John Kingdom

My post-graduate training and subsequent academic career in the UK and Toronto, Canada, now spanning 38 years, has been characterized by a focus on basic science, translational and clinical research aspects of “placentology”; an emerging discipline within Maternal-Fetal Medicine dedicated towards understanding the basis of the major placental dysfunction disorders so as to improve clinical outcomes.

Since 1999 I have developed a multidisciplinary “placenta clinic” at a major academic perinatal center, served as MFM fellowship director in Canada’s largest program for 10 years, and moved on through the MFM Division Head position to become Chair of OBGYN since July 2013. I therefore bring to the project not only my advanced clinical skills in management of complex pregnancies (for research recruitment, antenatal and delivery management), but also a range of translational research experience at this top-5 ranked Medical School for the past 23 years.

I am an acknowledged leader in fetal/placental imaging in screening and management of major placental complications, especially preeclampsia and FGR. I am actively involved in training MFM fellows and graduate students and post-docs, who focus on these pregnancy complications in their chosen research.

I have a sustained interest and publication track record in all major placental complications, and hold several cross appointments in Physiology, Medical Imaging and in Pathology, so as to contribute these dimensions to the proposal at a competitive level. My peer-reviewed grant activity, including a recent five-year Human Placenta project grant from the NIH (PI John Sled) and my publication productivity attest to these skills.

I enjoy creative academic writing and mentorship of senior trainees and junior faculty, and so bring these additional skills to multidisciplinary research proposals such as this.

Research Synopsis

1. Placental imaging and pathology of FGR

My early publications arising from my MD thesis focused on dysregulation of feto-placental vasomotor tone in IUGR, but then led on to an interest in the microvasculature; my most significant early publication was the demonstration of the major capillary defects in placental villi in the most extreme forms of FGR which led on to an international workshop on the placental basis of fetal hypoxia for which I was awarded the International Placenta Association Castellucci Prize in 1997.

My interest in placental pathology of FGR has been sustained in Toronto due to our clinical resources and to a long-standing productive relationship (27 publications) with a series of Section Head perinatal pathologists (Dr.s S. Keating, Eric Morgen & A. Parks).

• Krebs C, Macara LM, Leiser R, Bowman AW, Greer IA, Kingdom JC. Intrauterine growth restriction with absent end-diastolic flow velocity in the umbilical artery is associated with maldevelopment of the placental terminal villous tree.. Am J Obstet Gynecol. 1996 Dec;175(6):1534-42.
• Kingdom JC, Kaufmann P. Placenta. Oxygen and placental villous development: origins of fetal hypoxia. 1997 Nov;18(8):613-21; discussion 623-6
• Proctor LK, Toal M, Keating S, Chitayat D, Okun N, Windrim RC, Smith GC, Kingdom JC. Placental size and the prediction of severe early-onset intrauterine growth restriction in women with low pregnancy-associated plasma protein-A. Ultrasound Obstet Gynecol. 2009 Sep;34(3):274-82. 
• Porat S, Fitzgerald B, Wright E, Keating S, Kingdom JC. Placental hyperinflation and the risk of adverse perinatal outcome. Ultrasound Obstet Gynecol. 2013 Sep;42(3):315-21. 

2. Non-anticoagulant actions of heparin

Heparin, in particular low-molecular weight heparin (LMWH) appears to prevent recurrences of the most severe forms of placental dysfunction.

Following delivery the placentas are commonly infarcted, therefore there is a widely-held view amongst MFMs and OBs that heparin is a “placental anticoagulant”. I believe this to be wrong. We have shown that multifocal infarction associates strongly with disorders of the development of placental villi, rather than with any demonstrable maternal thrombophilia.

Next, I led a novel design pilot randomized control trial of heparin in this context, recruiting women based on multiply-abnormal tests of placental function and subjecting their placentas to pathologic analysis. Most placentas were abnormal, but no differences in infarction rates were seen between the 2 trial arms.

In-vitro, I mentored a resident and my then post-doc, to demonstrate that heparin and especially LMWH, was able to reverse the strongly anti-angiogenic properties of media conditioned by 1st trimester placental villi, for which the resident (now on faculty at UofT), won the American College of OBGYN Resident Research prize. In tandem, we were able to show that heparin and LMWH both achieve these pro-angiogenic responses despite elevating 3-4-fold circulating levels of the VEGF decoy protein sflt-1, based on which we have coined the term the “heparin-sflt-1 paradox” of pre-eclampsia. These observations drive my current CIHR grants. 

• Franco C, Walker M, Robertson J, Fitzgerald B, Keating S, McLeod A, Kingdom JC. Placental infarction and thrombophilia. Obstet Gynecol. 2011 Apr;117(4):929-34. 
• D'Souza R, Keating S2, Walker M1, Drewlo S1, Kingdom J. Unfractionated heparin and placental pathology in high-risk pregnancies: secondary analysis of a pilot randomized controlled trial. Placenta. 2014 Oct;35(10):816-23. 
• Sobel ML, Kingdom J, Drewlo S. Angiogenic response of placental villi to heparin. Obstet Gynecol. 2011 Jun;117(6):1375-83. 
• Drewlo S, Levytska K, Sobel M, Baczyk D, Lye SJ, Kingdom JC. Heparin promotes soluble VEGF receptor expression in human placental villi to impair endothelial VEGF signaling. J Thromb Haemost. 2011 Dec;9(12):2486-97
• McLaughlin K, Snelgrove JW, Audette MC, Syed A, Hobson SR, Windrim RC, Melamed N, Carmona S, Kingdom JC. PlGF (Placental Growth Factor) Testing in Clinical Practice: Evidence from a Canadian Tertiary Maternity Referral Center. Hypertension. 2021 Jun;77(6):2057-2065. 
• McLaughlin K, Hobson SR, Ravi Chandran A, Agrawal A, Windrim RC, Parks WT, Bowman AW, Sovio U, Smith GC, Kingdom JC. Circulating Maternal Placenta Growth Factor Responses to Low Molecular Weight Heparin in Pregnant Patients at Risk of Placental Dysfunction: A Pilot Study. Am J Obstet Gynecol. 2021 Aug 27:S0002-9378(21)00961-3. 

3. Molecular Placental Pathology of Pre-eclampsia and FGR

My National grant funding for the period 2003-2012 was focused on the molecular control of syncytiotrophoblast formation and shedding, and its disruption in diseased states.

My major contribution in this period was the development of the ‘floating villous explant model”, as opposed to netwell explants, such that the in-vivo system whereby villi are bathed in blood, is recapitulated. We were able to demonstrate that the human homolog (GCM1) of the murine trophoblast transcription factor glial cell missing-1 (Gcm-1) had an analgous function. Earlier, our work exploring the role of fibroblast growth factor-4 (FGF4) in this system uncovered the bi-potential behavior of villous cytotrophopblasts, since when the outer syncytiotrophoblast layer is cleaved off enzymatically, the exposure to FGF4 redirects the exposed cytotrophoblasts to proliferate along the extra-villous pathway.

More recently, we have demonstrated the upstream regulation of GCM1 by DREAM and have now gone on to show that the post-transcriptional regulatory process of hyperSUMOylation is present in severe pre-eclamptic placentas and may be induced by hypoxia-reperfusion injury and pro-inflammatory cytokines - 2015 Society for Reproductive Investigation abstract. We are currently studying how this post-transcriptional phenomenon may explain shifts in secretion from placental villi of pro-angiogenic to anti-angiogenic molecules that contribute to the maternal vasculopathy of severe pre-eclampsia. 

• Baczyk D, Drewlo S, Proctor L, Dunk C, Lye S, Kingdom J. Glial cell missing-1 transcription factor is required for the differentiation of the human trophoblast. Cell Death Differ. 2009 May;16(5):719-27. 
• Baczyk D, Dunk C, Huppertz B, Maxwell C, Reister F, Giannoulias D, Kingdom JC. Bi-potential behaviour of cytotrophoblasts in first trimester chorionic villi. Placenta. 2006 Apr-May;27(4-5):367-74. 
• Baczyk D, Kibschull M, Mellstrom B, Levytska K, Rivas M, Drewlo S, Lye SJ, Naranjo JR, Kingdom JC.
• DREAM mediated regulation of GCM1 in the human placental trophoblast. PLoS One. 2013;8(1):e51837. 
• Baczyk D, Drewlo S, Kingdom JC. Emerging role of SUMOylation in placental pathology. Placenta. 2013 Jul;34(7):606-12. 
• Armistead B, Kadam L, Siegwald E, McCarthy FP, Kingdom JC, Kohan-Ghadr HR, Drewlo S.Induction of the PPARγ (Peroxisome Proliferator-Activated Receptor γ)-GCM1 (Glial Cell Missing 1) Syncytialization Axis Reduces sFLT1 (Soluble fms-Like Tyrosine Kinase 1) in the Preeclamptic Placenta. Hypertension. 2021 Jul;78(1):230-240.

4. Screening and Intervention to Prevent Placental Complications of Pregnancy 

We developed the concept of screening for “placental health” by incorporating placental morphologic assessment into an algorithm comprising uterine artery Doppler and maternal blood tests, initially in high-risk women. Subsequently we launched this as a screening program, to conduct a pilot randomized control trial of unfractionated heparin in screen-positive women to test the hypothesis that heparin would improve clinical outcomes via a non-anticoagulant mechanism.

We extended this work by performing non-invasive hemodynamic studies in screen-positive women, to show an asymptomatic phenotype (low cardiac output, high systemic vascular resistance, elevated circulating uric acid and sflt-1) that precedes overt preeclampsia by up to 4 weeks. We subsequently conducted the “placental health study” in 976 healthy nulliparous women, incorporating a structured clinical assessment, biomarkers, uterine artery Doppler and placental morphology, to predict chronic placental vascular disease.

• Toal M, Chan C, Fallah S, Alkazaleh F, Chaddha V, Windrim RC, Kingdom JC. Usefulness of a placental profile in high-risk pregnancies. Am J Obstet Gynecol. 2007 Apr;196(4):363.e1-7.
• Franco C, Walker M, Robertson J, Fitzgerald B, Keating S, McLeod A, Kingdom JC. Placental infarction and thrombophilia. Obstet Gynecol. 2011 Apr;117(4):929-34. 
• Doherty A, Carvalho JC, Drewlo S, El-Khuffash A, Downey K, Dodds M, Kingdom J. Altered hemodynamics and hyperuricemia accompany an elevated sFlt-1/PlGF ratio before the onset of early severe preeclampsia. J Obstet Gynaecol Can. 2014 Aug;36(8):692-700.
• Wright E, Audette MC, Ye X, Keating S, Hoffman B, Lye SJ, Shah PS, Kingdom JC. Maternal vascular malperfusion and adverse perinatal outcomes in low risk nulliparous women. Obstet Gynecol. 2017 Nov;130(5):1112-1120.
• McLaughlin K, Snelgrove JW, Audette MC, Syed A, Hobson SR, Windrim RC, Melamed N, Carmona S, Kingdom JC. PlGF (Placental Growth Factor) Testing in Clinical Practice: Evidence from a Canadian Tertiary Maternity Referral Center. Hypertension. 2021 Jun;77(6):2057-2065. 
• McLaughlin K, Snelgrove JW, Sienas LE, Easterling TR, Kingdom JC, Albright CM. Phenotype-Directed Management of Hypertension in Pregnancy. J Am Heart Assoc. 2022 Apr 5;11(7):e023694

Selected Publications

Co-Investigator. Volume-based outcomes for hysterectomy for Placenta Accreta Spectrum (PAS) disorders. Department of Obstetrics and Gynaecology, Mount Sinai Hospital/University Health Network Research Fund. Knox Ritchie Award. PI: Wilson Chan, Supervisor: Ally Murji; Co-Investigators: John Snelgrove; John Kingdom; Sebastian Hobson; Lisa Allen. 10,000 CAD. 2021 Jul – 2022 Jun

PI. Maternal Placenta Growth Factor (PlGF) testing as a Novel Strategy to Improve Patient/Staff Safety and Redirect Limited Obstetrical Ultrasound Resources. Roche Diagnostics, Division de/of Hoffmann-La Roche Limitée/Limited. Grant Program: COVID-19 Innovation Challenge. Co-Applicants: McLaughlin, K; Hobson, S Snelgrove, J; Windrim, R; Shapiro, J Carmona, S; Keunen, J. 560,000 CAD. 2020 Jul – 2023 Jun 

PI. Maternal Placenta Growth Factor (PlGF) testing as a Novel Strategy to Improve Patient/Staff Safety and Redirect Limited Obstetrical Ultrasound Resources. 2020 MSH UHN AMO COVID-19 Innovation Fund. Co-Applicants: McLaughlin,K; Hobson, S; Snelgrove, J; Windrim, R; Shapiro, J; Carmona, S; Keunen, J. 286,000 CAD. 2020. Apr – 2022 Mar 

Co-Applicant. The Artificial Placenta. Canadian Institutes of Health Research (CIHR). Project Grant: Fall 2019 and Spring 2020. Application #: 426942. PI: Seed M; Co-Applicants: Belik, J; Chaturvedi, R; De Queiroz Taniguchi, L; Flake, A; Floh, A; Haller, C; Jaeggi, E; Kingdom J; Macgowan, C; Maxwell, C; Maynes, J; McVey, M; Morrison, J; Collaboator: Selvaganapathy, Ri. 738,225 CAN. 2020 Apr – 2025 Mar 

Co-Applicant. Predicting and preventing brain injury in the antenatal period. Canadian Institutes of Health Research (CIHR). Project Grant: Fall 2019 and Spring 2020. Application #: 426282. PI: Sled, J Co-Applicant: Kingdom, J; Macgowan, C; Seed, M. 891,225 CAN. 2020 Apr – 2025 Mar 

Co-I. Understanding early life origins of sex difference in insulin sensitivity. Canadian Institutes of Health Research (CIHR). Catalyst Grant: Sex as a Variable in Biomedical Research – Institute for Gender and Health. Application #: 397411. PI: Luo, ZC.Collaborators: Briollais, L; Kingdom, J; Lye, S; Murphy, K; Pausova, Z. 75,000 CAD. 2018 May- 2020 Apr 

Co-Applicant. Toronto Perinatal Brain Protection Research Collaboration. Canadian Foundation for Innovation (CFI). Project Innovation Fund 2017. Application #: 36342. PI: Lee, S. Collaborators: Barrett, J; Cunningham, C; Kelly, E ;Kingdom, J; Macgowan, C; Miller, S; Scherer, S; Seed, M; Sled, J. Other users: Morgen, E; Mabbott, D; White, L; Blaser, S; Ryan, G; Windrim, R; Keunen, J; Shah, P; Jain, A; Deshpande, P; Melamed, N; Ng, E; Church, P; Glanc, P; Machnowska, M. 937,350 CAD. 2018 Mar – 2020 Mar 

Co-Applicant. In vitro optimization of oxytocin-induced myometrial contractility by propranolol: Potential applications in induction of labor and prevention of postpartum hemorrhage. Canadian Institutes of Health Research (CIHR). Project Grant – Fall 2017 and Spring 2018. Application #: RN356383-401071. PI: Balki, M; Co-Applicant: Kingdom, J; Collaborator(s): Carvalho, J; Lye, S. 91,800 CAD. 2018 Mar – 2019 Aug 

Co-Applicant. Ultrasound detection of placental pathology based on hemodynamics pulse wave reflection. Canadian Institutes of Health Research (CIHR). Project Grant – Fall 2016. Application #: 375704. PI: Sled, J; Macgowan, C. Collaborator(s): Kingdom, J. 799,425 CAD. 2017 Apr - 2022 Mar 

Co-I. Maternal hyperoxygenation in congenital heart disease. Thrasher Research Fund. PI: Seed, Michael. Collaborator(s): Co-PI: Miller, S; Honsberger, L; Co-I: Kingdom, J; McGowan, Cr. 248,61 USD. 2016 May - 2019 Apr 

Co-PI. Dynamic 3D MRI of the fetus: a new method for detecting abnormal blood flow and oxygenation during pregnancy. Canadian Institutes of Health Research (CIHR). Program Grant. Application #: 363519. PI: Macgowan, C;Collaborator(s): Kingdom, J; Seed, Michael T; Sled, JG. 542,795 CAD. 2016 Mar - 2021 Feb 

Co-I. Using novel population-based datasets to produce and implement clinical prediction models for preterm preeclampsia, stillbirth, maternal ICU and long-term cardiovascular disease among Canadian women. Canadian Institutes of Health Research (CIHR). Project Grant. Application #: 148512. PI: Ray, J. Collaborator(s): Berger, H; Blake, J; Geary, M; Kingdom, J; Maguire, J; Meloche, J; Morgen, E; Naugler, C; Park, A; Urquia, M; Van Wagner, V. 336,380 CAD. 2016 Mar - 2020 Feb 

Co-PI. The haemodynamics of intrauterine growth restriction. Canadian Institutes of Health Research (CIHR). Project Grant. Application #: 364866. PI: Seed, M; Kingdom, J; Morrison, Janna. Collaborator(s): Keunen, J; MacGowan, C; Sled, J. 676,584 CAD. 2016 Mar – 2019 Feb 

Co-PA. Brain development following late onset intrauterine growth restriction. Canadian Institutes of Health Research (CIHR). Project Grant. Application #: 364886. PI: Seed, M; Kingdom, J; Widjaja E. Collaborator(s): Keating, S; Kelly, E; Keunen, J; Manlhiot, C; Miller, S. 550,440 CAD. 2016 Mar - 2019 Feb 

Co-I. Environmental factors in placental pathology: a new diagnostic method based on umbilical vessel wave mechanics. National Institutes of Health (NIH) (USA). Research Project Cooperative Agreement. Application #: 1U10HD087177-01. PI: Sled, J. Collaborator(s): Baschat, A; Kingdom, J; Macgowan, C; Serghides, L; Keating, S; Murphy, K. 2,507,213 USD. 2015 Sep - 2019 Aug 

Co-I. Cardiovascular physiology and brain development in newborns with congenital heart disease. Canadian Institute of Health Research (CIHR). Operating Grant. Application #: 341324. PI: Miller, S; Seed, M. Collaborator(s): Blaser, S; Brant, R; Chau, V; Hickey, E; Kingdom, J; Ly, L; Macgowan, C; Schwartz, S; Sled, J. 1,008,289 CAD. 2015 Mar - 2021 Feb 

Co-I. Pregnancy complications and development health: mechanisms, diagnostics and therapeutics. Canadian Institutes of Health Research (CIHR). Foundation Scheme - Live Pilot. Application #: 333060. PI: Lye, S. Collaborator(s): Adams Waldorf, K; Bocking, A; Connor, K; DeSantis, T; Dong, X; Dunk, C;; Gingras, AC; Gravett, M; Hood, LE; Keating, S; Kibschull, M; Kingdom, J Mesiano, S; Nadeem, L; Price, N; Sadovsky, Y; Scherer, S; Shynlova, O; Zhang, J. 5,575,713 CAD. 2014 Sep - 2021 Aug 

PI. Villious Trophoblast Turnover. Canadian Institutes of Health Research (CIHR). Operating Grant. Application #: 326.174. Collaborator(s): Cox, BJ. 719,235 CAD. Renewal. 2014 Mar - 2023 Feb 

Appointments

2013 Jul - Present: Gordon C. Leitch Chair, Department of Obstetrics & Gynaecology, Temerty Faculty of Medicine, University of Toronto, Ontario, Canada

2012 Jul - 2013 Dec: U of T Maternal-Fetal Medicine Division Head, Maternal-Fetal Medicine, Obstetrics and Gynaecology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

2005 Jul - 2016 Mar: Rose Torno Chair in Reproductive Biology, Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Ontario, Canada

2004 Nov - Present: Professor, Obstetrics and Gynaecology, Faculty of Medicine, University of Toronto, 
Ontario, Canada

1998 Mar - Present: Staff Obstetrician, Maternal Fetal Medicine Division, Department of Obstetrics & Gynecology, Mount Sinai Hospital, Toronto, Ontario, Canada

1995 Mar - 1998 Feb: Senior Lecturer/Consultant, Obstetrics and Gynaecology (Fetal Medicine), University College London, London, United Kingdom

Honours and awards

APOG Excellence in Research Award, University of Toronto, Canada. (Postgraduate MD, Core Program) APOG winner for University of Toronto. (2010 Nov)

Anderson for Education Administration Excellence, The John Wightman-Berris Academy, Canada. (Distinction) Presented at the Wightman-Berris Academy Award Ceremony, May 2006, Faculty of Medicine, University of Toronto at Mount Sinai Hospital & University Health Network. (2006 May)

Award for Teaching Excellence, Dept of Obstetrics & Gynaecology, Faculty of Medicine, University of Toronto, Canada. (Postgraduate MD) PAIRO Excellence in Clinical Teaching Awards Committee, Professional Association of Internes and Residents of Ontario. Presented at the PAIRO Excellence in Clinical Teaching Awards and Resident Advocate Award Banquet. Date: Awarded May 15, 2004. (2004 Jan)

Adriana and Luisa Castellucci Prize, The 7th European Placenta Group Meeting, Vigso, Denmark, 13-17 December 1997 The IFPA Award in Placentology (formerly called the Adriana and Luisa Castellucci Award,1995-2001. (1997 Dec)