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Sean W Limesand - One of the best experts on this subject based on the ideXlab platform.
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fetal adaptations in insulin secretion result from high catecholamines during Placental Insufficiency
The Journal of Physiology, 2017Co-Authors: Sean W Limesand, Paul J RozanceAbstract:Placental Insufficiency and intrauterine growth restriction (IUGR) of the fetus affects approximately 8% of all pregnancies and is associated with short- and long-term disturbances in metabolism. In pregnant sheep, experimental models with a small, defective placenta that restricts delivery of nutrients and oxygen to the fetus result in IUGR. Low blood oxygen concentrations increase fetal plasma catecholamine concentrations, which lower fetal insulin concentrations. All of these observations in sheep models with Placental Insufficiency are consistent with cases of human IUGR. We propose that sustained high catecholamine concentrations observed in the IUGR fetus produce developmental adaptations in pancreatic β-cells that impair fetal insulin secretion. Experimental evidence supporting this hypothesis shows that chronic elevation in circulating catecholamines in IUGR fetuses persistently inhibit insulin concentrations and secretion. Elevated catecholamines also allow for maintenance of a normal fetal basal metabolic rate despite low fetal insulin and glucose concentrations while suppressing fetal growth. Importantly, a compensatory augmentation in insulin secretion occurs following inhibition or cessation of catecholamine signalling in IUGR fetuses. This finding has been replicated in normally grown sheep fetuses following a seven-day norepinephrine infusion. Together, these programmed effects will potentially create an imbalance between insulin secretion and insulin stimulated glucose utilization in the neonate which likely explains the transient hyperinsulinism and hypoglycemia in some IUGR infants. This article is protected by copyright. All rights reserved
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elevated plasma norepinephrine inhibits insulin secretion but adrenergic blockade reveals enhanced β cell responsiveness in an ovine model of Placental Insufficiency at 0 7 of gestation
Journal of Developmental Origins of Health and Disease, 2013Co-Authors: Antoni R Macko, Laura D. Brown, Amy C Kelly, Xiaochuan Chen, Dustin T Yates, Alice S Green, Sean W LimesandAbstract:In pregnancies complicated by Placental Insufficiency (PI), fetal hypoglycemia and hypoxemia progressively worsen during the third trimester, which increases circulating norepinephrine (NE). Pharmacological adrenergic blockade (ADR-block) at 0.9 gestation revealed that NE inhibits insulin secretion and enhanced β-cell responsiveness in fetuses with PI-induced intrauterine growth restriction (IUGR). NE concentrations in PI fetuses at 0.7 gestation were threefold greater compared with age-matched controls, but the levels were similar to near-term controls. Therefore, our objective was to determine whether elevations in plasma NE concentrations inhibit insulin secretion and produce compensatory β-cell responsiveness in PI fetuses at 0.7 gestation. Fetal insulin was measured under basal, glucose-stimulated insulin secretion (GSIS) and glucose-potentiated arginine-stimulated insulin secretion (GPAIS) conditions in the absence and presence of an ADR-block. Placental weights were 38% lower (P < 0.05) in PI fetus than in controls, but fetal weights were not different. PI fetuses had lower (P < 0.05) basal blood oxygen content, plasma glucose, insulin-like growth factor-1 and insulin concentrations and greater plasma NE concentrations (891 ± 211 v. 292 ± 65 pg/ml; P < 0.05) than controls. GSIS was lower in PI fetuses than in controls (0.34 ± 0.03 v. 1.08 ± 0.06 ng/ml; P < 0.05). ADR-block increased GSIS in PI fetuses (1.19 ± 0.11 ng/ml; P < 0.05) but decreased GSIS in controls (0.86 ± 0.02 ng/ml; P < 0.05). Similarly, GPAIS was 44% lower (P < 0.05) in PI fetuses than in controls, and ADR-block increased (P < 0.05) GPAIS in PI fetuses but not in controls. Insulin content per islet was not different between treatments. We conclude that elevations in fetal plasma NE suppress insulin concentrations, and that compensatory β-cell stimulus-secretion responsiveness is present before IUGR.
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reductions in insulin concentrations and β cell mass precede growth restriction in sheep fetuses with Placental Insufficiency
American Journal of Physiology-endocrinology and Metabolism, 2013Co-Authors: Sean W Limesand, Paul J Rozance, Antoni R Macko, Miranda J Anderson, Amy C Kelly, William W. HayAbstract:In pregnancy complicated by Placental Insufficiency (PI) and intrauterine growth restriction (IUGR), the fetus near term has reduced basal and glucose-stimulated insulin concentrations and reduced ...
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developmental programming in response to intrauterine growth restriction impairs myoblast function and skeletal muscle metabolism
Journal of Pregnancy, 2012Co-Authors: Dustin T Yates, Antoni R Macko, Xiaochuan Chen, M Nearing, R P Rhoads, Sean W LimesandAbstract:Fetal adaptations to Placental Insufficiency alter postnatal metabolic homeostasis in skeletal muscle by reducing glucose oxidation rates, impairing insulin action, and lowering the proportion of oxidative fibers. In animal models of intrauterine growth restriction (IUGR), skeletal muscle fibers have less myonuclei at birth. This means that myoblasts, the sole source for myonuclei accumulation in fibers, are compromised. Fetal hypoglycemia and hypoxemia are complications that result from Placental Insufficiency. Hypoxemia elevates circulating catecholamines, and chronic hypercatecholaminemia has been shown to reduce fetal muscle development and growth. We have found evidence for adaptations in adrenergic receptor expression profiles in myoblasts and skeletal muscle of IUGR sheep fetuses with Placental Insufficiency. The relationship of β-adrenergic receptors shifts in IUGR fetuses because Adrβ2 expression levels decline and Adrβ1 expression levels are unaffected in myofibers and increased in myoblasts. This adaptive response would suppress insulin signaling, myoblast incorporation, fiber hypertrophy, and glucose oxidation. Furthermore, this β-adrenergic receptor expression profile persists for at least the first month in IUGR lambs and lowers their fatty acid mobilization. Developmental programming of skeletal muscle adrenergic receptors partially explains metabolic and endocrine differences in IUGR offspring, and the impact on metabolism may result in differential nutrient utilization.
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catecholamines mediate multiple fetal adaptations during Placental Insufficiency that contribute to intrauterine growth restriction lessons from hyperthermic sheep
Journal of Pregnancy, 2011Co-Authors: Dustin T Yates, Alice S Green, Sean W LimesandAbstract:Placental Insufficiency (PI) prevents adequate delivery of nutrients to the developing fetus and creates a chronic state of hypoxemia and hypoglycemia. In response, the malnourished fetus develops a series of stress hormone-mediated metabolic adaptations to preserve glucose for vital tissues at the expense of somatic growth. Catecholamines suppress insulin secretion to promote glucose sparing for insulin-independent tissues (brain, nerves) over insulin-dependent tissues (skeletal muscle, liver, and adipose). Likewise, premature induction of hepatic gluconeogenesis helps maintain fetal glucose and appears to be stimulated by both norepinephrine and glucagon. Reduced glucose oxidation rate in PI fetuses creates a surplus of glycolysis-derived lactate that serves as substrate for hepatic gluconeogenesis. These adrenergically influenced adaptive responses promote in utero survival but also cause asymmetric intrauterine growth restriction and small-for-gestational-age infants that are at greater risk for serious metabolic disorders throughout postnatal life, including obesity and type II diabetes.
Russell V Anthony - One of the best experts on this subject based on the ideXlab platform.
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an animal model of Placental Insufficiency induced intrauterine growth restriction
Seminars in Perinatology, 2008Co-Authors: James S Barry, Paul J Rozance, Russell V AnthonyAbstract:Intrauterine growth restriction (IUGR), often associated with functional Placental Insufficiency, results in increased perinatal mortality and morbidity. For obvious reasons, many questions regarding the progression of IUGR pregnancies cannot be addressed experimentally in humans, predicating the use of animal models. Although no animal model fully recapitulates human pregnancy, the pregnant sheep has been used extensively to investigate maternal-fetal interactions. In sheep, surgical placement of catheters in both the maternal and fetal vasculature allows repeated sampling from nonanesthetized pregnancies. Considerable insight has been gained on Placental oxygen and nutrient transfer and utilization from use of pregnant sheep, often confirmed in the human once appropriate technologies became available. This review will focus on one sheep model, used to examine the impact of Placental Insufficiency-induced IUGR on oxygen and nutrient transport and utilization.
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the relationship between transPlacental o2 diffusion and Placental expression of plgf vegf and their receptors in a Placental Insufficiency model of fetal growth restriction
The Journal of Physiology, 2003Co-Authors: Timothy R H Regnault, Russell V Anthony, B De Vrijer, Meredith L Davidsen, Henry L Galan, Randall B Wilkening, Karen A Trembler, Frederick C BattagliaAbstract:Placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) are involved in Placental angiogenesis through interactions with the VEGFR-1 and VEGFR-2 receptors. The placenta of pregnancies whose outcome is fetal growth restriction (FGR) are characterized by abnormal angiogenic development, classically associated with hypoxia. The present study evaluated the near-term expression of this growth factor family in an ovine model of Placental Insufficiency–FGR, in relationship to uteroPlacental oxygenation. Compared to controls, FGR pregnancies demonstrated a 37 % increase in uterine blood flow (FGR vs. control, 610.86 ± 48.48 vs. 443.17 ± 37.39 ml min−1 (kg fetus)−1; P < 0.04), which was associated with an increased maternal uterine venous PO2 (58.13 ± 1.00 vs. 52.89 ± 1.26 mmHg; P < 0.02), increased umbilical artery systolic/diastolic ratio (3.90 ± 0.33 vs. 2.12 ± 0.26, P < 0.05), and fetal hypoxia (arterial PO2; 12.79 ± 0.97 vs. 18.65 ± 1.6 mmHg, P < 0.005). Maternal caruncle PlGF mRNA was increased in FGR (P < 0.02), while fetal cotyledon VEGF mRNA was reduced (P < 0.02). VEGFR-1 mRNA was also reduced in FGR fetal cotyledon (P < 0.001) but was not altered in caruncle tissue. Immunoblot analysis of PlGF and VEGF demonstrated single bands at 19 000 and 18 600 Mr, respectively. Caruncle PlGF concentration was increased (P < 0.04), while cotyledon VEGF was decreased (P < 0.05) in FGR placentae. The data establish that uterine blood flow is not reduced in relationship to metabolic demands in this FGR model and that the transPlacental PO2 gradient is increased, maintaining umbilical oxygen uptake per unit of tissue. Furthermore, these data suggest that an increased transPlacental gradient of oxygen generates changes in angiogenic growth factors, which may underline the pathophysiology of the post-Placental hypoxic FGR.
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Placental expression of vegf plgf and their receptors in a model of Placental Insufficiency intrauterine growth restriction pi iugr
Placenta, 2002Co-Authors: Timothy R H Regnault, Russell V Anthony, Ryan J Orbus, B De Vrijer, Meredith L Davidsen, Henry L Galan, Randall B WilkeningAbstract:Placental development requires adequate and organized interaction of vascular growth factors and their receptors, including vascular endothelial growth factor (VEGF) and Placental growth factor (PlGF). Both VEGF and PlGF, acting through the tyrosine kinase receptors VEGFR-1 and VEGFR-2, have been implicated in playing a role in ovine Placental vascular development. The present studies describe the Placental expression of components of the VEGF family at two maturational time points (55 and 90 days post coitus, dpc) in a hyperthermic-induced ovine model of Placental Insufficiency-intrauterine growth restriction (PI-IUGR). Both caruncular and cotyledonary VEGF and PlGF mRNA concentration increased with gestational age (P< 0.05), whereas only cotyledonary VEGF and PlGF protein concentration increased over gestation (P< 0.002). At 55 dpc, VEGF mRNA concentration was elevated in hyperthermic (HT) ewes, compared to control thermoneutral (TN) animals (TN; 0.52+/-0.08 vs HT; 1.27+/-0.17 VEGF/GAPDH, P< 0.001). At 90 dpc, expression of PlGF and VEGF mRNA was not altered by the HT treatment. Both TN cotyledonary VEGFR-1 and VEGFR-2 mRNA expression levels rose significantly over the period studied (P< 0.05 and P< 0.01 respectively). Receptor mRNA concentration in HT cotyledonary tissue was significantly reduced at 90 dpc (VEGFR-1; TN 0.21+/-0.02 vs HT 0.11+/-0.01 VEGFR-1/actin, P< 0.05, VEGFR-2; TN 0.18+/-0.05 vs HT 0.07+/-0.01 VEGFR-2/actin, P< 0.01). Soluble VEGFR-1 (sVEGFR-1) mRNA was not detected in these tissues. These alterations in growth factor and growth factor receptor mRNA expression, as a result of environmental heat stress early in Placental development, could impair normal Placental vascular development. Furthermore, alterations in VEGF, VEGFR-1 and VEGFR-2 mRNA expression, during the period of maximal Placental growth, may contribute to the development of Placental Insufficiency, and ultimately intrauterine growth restriction.
Richard Harding - One of the best experts on this subject based on the ideXlab platform.
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fetal growth restriction induced by chronic Placental Insufficiency has long term effects on the retina but not the optic nerve
Investigative Ophthalmology & Visual Science, 2005Co-Authors: Michelle Loeliger, Samantha Louey, Richard Harding, Megan L Cock, Jhodie R Duncan, Sandra ReesAbstract:Purpose Reduced birth weight is associated with an increased risk of visual impairments. This study was undertaken to determine whether prenatal exposure to a chronic compromise sufficient to cause fetal growth restriction (FGR) results in long-term alterations to the retina and optic nerve. Methods FGR was induced by umbilicoPlacental embolization (UPE) in two cohorts of pregnant ewes from (1) 120 days of gestation (dg) until 140 dg and (2) 120 dg until term ( approximately 147 dg). Control fetuses were not subjected to UPE. The structure and neurochemistry of the retina and number and structure of ganglion cell axons were assessed in near-term (140 dg) and adult animals (2.3 years). Results In near-term FGR fetuses compared with control fetuses there were significant reductions (P 0.05) between groups. Conclusions Chronic Placental Insufficiency in late gestation results in long-lasting effects on specific retinal components, including photoreceptor outer segments and TH-IR amacrine cells. Other alterations observed at term, including reductions in growth and myelination of optic nerve axons, do not persist, suggesting delayed rather than permanently compromised development. Alterations persisting into adulthood could affect visual function.
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morphologic alterations in ovine placenta and fetal liver following induced severe Placental Insufficiency
Journal of The Society for Gynecologic Investigation, 2004Co-Authors: Robert Gagnon, Cecilia Y Cheung, Ljubica Bogic, Richard HardingAbstract:Umbilical-Placental embolization with microspheres has been used as a model of Placental Insufficiency and intrauterine growth restriction (IUGR). However, the effects of embolization on Placental structure and organ morphology of the resulting IUGR fetus are relatively unexplored. In this study using ovine fetuses, we determined the location and distribution of microspheres within the placenta and explored the extent of Placental and fetal organ morphologic changes induced by Placental embolization. We hypothesized that microspheres administered into the umbilical circulation over 4 days would cause Placental damage without significant morphologic alterations in fetal kidney or liver. Eleven pregnant sheep at 118 ± 1 (SE) days’ gestation were studied. In six fetuses, embolization was induced by injections of 15-μm diameter microspheres on 4 successive days into the fetal descending aorta proximal to the umbilical arteries. Five fetuses served as time controls. In embolized fetuses, microspheres were detected in the placenta embedded in the fetal cytotrophoblastic layer or maternal parenchyma adjacent to villous cytotrophoblasts. Fetal cytotrophoblasts appeared normal except for loss of distinct separation between fetal and maternal cell layers. Microspheres were also detected in the fetal membranes within capillaries. The body weights of embolized fetuses were lower than controls, as were the body weight—normalized liver but not kidney weights. In the liver of the embolized fetuses, the number of hematopoietic cell clusters was markedly reduced, whereas the fetal kidneys appeared normal. We conclude that after 4 days of umbilical-Placental embolization, microspheres were concentrated at the fetal villi proximal to the apical maternal-fetal interface and in the fetal membranes. There were noticeable morphologic changes in the embolized placentas, with no apparent gross damage to the placenta. The reduction in fetal liver weight and liver extramedullar hematopoietic cell abundance associated with embolization may predispose the fetus to alterations in liver function thai could persist after birth.
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amniotic fluid and fetal urinary responses to severe Placental Insufficiency in sheep
American Journal of Obstetrics and Gynecology, 2002Co-Authors: Robert Gagnon, Richard Harding, Robert A BraceAbstract:Objective: Our purpose was to test the hypothesis that severe Placental Insufficiency leads to reductions in fetal urine production and amniotic fluid volume in late-gestation fetal sheep. Study Design: At 0.85 of gestation, chronically catheterized fetal sheep with ligated urachus were either embolized for 5 days by repeated injection of boluses of 15-μm microspheres into the common fetal umbilical artery until fetal arterial oxygen content was reduced by 50% (n = 6) or were infused with saline solution (n = 6). Amniotic fluid volume was measured daily before embolization by means of an indicator dilution technique and by drainage at autopsy. Fetal urine production, heart rate, and mean arterial blood pressure were measured continuously for 1 hour before embolization and 1 hour after embolization each day. Fetal arterial blood gases, oxygen content, electrolytes, and osmolality were also monitored. Results: Five days of Placental Insufficiency, which reduced fetal arterial oxygen content by 50% and arrested fetal growth, resulted in a reduced amniotic fluid volume without a reduction in fetal urine production. Compared with that of controls, amniotic fluid volume was reduced over the 5-day period by 547 ± 144 mL (−62%, P <.01). Amniotic fluid composition was also altered, with a significant increase in lactate and sodium concentrations and osmolality on days 4 to 5. On days 2 to 5, there was a progressive increase in amniotic fluid osmolality above that of controls, which paralleled the changes in amniotic fluid sodium concentration (P <.05). Fetuses became hypertensive on days 2 to 4 of embolization, although this response was attenuated by day 5. Conclusions: Chronic severe Placental Insufficiency caused a reduction in amniotic fluid volume not attributable to reduced fetal urine production. Changes in amniotic fluid composition induced by Placental Insufficiency suggest an excess intramembranous absorption of amniotic fluid water, in relation to solutes, into the fetal and maternal compartments, which may lead to the development of oligohydramnios. (Am J Obstet Gynecol 2002;186:1076-84)
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compromised respiratory function in postnatal lambs after Placental Insufficiency and intrauterine growth restriction
Pediatric Research, 2001Co-Authors: Belinda Jane Joyce, Samantha Louey, Megan L Cock, Marcus G Davey, Stuart B Hooper, Richard HardingAbstract:Epidemiologic studies have shown persistent effects of low birth weight on respiratory function and lung health, but underlying mechanisms are not understood. Our aim was to determine the effects of intrauterine growth restriction (IUGR), a major cause of low birth weight, on postnatal respiratory function. IUGR was induced by umbilico-Placental embolization during late gestation in chronically catheterized sheep. Umbilico-Placental embolization was performed between 120 d of gestation and term ( approximately 146 d) during which fetuses were hypoxemic and hypoglycemic relative to controls. Umbilico-Placental embolization led to a 48% reduction in birth weight compared with controls, and throughout the postnatal study period IUGR lambs (n = 8) remained lighter than controls (n = 8). Respiratory function was repeatedly studied in lambs for 8 wk after birth; during this period, IUGR lambs were mildly hypoxemic and tended to be hypercapnic compared with controls. In IUGR lambs, relative to controls, O(2) consumption (mL/min/kg) and minute ventilation (mL/kg) were increased and pulmonary diffusing capacity (adjusted for functional residual capacity) was decreased. Functional residual capacity, measured by helium dilution, and total lung capacity (measured at 30 cm H(2)O) were smaller in IUGR lambs than in controls. When adjusted for functional residual capacity, static lung compliance was reduced and chest wall compliance was increased in IUGR lambs. At 8 wk, pulmonary DNA and protein concentrations were decreased in IUGR lambs relative to controls. We conclude that restriction of fetal growth by Placental Insufficiency induces alterations in the lungs and chest wall that result in persistent impairments in respiratory function during early postnatal life.
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fetal brain injury following prolonged hypoxemia and Placental Insufficiency a review
Comparative Biochemistry and Physiology A-molecular & Integrative Physiology, 1998Co-Authors: Sandra Rees, Carina Mallard, Sibilah Breen, M Stringer, Megan L Cock, Richard HardingAbstract:Abstract It is well-established that severe, acute episodes of hypoxemia can damage the brain before birth, but the effects of more sustained hypoxemia are less well understood. We have used fetal sheep in a series of studies aimed at determining the effects of prolonged hypoxemia, induced by Placental Insufficiency of differing severity and duration, on fetal brain structure. Restriction of Placental, and hence fetal, growth by carunclectomy caused impaired development of neural processes and connections in the hippocampus, cerebellum, and visual cortex; neuronal migration and neuronal numbers did not appear to be affected. Twenty days of Placental Insufficiency during late gestation induced by umbilicoPlacental embolisation also caused abnormalities in brain structure; the cerebellum, which develops late in gestation, was particularly affected. In the cortex, there was evidence of white matter lesions, an increase in the size of capillaries and a proliferation of astroglia. We also examined the effects of shorter periods of hypoxemia (6–12 hr) near mid-gestation on brain structure; fetuses were allowed to recover for 7 or 35 days after the hypoxemic challenge. The major changes were mild focal damage in the cortical white matter, a reduction in the number of Purkinje cells, a delay in the growth of neural processes in the cerebellum and proliferation of blood vessels. The hippocampus was also affected, in particular the areal density of pyramidal cells was reduced. The use of several classes of pharmacological agents with the potential to protect neurons from hypoxemic injury is discussed in relation to the developing brain.
John Kingdom - One of the best experts on this subject based on the ideXlab platform.
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unfractionated heparin for second trimester Placental Insufficiency a pilot randomized trial
Journal of Thrombosis and Haemostasis, 2011Co-Authors: John Kingdom, Melissa Walker, L K Proctor, Sarah Keating, P S Shah, Anne Mcleod, Johannes Keunen, Rory Windrim, Jodie M DoddAbstract:Summary. Objective: To conduct a pilot randomized controlled trial of unfractionated heparin (UFH) in women considered at high risk of Placental Insufficiency in the second trimester. Methods: Women with either false-positive first trimester (pregnancy-associated Placental protein-A [PAPP-A] 2.0 MoM, inhibin > 3.0 MoM, human chorionic gonadotropin > 4.0 MoM) serum screening tests or medical/obstetric risk factors were screened for Placental Insufficiency by sonographic evaluation of the placenta and uterine artery Doppler between 18 and 22 weeks. Thrombophilia screen-negative women with two or three abnormal test categories were randomized by 23+6 weeks to self-administration of subcutaneous unfractionated heparin (UFH) 7500 IU twice daily until birth or 34 weeks, or to standard care. Maternal anxiety and other maternal-infant outcomes were determined. Results: Thirty-two out of 41 eligible women consented, with 16 women randomized to UFH and 16 to standard care. There was no statistically significant difference identified between the two treatment groups (standard care vs. UFH) for the following: maternal anxiety score (mean [standard deviation]), 14.2 [± 1.6] vs. 14.0 [± 1.8]; birth weight (median [range]), 1795 [470–3295]g vs. 1860 [730–3050]g; perinatal death, 3 vs. 0; severe preeclampsia, 2 vs. 6; Placental weight < 10th percentile, 7 vs. 4; or Placental infarction, 4 vs. 3. Conclusion: Our study design identified women at high risk of adverse maternal-infant outcomes attributable to Placental Insufficiency. Women with evidence of Placental Insufficiency were willing to undergo randomization and self-administration of UFH without increased maternal anxiety.
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sonographic maturation of the placenta at 30 to 34 weeks is not associated with second trimester markers of Placental Insufficiency in low risk pregnancies
Journal of obstetrics and gynaecology Canada, 2010Co-Authors: Melissa Walker, John Kingdom, Peter C Hindmarsh, Michael GearyAbstract:Objective Advanced Placental maturation (Grannum [G] grade 3) before term is associated with adverse perinatal outcomes associated with Placental Insufficiency. The nature and timing of the underlying pathology of this process is presently unclear. We hypothesized that advanced Placental maturation at 30 to 34 weeks’ gestation is not associated with established second trimester markers of severe Placental dysfunction.
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hypospadias in males with intrauterine growth restriction due to Placental Insufficiency the Placental role in the embryogenesis of male external genitalia
American Journal of Medical Genetics Part A, 2010Co-Authors: Yoav Yinon, John Kingdom, L K Proctor, Sarah Keating, Edmond Kelly, Joao Pippi L Salle, Diane K Wherrett, Ori Nevo, David ChitayatAbstract:Our aim was to define the association between early onset intra-uterine growth restriction (IUGR) due to Placental Insufficiency and hypospadias in males. We prospectively studied a cohort of small-for-gestational age (SGA) male infants with hypospadias managed by a multidisciplinary team over a 5-year period. Thirty SGA male infants were diagnosed with hypospadias/abnormal genitalia after birth, and four of them were diagnosed antenatally. Five cases occurred in the smaller pair of discordant IUGR twins, where the larger co-twin had normal male genitalia. Serial ultrasounds demonstrated features of early-onset IUGR in all cases at a median gestational age of 21 weeks (range 14-31weeks). Twenty-one (70%) pregnancies were subsequently complicated by absent/reversed end-diastolic flow in the umbilical arteries indicating severe IUGR, and 17 (57%) women developed severe pre-eclampsia. There were 27 (90%) live births at a median gestational age of 31 weeks (range 27-37); 23 (77%) of the neonates had birth weights <3rd centile. All newborns had normal male karyotypes. In 62% (18/29) the hypospadias was severe. A correlation was found between the severity of the IUGR and the severity of hypospadias as significantly more infants with severe hypospadias were less than the 3rd centile compared to the mild-moderate hypospadias group: 94% (17/18) versus 55% (6/11), respectively (P = 0.02). In conclusion, SGA male newborns with hypospadias exhibit a high rate of early-onset severe IUGR due to Placental Insufficiency. Early Placental development likely influences male external genitalia formation. Careful sonographic evaluation of the genitalia is advised when early-onset Placentally mediated IUGR is found.
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screening for Placental Insufficiency in high risk pregnancies is earlier better
Placenta, 2008Co-Authors: S L Costa, L K Proctor, Rory Windrim, Jodie M Dodd, Meghana Toal, Nanette Okun, J A Johnson, John KingdomAbstract:Abstract Objective To compare a profile of Placental function between the first and second trimesters in pregnancies at high risk of adverse perinatal outcomes attributable to Placental Insufficiency. Study design Prospective cohort study in 61 singleton pregnancies. Uterine artery Doppler and Placental morphology (shape and texture) were determined at 11–13 +6 weeks and at 18–23 +6 weeks. First trimester (pregnancy-associated Placental protein-A [PAPP-A]) and second trimester (total hCG and alpha fetoprotein [AFP]) serum biochemistry were determined. The two screening periods were compared for the prediction of a range of severe adverse perinatal outcomes (intrauterine growth restriction [IUGR], abruption, severe pre-eclampsia/HELLP syndrome, delivery Results Adverse perinatal outcomes occurred in 14 (23%) women; 3 (4.9%) losses 20 weeks, 4 (6.6%) IUGR, 7 (11.5%) severe pre-eclampsia/HELLP syndrome, and 10 (16.4%) deliveries p = 0.025], as was ≥1 abnormal second trimester tests [+LR: 5.9, 95% CI: 1.6–24; −LR: 0.68, 95% CI: 0.59–0.89; p = 0.005] or ≥2 abnormal second trimester tests [+LR: 3.6, 95% CI: 1.3–7.7; −LR: 0.58, 95% CI: 0.27–0.94; p = 0.035]. No combination of first trimester tests significantly predicted severe adverse perinatal outcomes. A study sample size of 822 women with similar high-risk characteristics would be needed in order to refute the conclusion that present methods of first trimester screening are not inferior to second trimester screening for severe Placental Insufficiency ( p = 0.05, power 80%, z -test). Conclusions In clinically high-risk pregnancies, prediction of adverse perinatal outcomes using Placental function testing is more effective in the second compared with the first trimester.
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ultrasound detection of Placental Insufficiency in women with unexplained abnormal maternal serum screening results
Clinical Genetics, 2005Co-Authors: W Whittle, Vandana Chaddha, P Wyatt, Berthold Huppertz, John KingdomAbstract:Serious Placental Insufficiency results in perinatal death or preterm birth from ischemic-thrombotic pathology, a process which has its origins in Placental maldevelopment in the first trimester. A proportion of at-risk pregnancies may be identified from abnormalities in first or second trimester serum screening data, uterine artery Doppler waveforms or Placental shape and texture at the time of the 18-20-week anatomical examination. In combination, these tests may be capable of recognizing a subset of at-risk pregnancies with 50% positive predictive values. Early recognition before fetal viability affords opportunities to direct women to regional perinatal care centres for enhanced maternal-fetal surveillance, corticosteroids to enhance fetal lung maturation, prophylactic measures to prevent pre-eclampsia and optimal decision making around the time of delivery. The creation of regional screening programs to use screening data with a Placental focus is likely to be cost-effective, because existing patterns of care are utilized. More importantly, this strategy can direct women to participate in clinical research programs designed to reduce morbidity and mortality from this common group of conditions.
William W. Hay - One of the best experts on this subject based on the ideXlab platform.
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role of Placental Insufficiency and intrauterine growth restriction on the activation of fetal hepatic glucose production
Molecular and Cellular Endocrinology, 2016Co-Authors: Stephanie R Wesolowski, William W. HayAbstract:Abstract Glucose is the major fuel for fetal oxidative metabolism. A positive maternal–fetal glucose gradient drives glucose across the placenta and is sufficient to meet the demands of the fetus, eliminating the need for endogenous hepatic glucose production (HGP). However, fetuses with intrauterine growth restriction (IUGR) from pregnancies complicated by Placental Insufficiency have an early activation of HGP. Furthermore, this activated HGP is resistant to suppression by insulin. Here, we present the data demonstrating the activation of HGP in animal models, mostly fetal sheep, and human pregnancies with IUGR. We also discuss potential mechanisms and pathways that may produce and support HGP and hepatic insulin resistance in IUGR fetuses.
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Impact of Placental Insufficiency on fetal skeletal muscle growth.
Molecular and cellular endocrinology, 2016Co-Authors: Laura D. Brown, William W. HayAbstract:Intrauterine growth restriction (IUGR) caused by Placental Insufficiency is one of the most common and complex problems in perinatology, with no known cure. In pregnancies affected by Placental Insufficiency, a poorly functioning placenta restricts nutrient supply to the fetus and prevents normal fetal growth. Among other significant deficits in organ development, the IUGR fetus characteristically has less lean body and skeletal muscle mass than their appropriately-grown counterparts. Reduced skeletal muscle growth is not fully compensated after birth, as individuals who were born small for gestational age (SGA) from IUGR have persistent reductions in muscle mass and strength into adulthood. The consequences of restricted muscle growth and accelerated postnatal "catch-up" growth in the form of adiposity may contribute to the increased later life risk for visceral adiposity, peripheral insulin resistance, diabetes, and cardiovascular disease in individuals who were formerly IUGR. This review will discuss how an insufficient placenta results in impaired fetal skeletal muscle growth and how lifelong reductions in muscle mass might contribute to increased metabolic disease risk in this vulnerable population.
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reductions in insulin concentrations and β cell mass precede growth restriction in sheep fetuses with Placental Insufficiency
American Journal of Physiology-endocrinology and Metabolism, 2013Co-Authors: Sean W Limesand, Paul J Rozance, Antoni R Macko, Miranda J Anderson, Amy C Kelly, William W. HayAbstract:In pregnancy complicated by Placental Insufficiency (PI) and intrauterine growth restriction (IUGR), the fetus near term has reduced basal and glucose-stimulated insulin concentrations and reduced ...