{
  "abstract": "Abstract Objective To test the hypothesis that women assigned to a natural ovulation regimen before frozen embryo transfer compared with a programmed regimen would have an increased chance of a healthy live birth and a reduced risk of pre-eclampsia or eclampsia.Design Multicentre, randomised, parallel group, assessor blinded clinical trial.Setting 24 academic fertility centres in China.Participants 4376 ovulatory women (aged 20-40 years) planning to undergo a frozen single blastocyst transfer.Interventions Eligible participants were randomised (1:1) to receive a natural ovulation regimen or a programmed regimen of hormone replacement for endometrial preparation. Endometrial preparation and frozen embryo transfer timing were determined in the natural ovulation regimen group by monitoring natural follicle development and measuring serum levels of luteinising hormone, oestradiol, and progesterone. In the programmed regimen group, endometrial preparation was achieved by sequential administration of oestrogen and progesterone.Main outcomes and measures Primary outcomes were a healthy live birth and pre-eclampsia or eclampsia after a frozen embryo transfer. Secondary outcomes were cycle cancellation, biochemical pregnancy, clinical pregnancy, ongoing pregnancy, pregnancy loss, ectopic pregnancy, live birth, birth weight, and maternal, fetal, and neonatal complications.Results In the intention-to-treat analyses, 910 (41.6%) of 2185 patients in the natural ovulation regimen group and 890 (40.6%) of 2191 in the programmed regimen group achieved a healthy live birth (relative ratio 1.03 (95% confidence interval (CI) 0.96 to 1.10); P=0.49). The risk of pre-eclampsia was lower in the natural ovulation regimen group among patients who achieved clinical pregnancy than in the programmed regimen group (2.9% (38 of 1302) v 4.6% (61 of 1326); 0.63 (0.43 to 0.94); P=0.02). The incidences of early pregnancy loss (12.1% (158 of 1302) v 15.2% (201 of 1326); 0.80 (0.66 to 0.97)), placental accreta spectrum (1.8% (24 of 1302) v 3.6% (48 of 1326); 0.51 (0.31 to 0.83)), caesarean section (69.5% (776 of 1117) v 75.6% (831 of 1100); 0.92 (0.87 to 0.97)), and postpartum haemorrhage (2.0% (22 of 1117) v 6.1% (67 of 1100); 0.32 (0.20 to 0.52)) were lower in the natural ovulation regimen group. No differences between groups were observed for birth weight or neonatal complications. The rate of cycle cancellation was higher in the natural ovulation regimen (16.2% (354 of 2185) v 11.5% (251 of 2191), P<0.001). The prespecified per protocol and subgroup analyses yielded results consistent with the intention-to-treat analyses.Conclusions In ovulatory women, a natural ovulation regimen for endometrial preparation was as effective as programmed regimen in terms of achieving a healthy live birth after frozen embryo transfer, but with a lower risk of maternal complications during pregnancy.Trial registration Chinese Clinical Trial Registry ChiCTR2200057990.",
  "authors": [
    {
      "affiliations": [
        "State Key Laboratory of Reproductive Medicine and Offspring Health, Centre for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250021, China",
        "National Research Centre for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China",
        "Key Laboratory of Reproductive Endocrinology, Ministry of Education, Shandong University, Jinan, China",
        "Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No 2021RU001), Jinan, China"
      ],
      "name": "Daimin Wei"
    },
    {
      "affiliations": [
        "State Key Laboratory of Reproductive Medicine and Offspring Health, Centre for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250021, China",
        "National Research Centre for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China",
        "Key Laboratory of Reproductive Endocrinology, Ministry of Education, Shandong University, Jinan, China",
        "Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No 2021RU001), Jinan, China",
        "Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China"
      ],
      "name": "Yingying Qin"
    },
    {
      "affiliations": [
        "Department of Reproductive Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China",
        "Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China"
      ],
      "name": "Yun Sun"
    },
    {
      "affiliations": [
        "State Key Laboratory of Reproductive Medicine and Offspring Health, Centre for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250021, China",
        "National Research Centre for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China",
        "Key Laboratory of Reproductive Endocrinology, Ministry of Education, Shandong University, Jinan, China",
        "Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No 2021RU001), Jinan, China"
      ],
      "name": "Junhao Yan"
    },
    {
      "affiliations": [
        "State Key Laboratory of Reproductive Medicine and Offspring Health, Centre for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250021, China",
        "National Research Centre for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China",
        "Key Laboratory of Reproductive Endocrinology, Ministry of Education, Shandong University, Jinan, China",
        "Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No 2021RU001), Jinan, China"
      ],
      "name": "Han Zhao"
    },
    {
      "affiliations": [
        "Centre for Reproductive Medicine, the Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China"
      ],
      "name": "Yichun Guan"
    },
    {
      "affiliations": [
        "Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Shengjing Hospital of China Medical University, Shenyang, China"
      ],
      "name": "Jichun Tan"
    },
    {
      "affiliations": [
        "State Key Laboratory of Reproductive Medicine and Offspring Health, Centre for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250021, China",
        "National Research Centre for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China",
        "Key Laboratory of Reproductive Endocrinology, Ministry of Education, Shandong University, Jinan, China",
        "Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No 2021RU001), Jinan, China"
      ],
      "name": "Ting Guo"
    },
    {
      "affiliations": [
        "State Key Laboratory of Reproductive Medicine and Offspring Health, Centre for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250021, China",
        "National Research Centre for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China",
        "Key Laboratory of Reproductive Endocrinology, Ministry of Education, Shandong University, Jinan, China",
        "Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No 2021RU001), Jinan, China"
      ],
      "name": "Ze Wang"
    },
    {
      "affiliations": [
        "NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Sciences, Central South University, Changsha, China"
      ],
      "name": "Fei Gong"
    },
    {
      "affiliations": [
        "Centre for Reproductive Medicine, Women and Children’s Hospital, Qingdao University, Qingdao, China"
      ],
      "name": "Cuifang Hao"
    },
    {
      "affiliations": [
        "State Key Laboratory of Reproductive Medicine and Offspring Health, Clinical Centre of Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China"
      ],
      "name": "Xiang Ma"
    },
    {
      "affiliations": [
        "Centre for Reproductive Medicine, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, China"
      ],
      "name": "Cuilian Zhang"
    },
    {
      "affiliations": [
        "Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Aijun Zhang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Reproductive Medicine and Offspring Health, Centre for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250021, China",
        "National Research Centre for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China",
        "Key Laboratory of Reproductive Endocrinology, Ministry of Education, Shandong University, Jinan, China",
        "Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No 2021RU001), Jinan, China"
      ],
      "name": "Ling Geng"
    },
    {
      "affiliations": [
        "State Key Laboratory of Reproductive Medicine and Offspring Health, Centre for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250021, China",
        "National Research Centre for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China",
        "Key Laboratory of Reproductive Endocrinology, Ministry of Education, Shandong University, Jinan, China",
        "Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No 2021RU001), Jinan, China"
      ],
      "name": "Mei Sun"
    },
    {
      "affiliations": [
        "State Key Laboratory of Reproductive Medicine and Offspring Health, Centre for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250021, China",
        "National Research Centre for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China",
        "Key Laboratory of Reproductive Endocrinology, Ministry of Education, Shandong University, Jinan, China",
        "Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No 2021RU001), Jinan, China"
      ],
      "name": "Xiufang Li"
    },
    {
      "affiliations": [
        "Centre for Reproductive Medicine, Women’s Hospital of Nanjing Medical University, Nanjing Women and Children's Healthcare Hospital, Nanjing, China"
      ],
      "name": "Xiufeng Ling"
    },
    {
      "affiliations": [
        "Medical Centre for Human Reproduction, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China"
      ],
      "name": "Qun Lu"
    },
    {
      "affiliations": [
        "Centre for Reproductive Medicine, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China"
      ],
      "name": "Hongchu Bao"
    },
    {
      "affiliations": [
        "Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Qilu Hospital of Shandong University, Jinan, China"
      ],
      "name": "Lan Chao"
    },
    {
      "affiliations": [
        "Centre for Reproductive Medicine, West China Second University Hospital of Sichuan University, Chengdu, China"
      ],
      "name": "Wei Huang"
    },
    {
      "affiliations": [
        "Centre for Reproduction and Genetics, Department of Obstetrics and Gynaecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China"
      ],
      "name": "Qinghua Shi"
    },
    {
      "affiliations": [
        "Centre for Reproductive Medicine, General Hospital of Ningxia Medical University, Yinchuan, China"
      ],
      "name": "Junli Zhao"
    },
    {
      "affiliations": [
        "Department of Reproductive Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China",
        "Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China"
      ],
      "name": "Yao Lu"
    },
    {
      "affiliations": [
        "Centre for Reproductive Medicine, the Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China"
      ],
      "name": "Sheling Wu"
    },
    {
      "affiliations": [
        "NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Sciences, Central South University, Changsha, China"
      ],
      "name": "Shunji Zhang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Reproductive Medicine and Offspring Health, Clinical Centre of Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China"
      ],
      "name": "Jing Wang"
    },
    {
      "affiliations": [
        "Centre for Reproductive Medicine, Women and Children’s Hospital, Qingdao University, Qingdao, China"
      ],
      "name": "Meiling Guo"
    },
    {
      "affiliations": [
        "Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, China"
      ],
      "name": "Xiaoxi Sun"
    },
    {
      "affiliations": [
        "Department of Reproductive Medicine, The First Affiliated Hospital, Hainan Medical University, Haikou, China"
      ],
      "name": "Yanlin Ma"
    },
    {
      "affiliations": [
        "Centre for Reproductive Medicine, Jiangxi Maternal and Child Health Hospital, Nanchang, China"
      ],
      "name": "Qiongfang Wu"
    },
    {
      "affiliations": [
        "Department of Reproductive Medicine, Xiangya Hospital, Central South University, Changsha, China"
      ],
      "name": "Yanping Li"
    },
    {
      "affiliations": [
        "Centre for Reproductive Medicine, Guangdong Second Provincial General Hospital, Guangzhou, China"
      ],
      "name": "Xianghong Ou"
    },
    {
      "affiliations": [
        "Centre for Reproductive Medicine, The Second Hospital Affiliated to Shandong University of Traditional Chinese Medicine, Jinan, China"
      ],
      "name": "Zhou Fang"
    },
    {
      "affiliations": [
        "Centre for Reproductive Medicine, Renmin Hospital of Wuhan University, Wuhan, China"
      ],
      "name": "Jiao Chen"
    },
    {
      "affiliations": [
        "Department of Reproductive Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, China"
      ],
      "name": "Guimin Hao"
    },
    {
      "affiliations": [
        "Department of Biostatistics, Yale University School of Public Health, New Haven, CT, USA"
      ],
      "name": "Heping Zhang"
    },
    {
      "affiliations": [
        "Department of Obstetrics and Gynaecology, Penn State College of Medicine, Hershey, PA, USA"
      ],
      "name": "Richard S Legro"
    },
    {
      "affiliations": [
        "State Key Laboratory of Reproductive Medicine and Offspring Health, Centre for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250021, China",
        "National Research Centre for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China",
        "Key Laboratory of Reproductive Endocrinology, Ministry of Education, Shandong University, Jinan, China",
        "Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No 2021RU001), Jinan, China"
      ],
      "name": "Zi-Jiang Chen"
    },
    {
      "affiliations": [],
      "name": "on behalf of the PnROVE Study Group"
    }
  ],
  "title": "Natural ovulation versus programmed regimens before frozen embryo transfer in ovulatory women: multicentre, randomised clinical trial",
  "uid": "b2e92a36-fc37-5e05-9757-89d6fd257096"
}