John Kingdom

Gordon C. Leitch Chair, Department of Obstetrics and Gynaecology, University of Toronto
Rose Torno Chair in Obstetrics & Gynaecology, Medical Imaging, Pathology & Physiology
Rose Torno Chair in Obstetrics & Gynaecology at Mount Sinai Hospital

Research Synopsis

Areas of Expertise:         
Placental Development and Pathology
Ultrasound Imaging of the Placenta
Molecular pathology of preeclampsia/IUGR
Non-anticoagulant actions of Heparin
Screening for “Placental Insufficiency” disorders
Invasive placentation

Research Interests:  All my research efforts are focused on aspects of placental development and pathology.

My clinical research interests focus on screening and prevention of placental complications of pregnancy. These interests focus on placental pathology and include an interest in invasive placentation (placenta accrete).
My basic science interests focus on; the molecular control of syncytio-trophoblast formation and function, the interactions of the placenta with heparin and the molecular pathology of the placenta in pregnancies complicated by severe pre-eclampsia and/or severe intrauterine growth restriction.

Keywords:  Development, Doppler, Hemodynamics, Heparin, Molecular Biology, Pathology, Placenta, Placental Ultrasound, Pre-eclampsia, Trophoblast

Detailed Description:  Severe placental dysfunction is characterized by reduced/unstable utero-placental blood flow (from the mother to the inter-villous space of the placenta) and defective elaboration of the floating (chorionic) villi that extract nutrients and oxygen for the developing fetus. The histopathology includes variable degrees of; vasculopathy of the decidual portions of the utero-placental arteries, arrested feto-placental angiogenesis and defects in the outer syncytiotrophoblast (SCT) layer covering the floating villi. Secondary pathologies (hemorrhage, infarction, maternally-derived inflammation) compound the initial developmental abnormalities of the extra-villous and villous trophoblast.

My laboratory at the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, focuses on the physiologic control mechanisms controlling SCT formation, which is a balance between cytotrophoblast proliferation and cell—syncytium fusion of post-mitotic differentiated cells, and the communication pathways (involving soluble proteins and micro-particles), between the syncytiotrophoblast and the maternal arterial vasculature.  The two major clinical manifestations of severe placental dysfunction in humans are severe forms of pre-eclampsia [sPE] and IUGR.  sPE refers to hypertension accompanied by multi-organ dysfunction, especially renal injury; it is a systemic vasculopathy characterized by excess secretion, by the SCT layer of the placenta, of splice-variant anti-angiogenic proteins including sFlt1 and by the excess production of an array of micro-particles, especially exosomes that transport micro-RNAs in a protected manner around the body. Serum from women with sPE arrests in-vitro angiogenesis but is reversed by pre-exposure of placental villi to heparin. In human trials, heparin reduces the risk of recurrent sPE, though curiously this is accompanied by an elevation in sFlt1. Our current hypothesis, funded by a March 2013 competition CIHR grant, is that heparin exerts complex non-anti-coagulant actions – specifically heparin may promote re-formation of the SCT where expression of nitric oxide synthase and hemoxygenase may lead to restoration of the production of vasodilator gases (NO and CO) that in part mediate systemic vasodilation of normal pregnancy. Heparin may also interfere with the release or entry, of exosomes into target cells. 

My laboratory is integrated within the 6th floor reproductive sciences program at the Lunenfeld directed by Dr. Stephen Lye. The heparin research program has an in-vivo mouse aim, which is conducted in collaboration with Dr. John Sled (and until 2014, Dr S Lee Adamson).  The human trophoblast biology research collaborates with Main Campus (Dr. Brian Cox, PhD, Department of Physiology) for his expertise in systems biology and with Dr. Jeff Wrana (also at LTRI) for his expertise in micro-particle biology and miRNA sequencing.

These basic research programs are integrated with the Placenta Clinic at Mount Sinai Hospital (www.mountsinai.on.ca/care/placenta-clinic) where my clinical research program focuses on screening, diagnosis and management of pregnancies at risk of a variety of placental complications. This program, together with the larger Maternal-Fetal Medicine Division, manages a large number of pregnancies with these problems. At delivery, our Biobank team samples the delivered placenta using protocols for future molecular pathology, genetics and epigenetics studies on a case-control basis. This program is integrated with our specialty perinatal pathology program (Dr. Sarah Keating, MD) for correlative research studies. A variety of clinical and translational research questions are pursued by trainees in this environment. The “placental health study in Nulliparous Women” is a recently-completed prospective two-year screening program funded by MSH-UHN AFP Innovation fund,, in 1100 women at Mount Sinai Hospital. The program is evaluating the ability of clinical risk scoring, blood tests, and ultrasound imaging of the placenta, to identify women at most risk of sPE and/or IUGR/stillbirth. Our current work in this area is examining the role of advanced 3D ultrasound imaging methods to refine the “placental morphology” component, together with the incorporation of pro-/anti-angiogenic markers (sflt1 and PlGF) to maximize the precision of our screening algorithm.

The placenta clinic support a comprehensive program of research at SickKids investigating how the fetal heart protects the fetal brain by ensuring that it is properly oxygenated, and in turn how these regulatory mechanism can fail in both IUGR pregnancies and in pregnancies where the fetus is found to have complex congenital heart disease.

The placenta clinic interacts with the Department of Cardiology at Mount Sinai Hospital to understand the in-vivo hemodynamic actions of heparin that may promote optimal vascular function to reduce the risk of severe pre-eclampsia in women at high risk, based on placental function testing ion the 16-22 week window.

Recent Publications

Two-dimensional sonographic assessment of maximum placental length and thickness in the second trimester: a reproducibility study.
Milligan N, Rowden M, Wright E, Melamed N, Lee YM, Windrim RC, Kingdom JC. J Matern Fetal Neonatal Med. 2014 Nov 25:1-7. [Epub ahead of print]
PMID:25367554

Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open-label randomised trial.
Rodger MA, Hague WM, Kingdom J, Kahn SR, Karovitch A, Sermer M, Clement AM, Coat S, Chan WS, Said J, Rey E, Robinson S, Khurana R, Demers C, Kovacs MJ, Solymoss S, Hinshaw K, Dwyer J, Smith G, McDonald S, Newstead-Angel J, McLeod A, Khandelwal M, Silver RM, Le Gal G, Greer IA, Keely E, Rosene-Montella K, Walker M, Wells PS; TIPPS Investigators.
Lancet. 2014 Nov 8;384(9955):1673-83. doi: 10.1016/S0140-6736(14)60793-5. Epub 2014 Jul 24.
PMID: 25066248

Low pregnancy-associated plasma protein A level in the first trimester.
Huynh L, Kingdom J, Akhtar S.
Can Fam Physician. 2014 Oct;60(10):899-903.
PMID: 25316741

Unfractionated heparin and placental pathology in high-risk pregnancies: secondary analysis of a pilot randomized controlled trial.
D'Souza R, Keating S, Walker M, Drewlo S, Kingdom J.
Placenta. 2014 Oct;35(10):816-23. doi: 10.1016/j.placenta.2014.07.010. Epub 2014 Jul 24.
PMID: 25128485

Identification of a novel neutrophil population: proangiogenic granulocytes in second-trimester human decidua.
Amsalem H, Kwan M, Hazan A, Zhang J, Jones RL, Whittle W, Kingdom JC, Croy BA, Lye SJ, Dunk CE.
J Immunol. 2014 Sep 15;193(6):3070-9. doi: 10.4049/jimmunol.1303117. Epub 2014 Aug 18.
PMID: 25135830

Comparative efficacy of uterotonic agents: in vitro contractions in isolated myometrial strips of labouring and non-labouring women.
Balki M, Erik-Soussi M, Kingdom J, Carvalho JC.
Can J Anaesth. 2014 Sep;61(9):808-18. doi: 10.1007/s12630-014-0190-1. Epub 2014 Jun 7.
PMID: 24906304

Intrapartum interventions for singleton pregnancies arising from assisted reproductive technologies.
Sun LM, Lanes A, Kingdom JC, Cao H, Kramer M, Wen SW, Wu J, Chen Y, Walker MC.
J Obstet Gynaecol Can. 2014 Sep;36(9):795-802.
PMID: 25222358

Web-based education and attitude to delivery by caesarean section in nulliparous women.
Kulkarni A, Wright E, Kingdom J.
J Obstet Gynaecol Can. 2014 Sep;36(9):768-75.
PMID: 25222355

Altered hemodynamics and hyperuricemia accompany an elevated sFlt-1/PlGF ratio before the onset of early severe preeclampsia.
Doherty A, Carvalho JC, Drewlo S, El-Khuffash A, Downey K, Dodds M, Kingdom J.
J Obstet Gynaecol Can. 2014 Aug;36(8):692-700.
PMID: 25222164

Klippel-Trenaunay-Weber syndrome-associated arterial and venous malformations in the lower uterine segment.
Bouchard-Fortier G, El-Chaar D, Hawrylyshyn P, Kingdom J, Lyons E.
J Obstet Gynaecol Can. 2014 Aug;36(8):665-6. English, French. No abstract available.
PMID: 25222156

Appointments