John Kingdom

University of Toronto, Toronto, Ontario, Canada

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Publications (196)644.94 Total impact

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    ABSTRACT: To compare the in vitro contractile responses to oxytocin, ergonovine, prostaglandin F2 alpha (PGF2α), and misoprostol in isolated myometrium from non-labouring and labouring pregnant women.
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    ABSTRACT: An increasingly common challenge in antenatal care of the small for gestational age (SGA) fetus is the distinction between the constitutionally (physiologically) small fetus and the fetus affected by pathological intrauterine growth restriction (IUGR). We discuss here the rationale and the evidence for the use of customized growth percentiles for the purpose of distinguishing between the fetus with true IUGR and the fetus with constitutional SGA. We also provide estimates of the potential effects of adopting ethnicity-specific birth weight curves on the rates of SGA and large for gestational age status in multi-ethnic metropolitan cities in North America and Europe, such as the City of Toronto. Using customized growth percentiles would result in a considerable decline in the rate of a false-positive diagnosis of SGA among visible minorities, and improve the detection rate of true large for gestational age fetuses among these groups.
    Journal of obstetrics and gynaecology Canada: JOGC = Journal d'obstetrique et gynecologie du Canada: JOGC 02/2014; 36(2):164-70.
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    ABSTRACT: Preeclampsia (PE) is characterized by exaggerated apoptosis of the villous trophoblast of placental villi. Since p53 is a critical regulator of apoptosis we hypothesized that excessive apoptosis in PE is mediated by abnormal expression of proteins participating in the p53 pathway and that modulation of the p53 pathway alters trophoblast apoptosis in vitro. Fresh placental villous tissue was collected from normal pregnancies and pregnancies complicated by PE; Western blotting and real-time PCR were performed on tissue lysate for protein and mRNA expression of p53 and downstream effector proteins, p21, Bax and caspases 3 and 8. To further assess the ability of p53 to modulate apoptosis within trophoblast, BeWo cells and placental villous tissue were exposed to the p53-activator, Nutlin-3, alone or in combination with the p53-inhibitor, Pifithrin-α (PFT- α). Equally, Mdm2 was knocked-down with siRNA. Protein expression of p53, p21 and Bax was significantly increased in pregnancies complicated by PE. Conversely, Mdm2 protein levels were significantly depleted in PE; immunohistochemistry showed these changes to be confined to trophoblast. Reduction in the negative feedback of p53 by Mdm2, using siRNA and Nutlin-3, caused an imbalance between p53 and Mdm2 that triggered apoptosis in term villous explants. In the case of Nutlin, this was attenuated by Pifithrin-α. These data illustrate the potential for an imbalance in p53 and Mdm2 expression to promote excessive apoptosis in villous trophoblast. The upstream regulation of p53 and Mdm2, with regard to exaggerated apoptosis and autophagy in PE, merits further investigation.
    PLoS ONE 01/2014; 9(1):e87621. · 3.73 Impact Factor
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    ABSTRACT: Common pregnancy complications, such as severe preeclampsia and intrauterine growth restriction, disrupt pregnancy progression and impair maternal and fetal wellbeing. Placentas from such pregnancies exhibit lesions principally within the syncytiotrophoblast (SCT), a layer in direct contact with maternal blood. In humans and mice, glial cell missing-1 (GCM-1) promotes differentiation of underlying cytotrophoblast cells into the outer SCT layer. GCM-1 may be regulated by the transcription factor peroxisome proliferator-activated receptor-gamma (PPAR- γ ); in mice, PPAR- γ promotes labyrinthine trophoblast differentiation via Gcm-1, and, as we previously demonstrated, PPAR- γ activation ameliorates disease features in rat model of preeclampsia. Here, we aimed to characterize the baseline activity of PPAR- γ in the human choriocarcinoma BeWo cell line that mimics SCT formation in vitro and modulate PPAR- γ activity to study its effects on cell proliferation versus differentiation. We report a novel negative autoregulatory mechanism between PPAR- γ activity and expression and show that blocking PPAR- γ activity induces cell proliferation at the expense of differentiation, while these remain unaltered following treatment with the agonist rosiglitazone. Gaining a deeper understanding of the role and activity of PPAR- γ in placental physiology will offer new avenues for the development of secondary prevention and/or treatment options for placentally-mediated pregnancy complications.
    PPAR Research 01/2014; 2014:637251. · 2.69 Impact Factor
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    ABSTRACT: Background Thrombophilias are common disorders that increase the risk of pregnancy-associated venous thromboembolism and pregnancy loss and can also increase the risk of placenta-mediated pregnancy complications (severe pre-eclampsia, small-for-gestational-age infants, and placental abruption). We postulated that antepartum dalteparin would reduce these complications in pregnant women with thrombophilia. Methods In this open-label randomised trial undertaken in 36 tertiary care centres in five countries, we enrolled consenting pregnant women with thrombophilia at increased risk of venous thromboembolism or with previous placenta-mediated pregnancy complications. Eligible participants were randomly allocated in a 1:1 ratio to either antepartum prophylactic dose dalteparin (5000 international units once daily up to 20 weeks' gestation, and twice daily thereafter until at least 37 weeks' gestation) or to no antepartum dalteparin (control group). Randomisation was done by a web-based randomisation system, and was stratified by country and gestational age at randomisation day with a permuted block design (block sizes 4 and 8). At randomisation, site pharmacists (or delegates) received a randomisation number and treatment allocation (by fax and/or e-mail) from the central web randomisation system and then dispensed study drug to the local coordinator. Patients and study personnel were not masked to treatment assignment, but the outcome adjudicators were masked. The primary composite outcome was independently adjudicated severe or early-onset pre-eclampsia, small-for-gestational-age infant (birthweight <10th percentile), pregnancy loss, or venous thromboembolism. We did intention-to-treat and on-treatment analyses. This trial is registered with, number NCT00967382, and with Current Controlled Trials, number ISRCTN87441504. Findings Between Feb 28, 2000, and Sept 14, 2012, 292 women consented to participate and were randomly assigned to the two groups. Three women were excluded after randomisation because of ineligibility (two in the antepartum dalteparin group and one in the control group), leaving 146 women assigned to antepartum dalteparin and 143 assigned to no antepartum dalteparin. Some patients crossed over to the other group during treatment, and therefore for on-treatment and safety analysis there were 143 patients in the dalteparin group and 141 in the no dalteparin group. Dalteparin did not reduce the incidence of the primary composite outcome in both intention-to-treat analysis (dalteparin 25/146 [17·1%; 95% CI 11·4–24·2%] vs no dalteparin 27/143 [18·9%; 95% CI 12·8–26·3%]; risk difference −1·8% [95% CI −10·6% to 7·1%)) and on-treatment analysis (dalteparin 28/143 [19·6%] vs no dalteparin 24/141 [17·0%]; risk difference +2·6% [95% CI −6·4 to 11·6%]). In safety analysis, the occurrence of major bleeding did not differ between the two groups. However, minor bleeding was more common in the dalteparin group (28/143 [19·6%]) than in the no dalteparin group (13/141 [9·2%]; risk difference 10·4%, 95% CI 2·3–18·4; p=0·01). Interpretation Antepartum prophylactic dalteparin does not reduce the occurrence of venous thromboembolism, pregnancy loss, or placenta-mediated pregnancy complications in pregnant women with thrombophilia at high risk of these complications and is associated with an increased risk of minor bleeding. Funding Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and Pharmacia and UpJohn.
    Lancet. 01/2014;
  • Rory C Windrim, Melissa G Walker, John C P Kingdom
    Journal of obstetrics and gynaecology Canada: JOGC = Journal d'obstetrique et gynecologie du Canada: JOGC 10/2013; 35(10):882.
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    ABSTRACT: Oxytocin receptor desensitization has been shown to occur in humans at biomolecular level and in isolated rat myometrium; however, its effect on human myometrial contractility has not been demonstrated. The objective of this in vitro study was to investigate the contractile response of human pregnant myometrium to oxytocin after pretreatment with different concentrations of oxytocin for variable durations. Myometrial samples were obtained from 62 women undergoing elective cesarean deliveries under regional anesthesia. The strips were pretreated with oxytocin 10(-10), 10(-8), 10(-5) M, or physiological salt solution (control) for 2, 4, 6, or 12 h, followed by a dose-response testing with oxytocin 10(-10) to 10(-5) M. Amplitude and frequency of contractions, motility index, and area under the curve during the dose-response period were recorded, analyzed with linear regression models, and compared among groups. Pretreatment with oxytocin 10(-5) and 10(-8) M significantly reduced motility index (estimate [standard error]: -0.771 [0.270] square root units, P = 0.005 and -0.697 [0.293], P = 0.02, respectively) and area under the curve (-3.947 [1.909], P = 0.04 and -4.241 [2.189], P = 0.05, respectively) compared with control group, whereas pretreatment with oxytocin 10-(10) M did not significantly attenuate contractions. Increase in duration of oxytocin pretreatment from 2 to 12 h significantly decreased amplitude (type 3 generalized estimating equation analysis: chi-square = 14.0; df = 3; P = 0.003), motility index (chi-square = 9.3; df = 3; P = 0.03), and area under the curve (chi-square = 10.5; df = 3; P = 0.02), but not the frequency of oxytocin-induced contractions. Pretreatment with oxytocin decreases oxytocin-induced myometrial contractions in a concentration and time-dependent manner, likely as a function of the oxytocin receptor desensitization phenomenon.
    Anesthesiology 09/2013; 119(3):552-61. · 5.16 Impact Factor
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    ABSTRACT: Background: Intrauterine growth restriction (IUGR) is an obstetrical complication, which by definition would screen in 10% of fetuses in the general population. The challenge is to identify the subset of pregnancies affected with pathological growth restriction in order to allow intervention that would decrease morbidity and mortality. Objective: The purpose of this guideline is to provide summary statements and recommendations and to establish a framework for screening, diagnosis, and management of pregnancies affected with IUGR. Methods: Affected pregnancies are compared with pregnancies in which the fetus is at an appropriate weight for its gestational age. History, physical examination, and laboratory investigations including biochemical markers and ultrasound characteristics of IUGR are reviewed, and a management strategy is suggested. Evidence: Published literature in English was retrieved through searches of PubMed or MEDLINE, CINAHL, and The Cochrane Library in January 2013 using appropriate controlled vocabulary via MeSH terms (fetal growth restriction and small for gestational age) and key words (fetal growth, restriction, growth retardation, IUGR, low birth weight, small for gestational age). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). Benefits, harms, and costs: Implementation of the recommendations in this guideline should increase clinician recognition of IUGR and guide intervention where appropriate. Optimal long-term follow-up of neonates diagnosed as IUGR may improve their long-term health. Summary Statements 1. The definition of small-for-gestational age for a fetus in utero is an estimated fetal weight that measures < 10th percentile on ultrasound. This diagnosis does not necessarily imply pathologic growth abnormalities, and may simply describe a fetus at the lower end of the normal range. (III) 2. Intrauterine growth restriction refers to a fetus with an estimated fetal weight < 10th percentile on ultrasound that, because of a pathologic process, has not attained its biologically determined growth potential. (III) A clinical estimation of fetal weight or symphysis-fundal height has poor sensitivity and specificity and should not be relied upon to diagnose intrauterine growth restriction. Intrauterine growth restriction should be considered in the differential diagnosis when the fetus is found to be small for gestational age. (II-1) 3. Effective screening for intrauterine growth restriction requires accurate dating and includes a review of the mother's menstrual history, relevant assisted reproductive technology information, and either a first trimester or early second trimester dating ultrasound. (I) 4. Symphysis-fundal height determination is of limited value in routine obstetrical care, but continues to be the only physical examination screening test available. (I) 5. Fetal weight determination in fetuses between the 10th and 90th percentiles by ultrasound biometry alone has at least a 10% error rate across gestation, but is effective equally when measuring with abdominal circumference alone or in combination with head size (biparietal diameter or head circumference) and/or femur length to establish an estimated fetal weight. (II-2) 6. Determining whether intrauterine growth restriction is symmetric or asymmetric is of less clinical importance than careful re-evaluation of fetal anatomy and uterine and umbilical artery Doppler studies. (I) 7. In women with risk factors for intrauterine growth restriction, uterine artery Doppler screening at 19 to 23 weeks may identify pregnancies at risk of antepartum stillbirth and preterm delivery due to intrauterine growth restriction and placental disease. (II-2) 8. In pregnancies in which intrauterine growth restriction due to uteroplacental vascular insufficiency is diagnosed, maternal surveillance for the development of severe preeclampsia with adverse features is warranted. (II-1) 9. Once surveillance of a fetus with intrauterine growth restriction is instituted, umbilical artery Doppler studies and biophysical profile scoring can be used as short-term predictors of fetal well-being. (I) 10. In the presence of abnormal umbilical artery Doppler studies, further investigation of the fetal circulatory system by Doppler examination of the middle cerebral artery, ductus venosus, and umbilical vein can be considered. (II-2) 11. For a fetus with intrauterine growth restriction, the decision for obstetrical intervention, including Caesarean section, in cases of abnormal fetal heart rate or malpresentation is largely based on fetal viability, as assessed by ultrasound. (II-2) 12. Maternal surveillance for the development of preeclampsia is warranted. (II-2) Recommendations 1. Women should be screened for clinical risk factors for intrauterine growth restriction by means of a complete history. (II-2B) 2. Women should be counselled on smoking cessation at any time during pregnancy. (II-2A) 3. First and second trimester screening tests for aneuploidy maybe useful tests of placental function. If two screening test results are abnormal, health care providers should be aware that the fetus is at increased risk of preterm intrauterine growth restriction and associated stillbirth. (II-1A) 4. If intrauterine growth restriction is suspected, further assessment can assist in making the diagnosis. If available, detailed ultrasound examination of the placenta (looking for evidence of a small, thickened placenta, or abnormal morphology) and uterine artery Dopplers should be considered at 19 to 23 weeks. In the absence of available diagnostic testing, closer surveillance should be offered. A maternal-fetal medicine consultation can be considered if the placenta appears abnormal on ultrasound, especially in the context of a growth-restricted fetus and abnormal uterine artery Doppler. In a rural setting, the caregiver needs to decide whether the patient should be delivered immediately, or whether transfer to a tertiary centre is appropriate. A telephone consultation and telemedicine may help. (II-2A) 5. In women without risk factors for intrauterine growth restriction, comprehensive third trimester ultrasound examination including biophysical profile, fetal biometry, amniotic fluid volume, and umbilical artery Doppler studies is not recommended. (II-2D) 6. Low-dose aspirin should be recommended to women with a previous history of placental insufficiency syndromes including intrauterine growth restriction and preeclampsia. It should be initiated between 12 and 16 weeks' gestation and continued until 36 weeks. (I-A) 7. Low-dose aspirin should also be recommended to women with two or more current risk factors in pregnancy including, but not limited to, pre-gestational hypertension, obesity, maternal age > 40 years, history of use of artificial reproductive technology, pre-gestational diabetes mellitus (type I or II), multiple gestation, previous history of placental abruption, and previous history of placental infarction. It should be initiated between 12 and 16 weeks' gestation and continued until 36 weeks. (I-A) 8. Umbilical artery Doppler studies are not recommended as a routine screening test in uncomplicated pregnancies. (I-E) 9. An ultrasound examination for estimated fetal weight and amniotic fluid volume should be considered after 26 weeks if the symphysis-fundal height measurement in centimetres deviates by 3 or more from the gestational age in weeks or there is a plateau in symphysis-fundal height. (II-2B) 10. In cases in which the fetus measures < 10th percentile by estimated fetal weight or abdominal circumference measurement, the underlying cause of intrauterine growth restriction may be established by an enhanced ultrasound examination to include a detailed review of fetal anatomy, placental morphology, and Doppler studies of the uterine and umbilical arteries. (II-2A) 11. In cases of intrauterine growth restriction, determination of amniotic fluid volume should be performed to aid in the differential diagnosis of intrauterine growth restriction and increase the accuracy of the diagnosis of placental insufficiency. (II-2B) 12. Umbilical artery Doppler should be performed in all fetuses with an estimated fetal weight or an abdominal circumference < 10th percentile. (I-A) 13. In pregnancies affected by intrauterine growth restriction, umbilical artery Doppler studies after 24 weeks may prompt intervention that reduces perinatal mortality and severe perinatal morbidity due to intrauterine growth restriction. (I-A) 14. In pregnancies in which intrauterine growth restriction has been identified, invasive testing to rule out aneuploidy may be offered where fetal abnormalities are suspected, soft markers are seen, or no supportive evidence of underlying placental insufficiency is evident. (II-2A) 15. In patients presenting with intrauterine growth restriction, maternal screening for infectious etiology may be considered. (II-2A) 16. When intrauterine growth restriction is diagnosed, surveillance should be initiated. Serial ultrasound estimation of fetal weight (every 2 weeks), along with umbilical artery Doppler studies should be initiated. If available, a placental assessment and other Doppler studies such as middle cerebral artery, umbilical vein, and ductus venosis can be performed. Increased frequency of surveillance may be required. (II-2A) 17. (ABSTRACT TRUNCATED)
    Journal of obstetrics and gynaecology Canada: JOGC = Journal d'obstetrique et gynecologie du Canada: JOGC 08/2013; 35(8):741-8.
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    ABSTRACT: OBJECTIVES: To review the association between associated ultrasound findings, placental pathology and prognosis in pregnancies complicated by massive subchorionic thrombo-hematoma(MTH)/Breus' mole. METHOD: We identified 14 cases of MTH from January 2004 to December 2012. MTH was defined by: > 1 cm thickness hematoma, and extensive (≥ 50%) involvement of the fetal surface of the placenta. Patient information, details of initial presentation and perinatal outcome were obtained from the manual and electronic chart records. Ultrasound findings were related to pregnancy outcomes and associated placental pathology. Participants were stratified based on birth outcome into survivors (live births, n = 7) and non-survivors (NND or IUFD/TOP, n = 7). RESULTS: All 14 cases of MTH were suspected on ultrasound and confirmed by pathology assessment. All cases in the non-survivors group had abnormal umbilical artery Doppler waveforms compared to none in the survivors (p = 0.02). All cases in the non-survivor group had extreme preterm deliveries (p = 0.02). Birth weight was significantly reduced in the non-survivor group (p = 0.001), and 5/7 cases were diagnosed with severe intrauterine growth restriction, compared to none in the survivor group (p = 0.02). CONCLUSION: MTH/Breus' mole may be diagnosed in the second trimester by ultrasound assessment of the placenta. Normal fetal growth and umbilical artery Doppler waveforms are associated with perinatal survival. This article is protected by copyright. All rights reserved.
    Prenatal Diagnosis 06/2013; · 2.68 Impact Factor
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    ABSTRACT: : To estimate obstetric and neonatal outcomes after induction of labor at 37 weeks of gestation compared with expectant management in pregnancies complicated by fetal gastroschisis. : The management of 296 pregnancies involving fetal gastroschisis (1980-2011) was reviewed from a single perinatal center. Ultrasound surveillance and nonstress testing were performed every 2 weeks from 30 weeks of gestation, weekly from 34 weeks of gestation, and twice weekly after 35 weeks of gestation until delivery. Labor was induced if fetal well-being testing was abnormal and, since 1994, labor was routinely induced at 37 weeks of gestation. : Of 153 pregnancies reaching 37 weeks of gestation, labor was induced in 77 (26%) and 76 (25.7%) were allowed to labor spontaneously. There were no significant differences in mean maternal age (22 years in both), parity (56% compared with 66% nulliparous), presence of other fetal anomalies (12% compared with 9%), cesarean delivery rate (20% in both), 5-minute Apgar score less than 7 (10% compared with 12%), meconium at birth (36% compared with 49%), or respiratory distress syndrome (16% compared with 7%) between the induced and expectantly managed groups. However, neonatal sepsis (25% compared with 42%; P=.02) and a composite outcome of neonatal death and bowel damage (necrosis, atresia, perforation, adhesion; 8% compared with 21%; P=.02) were more common in expectantly managed pregnancies. Moreover, time to oral feeds (-3.4 days), time on total parenteral nutrition (-6.2 days), and hospital stay (-6.7 days) were reduced when labor was induced. : In fetuses with gastroschisis, induction of labor at 37 weeks of gestation was associated with reduced risks of sepsis, bowel damage, and neonatal death compared with pregnancies managed expectantly beyond 37 weeks of gestation. : II.
    Obstetrics and Gynecology 05/2013; 121(5):990-8. · 4.80 Impact Factor
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    ABSTRACT: Objective: To assess the effectiveness of a multidisciplinary team approach to reduce severe maternal morbidity in women with invasive placenta previa. Methods: We conducted a prospective study of 33 women with placenta previa and increta-percreta (diagnosed by ultrasound and/or magnetic resonance imaging) delivering at Mount Sinai Hospital, Toronto, following the introduction in January 2008 of a team-based approach to women with this condition. We included women who delivered by June 2012. We reviewed antenatal outpatient and inpatient records for use of six pre-defined team components by the attending staff obstetrician: (1) antenatal maternal-fetal medicine consultation, (2) surgical gynaecology consultation, (3) antenatal MRI, (4) interventional radiology consultation and preoperative placement of balloon catheters in the anterior divisions of the internal iliac arteries, (5) pre-planned surgical date, and (6) surgery performed by members of the invasive placenta surgical team. Antenatal course, delivery, and postpartum details were recorded to derive a five-point composite severe maternal morbidity score based on the presence or absence of: (1) ICU admission following delivery, (2) transfusion > 2 units of blood, (3) general anaesthesia start or conversion, (4) operating time in highest quartile (> 125 minutes), and (5) significant postoperative complications (readmission, prolonged postpartum stay, and/or pulmonary embolism). Results: All 33 women survived during this time period. Two thirds (22/33) had either five or six of the six components of multidisciplinary care. Increasing use of multidisciplinary team components was associated with a significant reduction in composite morbidity (R2 = 0.228, P = 0.005). Conclusion: Team-based assessment and management of women with invasive placenta previa is likely to improve maternal outcomes and should be encouraged on a regional basis.
    Journal of obstetrics and gynaecology Canada: JOGC = Journal d'obstetrique et gynecologie du Canada: JOGC 05/2013; 35(5):417-25.
  • D Baczyk, S Drewlo, J C P Kingdom
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    ABSTRACT: INTRODUCTION: Small ubiquitin-like modifiers (SUMO) conjugate to target proteins in a dynamic, reversible manner to function as post-translational modifiers. SUMOylation of target proteins can impinge on their localization, in addition to their activity or stability. Differential expression of deSUMOylating enzymes (SENP 1 and 2) contributes to altered mammalian placental development and function in mice. Severe preeclampsia (sPE) is associated with abnormal placental development and chronic ischemic injury. Extra- and intracellular stimuli/stressors that include hypoxic-activated pathways are known modulators of SUMOylation. In this current study we hypothesized that placentas from sPE patients will display up regulation in the SUMO regulatory pathway. METHODS: Utilizing qRT-PCR, immuno-blotting and Western techniques, we determined the expression levels of SUMO pathway genes in healthy and diseased placentas. We also exposed placental explants to hypoxia to study the effect on the SUMOylation pathway. RESULTS: We observed steady-state expression of SUMO1-3, SUMO-conjugated enzyme-UBC9 and deSUMOylating enzymes - SENPs, throughout normal gestation. An elevated level of free SUMO1-3 and SUMO-protein conjugates was observed in sPE placentas. Furthermore, placental UBC9 levels were strikingly increased in the same sPE patients. Hypoxia-induced SUMOylation in first trimester placental explants. DISCUSSION: Our data demonstrate an elevated steady-state of SUMOylation in sPE placentas compared with gestational aged-matched controls. The observed hyper-SUMOylation in sPE placentas correlates with elevated expression of UBC9 rather than with reduced expression of SENPs Hypoxia may contribute to alterations in placental SUMOylation pathway. CONCLUSION: Increased placental SUMOylation may contribute to the pathogenesis of serious placental pathology that causes extreme preterm birth.
    Placenta 04/2013; · 3.12 Impact Factor
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    ABSTRACT: Objective: The objective of this study was to determine whether a web-based education strategy could improve maternal knowledge of placental complications of pregnancy and reduce maternal anxiety in high risk-pregnancies. Methods: Prospective study in the Placenta Clinic at Mount Sinai Hospital, Toronto, Ontario. Maternal demographics and Internet usage were recorded at the patient's baseline appointment. Placental knowledge was determined using structured verbal and illustrative assessments. The six-item State-Trait Anxiety Inventory (STAI) was administered to assess baseline maternal anxiety. Women were asked to visit the Placenta Clinic website for a minimum of 15 minutes before their follow-up appointment, at which time their placental knowledge and STAI assessments were repeated. Results: Eighteen women were included in the study. Patient knowledge at the baseline appointment was generally poor (median score 10.5 out of a maximum score of 27, range 1 to 22), with major deficits in basic placental knowledge, placenta previa/increta, and preeclampsia. At the follow-up appointment, placental knowledge was significantly improved (median score 23, range 10 to 27; P < 0.001). Educational status (high school or less vs. college or more) had no effect on either baseline knowledge or knowledge improvement. Maternal anxiety at baseline (median score 12 out of a maximum score of 24, range 6 to 23) was significantly reduced at the follow-up appointment (median score 8.5, range 6 to 20; P = 0.005). Conclusion: Deficits in maternal knowledge of placental complications of pregnancy in high-risk pregnant women were substantial but easily rectified with a disease-targeted web-based educational resource. This intervention significantly improved patient knowledge and significantly reduced maternal anxiety.
    Journal of obstetrics and gynaecology Canada: JOGC = Journal d'obstetrique et gynecologie du Canada: JOGC 04/2013; 35(4):334-9.
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    ABSTRACT: Increased vascular impedance in the fetoplacental circulation is associated with fetal hypoxia and growth restriction. We sought to investigate the role of hydrogen sulfide (H(2)S) in regulating vasomotor tone in the fetoplacental vasculature. H(2)S is produced endogenously by catalytic activity of cystathionine β-synthase and cystathionine γ-lyase (CSE). Immunohistochemical analysis localized CSE to smooth muscle cells encircling arteries in stem villi. Immunoreactivity was reduced in placentas from pregnancies with severe early-onset growth-restriction and preeclampsia displaying abnormal umbilical artery Doppler waveforms compared with preeclamptic placentas with normal waveforms and controls. These findings were confirmed at the protein and mRNA levels. MicroRNA-21, which negatively regulates CSE expression, was increased in placentas with abnormal Doppler waveforms. Exposure of villus explants to hypoxia-reoxygenation significantly reduced CSE protein and mRNA and increased microRNA-21 expression. No changes were observed in cystathionine β-synthase expression, immunolocalized principally to the trophoblast, in pathologic placentas or in vitro. Finally, perfusion of normal placentas with an H(2)S donor, after preconstriction with a thromboxane mimetic, resulted in dose-dependent vasorelaxation. Glibenclamide and N(G)-nitro-l-arginine methyl ester partially blocked the effect, indicating that H(2)S acts through ATP-sensitive K(+) channels and nitric oxide synthesis. These results demonstrate that H(2)S is a powerful vasodilator of the placental vasculature and that expression of CSE is reduced in placentas associated with increased vascular resistance.
    American Journal Of Pathology 02/2013; · 4.60 Impact Factor
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    ABSTRACT: The trophoblast transcription factor glial cell missing-1 (GCM1) regulates differentiation of placental cytotrophoblasts into the syncytiotrophoblast layer in contact with maternal blood. Reduced placental expression of GCM1 and abnormal syncytiotrophoblast structure are features of hypertensive disorder of pregnancy - preeclampsia. In-silico techniques identified the calcium-regulated transcriptional repressor - DREAM (Downstream Regulatory Element Antagonist Modulator) - as a candidate for GCM1 gene expression. Our objective was to determine if DREAM represses GCM1 regulated syncytiotrophoblast formation. EMSA and ChIP assays revealed a direct interaction between DREAM and the GCM1 promoter. siRNA-mediated DREAM silencing in cell culture and placental explant models significantly up-regulated GCM1 expression and reduced cytotrophoblast proliferation. DREAM calcium dependency was verified using ionomycin. Furthermore, the increased DREAM protein expression in preeclamptic placental villi was predominantly nuclear, coinciding with an overall increase in sumolylated DREAM and correlating inversely with GCM1 levels. In conclusion, our data reveal a calcium-regulated pathway whereby GCM1-directed villous trophoblast differentiation is repressed by DREAM. This pathway may be relevant to disease prevention via calcium-supplementation.
    PLoS ONE 01/2013; 8(1):e51837. · 3.73 Impact Factor
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    ABSTRACT: OBJECTIVE: The aims of this study were to develop a nomogram of umbilical cord diameter (UCD) for pathologic examination of the placenta, to identify the umbilical cord components responsible for variations in UCD, and to examine the relationship between UCD and other placental pathologic features and perinatal outcome. STUDY DESIGN: We prospectively collected 497 umbilical cords between 18 and 41 weeks' gestation over a 1-year period. Fresh-tissue UCD were grouped according to gestational age and compared to sonographic and histological measurements. Associations between UCD percentile and placental pathologic findings or obstetrical outcomes were examined. RESULTS: Mean UCD increased with gestational age until a plateau at 1.0 cm in the third trimester, a value that was 0.56 cm less than sonographic measurements prior to delivery and 0.17 cm greater than UCD measured histologically. Umbilical cord components varied with UCD percentile, with umbilical vessel area increased in thick cords (p < 0.001) and Wharton's jelly area reduced in thin cords (p = 0.002). Thin umbilical cords were associated with at least one pathologic histological placental finding (p = 0.02), low placental weight (p < 0.001), single umbilical artery (p = 0.02), marginal cord insertion (p = 0.01), and low infant birth weight (p < 0.001). CONCLUSIONS: This study provides reference curves for post-delivery UCD from 18 to 41 weeks' gestation for use by perinatal pathologists. We show that increased UCD is a function of increased umbilical blood vessel volume and decreased UCD is a function of decreased Wharton's jelly volume. UCD shows a strong association with placental and infant birth weight.
    Placenta 11/2012; · 3.12 Impact Factor
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    ABSTRACT: Maternal placental syndromes (MPS)-gestational hypertension, pre-eclampsia and placental abruption/infarction-are more prevalent in women with features of the metabolic syndrome (MetSyn). Both MPS and the MetSyn predispose to left ventricular impairment and sympathetic dominance after delivery. Whether this translates into a higher risk of heart failure (HF) and cardiac dysrhythmias is not known. To determine the risk of new onset of HF and dysrhythmias among women after a prior MPS-affected pregnancy. A retrospective cohort study was carried out of 1,130,764 individual women with a delivery in Ontario between 1992 and 2009, excluding those with cardiac or thyroid disease 1 year before delivery. The risk of a composite outcome of a hospitalisation for HF or an atrial or ventricular dysrhythmia was compared in women with and without MPS, starting 1 year after delivery. 75,242 individuals (6.7%) experienced a MPS. After a median duration of 7.8 years, the composite outcome occurred in 148 women with MPS (2.54 per 10,000 person-years) and 1062 women without MPS (1.28 per 10,000 person-years) (crude HR=2.00, 95% CI 1.68 to 2.38). The mean age at composite outcome was 37.8 years. The HR was 1.61 (95% CI 1.35 to 1.91) after adjustment for demographic characteristics, diabetes, obesity, dyslipidaemia and drug dependence or tobacco use, as well as coronary artery disease or thyroid disease >1 year after delivery. The adjusted HRs were minimally reduced by further adjusting for chronic hypertension (1.51, 95% CI 1.26 to 1.80) and were higher in women with MPS plus preterm delivery and poor fetal growth (2.42, 95% CI 1.25 to 4.67). Women with MPS are at higher risk of premature HF and dysrhythmias, especially when perinatal morbidity is present.
    Heart (British Cardiac Society) 05/2012; 98(15):1136-41. · 5.01 Impact Factor
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    ABSTRACT: Distal villous hypoplasia is a form of placental villous maldevelopment that has the potential to cause significant intrauterine growth restriction with adverse consequences for fetal viability, neurodevelopmental outcome and adult cardiovascular health. It is characterized by a sparse, poorly developed distal villous tree with abnormally shaped, elongated, slender villi and widening of the intervillous space. Generally, villi show widespread trophoblast abnormalities with thinning of the villous trophoblast layer, reduction in cytotrophoblast numbers, evidence of a widespread increase in syncytiotrophoblast nuclear senescence and wave-like syncytial knots. Investigation of pregnancies with false positive serum screening tests for fetal aneuploidy/structural defects can help identify pregnancies at risk of placental insufficiency, particularly when combined with ultrasound assessment of placental morphology at 19–22 weeks. Identification of pregnancies with multiple abnormal tests of placental function permits high-risk specialist referral to optimize maternal-fetal outcome.
    Diagnostic Histopathology. 05/2012; 18(5):195–200.
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    Journal of obstetrics and gynaecology Canada: JOGC = Journal d'obstetrique et gynecologie du Canada: JOGC 05/2012; 34(5):472-4.
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    ABSTRACT: Oxytocin pretreatment of pregnant rat myometrium has been shown to reduce the contractions produced by further administration of oxytocin, as a function of the desensitization phenomenon. It is unclear whether this phenomenon affects the contractions produced by various prostaglandins that are used in the management of postpartum hemorrhage. The objective of this study was to investigate the contractile effects of various prostaglandins after oxytocin pretreatment and to compare their relative efficacies in vitro on pregnant rat myometrial strips. Myometrial samples from 29 pregnant Wistar rats at term were isolated and pretreated with oxytocin (10(-8) mol/L, experimental group) or physiological salt solution (control group) for 1 hour. They were then subjected to dose-response testing with oxytocin (n = 32), PGF2α (n = 16), dinoprostone (n = 14), alprostadil (n = 14), or misoprostol (n = 15) with cumulative increases in the organ bath concentrations from 10(-10) to 10(-5) mol/L. The contractile efficacies of various prostaglandins and oxytocin during the dose response were analyzed using mixed linear modeling and compared between the groups. There was no significant difference in the amplitude, frequency, motility index (amplitude × frequency), or area under the curve of all prostaglandins between the groups pretreated with oxytocin and the control group. However, there was a significant decrease in the frequency (P = .02) and motility index (P = .05) in the dose-response curves of oxytocin in the groups pretreated with oxytocin compared with the control groups. Overall, oxytocin produced superior contractions compared with all other prostaglandins, while dinoprostone and misoprostol produced the weakest contractions. The uterotonic effects of various prostaglandins are not affected by oxytocin desensitization; and despite desensitization, oxytocin provides superior contractions compared with the prostaglandins.
    Reproductive sciences (Thousand Oaks, Calif.) 04/2012; 19(9):968-75. · 2.31 Impact Factor

Publication Stats

4k Citations
644.94 Total Impact Points


  • 1998–2014
    • University of Toronto
      • • Department of Obstetrics and Gynaecology
      • • Hospital for Sick Children
      • • Institute of Medical Sciences
      Toronto, Ontario, Canada
    • RWTH Aachen University
      • Institut für Neuroanatomie
      Aachen, North Rhine-Westphalia, Germany
  • 2000–2013
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada
  • 1999–2013
    • Mount Sinai Hospital, Toronto
      • • Department of Obstetrics and Gynecology
      • • Department of Anesthesia
      • • Department of Fetal Medicine
      Toronto, Ontario, Canada
  • 2012
    • University of Ottawa
      • Interdisciplinary School of Health Sciences
      Ottawa, Ontario, Canada
  • 2011
    • SickKids
      Toronto, Ontario, Canada
  • 2005–2011
    • Mount Sinai Hospital
      New York City, New York, United States
    • University College London Hospitals NHS Foundation Trust
      Londinium, England, United Kingdom
  • 2010
    • University of Adelaide
      • Discipline of Obstetrics and Gynaecology
      Adelaide, South Australia, Australia
  • 2009
    • University of Cambridge
      • Centre for Trophoblast Research
      Cambridge, ENG, United Kingdom
    • Shanghai Jiao Tong University
      Shanghai, Shanghai Shi, China
    • McMaster University
      Hamilton, Ontario, Canada
  • 2006
    • Universität Ulm
      • Clinic of Gynecology and Obstetrics
      Ulm, Baden-Wuerttemberg, Germany
    • Leiden University Medical Centre
      • Department of Obstetrics
      Leiden, South Holland, Netherlands
    • Medical University of Graz
      • Institut für Zellbiologie, Histologie und Embryologie
      Graz, Styria, Austria
  • 2004–2006
    • University Hospital RWTH Aachen
      Aachen, North Rhine-Westphalia, Germany
  • 1997–2005
    • University College London
      • Institute of Child Health
      London, ENG, United Kingdom
  • 2003
    • University of Nottingham
      • School of Biomedical Sciences
      Nottingham, ENG, United Kingdom
  • 1996
    • Justus-Liebig-Universität Gießen
      • Institut für Veterinär-Anatomie, -Histologie und -Embryologie
      Gießen, Hesse, Germany
  • 1993
    • University of Glasgow
      Glasgow, Scotland, United Kingdom
  • 1990
    • Medical Research Council (UK)
      Londinium, England, United Kingdom