Autistic Disorder; Endometrium; Female Urogenital Diseases and Pregnancy Complications; Infertility; Placenta; Pregnancy; Reproductive Medicine
Public Health Interests
Autism; Infertility; Pregnancy; Prenatal/Fetal Development
WHRY Pilot Project Program Investigators
Harvey J. Kliman has, in addition to an M.D., a Ph.D. in cellular biochemistry from the University of Chicago. He is currently a Research Scientist in the Department of Obstetrics and Gynecology, Yale University School of Medicine and the Director of the Reproductive and Placental Research Unit with a special interest in infertility and pregnancy complications. He has three areas of research interest:
- Implantation research;
- Using the placenta to predict autism and other genetic abnormalities;
- Validating and putting into clinical practice the Estimated Placental Volume (EPV) methodology.
Extensive Research Description
Harvey J. Kliman is currently a Research Scientist in the Department of Obstetrics and Gynecology, Yale University School of Medicine and the Director of the Reproductive and Placental Research Unit with a special interest in infertility and pregnancy
complications. His has three areas of research interest: Menstrual Cycle Regulation and Embryo Implantation Research
Menstrual cycle regulation is a critical step in embryo implantation and successfully achieving pregnancy. Since a majority of cases of unexplained infertility may result from implantation failure, there is a need to assess the endometrium accurately for defects that could preclude implantation. Current tools for endometrial evaluation, however, are limited. Based on endometrial expression of cyclin E and p27, we have developed a patented endometrial function test (EFT®) which allows us to evaluate at a molecular level the menstrual cycle regulatory cyclins and to differentiate between normally and abnormally developing, endometrium. Ultimately, we hope this test will prove useful to reproductive endocrinologists in evaluating menstrual cycle irregularities as well as implantation potential. In addition, given that cyclin E and p27 are regulated by estrogen and progesterone, this test may have a role in evaluating the effects of these hormones’ exogenous administration in infertility treatments as well as in other circumstances such as hormone replacement therapy of peri- and post-menopausal women and in clinical conditions that are known to alter or disrupt normal menstrual cycle function. Currently the EFT is used to evaluate patients with infertility and recurrent pregnancy loss. The full potential of these markers will need to be established with prospective, case-controlled multi-center trials that examine different groups of infertility patients to investigate the accuracy of the EFT in predicting pregnancy outcomes in natural cycles, IVF, and donor oocyte patients, work that is currently underway in our laboratory.
Structural Defects in the Placenta Suggest the Presence of Genetic Defects in the Fetus At the basis of the structure of biological systems are genes that regulate the development of the cells that make up the tissues and organs. We humans start off as a symmetrical ball of cells. Even as our first 50 cells begin to separate themselves into an inner cell mass (which will become the embryo, fetus and, eventually, baby) and the trophoblasts (which will become the placenta), genes are regulating the creation of the developmental axes that will form the basis of the entire organism. Defects in the genes that regulate these processes lead to a wide range of embryonic, fetal and neonatal defects, from minor cosmetic abnormalities, to disasters that terminate pregnancy within a few days to weeks after fertilization. Since the placenta and fetus share the same genome, genetic defects in the fetus are often mirrored in the placenta as abnormal growth patterns. The cellular basis of these placental growth patterns is the dynamic relationship between cytotrophoblast replication and differentiation towards syncytiotrophoblast. We have identified an abnormal growth pattern of the trophoblast layers which appears to be associated with genetic defects in the fetus: trophoblast invaginations. When these deep pits are cut in cross section they appear as trophoblast inclusions. We have shown that compared to the placentas from normal children there is a significantly increased frequency of trophoblast inclusions in cases of known chromosomal diseases, such as trisomy 21, 13 and 18, as well as triploidy (three sets of chromosomes). More recently we have demonstrated an increased frequency of inclusions in cases of subtle genetic diseases, including autism.
Novel method of determining placental volume reduces the risk of intrauterine growth restriction (IUGR) and intrauterine fetal demise (IUFD)
We have developed a mathematical solution to accurately estimate intrauterine placental volume. Care givers of pregnant women currently only track the growth of the fetus without any insight into the growth of the placenta, despite its importance in prenatal development. The placenta is the critical organ responsible for both respiratory and nutritional support of the fetus. In situations where the placenta is significantly small or large for gestational age, a care giver may not have any warning that the fetus is compromised or near death until it is too late. Fetal complications due to placental abnormalities occur in as many as 20% of pregnancies. Clinical intervention is possible with early detection. This invention allows for assessment of in utero placental volume using three basic measurements: width, height and thickness of the placenta. There are no alternative Currently there are no simple, reliable or convenient methods to determine the volume and/or weight of a placenta prior to delivery available today. We propose to use this method to generate normative data on a large population of pregnant women which can be used to automatically flag abnormal placental size. Such normative data will form the basis for the generation of tables which can be incorporated into future ultrasound devices. This will empower future caregivers to identify and intervene in cases where an IUFD would have been the first indication of any problems. This method will create a “placenta tank” gauge where none has existed.This compromises a health care provider’s ability to assess the state of a pregnancy since the placenta is the critical organ responsible for both respiratory and nutritional support of the fetus. Currently care givers of pregnant women only track the growth of the fetus without any insight into the growth the placenta. In situations where the placenta is significantly small or large for gestational age a care giver may not have any warning that the fetus is compromised or near death until it is too late. This invention teaches the use of mathematical equations to estimate the in utero placental volume using three basic measurements: width, height and thickness of the placenta.
Implantation research Using the placenta to predict autism and other genetic abnormalities
Validating and putting into clinical practice the Estimated Placental Volume (EPV) methodology
Luteal start vaginal micronized progesterone improves pregnancy success in women with recurrent pregnancy loss.
Stephenson MD, McQueen D, Winter M, Kliman HJ. Fertil Steril. 2017 Mar;107(3):684-690.e2. doi: 10.1016/j.fertnstert.2016.11.029. Epub 2017 Jan 9.
Utilizing two-dimensional ultrasound to develop normative curves for estimated placental volume.
Arleo EK, Troiano RN, da Silva R, Greenbaum D, Kliman HJ. Am J Perinatol. 2014 Sep;31(8):683-8. doi: 10.1055/s-0033-1357265. Epub 2013 Oct 9.
Trophoblast Inclusions are Significantly Increased in the Placentas of Children in Families at Risk for Autism
Walker CK, Anderson KW, Milano KM, Ye S, Tancredi DJ, Pessah IN, Hertz-Picciotto I, Kliman HJ. (2013) Trophoblast Inclusions are Significantly Increased in the Placentas of Children in Families at Risk for Autism, Biological Psychiatry, http://dx.doi.org/10.1016/j.biopsych.2013.03.006
Placental protein 13 and decidual zones of necrosis: an immunologic diversion that may be linked to preeclampsia.
Kliman HJ, Sammar M, Gimpel Y, Lynch SK, Milano SK, Pick E, Bejar J, Arad A, Lee JJ, Meiri H, Gonen R. (2012) Placental protein 13 and decidual zones of necrosis: an immunologic diversion that may be linked to preeclampsia. Reproductive Sciences, 19:12-26.
Determination of placental weight using two-dimensional sonography and volumetric mathematic modeling
Azpurua HJ, Funai EF, Coraluzzi L, Sasson I, Doherty L, Kliman M, Kliman HJ. (2010) Determination of placental weight using two-dimensional sonography and volumetric mathematic modeling, Am J Perinatology, 27:151-155.
Timing of Fetal Meconium Absorption by Amnionic Macrophages.
Funai EF, Labowsky AT, Drewes CE, Kliman HJ. (2009) Timing of Fetal Meconium Absorption by Amnionic Macrophages. Am J Perinatology, 26:93-7.
The fetus, not the mother, elicits maternal immunologic rejection: lessons from discordant dizygotic twin placentas.
Yusuf K, Kliman HJ. (2008) The fetus, not the mother, elicits maternal immunologic rejection: lessons from discordant dizygotic twin placentas. J Perinat Med, 36:291-296.
Placental Trophoblast Inclusions in Autism Spectrum Disorder.
Anderson GM, Jacobs-Stannard A, Chawarska K, Volkmar FR, Kliman HJ. (2007) Placental Trophoblast Inclusions in Autism Spectrum Disorder. Biological Psychiatry, 61:487-91.
The Placenta May Predict the Baby.
Kliman HJ, Segel L, The Placenta May Predict the Baby., Journal of Theoretical Biology, 225(1):143-5, Nov 2003 Abstract
Improved Endometrial Assessment Using Cyclin E and P27
Dubowy RL, Feinberg RF, Keefe DL, Doncel GF, Williams SC, McSweet JC, Kliman HJ, Improved Endometrial Assessment Using Cyclin E and P27, Fertility and Sterility, 80(1):146-56, July 2003 Abstract
Full List of PubMed Publications
- 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 Jan 26; 2018 Jan 26. PMID: 29381782
- 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. Sci Immunol. 2018 Jan 5. PMID: 29305462
- 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. Am J Obstet Gynecol. 2018 Jan; 2017 Oct 31. PMID: 29097177
- Isakov KMM, Emerson JW, Campbell KH, Galerneau F, Anders AM, Lee YK, Subramanyam P, Roberts AE, Kliman HJ: Estimated Placental Volume and Gestational Age. Am J Perinatol. 2017 Dec 27; 2017 Dec 27. PMID: 29281842
- Stephenson MD, McQueen D, Winter M, Kliman HJ: Luteal start vaginal micronized progesterone improves pregnancy success in women with recurrent pregnancy loss. Fertil Steril. 2017 Mar; 2017 Jan 9. PMID: 28081870
- Flannery CA, Saleh FL, Choe GH, Selen DJ, Kodaman PH, Kliman HJ, Wood TL, Taylor HS: Differential Expression of IR-A, IR-B and IGF-1R in Endometrial Physiology and Distinct Signature in Adenocarcinoma. J Clin Endocrinol Metab. 2016 Jul; 2016 Apr 18. PMID: 27088794
- Kliman HJ: Comment on "the placenta harbors a unique microbiome". Sci Transl Med. 2014 Sep 17. PMID: 25232175
- Arleo EK, Troiano RN, da Silva R, Greenbaum D, Kliman HJ: Utilizing two-dimensional ultrasound to develop normative curves for estimated placental volume. Am J Perinatol. 2014 Sep; 2013 Oct 9. PMID: 24108663
- Walker CK, Anderson KW, Milano KM, Ye S, Tancredi DJ, Pessah IN, Hertz-Picciotto I, Kliman HJ: Trophoblast inclusions are significantly increased in the placentas of children in families at risk for autism. Biol Psychiatry. 2013 Aug 1; 2013 Apr 25. PMID: 23623455
- Trivedi S, Joachim M, McElrath T, Kliman HJ, Allred EN, Fichorova RN, Onderdonk A, Heitor F, Chaychi L, Leviton A, Majzoub JA, Extremely Low Gestational Age Newborns (ELGAN) study investigators.: Fetal-placental inflammation, but not adrenal activation, is associated with extreme preterm delivery. Am J Obstet Gynecol. 2012 Mar; 2011 Dec 16. PMID: 22264652
- Kliman HJ, Sammar M, Grimpel YI, Lynch SK, Milano KM, Pick E, Bejar J, Arad A, Lee JJ, Meiri H, Gonen R: Placental protein 13 and decidual zones of necrosis: an immunologic diversion that may be linked to preeclampsia. Reprod Sci. 2012 Jan; 2011 Oct 11. PMID: 21989657
- Azpurua H, Funai EF, Coraluzzi LM, Doherty LF, Sasson IE, Kliman M, Kliman HJ: Determination of placental weight using two-dimensional sonography and volumetric mathematic modeling. Am J Perinatol. 2010 Feb; 2009 Aug 3. PMID: 19653142
- Funai EF, Labowsky AT, Drewes CE, Kliman HJ: Timing of fetal meconium absorption by amnionic macrophages. Am J Perinatol. 2009 Jan; 2008 Nov 21. PMID: 19031358
- Hecht JL, Allred EN, Kliman HJ, Zambrano E, Doss BJ, Husain A, Pflueger SM, Chang CH, Livasy CA, Roberts D, Bhan I, Ross DW, Senagore PK, Leviton A, Elgan Study Investigators.: Histological characteristics of singleton placentas delivered before the 28th week of gestation. Pathology. 2008 Jun. PMID: 18446627
- Rackow BW, Kliman HJ, Taylor HS: GnRH antagonists may affect endometrial receptivity. Fertil Steril. 2008 May; 2008 Apr 14. PMID: 18410932
- Yusuf K, Kliman HJ: The fetus, not the mother, elicits maternal immunologic rejection: lessons from discordant dizygotic twin placentas. J Perinat Med. 2008. PMID: 18598117
- Hecht JL, Onderdonk A, Delaney M, Allred EN, Kliman HJ, Zambrano E, Pflueger SM, Livasy CA, Bhan I, Leviton A, ELGAN Study Investigators.: Characterization of chorioamnionitis in 2nd-trimester C-section placentas and correlation with microorganism recovery from subamniotic tissues. Pediatr Dev Pathol. 2008 Jan-Feb. PMID: 18237241
- Anderson GM, Jacobs-Stannard A, Chawarska K, Volkmar FR, Kliman HJ: Placental trophoblast inclusions in autism spectrum disorder. Biol Psychiatry. 2007 Feb 15; 2006 Jun 23. PMID: 16806106
- Catalanotti JS, Spandorfer SD, Barmat LI, Rosenwaks Z, McSweet JC, Kliman HJ: Mouse ascites Golgi mucin expression abnormalities in natural cycle endometrial biopsies predict subsequent in vitro fertilization-embryo transfer (IVF-ET) failure in patients with previous IVF-ET failures. Fertil Steril. 2006 Jan. PMID: 16412771
- Sarno JL, Kliman HJ, Taylor HS: HOXA10, Pbx2, and Meis1 protein expression in the human endometrium: formation of multimeric complexes on HOXA10 target genes. J Clin Endocrinol Metab. 2005 Jan; 2004 Oct 19. PMID: 15494461
- Rejniak KA, Kliman HJ, Fauci LJ: A computational model of the mechanics of growth of the villous trophoblast bilayer. Bull Math Biol. 2004 Mar. PMID: 14871565
- Kliman HJ, Segel L: The placenta may predict the baby. J Theor Biol. 2003 Nov 7. PMID: 14559066
- Dubowy RL, Feinberg RF, Keefe DL, Doncel GF, Williams SC, McSweet JC, Kliman HJ: Improved endometrial assessment using cyclin E and p27. Fertil Steril. 2003 Jul. PMID: 12849817
- Meaddough EL, Olive DL, Gallup P, Perlin M, Kliman HJ: Sexual activity, orgasm and tampon use are associated with a decreased risk for endometriosis. Gynecol Obstet Invest. 2002. PMID: 12053101