿的生殖医学资讯。

本篇内容由翻译志愿者李紫檀翻译，蔡贺博士审校，供大家学习交流！

Study question

研究问题

Is dydrogesterone exposure during early pregnancy associated with the reporting of birth defects ?

怀孕早期使用地屈孕酮是否与出生缺陷的报告有关？

Summary answer

总结回答

We observed an increased reporting of birth defects, such as congenital heart defects and hypospadias, with dydrogesterone, especially compared to progesterone use.

我们发现在使用地屈孕酮时，先天性心脏缺陷和尿道下裂等出生缺陷的报告增加，尤其是在应用地屈孕酮和黄体酮相比较时。

What is known already

已知情况

In assisted reproductive technology (ART), intravaginal administration of progesterone is the standard of care to overcome luteal phase progesterone deficiency induced by ovarian stimulation. In the recent years, the Lotus I and Lotus II randomized controlled clinical trials, demonstrated that oral dydrogesterone, a synthetic progesterone derivative, was non-inferior for pregnancy rate at 12 weeks of gestation and could be an alternative to micronized vaginal progesterone (MVP). Safety profiles in both mother and child were similar. However, concerns have been raised recently regarding an association between dydrogesterone usage during early pregnancy and congenital heart disease in the offspring.

在辅助生殖技术中，阴道内孕酮给药是克服卵巢刺激引起的黄体期孕酮缺乏的标准治疗方法。近年来，Lotus I和Lotus II两项随机对照临床试验表明，合成孕酮衍生物口服地屈孕酮在孕12周时的妊娠率方面不逊于微化阴道孕酮，可作为其替代选择。在母体和子代安全性方面也无差异。然而，最近有人担心怀孕早期使用地屈孕酮与子代先天性心脏病之间有关联。

Study design, size, duration

研究设计、规模、持续时间

We performed a case-non case study, similar in the concept to case-control study, using the international pharmacoviligance database, VigiBase. Study cohort consisted in spontaneous reports regarding pregnant women identified using the ad-hoc standardized query (SMQ “Pregnancy and neonatal topics”). Birth defect cases were reports containing a term related to “congenital, familial and genetic disorders” System Organ Classes (SOCs) (excluding genetic, infectious and metabolic abnormalities). Non-cases were reports of any other adverse drug reaction.

我们使用国际药物活力数据库中的药物不良反应数据库进行了一项病例-非病例研究，其概念类似于病例-对照研究。研究队列是基于自发报告的孕妇相关数据组成的，通过使用专门的标准查询（“妊娠和新生儿主题”的标准化医药监管活动用医学字典查询）来确定。出生缺陷病历是指包含与“先天性、家族性和遗传性疾病”系统器官类别（不包括遗传、感染和代谢异常）相关的术语的报告。非病例是指任何其他药物不良反应的报告。

Participants/materials, setting, methods

受试者/材料、环境、方法

Through a case–non case study conducted since database inception to 12/31/2021, we first compared the reporting of birth defects with dydrogesterone to that of any other drug, then to any other drug used for ART. Secondly, we performed a comparison on the reporting of birth defects for dydrogesterone with progesterone. Results are presented as reporting odds ratio (ROR) and their 95% confidence interval (95%CI). For each comparison, two sensitivity analyses were performed.

通过从数据库建立到2021年12月31日进行的病例-非案例研究，我们首先比较了地屈孕酮与其他任何药物之间的出生缺陷报告情况，然后与用于辅助生殖技术的其他任何药物进行了比较。其次，我们对地屈孕酮和孕酮的出生缺陷报告进行了比较。结果以报告比值比及其95%置信区间的形式呈现。每次比较都进行了两项敏感性分析。

Main results and the role of chance

主要结果及机会因素的作用

Among 29,120,563 individual case safety reports, 50,653 were related to the use of drugs for ART. Of these, 375 were cases of birth defects, including 60 (16%) with dydrogesterone. Dydrogesterone cases were mostly reported from Europe (73%) by physicians (82%). No other teratogenic drug was suspected in the onset of birth defect for dydrogesterone. 44 cases out of 60 (73.3%) were compatible with major birth defect (MBD) cases according to EUROCAT classification. These cases contained a total of 55 MBD, consisting mainly in genital defects such as hypospadias (n = 18, 32.7%), congenital heart defects (n =15, 27.3%) limb defects (n= 10, 18.2%) and digestive system defects (n =6, 10.9%). In the primary analysis, a significant disproportionate reporting of birth defects was found with dydrogesterone when compared to any other drug (ROR 5.4, 95%CI [3.9-7.6]) and to any other ART agent (ROR 5.9, 95%CI [4.2-8.4]). In the head-to-head comparison to progesterone, we found an increased reporting of birth defect with dydrogesterone (ROR 5.4, 95%CI [3.7- 7.9]).These results were confirmed in both sensitivity analyses.

在29120563份个体病例安全报告中，50653份与辅助生殖技术中的药物使用有关。其中，375例是出生缺陷病例，其中60例（16%）与地屈孕酮有关。大部分地屈孕酮病例来自欧洲（73%），由医生（82%）提供。在地屈孕酮引发的出生缺陷的发病中，没有发现同时使用其他可能的致畸性药物。根据欧洲先天畸形监测与信息系统分类，60例病例中有44例（73.3%）与重大先天畸形病历相符。这些病例中共包含55例重大先天畸形，主要是生殖器缺陷，如尿道下裂（n=18, 32.7%）、先天性心脏缺陷（n=15, 27.3%）、肢体缺陷（n=10, 18.2%）和消化系统缺陷（n=6, 10.9%）。在初步分析中，地屈孕酮与其他任何药物相比，出生缺陷比例升高（报告比值比为5.4，95%置信区间为[3.9-7.6]），，同时地屈孕酮与其他辅助生殖技术药物相比也是如此（报告比值比为5.9，95%置信区间为[4.2-8.4]）。我们发现地屈孕酮引发的出生缺陷报告有所增加（相对报告比为5.4，95%置信区间为[3.7-7.9]）。这些结果在两项敏感性分析中都得到了证实。

Limitations, reasons for caution

局限性与注意事项

First, under-reporting, being inherent to pharmacovigilance systems, impedes the measurement of the incidence of adverse drug reaction and can limit the sensitivity of signal detection. Second, drug causality, not being the same for all cases, is challenging for such events and requires further assessment. However, sensitivity analyses showed consistent results.

首先，由于药物监测系统的固有特性，漏报可能会影响对药物不良反应发生率的监测，并可能限制检测的灵敏度。其次，并非所有病例的药物因果关系都相同，这对此类事件具有挑战性，其药物因果关系需要进一步评估。然而，敏感性分析显示了一致的结果。

Wider implications of the findings

研究结果的更广泛影响

Physicians should be aware of this potential risk and caution should be used when prescribing dydrogesterone for luteal phase support. Further data are needed to confirm that safety signal.

医生应意识到这种潜在风险，在开具地屈孕酮用于黄体期支持时应保持谨慎。对该药物的安全性尚需要获得进一步的数据。

文章来源：

A Henry, P Santulli, M Bourdon, J M Treluyer, L Chouchana, O-150 Birth defects reporting and the use of oral dydrogesterone in assisted reproductive technology : a global pharmacovigilance study, Human Reproduction, Volume 38, Issue Supplement_1, June 2023, dead093.177, https://doi.org/10.1093/humrep/dead093.177