PDF(Pubmed)
Abstract：
OBJECTIVE: Is exposure to dydrogesterone a risk factor for congenital anomalies when given in the first trimester for recurrent/threatened pregnancy loss or as luteal support in assisted reproductive technology (ART)?
CONCLUSIONS: Dydrogesterone, when given in the first trimester for recurrent/threatened pregnancy loss or as luteal support in ART, is not a relevant additional risk factor for congenital anomalies.
BACKGROUND: Despite large clinical trials and meta-analyses that show no association between dydrogesterone and congenital anomalies, some recently retracted publications have postulated an association with teratogenicity. Dydrogesterone is also often rated as less safe than bioidentical progestins.
UNASSIGNED: A systematic review was conducted according to a pre-specified protocol with searches on Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Clinicaltrials.gov. The search was limited to human studies, with no restrictions on language, geographical region, or date. The search algorithm used a PICO (Population, Intervention, Comparison, Outcome)-style approach combining both simple search terms and medical subject heading terms. As congenital anomalies are mostly reported as secondary outcomes, the search term \'safety\' was added.
METHODS: Interventional study and observational study (OS) designs were eligible for inclusion. Inclusion criteria were: women >17 years old treated for threatened miscarriage, recurrent pregnancy loss, and/or ART; the use of dydrogesterone in the first trimester compared with placebo, no treatment or other interventions; and reporting of congenital anomalies in newborns or infants ≤12 months old (primary outcome). Two authors (A.K., M.R.N.) independently extracted the following data: general study information, study population details, intervention and comparator(s), and frequencies of congenital anomalies (classification, time of determination, and type). Risk of bias focused on the reporting of congenital malformations and was assessed using the Cochrane Risk of Bias Tool Version 2 or the ROBINS-I tool. The GRADEproGDT platform was used to generate the GRADE summary of findings table.
RESULTS: Of the 897 records retrieved during the literature search, 47 were assessed for eligibility. Nine studies were included in the final analysis: six randomized controlled trials (RCTs) and three OSs. Among the RCTs, three had a low risk and three a high risk of bias. Two of the OSs were considered to have a serious risk of bias and one with critical risk of bias and was excluded for the evidence syntheses. The eight remaining studies included a total of 5070 participants and 2680 live births from 16 countries. In the meta-analysis of RCTs only, the overall risk ratio (RR) was 0.92 [95% CI 0.55; 1.55] with low certainty. When the two OSs were included, the overall RR was 1.11 [95% CI 0.73; 1.68] with low certainty.
CONCLUSIONS: The studies included in the analysis do not report congenital anomalies as the primary outcome; reporting of congenital anomalies was often not standardized.
CONCLUSIONS: This systematic literature review and meta-analysis provide clear reassurance to both clinicians and patients that dydrogesterone is not associated with congenital anomalies above the rate that might be expected due to environmental and genetic factors. The results of this work represent the highest current level of evidence for the question of congenital anomalies, which removes the existing uncertainty caused by poor quality and retracted studies.
BACKGROUND: Editorial support was provided by Highfield Communication Consultancy, Oxford, UK, sponsored by Abbott Products Operations AG, Allschwil, Switzerland. A.K., J.A.G.-V., L.P.S., J.N.v.d.A., and J.F.S. received honoraria from Abbott for preparation and participation in an advisory board. J.A.G.-V. received grants and lecture fees from Merck, Organon, Ferring, Gedeon Richter, and Theramex. M.R.N. has no conflicts of interest. J.N.v.d.A. and J.A.G.-V. have no other conflicts of interest. A.K. received payment from Abbott for a talk at the IVF Worldwide congress on 22 September 2023. J.F.S. has received grants from the National Institutes of Health, royalties/licences from Elsevier and Prescient Medicine (SOLVD Health), consulting fees from Burroughs Wellcome Fund (BWF) and Bayer, honoraria from Magee Women\'s Research Institute, Wisconsin National Primate Research Centre, University of Kansas and Oakridge National Research Laboratory, Agile, Daiichi Sankyo/American Regent, and Bayer, and travel support to attend meetings for the International Academy of Human Reproduction (IAHR). J.F.S. has patents related to diagnosis and treatment of PCOS and prediction of preterm birth. J.F.S. participates on advisory boards for SOLVD Health, Wisconsin National Primate Research Centre, and FHI360, was the past President board member of the Society for Reproductive Investigation, has a leadership role for the following organizations: Scientific Advisory Board, SOLVD Health, EAB Chair for contraceptive technology initiative, FHI360, EAB member, Wisconsin National Primate Research Centre, Advisory Board for MWRI Summit, Chair of BWF NextGen Pregnancy Research Panel, Medical Executive Committee at the Howard, and Georgeanna Jones Foundation, and is Vice President, IAHR. L.P.S. has received consulting fees from Shield Pharmaceuticals, Scynexis, Organon, Natera, Celula China, AiVF, Agile, Daiichi Sankyo, American Regent, and Medicem, honoraria from Agile, Daiichi Sankyo/American Regent, and Bayer, and travel support from BD Diagnostics. L.P.S. participates on the data safety monitoring board for Astellas and is a Chair of DSMB for fezolinetant. Abbott played no role in the funding of the study or in study design, data collection, data analysis, data interpretation, or writing of the report.
BACKGROUND: PROSPERO 2022 CRD42022356977.
CONCLUSIONS: Dydrogesterone, when given in the first trimester for recurrent/threatened pregnancy loss or as luteal support in ART, is not a relevant additional risk factor for congenital anomalies.
BACKGROUND: Despite large clinical trials and meta-analyses that show no association between dydrogesterone and congenital anomalies, some recently retracted publications have postulated an association with teratogenicity. Dydrogesterone is also often rated as less safe than bioidentical progestins.
UNASSIGNED: A systematic review was conducted according to a pre-specified protocol with searches on Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Clinicaltrials.gov. The search was limited to human studies, with no restrictions on language, geographical region, or date. The search algorithm used a PICO (Population, Intervention, Comparison, Outcome)-style approach combining both simple search terms and medical subject heading terms. As congenital anomalies are mostly reported as secondary outcomes, the search term \'safety\' was added.
METHODS: Interventional study and observational study (OS) designs were eligible for inclusion. Inclusion criteria were: women >17 years old treated for threatened miscarriage, recurrent pregnancy loss, and/or ART; the use of dydrogesterone in the first trimester compared with placebo, no treatment or other interventions; and reporting of congenital anomalies in newborns or infants ≤12 months old (primary outcome). Two authors (A.K., M.R.N.) independently extracted the following data: general study information, study population details, intervention and comparator(s), and frequencies of congenital anomalies (classification, time of determination, and type). Risk of bias focused on the reporting of congenital malformations and was assessed using the Cochrane Risk of Bias Tool Version 2 or the ROBINS-I tool. The GRADEproGDT platform was used to generate the GRADE summary of findings table.
RESULTS: Of the 897 records retrieved during the literature search, 47 were assessed for eligibility. Nine studies were included in the final analysis: six randomized controlled trials (RCTs) and three OSs. Among the RCTs, three had a low risk and three a high risk of bias. Two of the OSs were considered to have a serious risk of bias and one with critical risk of bias and was excluded for the evidence syntheses. The eight remaining studies included a total of 5070 participants and 2680 live births from 16 countries. In the meta-analysis of RCTs only, the overall risk ratio (RR) was 0.92 [95% CI 0.55; 1.55] with low certainty. When the two OSs were included, the overall RR was 1.11 [95% CI 0.73; 1.68] with low certainty.
CONCLUSIONS: The studies included in the analysis do not report congenital anomalies as the primary outcome; reporting of congenital anomalies was often not standardized.
CONCLUSIONS: This systematic literature review and meta-analysis provide clear reassurance to both clinicians and patients that dydrogesterone is not associated with congenital anomalies above the rate that might be expected due to environmental and genetic factors. The results of this work represent the highest current level of evidence for the question of congenital anomalies, which removes the existing uncertainty caused by poor quality and retracted studies.
BACKGROUND: Editorial support was provided by Highfield Communication Consultancy, Oxford, UK, sponsored by Abbott Products Operations AG, Allschwil, Switzerland. A.K., J.A.G.-V., L.P.S., J.N.v.d.A., and J.F.S. received honoraria from Abbott for preparation and participation in an advisory board. J.A.G.-V. received grants and lecture fees from Merck, Organon, Ferring, Gedeon Richter, and Theramex. M.R.N. has no conflicts of interest. J.N.v.d.A. and J.A.G.-V. have no other conflicts of interest. A.K. received payment from Abbott for a talk at the IVF Worldwide congress on 22 September 2023. J.F.S. has received grants from the National Institutes of Health, royalties/licences from Elsevier and Prescient Medicine (SOLVD Health), consulting fees from Burroughs Wellcome Fund (BWF) and Bayer, honoraria from Magee Women\'s Research Institute, Wisconsin National Primate Research Centre, University of Kansas and Oakridge National Research Laboratory, Agile, Daiichi Sankyo/American Regent, and Bayer, and travel support to attend meetings for the International Academy of Human Reproduction (IAHR). J.F.S. has patents related to diagnosis and treatment of PCOS and prediction of preterm birth. J.F.S. participates on advisory boards for SOLVD Health, Wisconsin National Primate Research Centre, and FHI360, was the past President board member of the Society for Reproductive Investigation, has a leadership role for the following organizations: Scientific Advisory Board, SOLVD Health, EAB Chair for contraceptive technology initiative, FHI360, EAB member, Wisconsin National Primate Research Centre, Advisory Board for MWRI Summit, Chair of BWF NextGen Pregnancy Research Panel, Medical Executive Committee at the Howard, and Georgeanna Jones Foundation, and is Vice President, IAHR. L.P.S. has received consulting fees from Shield Pharmaceuticals, Scynexis, Organon, Natera, Celula China, AiVF, Agile, Daiichi Sankyo, American Regent, and Medicem, honoraria from Agile, Daiichi Sankyo/American Regent, and Bayer, and travel support from BD Diagnostics. L.P.S. participates on the data safety monitoring board for Astellas and is a Chair of DSMB for fezolinetant. Abbott played no role in the funding of the study or in study design, data collection, data analysis, data interpretation, or writing of the report.
BACKGROUND: PROSPERO 2022 CRD42022356977.
摘要：
目标：在妊娠早期给予复发性/先兆妊娠流产或辅助生殖技术（ART）中作为黄体支持时，暴露于地屈孕酮是先天性异常的危险因素吗？
结论：地屈孕酮，当在妊娠早期给予复发性/先兆妊娠丢失或作为ART的黄体支持时，不是先天性异常的相关额外风险因素。
背景：尽管大量的临床试验和荟萃分析显示地屈孕酮与先天性异常之间没有关联，一些最近撤回的出版物推测与致畸性有关.Dydrogestone通常也被认为比生物相同的孕激素安全性低。
■根据预先指定的方案进行了系统评价，并在Medline上进行了搜索，Embase,Cochrane中央对照试验登记册（中央），和临床试验。搜索仅限于人类研究，语言没有限制，地理区域,或日期。搜索算法使用了PICO(人口，干预,比较,结果)风格的方法结合了简单的搜索术语和医学主题标题术语。由于先天性异常主要是次要结果，已添加搜索词“安全”。
方法：介入研究和观察性研究（OS）设计符合纳入条件。纳入标准是：17岁以上的女性因先兆流产而接受治疗，反复妊娠丢失,和/或ART；与安慰剂相比，在妊娠早期使用地屈孕酮，无治疗或其他干预措施;新生儿或≤12个月婴儿的先天性异常报告(主要结局)。两位作者（A.K.，M.R.N.）独立提取以下数据：一般研究信息，研究人口细节，干预和比较器(S)，和先天性异常的频率(分类，确定时间,和类型）。偏倚风险集中于先天性畸形的报告，并使用Cochrane偏倚风险工具版本2或ROBINS-I工具进行评估。使用GRADeproGDT平台生成GRADE调查结果汇总表。
结果：在文献检索过程中检索到的897条记录中，47人被评估为资格。最终分析包括9项研究：6项随机对照试验（RCT）和3项操作系统。在RCT中，其中3人的偏倚风险较低,3人的偏倚风险较高.其中两个操作系统被认为具有严重的偏倚风险，一个具有严重的偏倚风险，并被排除在证据综合之外。其余的8项研究包括来自16个国家的5070名参与者和2680名活产。仅在随机对照试验的荟萃分析中，总体风险比(RR)为0.92[95%CI0.55;1.55],且确定性较低.当包括两个操作系统时，总体RR为1.11[95%CI0.73;1.68]，确定性较低。
结论：分析中包含的研究并未将先天性异常报告为主要结局；先天性异常的报告通常未标准化。
结论：本系统文献综述和荟萃分析为临床医生和患者提供了明确的保证，即地屈孕酮与先天性异常的相关程度不超过环境和遗传因素可能导致的预期。这项工作的结果代表了目前有关先天性异常问题的最高证据水平，这消除了现有的不确定性造成的质量差和撤回的研究。
背景：编辑支持由HighfieldCommunicationConsultancy提供，牛津,英国,由雅培产品运营公司赞助，Allschwil,瑞士。A.K.,J.A.G.-V.,L.P.S.,J.N.v.d.A.,和J.F.S.从雅培获得酬金，以筹备和参加咨询委员会。J.A.G.-V.收到默克公司的赠款和讲课费，Organon,套圈,GedeonRichter,还有Theramex.M.R.N.没有利益冲突。J.N.v.d.A.和J.A.G.-V.没有其他利益冲突。A.K.在2023年9月22日的IVF全球大会上收到了雅培的付款。J.F.S.获得了美国国立卫生研究院的资助,Elsevier和PrescientMedicine（SOLVDHealth）的特许权使用费/许可证，伯劳斯惠康基金(BWF)和拜耳的咨询费，马吉妇女研究所酬金，威斯康星州国家灵长类动物研究中心，堪萨斯大学和Oakridge国家研究实验室，敏捷,DaiichiSankyo/美国丽晶，还有拜耳,以及参加国际人类生殖学会（IAHR）会议的旅行支持。J.F.S.拥有与PCOS的诊断和治疗以及早产预测相关的专利。J.F.S.参加SOLVD健康咨询委员会，威斯康星州国家灵长类动物研究中心，和FHI360，是生殖调查协会的前任主席董事会成员，在以下组织中发挥领导作用：科学顾问委员会，SOLVD健康，EAB避孕技术倡议主席，FHI360,EAB成员,威斯康星州国家灵长类动物研究中心，MWRI峰会咨询委员会，BWFNextGen妊娠研究小组主席，霍华德医院的医疗执行委员会，和GeorgeannaJones基金会,是副总统,IAHR。L.P.S.已收到ShieldPharmaceuticals的咨询费，镰刀菌,Organon,Natera,Celula中国,AiVF,敏捷,DaiichiSankyo,美国摄政王,还有Medicem,来自敏捷的酬金，DaiichiSankyo/美国丽晶，还有拜耳,和BD诊断的旅行支持。L.P.S.参加了Astellas的数据安全监测委员会，并且是fezolinetant的DSMB主席。雅培在研究的资助或研究设计中没有任何作用，数据收集，数据分析,数据解释，或撰写报告。
背景：PROSPERO2022CRD42022356977。
结论：地屈孕酮，当在妊娠早期给予复发性/先兆妊娠丢失或作为ART的黄体支持时，不是先天性异常的相关额外风险因素。
背景：尽管大量的临床试验和荟萃分析显示地屈孕酮与先天性异常之间没有关联，一些最近撤回的出版物推测与致畸性有关.Dydrogestone通常也被认为比生物相同的孕激素安全性低。
■根据预先指定的方案进行了系统评价，并在Medline上进行了搜索，Embase,Cochrane中央对照试验登记册（中央），和临床试验。搜索仅限于人类研究，语言没有限制，地理区域,或日期。搜索算法使用了PICO(人口，干预,比较,结果)风格的方法结合了简单的搜索术语和医学主题标题术语。由于先天性异常主要是次要结果，已添加搜索词“安全”。
方法：介入研究和观察性研究（OS）设计符合纳入条件。纳入标准是：17岁以上的女性因先兆流产而接受治疗，反复妊娠丢失,和/或ART；与安慰剂相比，在妊娠早期使用地屈孕酮，无治疗或其他干预措施;新生儿或≤12个月婴儿的先天性异常报告(主要结局)。两位作者（A.K.，M.R.N.）独立提取以下数据：一般研究信息，研究人口细节，干预和比较器(S)，和先天性异常的频率(分类，确定时间,和类型）。偏倚风险集中于先天性畸形的报告，并使用Cochrane偏倚风险工具版本2或ROBINS-I工具进行评估。使用GRADeproGDT平台生成GRADE调查结果汇总表。
结果：在文献检索过程中检索到的897条记录中，47人被评估为资格。最终分析包括9项研究：6项随机对照试验（RCT）和3项操作系统。在RCT中，其中3人的偏倚风险较低,3人的偏倚风险较高.其中两个操作系统被认为具有严重的偏倚风险，一个具有严重的偏倚风险，并被排除在证据综合之外。其余的8项研究包括来自16个国家的5070名参与者和2680名活产。仅在随机对照试验的荟萃分析中，总体风险比(RR)为0.92[95%CI0.55;1.55],且确定性较低.当包括两个操作系统时，总体RR为1.11[95%CI0.73;1.68]，确定性较低。
结论：分析中包含的研究并未将先天性异常报告为主要结局；先天性异常的报告通常未标准化。
结论：本系统文献综述和荟萃分析为临床医生和患者提供了明确的保证，即地屈孕酮与先天性异常的相关程度不超过环境和遗传因素可能导致的预期。这项工作的结果代表了目前有关先天性异常问题的最高证据水平，这消除了现有的不确定性造成的质量差和撤回的研究。
背景：编辑支持由HighfieldCommunicationConsultancy提供，牛津,英国,由雅培产品运营公司赞助，Allschwil,瑞士。A.K.,J.A.G.-V.,L.P.S.,J.N.v.d.A.,和J.F.S.从雅培获得酬金，以筹备和参加咨询委员会。J.A.G.-V.收到默克公司的赠款和讲课费，Organon,套圈,GedeonRichter,还有Theramex.M.R.N.没有利益冲突。J.N.v.d.A.和J.A.G.-V.没有其他利益冲突。A.K.在2023年9月22日的IVF全球大会上收到了雅培的付款。J.F.S.获得了美国国立卫生研究院的资助,Elsevier和PrescientMedicine（SOLVDHealth）的特许权使用费/许可证，伯劳斯惠康基金(BWF)和拜耳的咨询费，马吉妇女研究所酬金，威斯康星州国家灵长类动物研究中心，堪萨斯大学和Oakridge国家研究实验室，敏捷,DaiichiSankyo/美国丽晶，还有拜耳,以及参加国际人类生殖学会（IAHR）会议的旅行支持。J.F.S.拥有与PCOS的诊断和治疗以及早产预测相关的专利。J.F.S.参加SOLVD健康咨询委员会，威斯康星州国家灵长类动物研究中心，和FHI360，是生殖调查协会的前任主席董事会成员，在以下组织中发挥领导作用：科学顾问委员会，SOLVD健康，EAB避孕技术倡议主席，FHI360,EAB成员,威斯康星州国家灵长类动物研究中心，MWRI峰会咨询委员会，BWFNextGen妊娠研究小组主席，霍华德医院的医疗执行委员会，和GeorgeannaJones基金会,是副总统,IAHR。L.P.S.已收到ShieldPharmaceuticals的咨询费，镰刀菌,Organon,Natera,Celula中国,AiVF,敏捷,DaiichiSankyo,美国摄政王,还有Medicem,来自敏捷的酬金，DaiichiSankyo/美国丽晶，还有拜耳,和BD诊断的旅行支持。L.P.S.参加了Astellas的数据安全监测委员会，并且是fezolinetant的DSMB主席。雅培在研究的资助或研究设计中没有任何作用，数据收集，数据分析,数据解释，或撰写报告。
背景：PROSPERO2022CRD42022356977。
