Featured Publications
Trophoblast inclusions in the human placenta: Identification, characterization, quantification, and interrelations of subtypes
Kliman HJ, Firestein MR, Hofmann KM, Milano KM, Holzer PH, Brink LT, Odendaal HJ, Fifer WP. Trophoblast inclusions in the human placenta: Identification, characterization, quantification, and interrelations of subtypes. Placenta 2020, 103: 172-176. PMID: 33152642, PMCID: PMC8448462, DOI: 10.1016/j.placenta.2020.10.014.Peer-Reviewed Original Research
2023
Progress on the Endometrium
Frankfurter D, Kliman H. Progress on the Endometrium. Obstetrics And Gynecology Clinics Of North America 2023, 50: 677-694. PMID: 37914487, DOI: 10.1016/j.ogc.2023.09.002.Peer-Reviewed Original ResearchConceptsAbsence of pregnancyEvidence-based approachEndometrial assessmentStromal maturationEndometrial proliferationEndometrial pathologyInflammatory mediatorsOvarian steroidsImplantation failureBlastocyst implantationEndometrial sloughingDiagnostic measuresEndometriumOffer hopeDynamic tissueDevelopmental markersSingle testTissueInternal reproductionMaturationEndometriosisPregnancyDecidualizationInfertilityUterus
2022
Sex differences in early and term placenta are conserved in adult tissues
Olney K, Plaisier S, Phung T, Silasi M, Perley L, O’Bryan J, Ramirez L, Kliman H, Wilson M. Sex differences in early and term placenta are conserved in adult tissues. Biology Of Sex Differences 2022, 13: 74. PMID: 36550527, PMCID: PMC9773522, DOI: 10.1186/s13293-022-00470-y.Peer-Reviewed Original ResearchConceptsFirst trimester placentaLate first trimesterTerm placentaTrimester placentaFirst trimesterAdult tissuesGene expressionSex differencesLifelong health outcomesSex-differential gene expressionGenetic sexInnate immune responseFull-term placentaSex-linked genesInnate immune genesImmune responsePlacenta samplesHealth outcomesBrain tissuePlacentaGametologous genesDifferent timepointsSex chromosomesImmune genesSexInsulin increases placental triglyceride as a potential mechanism for fetal adiposity in maternal obesity
Anam AK, Cooke KM, Dratver MB, O'Bryan JV, Perley LE, Guller SM, Hwang JJ, Taylor HS, Goedeke L, Kliman HJ, Vatner DF, Flannery CA. Insulin increases placental triglyceride as a potential mechanism for fetal adiposity in maternal obesity. Molecular Metabolism 2022, 64: 101574. PMID: 35970449, PMCID: PMC9440306, DOI: 10.1016/j.molmet.2022.101574.Peer-Reviewed Original ResearchConceptsDe novo lipogenesisFetal adiposityFatty acid uptakeMaternal obesityObese womenNormal weightExcess adiposityVillous explantsInsulin receptorNewborns of mothersNormal-weight womenAcid uptakePlacental villous explantsTranscription factor SREBP-1Insulin-like growth factor 2Effect of insulinFatty acid oxidationPlacental triglyceridesPlacental responsesElevated triglyceridesMaternal hyperglycemiaWeight womenGrowth factor 2Diabetes riskPlacental metabolismPathologic Assessment of the Placenta: Evidence Compared With Tradition
Pinar H, Gordijn SJ, Grynspan D, Kingdom J, Roberts DJ, Kerzner L, Bates SV, Carreon CK, Leeman KT, Salafia C, Cohen M, Castro E, Ravishankar S, Kliman HJ, Dahlstrom J, Silver B, Heazell A. Pathologic Assessment of the Placenta: Evidence Compared With Tradition. Obstetrics And Gynecology 2022, 140: 341-342. PMID: 35852288, DOI: 10.1097/aog.0000000000004883.Peer-Reviewed Original ResearchTrophoblast inclusions and adverse birth outcomes
Firestein MR, Kliman HJ, Sania A, Brink LT, Holzer PH, Hofmann KM, Milano KM, Pini N, Shuffrey LC, Odendaal HJ, Fifer WP. Trophoblast inclusions and adverse birth outcomes. PLOS ONE 2022, 17: e0264733. PMID: 35231069, PMCID: PMC8887719, DOI: 10.1371/journal.pone.0264733.Peer-Reviewed Original ResearchConceptsBirth outcomesGestational ageLiveborn deliveryLive birthsFull-term live birthsChorionic villiPreterm live birthsSpecific placental pathologyFull-term birthInduction of laborAdverse birth outcomesGestational age birthweightSafe Passage StudyTrophoblast inclusionsGreater odds ratioWarrants further investigationPlacental infarctionPlacenta accretaPreterm birthPlacental pathologyVillous edemaPatient populationAlcohol exposureOdds ratioChorionic plate
2021
Bone Marrow-Derived Progenitor Cells Contribute to Remodeling of the Postpartum Uterus
Tal R, Kisa J, Abuwala N, Kliman HJ, Shaikh S, Chen AY, Lyu F, Taylor HS. Bone Marrow-Derived Progenitor Cells Contribute to Remodeling of the Postpartum Uterus. Stem Cells 2021, 39: 1489-1505. PMID: 34224633, PMCID: PMC9313624, DOI: 10.1002/stem.3431.Peer-Reviewed Original ResearchConceptsPostpartum uterusEndometrial stem/progenitor cellsBone marrow-derived progenitor cellsMarrow-derived progenitor cellsF4/80 macrophage markerUterine tissue regenerationProgenitor cellsC57BL/6J female micePostpartum day 1Cytokeratin-positive epithelial cellsBlood vessel endotheliumStem/progenitor cellsPrepregnancy levelsBM transplantsEndometrial regenerationEndometrial cellsFemale miceMacrophage markersPan-leukocytesLuminal epitheliumBone marrowDay 1BMDCsUterine cellsVessel endotheliumLoss of Cxcr4 in Endometriosis Reduces Proliferation and Lesion Number while Increasing Intraepithelial Lymphocyte Infiltration
Tal A, Tal R, Kliman HJ, Taylor HS. Loss of Cxcr4 in Endometriosis Reduces Proliferation and Lesion Number while Increasing Intraepithelial Lymphocyte Infiltration. American Journal Of Pathology 2021, 191: 1292-1302. PMID: 33964217, PMCID: PMC8261475, DOI: 10.1016/j.ajpath.2021.04.011.Peer-Reviewed Original ResearchConceptsEndometriosis lesionsEpithelial compartmentLesion numberDisruption of CXCR4Intraepithelial lymphocyte infiltrationAdult female miceLoss of CXCR4CXCL12-CXCR4 axisTotal lesion areaProgesterone receptor promoterEndometriosis inductionLymphocyte infiltrationCXCR4 expressionFemale miceHost miceControl lesionsProestrus stageEpithelial proliferationImmune evasionCXCR4LesionsTherapeutic potentialLesion areaReduces ProliferationEpithelial cellsMaternal respiratory SARS-CoV-2 infection in pregnancy is associated with a robust inflammatory response at the maternal-fetal interface
Lu-Culligan A, Chavan AR, Vijayakumar P, Irshaid L, Courchaine EM, Milano KM, Tang Z, Pope SD, Song E, Vogels CBF, Lu-Culligan WJ, Campbell KH, Casanovas-Massana A, Bermejo S, Toothaker JM, Lee HJ, Liu F, Schulz W, Fournier J, Muenker MC, Moore AJ, Team Y, Konnikova L, Neugebauer KM, Ring A, Grubaugh ND, Ko AI, Morotti R, Guller S, Kliman HJ, Iwasaki A, Farhadian SF. Maternal respiratory SARS-CoV-2 infection in pregnancy is associated with a robust inflammatory response at the maternal-fetal interface. Med 2021, 2: 591-610.e10. PMID: 33969332, PMCID: PMC8084634, DOI: 10.1016/j.medj.2021.04.016.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 infectionMaternal-fetal interfaceACE2 expressionNatural killerPregnant womenPlacental cellsAcute respiratory syndrome coronavirus 2 infectionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectionSARS-CoV-2-infected womenTerm placentaSyndrome coronavirus 2 infectionCoronavirus 2 infectionPotential immune mechanismsRobust inflammatory responseRobust immune responseCoronavirus disease 2019Detectable viral RNAInterferon-related genesLower ACE2 expressionMajority of placentasPregnancy complicationsPlacental histologyHofbauer cellsEarly pregnancyImmune activationGenetics, not the uterine environment, drive the formation of trophoblast inclusions: Insights from a twin study
Katz J, Holzer PH, Kliman HJ. Genetics, not the uterine environment, drive the formation of trophoblast inclusions: Insights from a twin study. Placenta 2021, 114: 133-138. PMID: 33941390, DOI: 10.1016/j.placenta.2021.04.010.Peer-Reviewed Original ResearchConceptsMean differenceUterine environmentTwin pairsTrophoblast inclusionsRetrospective case seriesCase seriesPregnancy lossIntrauterine environmentFetal geneticsMZ twinsDZ twinsDizygotic twin pairsMZ twin pairsGenetic abnormalitiesPlacentaZygosity groupsTwin individualsAverage numberMonozygoticTwin studiesMean absolute differenceAbsolute differenceDifferencesGroupFetuses
2019
An experimental test of the ovulatory homolog model of female orgasm
Pavlicev M, Zupan AM, Barry A, Walters S, Milano KM, Kliman HJ, Wagner GP. An experimental test of the ovulatory homolog model of female orgasm. Proceedings Of The National Academy Of Sciences Of The United States Of America 2019, 116: 20267-20273. PMID: 31570579, PMCID: PMC6789565, DOI: 10.1073/pnas.1910295116.Peer-Reviewed Original ResearchConceptsCopulation-induced ovulationOvulation rateEffects of fluoxetineHuman chorionic gonadotropinNeuro-endocrine mechanismsFluoxetine treatmentDaily dosesSerotonin functionChorionic gonadotropinSingle injectionPharmacological agentsFluoxetineFemale orgasmOvulationOrgasmRabbitsAnimalsGonadotropinDosesAdult bone marrow progenitors become decidual cells and contribute to embryo implantation and pregnancy
Tal R, Shaikh S, Pallavi P, Tal A, López-Giráldez F, Lyu F, Fang YY, Chinchanikar S, Liu Y, Kliman HJ, Alderman M, Pluchino N, Kayani J, Mamillapalli R, Krause DS, Taylor HS. Adult bone marrow progenitors become decidual cells and contribute to embryo implantation and pregnancy. PLOS Biology 2019, 17: e3000421. PMID: 31513564, PMCID: PMC6742226, DOI: 10.1371/journal.pbio.3000421.Peer-Reviewed Original ResearchConceptsBM transplantsDecidual cellsPregnancy lossMesenchymal stem cellsAdult bone marrow progenitorsDecidualization-related genesBone marrow progenitorsAdult bone marrowWT donorsPhysiologic contributionSuccessful pregnancyBMDC recruitmentStromal expansionImmune cellsEndometrial cellsDeficient miceUterine expressionUterine tissueDecidual stromaPregnancyBone marrowNonhematopoietic cellsBMDCsHemochorial placentaMarrow progenitorsClinical approach to recurrent implantation failure: evidence-based evaluation of the endometrium
Kliman HJ, Frankfurter D. Clinical approach to recurrent implantation failure: evidence-based evaluation of the endometrium. Fertility And Sterility 2019, 111: 618-628. PMID: 30929719, DOI: 10.1016/j.fertnstert.2019.02.011.Peer-Reviewed Original ResearchConceptsRecurrent implantation failureImplantation failureHigh-quality embryosEvidence-based evaluationInflammatory markersRetained productsInflammatory lesionsHistologic evaluationQuality embryosClinical approachGrowth disordersActionable findingsEndometriumFunctional testsPatientsMolecular eraComplete assessmentTissueCycling tissueEndometrialFailureBest optionLesionsEvaluation
2018
hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia
Mackie DI, Al Mutairi F, Davis RB, Kechele DO, Nielsen NR, Snyder JC, Caron MG, Kliman HJ, Berg JS, Simms J, Poyner DR, Caron KM. hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia. Journal Of Experimental Medicine 2018, 215: 2339-2353. PMID: 30115739, PMCID: PMC6122977, DOI: 10.1084/jem.20180528.Peer-Reviewed Original ResearchConceptsStructure-function insightsG protein-coupled receptorsNovel candidate genesFirst extracellular loopProtein-coupled receptorsReceptor activity modifying proteinMutant resultsPlasma membraneCandidate genesGenetic mouse modelsExtracellular loopFrame deletionBiochemical assaysGenetic ablationReceptor chaperoneLymphatic endothelialModifying proteinsCalcitonin receptor-like receptorHuman physiologyEmbryonic demiseChaperonesMouse modelLymphatic dysplasiaReceptorsGenesPathway of Maternal Serotonin to the Human Embryo and Fetus
Kliman HJ, Quaratella SB, Setaro AC, Siegman EC, Subha ZT, Tal R, Milano KM, Steck TL. Pathway of Maternal Serotonin to the Human Embryo and Fetus. Endocrinology 2018, 159: 1609-1629. PMID: 29381782, DOI: 10.1210/en.2017-03025.Peer-Reviewed Original ResearchAnimalsATP Binding Cassette Transporter, Subfamily B, Member 1Connexin 43FemaleFetusHumansMaternal-Fetal ExchangeMiceMonoamine OxidaseOctamer Transcription Factor-3PlacentaPregnancyPregnancy Trimester, FirstPregnancy Trimester, SecondSerotoninSerotonin Plasma Membrane Transport ProteinsTrophoblastsTryptophan HydroxylaseType I interferons instigate fetal demise after Zika virus infection
Yockey LJ, Jurado KA, Arora N, Millet A, Rakib T, Milano KM, Hastings AK, Fikrig E, Kong Y, Horvath TL, Weatherbee S, Kliman HJ, Coyne CB, Iwasaki A. Type I interferons instigate fetal demise after Zika virus infection. Science Immunology 2018, 3 PMID: 29305462, PMCID: PMC6049088, DOI: 10.1126/sciimmunol.aao1680.Peer-Reviewed Original ResearchConceptsZika virus infectionZIKV infectionI IFNsI interferonType I interferonGrowth restrictionFetal demiseVirus infectionSevere fetal growth restrictionType I IFNsChorionic villous explantsAdverse fetal outcomesCongenital viral infectionFetal growth restrictionMaternal-fetal barrierType IFunctional type IPlacental damageFetal outcomesPregnancy complicationsEarly pregnancyFetal resorptionZIKV diseasePregnant damsSpontaneous abortion
2017
Estimated Placental Volume and Gestational Age
Isakov KMM, Emerson JW, Campbell KH, Galerneau F, Anders AM, Lee YK, Subramanyam P, Roberts AE, Kliman HJ. Estimated Placental Volume and Gestational Age. American Journal Of Perinatology 2017, 35: 748-757. PMID: 29281842, DOI: 10.1055/s-0037-1615285.Peer-Reviewed Original ResearchConceptsGestational ageBirth weightPlacental volumeSignificant placental pathologyWeeks gestational agePlacental pathologyUltrasound scanClinical utilityNormative curvesMicroscopic evaluationPatientsFurther validationVariety of settingsAgePercentileEPVDifferent populationsSubanalysisGestationNewbornsPlacentaPathologyFirst-trimester screening for early and late preeclampsia using maternal characteristics, biomarkers, and estimated placental volume
Sonek J, Krantz D, Carmichael J, Downing C, Jessup K, Haidar Z, Ho S, Hallahan T, Kliman HJ, McKenna D. First-trimester screening for early and late preeclampsia using maternal characteristics, biomarkers, and estimated placental volume. American Journal Of Obstetrics And Gynecology 2017, 218: 126.e1-126.e13. PMID: 29097177, DOI: 10.1016/j.ajog.2017.10.024.Peer-Reviewed Original ResearchConceptsLate-onset preeclampsiaEarly-onset preeclampsiaFirst-trimester screeningWeeks' gestationMaternal characteristicsPlacental volumeUterine artery pulsatility indexArtery pulsatility indexRisk of preeclampsiaAddition of biomarkersDiagnosis of preeclampsiaDetection rateFalse positive rateMaternal biomarkersCombination of markersLate preeclampsiaPerinatal morbidityCohort studyOnset preeclampsiaArterial pressurePulsatility indexFirst trimesterMedical historySerum biomarkersMedical recordsPlacental 11 β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) expression very early during human pregnancy
Salvante KG, Milano K, Kliman HJ, Nepomnaschy PA. Placental 11 β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) expression very early during human pregnancy. Journal Of Developmental Origins Of Health And Disease 2017, 8: 149-154. PMID: 28112069, DOI: 10.1017/s2040174416000611.Peer-Reviewed Original ResearchConceptsProtective roleHydroxysteroid dehydrogenase type 2Intra-uterine growth restrictionType 2 expressionUterine endometrial glandsCritical protective roleDehydrogenase type 2Maternal-fetal exchangeHypothesized protective roleColumnar epithelial cellsGlucocorticoid exposureEndometrial glandsHuman pregnancyBirth weightGrowth restrictionCortisol exposurePlacental expressionBioactive cortisolHuman fetusesType 2Postnatal developmentPhysiologic stressEpithelial cellsImmunocytochemical analysisDevelopmental outcomesLuteal start vaginal micronized progesterone improves pregnancy success in women with recurrent pregnancy loss
Stephenson MD, McQueen D, Winter M, Kliman HJ. Luteal start vaginal micronized progesterone improves pregnancy success in women with recurrent pregnancy loss. Fertility And Sterility 2017, 107: 684-690.e2. PMID: 28081870, DOI: 10.1016/j.fertnstert.2016.11.029.Peer-Reviewed Original ResearchConceptsPregnancy successEndometrial biopsySubsequent pregnancyLH surgePregnancy lossVaginal micronized progesteroneObservational cohort studyUnexplained pregnancy lossRecurrent pregnancy lossCohort of womenCyclin E expressionMicronized progesteronePrior pregnancyCohort studyOngoing pregnancyConcomitant findingsEndometrial glandsOdds ratioInclusion criteriaMAIN OUTCOMEPregnancyE expressionWomenCohortWeeks