John Kingdom

Mount Sinai Hospital, New York City, New York, United States

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Publications (244)985.1 Total impact

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    ABSTRACT: Abstract Objectives: To determine the most reproducible method for the sonographic measurement of placental length. Methods: A prospective study of women with singleton pregnancies who underwent sonographic measurement of placental dimensions during mid-gestation. Two sonographers independently determined placental length using 3 different approaches (linear, curve-linear and panoramic) and placental thickness. Reproducibility was assessed by the Bland-Altman method and Interclass Correlation Coefficient (ICC). Results: Overall 34 women were included in the study. The curve-linear approach for the measurement of placental length was associated with the highest reproducibility (mean inter-observer difference of -0.10 cm) compared to the linear and panoramic approaches (mean difference -0.15 cm and -0.29 cm, respectively). Similarly, the ICC was highest for the curve-linear length approach (0.974) compared with the linear length and panoramic length approaches (0.956 and 0.926, respectively). Measurements of maximum placental thickness was also associated with a very good ICC (0.954). Conclusions: The curve-linear method for the measurement of placental length in the 2(nd) trimester appears to be the most reproducible approach. This technique may prove useful as an adjunct screening method, along with uterine artery Doppler and maximum placental thickness, to screen for major placental complications of pregnancy in the second trimester.
    Journal of Maternal-Fetal and Neonatal Medicine 11/2014; · 1.21 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.
    The Lancet 11/2014; · 39.21 Impact Factor
  • Lise Huynh, John Kingdom, Sabrina Akhtar
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    ABSTRACT: To review the recent evidence behind the association of low levels (ie, below the fifth percentile) of pregnancy-associated plasma protein A (PAPP-A) with adverse perinatal outcomes and to integrate new findings with the recommendations made by the Society of Obstetricians and Gynaecologists of Canada in 2008.
    Canadian family physician Medecin de famille canadien. 10/2014; 60(10):899-903.
  • Anjali Kulkarni, Emily Wright, John Kingdom
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    ABSTRACT: Objective: To measure the effect of a web-based educational tool on baseline knowledge of the risks and benefits of delivery by Caesarean section in healthy nulliparous women. Methods: We constructed a web-based educational tool to provide evidence-based information on the potential benefits and risks of CS for healthy nulliparous women in the second trimester. We included women with an uncomplicated singleton pregnancy who were receiving antenatal care at Mount Sinai Hospital. Eligible women logged into the website to undertake a pre-test survey. After completing this survey, they received access to the educational tool, followed by a link to a second survey. The surveys collected baseline demographics and assessed participants' knowledge of the perceived safety and risks of vaginal delivery and CS, their sources of information, and the influence of these sources on their views. Results: Seventy-three participants completed both surveys. Participants had a high baseline preference (84%) for vaginal delivery. The mean score for knowledge about vaginal delivery and CS increased significantly between the surveys, from 47% to 76% (P < 0. 001). There was no significant change in preference for mode of delivery between the two surveys. In both surveys, more participants responded that they were a "little fearful" or "not fearful at all" of vaginal deliveries. In the second survey, significantly more responded that they were "very fearful" or "fearful" of CS (P < 0.05). Increased knowledge about specific risks of vaginal delivery did not deter participants from preferring a vaginal delivery. However, knowledge of risks associated with CS made them more likely to have "very favourable" or "somewhat favourable" views of vaginal delivery. Ethnicity and country of birth were not found to have a significant effect on preferred mode of delivery. Conclusions: We demonstrated that a web-based educational tool significantly increased knowledge of the risks and benefits of vaginal delivery and CS. However, the educational intervention did not significantly change preferences.
    09/2014; 36(9):768-775.
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    ABSTRACT: Objective: To assess whether singleton pregnancies conceived by assisted reproductive technology (ART) are associated with an increased use of intrapartum interventions when compared with spontaneous singleton pregnancies. Methods: In total, 1327 ART pregnancies and 5222 spontaneous pregnancies during the period 2004 to 2008 were extracted from BORN (Better Outcomes Registry and Network) Ontario's information system. The incidences of common intrapartum interventions were compared, and different classification systems for Caesarean section were used to compare the indications for these between singleton pregnancies following ART with or without intracytoplasmic sperm injection and singleton spontaneously conceived pregnancies. Results: Compared with spontaneous singleton pregnancies, the ART group had increased incidences of internal electronic fetal monitoring (OR 1.60; 95% CI 1.37 to 1.87), artificial rupture of membranes (OR 1.39; 95% CI 1.17 to 1.66), oxytocin augmentation of labour (OR 1.51; 95% CI 1.28 to 1.77), induction of labour (OR 1.31; 95% CI 1.14 to 1.50), and Caesarean section (OR 1.40; 95% CI 1.24 to 1.60). Conclusion: Singleton pregnancies resulting from ART were associated with more frequent use of several intrapartum interventions, including Caesarean section.
    09/2014; 36(9):795-802.
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    ABSTRACT: The maternal leukocytes of the first-trimester decidua play a fundamental role in implantation and early development of the fetus and placenta, yet little is known regarding the second-trimester decidual environment. Our multicolor flow cytometric analyses of human decidual leukocytes detected an elevation in tissue resident neutrophils in the second trimester. These cells in both human and murine samples were spatially restricted to decidua basalis. In comparison with peripheral blood neutrophils (PMNs), the decidual neutrophils expressed high levels of neutrophil activation markers and the angiogenesis-related proteins: vascular endothelial growth factor-A, Arginase-1, and CCL2, similarly shown in tumor-associated neutrophils. Functional in vitro assays showed that second-trimester human decidua conditioned medium stimulated transendothelial PMN invasion, upregulated VEGFA, ARG1, CCL2, and ICAM1 mRNA levels, and increased PMN-driven in vitro angiogenesis in a CXCL8-dependent manner. This study identified a novel neutrophil population with a physiological, angiogenic role in human decidua.
    The Journal of Immunology 08/2014; · 5.36 Impact Factor
  • 08/2014; 36(8):665.
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    ABSTRACT: Objective: Early identification of women at risk of developing early-onset severe preeclampsia (sPE) is a key objective in obstetrics. An elevated ratio of serum soluble fms-like tyrosine kinase (sFlt-1) to placenta-like growth factor (PlGF) (sFlt-1/PlGF ratio) precedes overt hypertension. The longitudinal relationship between this biomarker, maternal hemodynamics, and maternal serum uric acid during the pre-clinical phase is unknown. Study Design: We followed 20 normotensive women at high risk of developing sPE from 20 weeks until delivery or 34 weeks' gestation. Non-invasive hemodynamic monitoring using bioreactance technology was performed at 20 to 22, 24 to 26, 28 to 30, and 32 to 34 weeks' gestation. Serum uric acid, sFlt-1, and PlGF were measured simultaneously. Results: Six of 20 women (30%) delivered before 33 weeks with sPE and had significantly higher mean total peripheral resistance (TPR), higher serum uric acid, and higher sFlt-1/PlGF ratios at 24 weeks' gestation than unaffected individuals. The area under the curve, cut-off values, and sensitivity and specificity to predict sPE at 24 weeks were as follows: TPR 0.84, 1250, 80%, 93%; sFlt-1/PlGF ratio 0.94, 55, 100%, 93%; and serum uric acid 0.99, 255 μmol/L, 100%, 93%. TPR and sFlt-1 were positively correlated in the sPE group before antihypertensive treatment (r = 0.65, P = 0.01). Serum uric acid correlated with both sFlt-1 (r = 0.65, P = 0.003) and sFlt-1/PlGF ratio (r = 0.54, P = 0.02). Conclusion: A combination of non-invasive determination of TPR together with measurement of serum uric acid may identify a subset of clinically high-risk women with evolving sPE, independent of the determination of the sFlt-1/PlGF ratio. The predictive ability of this integrated approach needs to be assessed in a larger cohort of women to further confirm its utility.
    08/2014; 36(8):692-700.
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    ABSTRACT: Heparin is often prescribed during pregnancy with the intention of improving perinatal outcomes on the basis that it exerts an anticoagulant action in the inter-villous space. Accumulating in-vitro and in-vivo evidence indicates that heparin's beneficial effects in pregnancy may result from 'non-anticoagulant' effects including the promotion of angiogenesis.
    Placenta 07/2014; · 3.29 Impact Factor
  • 07/2014; 36(7):642-7.
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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.
    Canadian Journal of Anaesthesia 06/2014; 61(9). · 2.50 Impact Factor
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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. · 3.53 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. · 1.64 Impact Factor
  • 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. · 6.17 Impact Factor
  • Placenta 09/2013; 34(9):A85. · 3.29 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: Severely-growth discordant monochorionic (MC) twins offer a unique opportunity to study fetal and placental growth based on a similar genetic background and maternal host environment where the healthy twin serves as an ideal control. Differences in development of monochorionic twins may therefore be due to differential epigenetic regulation of genes involved in placental development and function. Growth-discordant twins are known for abnormal angio-architecture in the placenta of the smaller twin. Since the reasons for this phenotype are mostly unknown this study was aimed to investigate expression and regulation of genes known to be involved in angiogenesis.We studied 10 severely growth-discordant monochorionic twin placentas (birth weight difference≥20%) without twin-twin-transfusion syndrome (TTTS) and 5 growth-concordant monochorionic twin placentas. Growth discordant twin placentas were phenotyped by histology. Placental mRNA expression of 88 angiogenesis related genes were measured by PCR array. Enzyme-linked immuno-sorbent assay (ELISA) and immuno-histochemistry were used to confirm PCR results. EpiTYPTER for DNA methylation was used to determine if methylation ratios were responsible for differential gene expression.The PCR array analysis showed significant mRNA up-regulation in the placental share of the smaller twin for several genes. These included Leptin (24.6 fold, p=0.017), Flt1 (fms-like tyrosine kinase 1, 2.4 fold, p=0.016) and Eng (Endoglin, 1.86 fold, p= 0.078). None of the other 84 angiogenesis related genes showed significant differences. ELISA confirmed significantly increased Leptin protein expression (49.22 vs. 11.03 pg/mL, p=0.049) in the smaller twin of the discordant growth cohort. Leptin expression in smaller twins' placentas was associated with elevated DNA methylation of the Leptin promotor region suggesting the inhibition of binding of a transcriptional activator / inhibitor in that region. We attempted to overcome the limitation of sample size by careful patient selection. We minimized any bias in placental sampling by random sampling from two different sites and by avoiding sampling from areas with grossly visible abnormalities using a standardized sampling protocol.In conclusion, the smaller twin's placenta is characterized by differentially-increased gene expressions for Flt1 and Eng mRNA that may be causally-associated with the villous pathology driven by abnormal feto-placental angiogenesis. The substantial up-regulation of Leptin mRNA may be epigenetically conferred and relevant to the post-natal risk of metabolic syndrome in IUGR offspring with placental pathology. Growth discordant MC twins offer unique insights into the epigenetic basis of perinatal programming.
    Molecular Human Reproduction 07/2013; · 3.48 Impact Factor
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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

Publication Stats

6k Citations
985.10 Total Impact Points


  • 2004–2013
    • Mount Sinai Hospital
      New York City, New York, United States
  • 1999–2013
    • Mount Sinai Hospital, Toronto
      • • Department of Obstetrics and Gynecology
      • • Department of Anesthesia
      • • Department of Fetal Medicine
      Toronto, Ontario, Canada
    • Università degli Studi di Torino
      • Dipartimento di Scienze Mediche
      Torino, Piedmont, Italy
  • 1998–2013
    • University of Toronto
      • • Department of Obstetrics and Gynaecology
      • • Institute of Medical Sciences
      • • Mount Sinai Hospital
      Toronto, Ontario, Canada
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada
    • University of London
      Londinium, England, United Kingdom
  • 2012
    • University of Ottawa
      • Interdisciplinary School of Health Sciences
      Ottawa, Ontario, Canada
  • 2004–2011
    • SickKids
      • Division of Cardiology
      Toronto, Ontario, Canada
  • 2010
    • University of Adelaide
      • Discipline of Obstetrics and Gynaecology
      Adelaide, South Australia, Australia
  • 2009
    • Shanghai Jiao Tong University
      Shanghai, Shanghai Shi, China
    • McMaster University
      Hamilton, Ontario, Canada
    • University of Cambridge
      • Centre for Trophoblast Research
      Cambridge, ENG, United Kingdom
  • 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
  • 1998–2006
    • University Hospital RWTH Aachen
      Aachen, North Rhine-Westphalia, Germany
  • 2005
    • University College London Hospitals NHS Foundation Trust
      Londinium, England, United Kingdom
    • Case Western Reserve University School of Medicine
      • Department of Pathology
      Cleveland, OH, United States
  • 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
  • 1998–2001
    • RWTH Aachen University
      • • Department of Gynaecology and Obstetrics
      • • Institut für Neuroanatomie
      Aachen, North Rhine-Westphalia, Germany
  • 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