2024
Fibroids and unexplained infertility treatment with epigallocatechin gallate: a natural compound in green tea (FRIEND) – protocol for a randomised placebo-controlled US multicentre clinical trial of EGCG to improve fertility in women with uterine fibroids
Al-Hendy A, Segars J, Taylor H, González F, Siblini H, Zamah M, Alkelani H, Singh B, Flores V, Christman G, Johnson J, Huang H, Zhang H. Fibroids and unexplained infertility treatment with epigallocatechin gallate: a natural compound in green tea (FRIEND) – protocol for a randomised placebo-controlled US multicentre clinical trial of EGCG to improve fertility in women with uterine fibroids. BMJ Open 2024, 14: e078989. PMID: 38216200, PMCID: PMC10806662, DOI: 10.1136/bmjopen-2023-078989.Peer-Reviewed Original ResearchConceptsUnexplained infertilityIntrauterine inseminationInstitutional review boardCumulative live birth rateUterine fibroidsLive birth rateCause of infertilityFood and Drug AdminstrationGonadotropin hormone-releasing hormoneGreen tea extractDouble-blind clinical trialNon-surgical treatment optionsTimed intrauterine inseminationUterine fibroid sizeOvarian stimulationQuality of Life Questionnaire scoresHormone-releasing hormoneLocal institutional review boardInfertility treatmentNational Institute of Child HealthInstitute of Child HealthMiscarriage rateBirth rateReproductive-age womenEndometrial quality
2023
Prednisone vs Placebo and Live Birth in Patients With Recurrent Implantation Failure Undergoing In Vitro Fertilization
Sun Y, Cui L, Lu Y, Tan J, Dong X, Ni T, Yan J, Guan Y, Hao G, Liu J, Zhang B, Wei D, Hong Y, He Y, Qi J, Xu B, Lu J, Zhang Q, Zhao S, Ji X, Du X, Zhang J, Liu J, Wang J, Huang Y, Huang D, Du Y, Vankelecom H, Zhang H, Chen Z. Prednisone vs Placebo and Live Birth in Patients With Recurrent Implantation Failure Undergoing In Vitro Fertilization. JAMA 2023, 329: 1460-1468. PMID: 37129654, PMCID: PMC10155063, DOI: 10.1001/jama.2023.5302.Peer-Reviewed Original ResearchConceptsRecurrent implantation failureFrozen-thawed embryo transferBiochemical pregnancy lossLive birthsImplant failurePlacebo groupPrednisone groupPreterm deliveryEmbryo transferPregnancy lossRisk of preterm deliveryRates of biochemical pregnancyEmbryo transfer cyclesGood-quality embryosLive birth rateLive birth outcomesTreatment of recurrent implantation failureStatistically significant between-group differencesHistory of 2Randomized clinical trialsProbability of implantationImmune-regulatory agentSignificant between-group differencesNeonatal complicationsWeeks gestation
2020
Factors associated with study protocol adherence and bio banking participation in reproductive medicine clinical trials and their relationship to live birth
Engmann L, Sun F, Legro RS, Diamond MP, Zhang H, Santoro N, Bartlebaugh C, Dodson W, Estes S, Ober J, Brzyski R, Easton C, Hernandez A, Leija M, Pierce D, Robinson R, Awonuga A, Cedo L, Cline A, Collins K, Krawetz S, Puscheck E, Singh M, Yoscovits M, Barnhart K, Coutifaris C, Lecks K, Martino L, Marunich R, Snyder P, Alvero R, Comfort A, Crow M, Schlaff W, Casson P, Hohmann A, Mallette S, Christman G, Ohl D, Ringbloom M, Tang J, Bates G, Mason S, DiMaria N, Usadi R, Lucidi R, Rhea M, Baker V, Turner K, Trussell J, DelBasso D, Huang H, Li Y, Makuch R, Patrizio P, Sakai L, Scahill L, Taylor H, Thomas T, Tsang S, Yan Q, Zhang M, Haisenleder D, Lamar C, DePaolo L, Herring A, Redmond J, Thomas M, Turek P, Wactawski-Wende J, Rebar R, Cato P, Dukic V, Lewis V, Schlegel P, Witter F. Factors associated with study protocol adherence and bio banking participation in reproductive medicine clinical trials and their relationship to live birth. Human Reproduction 2020, 35: 2819-2831. PMID: 33190149, PMCID: PMC8453415, DOI: 10.1093/humrep/deaa232.Peer-Reviewed Original ResearchConceptsPolycystic ovary syndromeClinical trial protocolMedicine clinical trialsU10 HD055942U10 HD38998Baseline characteristicsTrial protocolClinical trialsLive birthsPolycystic Ovary Syndrome IIU10 HD38992U10 HD39005U10 HD27049STUDY FUNDING/COMPETINGMultiple Intrauterine GestationsStudy protocol adherenceUS multicenter trialRegular ovulatory cyclesClinical trial findingsPolycystic ovarian morphologyPARTICIPANTS/MATERIALSROLE OF CHANCELower household incomeAfrican AmericansAspects of adherenceShort-term weight change and live birth among women with unexplained infertility and polycystic ovary syndrome undergoing ovulation induction
Vitek W, Sun F, Hoeger KM, Santoro N, Diamond MP, Zhang H, Legro RS, Network E, Coutifaris C, Christman G, Robinson R, Brzyski R, Schlaff W, Casson P, Trussell J, Eisenberg E, Lamar C, DePaolo L. Short-term weight change and live birth among women with unexplained infertility and polycystic ovary syndrome undergoing ovulation induction. Fertility And Sterility 2020, 114: 1032-1039. PMID: 33036790, PMCID: PMC7953832, DOI: 10.1016/j.fertnstert.2020.06.002.Peer-Reviewed Original ResearchConceptsPolycystic ovary syndromeShort-term weight changeUnexplained infertilityLive birth rateOvulation inductionOvary syndromeWeight changeWeight gainCycles of clomipheneBody mass indexMean weight changeBirth rateRandomized trialsMass indexRegular intercourseIntrauterine inseminationTreatment allocationLive birthsMAIN OUTCOMESecondary analysisWomenWeight assessmentBirthSyndromeInfertilityEndometrial thickness after ovarian stimulation with gonadotropin, clomiphene, or letrozole for unexplained infertility, and association with treatment outcomes
Quaas AM, Gavrizi SZ, Peck JD, Diamond MP, Legro RS, Robinson RD, Casson P, Christman GM, Zhang H, Hansen KR, Network E. Endometrial thickness after ovarian stimulation with gonadotropin, clomiphene, or letrozole for unexplained infertility, and association with treatment outcomes. Fertility And Sterility 2020, 115: 213-220. PMID: 32972733, PMCID: PMC7796980, DOI: 10.1016/j.fertnstert.2020.07.030.Peer-Reviewed Original ResearchConceptsLive birth rateEndometrial thicknessUnexplained infertilityOvarian stimulationRisk ratioLive birthsEMT groupHuman chorionic gonadotropin administrationHigher live birth rateIntrauterine insemination treatmentMean endometrial thicknessMultiple Intrauterine GestationsOvarian stimulation medicationChorionic gonadotropin administrationProspective cohort analysisUnadjusted risk ratioAdjusted risk ratioBirth rateOS-IUIThin endometriumIntrauterine gestationGonadotropin administrationStimulation medicationsClinical trialsTreatment outcomesIntrauterine insemination performance characteristics and post-processing total motile sperm count in relation to live birth for couples with unexplained infertility in a randomised, multicentre clinical trial
Hansen KR, Peck JD, Coward RM, Wild RA, Trussell JC, Krawetz SA, Diamond MP, Legro RS, Coutifaris C, Alvero R, Robinson RD, Casson P, Christman GM, Santoro N, Zhang H. Intrauterine insemination performance characteristics and post-processing total motile sperm count in relation to live birth for couples with unexplained infertility in a randomised, multicentre clinical trial. Human Reproduction 2020, 35: 1296-1305. PMID: 32432326, PMCID: PMC7316499, DOI: 10.1093/humrep/deaa027.Peer-Reviewed Original ResearchConceptsTotal motile sperm countLive birth rateHigher total motile sperm countUnexplained infertilityMulticentre clinical trialMotile sperm countClinical trialsLive birthsOvarian stimulationHCG injectionBirth ratePatient discomfortSperm countTreatment cyclesSecondary analysisEunice Kennedy Shriver National InstituteSTUDY FUNDING/COMPETINGLive birth successMultiple Intrauterine GestationsDuration of infertilityIUI treatment cyclesLive birth outcomesPARTICIPANTS/MATERIALSROLE OF CHANCEYears of ageLive birth after a freeze-only strategy versus fresh embryo transfer in three randomized trials considering progesterone concentration
Yu Y, Zhao S, Li Y, Niu Y, Wei D, Zhang S, Chen ZJ, Zhang H, Legro RS. Live birth after a freeze-only strategy versus fresh embryo transfer in three randomized trials considering progesterone concentration. Reproductive BioMedicine Online 2020, 41: 395-401. PMID: 32600942, DOI: 10.1016/j.rbmo.2020.04.021.Peer-Reviewed Original ResearchConceptsLive birth rateFresh embryo transferProgesterone concentrationsEmbryo transferOvulatory womenRandomized trialsBirth rateHuman chorionic gonadotrophin (HCG) administrationFresh embryo transfer groupCleavage-stage embryo transferFreeze-only strategyHigh ovarian responseInitial embryo transferPolycystic ovary syndromeChorionic gonadotrophin administrationEmbryo transfer groupFrozen embryo transferSingle blastocyst transferBetween-group differencesClinical pregnancyGonadotrophin administrationHCG administrationOvarian responseOvary syndromePrimary outcomeAndrogenicity and fertility treatment in women with unexplained infertility
Wang ET, Diamond MP, Alvero R, Casson P, Christman GM, Coutifaris C, Hansen KR, Sun F, Legro RS, Robinson RD, Usadi RS, Pisarska MD, Santoro NF, Zhang H, Network I. Androgenicity and fertility treatment in women with unexplained infertility. Fertility And Sterility 2020, 113: 636-641. PMID: 32192596, PMCID: PMC7088440, DOI: 10.1016/j.fertnstert.2019.10.034.Peer-Reviewed Original ResearchConceptsLive birth rateBody mass indexUnexplained infertilityClinical pregnancyMass indexPregnancy lossClinical markersLive birthsAndrogenic activityFree androgen index valuesHigher body mass indexMultivariable logistic regression modelMultiple Intrauterine GestationsNormal uterine cavityHigh waist circumferenceOvarian stimulation treatmentPatent fallopian tubesBirth rateLogistic regression modelsAndrogen markersSerum TTOvarian stimulationRegular mensesInfertility populationIntrauterine gestationThe effect of antioxidants on male factor infertility: the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial
Steiner AZ, Hansen KR, Barnhart KT, Cedars MI, Legro RS, Diamond MP, Krawetz SA, Usadi R, Baker VL, Coward RM, Huang H, Wild R, Masson P, Smith JF, Santoro N, Eisenberg E, Zhang H, Network R. The effect of antioxidants on male factor infertility: the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial. Fertility And Sterility 2020, 113: 552-560.e3. PMID: 32111479, PMCID: PMC7219515, DOI: 10.1016/j.fertnstert.2019.11.008.Peer-Reviewed Original ResearchConceptsMonths of treatmentMale factor infertilityFactor infertilityLive birthsSemen parametersPlacebo groupPrimary outcomeSperm concentrationPlacebo-controlled trialLive birth rateCumulative live birthDNA fragmentationFemale partnersSperm DNA fragmentation indexLycopene dailyVivo pregnancyClomiphene citrateSecondary outcomesEntire cohortAsthenospermic menFertility centerIntrauterine inseminationMonth 4Tubal patencyClinical trials
2019
First-line ovulation induction for polycystic ovary syndrome: an individual participant data meta-analysis
Wang R, Li W, Bordewijk E, Legro R, Zhang H, Wu X, Gao J, Morin-Papunen L, Homburg R, König T, Moll E, Kar S, Huang W, Johnson N, Amer S, Vegetti W, Palomba S, Falbo A, Özmen Ü, Nazik H, Williams C, Federica G, Lord J, Sahin Y, Bhattacharya S, Norman R, van Wely M, Mol B, Network+ R, Collaboration T. First-line ovulation induction for polycystic ovary syndrome: an individual participant data meta-analysis. Human Reproduction Update 2019, 25: 717-732. PMID: 31647106, DOI: 10.1093/humupd/dmz029.Peer-Reviewed Original ResearchConceptsPolycystic ovary syndromeClinical pregnancy rateClomiphene citrateLive birth rateOvulation inductionTime-to-pregnancyAnovulatory infertilityFrequent cause of anovulatory infertilityPregnancy rateCause of anovulatory infertilityBirth rateMetformin to CCOvulation induction agentsIncreased clinical pregnancyLive birthsPrimary randomised controlled trialsClinical pregnancyRandomised controlled trialsInfertilityIndividual participant dataIPD meta-analysesWomenPositive interactionsLetrozoleAccurate assessment of outcomesFresh versus frozen blastocyst transfer – Authors' reply
Wei D, Zhang H, Legro RS, Chen ZJ. Fresh versus frozen blastocyst transfer – Authors' reply. The Lancet 2019, 394: 1228. PMID: 31303315, DOI: 10.1016/s0140-6736(19)31390-x.Peer-Reviewed Original ResearchAssociation between testosterone, semen parameters, and live birth in men with unexplained infertility in an intrauterine insemination population
Trussell JC, Coward RM, Santoro N, Stetter C, Kunselman A, Diamond MP, Hansen KR, Krawetz SA, Legro RS, Heisenleder D, Smith J, Steiner A, Wild R, Casson P, Coutifaris C, Alvero RR, Robinson RB, Christman G, Patrizio P, Zhang H, Lindgren MC, Network R. Association between testosterone, semen parameters, and live birth in men with unexplained infertility in an intrauterine insemination population. Fertility And Sterility 2019, 111: 1129-1134. PMID: 30982604, PMCID: PMC6557574, DOI: 10.1016/j.fertnstert.2019.01.034.Peer-Reviewed Original ResearchMeSH KeywordsAdultBiomarkersDown-RegulationFemaleFertilityHumansInfertility, MaleInsemination, Artificial, HomologousLive BirthMaleMulticenter Studies as TopicPregnancyPregnancy RateRandomized Controlled Trials as TopicRisk FactorsSperm CountSperm MotilitySpermatogenesisTestosteroneTreatment OutcomeConceptsUnexplained infertilityLow TTMale partnersLive birthsSemen parametersSecondary analysisMultiple Intrauterine GestationsLive birth rateBody mass indexMulticenter clinical trialAbnormal sperm morphologyOvarian stimulationIntrauterine gestationPregnancy outcomesMass indexInfertility clinicClinical trialsMAIN OUTCOMETotal motile spermSemen analysisAbnormal spermatogenesisInfertilityLogistic regressionSperm concentrationSemen volume
2018
Comparison of sonohysterography to hysterosalpingogram for tubal patency assessment in a multicenter fertility treatment trial among women with polycystic ovary syndrome
Christianson MS, Legro RS, Jin S, Eisenberg E, Diamond MP, Hansen KR, Vitek W, Styer AK, Casson P, Coutifaris C, Christman GM, Alvero R, Puscheck EE, Christy AY, Sun F, Zhang H, Polotsky AJ, Santoro N. Comparison of sonohysterography to hysterosalpingogram for tubal patency assessment in a multicenter fertility treatment trial among women with polycystic ovary syndrome. Journal Of Assisted Reproduction And Genetics 2018, 35: 2173-2180. PMID: 30194618, PMCID: PMC6289919, DOI: 10.1007/s10815-018-1306-2.Peer-Reviewed Original ResearchConceptsPolycystic ovary syndromeSaline infusion sonohysterographyTubal patencyClinical pregnancyOvary syndromePolycystic Ovary Syndrome IITubal patency assessmentClinical pregnancy rateDuration of infertilityAcceptable imaging modalityIntrauterine pregnancyClomiphene citrateEctopic pregnancyInfertile womenResultsAmong womenMultivariable analysisPatency assessmentTreatment armsTreatment trialsPregnancy rateMethodsSecondary analysisHysterosalpingogramLarge cohortTubes patentPatencyThe Effect of Supraphysiological Estradiol on Pregnancy Outcomes Differs Between Women With PCOS and Ovulatory Women
Wei D, Yu Y, Sun M, Shi Y, Sun Y, Deng X, Li J, Wang Z, Zhao S, Zhang H, Legro RS, Chen ZJ. The Effect of Supraphysiological Estradiol on Pregnancy Outcomes Differs Between Women With PCOS and Ovulatory Women. The Journal Of Clinical Endocrinology & Metabolism 2018, 103: 2735-2742. PMID: 29718297, DOI: 10.1210/jc.2018-00613.Peer-Reviewed Original ResearchConceptsPolycystic ovary syndromeFrozen embryo transferFresh embryo transferLive birth rateOvulatory womenOvarian stimulationEmbryo transferSupraphysiological estradiolPregnancy outcomesEstradiol levelsBirth ratePeak estradiol levelsMulticenter Randomized TrialSimilar study designPCOS womenOvary syndromeOvarian responsePrimary outcomeRandomized trialsEstradiol exposureLive birthsMAIN OUTCOMEEmbryo implantationPg/Secondary analysisEffect of exposure to second-hand smoke from husbands on biochemical hyperandrogenism, metabolic syndrome and conception rates in women with polycystic ovary syndrome undergoing ovulation induction
Li J, Wu Q, Wu XK, Zhou ZM, Fu P, Chen XH, Yan Y, Wang X, Yang ZW, Li WL, Stener-Victorin E, Legro RS, Ng EH, Zhang H, Mol BWJ, Wang CC, Group F. Effect of exposure to second-hand smoke from husbands on biochemical hyperandrogenism, metabolic syndrome and conception rates in women with polycystic ovary syndrome undergoing ovulation induction. Human Reproduction 2018, 33: 617-625. PMID: 29471520, DOI: 10.1093/humrep/dey027.Peer-Reviewed Original ResearchConceptsPolycystic ovary syndromeNon-exposed womenSHS exposure statusSHS exposureMetabolic syndromeBiochemical hyperandrogenismObstetric outcomesOvary syndromeOvulation inductionSex hormonesExposure statusHigher serum total testosteroneSecond-hand smoke exposureSTUDY FUNDING/COMPETINGConception rateLower sex hormoneFree androgen indexSerum total testosteroneUterine blood flowLive birth rateNon-exposed groupSecond-hand smokePARTICIPANTS/MATERIALSROLE OF CHANCEAndrogen indexTransfer of Fresh versus Frozen Embryos in Ovulatory Women
Shi Y, Sun Y, Hao C, Zhang H, Wei D, Zhang Y, Zhu Y, Deng X, Qi X, Li H, Ma X, Ren H, Wang Y, Zhang D, Wang B, Liu F, Wu Q, Wang Z, Bai H, Li Y, Zhou Y, Sun M, Liu H, Li J, Zhang L, Chen X, Zhang S, Sun X, Legro R, Chen Z. Transfer of Fresh versus Frozen Embryos in Ovulatory Women. New England Journal Of Medicine 2018, 378: 126-136. PMID: 29320646, DOI: 10.1056/nejmoa1705334.Peer-Reviewed Original ResearchConceptsFresh embryo transferFrozen embryo transferLive birth rateOvarian hyperstimulation syndromeHyperstimulation syndromeElective frozen embryo transferOvulatory womenFrozen-embryo groupFresh embryo groupIn vitro fertilization cyclesHigher live birth ratesPolycystic ovary syndromeRate of implantsCleavage-stage embryosOverall pregnancy lossAnovulatory womenNeonatal complicationsClinical pregnancyOngoing pregnancyFrozen embryosEmbryo cryopreservationBetween-group differencesEmbryo transferLive birthsFertilization cycles
2017
Effect of Preconception Impaired Glucose Tolerance on Pregnancy Outcomes in Women With Polycystic Ovary Syndrome
Wei D, Zhang B, Shi Y, Zhang L, Zhao S, Du Y, Xu L, Legro RS, Zhang H, Chen ZJ. Effect of Preconception Impaired Glucose Tolerance on Pregnancy Outcomes in Women With Polycystic Ovary Syndrome. The Journal Of Clinical Endocrinology & Metabolism 2017, 102: 3822-3829. PMID: 28938429, DOI: 10.1210/jc.2017-01294.Peer-Reviewed Original ResearchConceptsOral glucose tolerance testPolycystic ovary syndromePregnancy outcomesI-IFGOvary syndromeGlucose toleranceHigh riskIntrinsic insulin resistanceAdverse pregnancy outcomesTotal testosterone levelsDuration of infertilityImpaired glucose tolerancePregnancy loss rateBody mass indexFrozen embryo transferGlucose tolerance testMain outcome measuresGestational diabetesObstetric complicationsSingleton newbornsSingleton pregnanciesGestational ageMass indexTwin pregnanciesInsulin levelsAssociation of uterine fibroids and pregnancy outcomes after ovarian stimulation–intrauterine insemination for unexplained infertility
Styer AK, Jin S, Liu D, Wang B, Polotsky AJ, Christianson MS, Vitek W, Engmann L, Hansen K, Wild R, Legro RS, Coutifaris C, Alvero R, Robinson RD, Casson P, Christman GM, Christy A, Diamond MP, Eisenberg E, Zhang H, Santoro N, Network I. Association of uterine fibroids and pregnancy outcomes after ovarian stimulation–intrauterine insemination for unexplained infertility. Fertility And Sterility 2017, 107: 756-762.e3. PMID: 28089575, PMCID: PMC5472203, DOI: 10.1016/j.fertnstert.2016.12.012.Peer-Reviewed Original ResearchMeSH KeywordsAbortion, SpontaneousAdultBlack or African AmericanDrug Therapy, CombinationFemaleFertilityFertility AgentsHumansInfertilityInsemination, ArtificialLeiomyomaLive BirthOvulationOvulation InductionPregnancyPregnancy RatePregnancy TestsProspective StudiesRisk FactorsTreatment OutcomeUnited StatesUterine NeoplasmsConceptsUnexplained infertilityUterine fibroidsPregnancy outcomesClinical trialsSerum antimüllerian hormone levelsBirth rateNon-African American womenGreater uterine volumeMultiple Intrauterine GestationsNormal uterine cavityClinical pregnancy rateAntimüllerian hormone levelsMulticenter clinical trialAmerican womenAfrican American womenClinical pregnancyIntrauterine gestationUterine volumeConception cyclesUterine cavityPregnancy lossHormone levelsPregnancy rateAntral folliclesMAIN OUTCOME
2016
Effect of pretreatment with oral contraceptives and progestins on IVF outcomes in women with polycystic ovary syndrome
Wei D, Shi Y, Li J, Wang Z, Zhang L, Sun Y, Zhou H, Xu Y, Wu C, Liu L, Wu Q, Zhuang L, Du Y, Li W, Zhang H, Legro RS, Chen ZJ. Effect of pretreatment with oral contraceptives and progestins on IVF outcomes in women with polycystic ovary syndrome. Human Reproduction 2016, 32: 354-361. PMID: 27999118, PMCID: PMC5870982, DOI: 10.1093/humrep/dew325.Peer-Reviewed Original ResearchConceptsPolycystic ovary syndromeFrozen embryo transferFresh embryo transferLive birth rateGnRH antagonist protocolOral contraceptivesSpontaneous mensesRate of pregnancyLive birthsEmbryo transferMenses inductionAntagonist protocolIVF cyclesOvarian stimulationOvary syndromePregnancy lossBirth rateMultivariate logistic regression analysisStudy designHigher pregnancy loss rateObese PCOS womenPregnancy loss rateSimilar pregnancy ratesPARTICIPANTS/MATERIALSLogistic regression analysisFresh versus Frozen Embryos for Infertility in the Polycystic Ovary Syndrome
Chen ZJ, Shi Y, Sun Y, Zhang B, Liang X, Cao Y, Yang J, Liu J, Wei D, Weng N, Tian L, Hao C, Yang D, Zhou F, Shi J, Xu Y, Li J, Yan J, Qin Y, Zhao H, Zhang H, Legro RS. Fresh versus Frozen Embryos for Infertility in the Polycystic Ovary Syndrome. New England Journal Of Medicine 2016, 375: 523-533. PMID: 27509101, DOI: 10.1056/nejmoa1513873.Peer-Reviewed Original ResearchConceptsPolycystic ovary syndromeOvarian hyperstimulation syndromeFresh embryo transferFrozen embryo transferFrozen-embryo transferOvary syndromeHyperstimulation syndromeLive birthsInfertile womenRate ratioFrozen embryosSignificant between-group differencesFresh embryo groupFirst IVF cycleLive birth rateFirst embryo transferBetween-group differencesNeonatal complicationsIVF cyclesPregnancy complicationsMulticenter trialPrimary outcomeNeonatal deathPregnancy lossHigh risk