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Peers de Nieuwburgh M, Hunt M, Chandrasekaran P, Vincent TL, Hayes KB, Randazzo IR, Gunder M, De Bie FR, Colson A, Lu M, Wen H, Michki SN, Rychik J, Debiève F, Katzen J, Young LR, Davey MG, Flake AW, Gaynor JW, Frank DB. Chronic Hypoxia in an EXTrauterine Environment for Neonatal Development Impairs Lung Development. Am J Respir Cell Mol Biol 2025; 72:441-452. [PMID: 39453404 DOI: 10.1165/rcmb.2024-0012oc] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 10/23/2024] [Indexed: 10/26/2024] Open
Abstract
Severe fetal hypoxia poses a significant risk to lung development, resulting in severe postnatal complications. Existing chronic hypoxia animal models lack the ability to achieve pathologically reduced fetal oxygen without compromising animal development, placental blood flow, or maternal health. Using an established model of isolated chronic hypoxia involving the Extrauterine Environment for Neonatal Development, we are able to investigate the direct impact of fetal hypoxia on lung development. Oxygen delivery to preterm fetal lambs (105-110 d gestational age) delivered by cesarean section was reduced, and animals were supported using the Extrauterine Environment for Neonatal Development through the canalicular or saccular stage of lung development. Fetal lambs in hypoxic conditions showed significant growth restriction compared with their normoxic counterparts. We also observed modest aberrant vascular remodeling in the saccular group after hypoxic conditions, with decreased macrovessel numbers and microvascular endothelial cell numbers and increased peripheral vessel muscularization. In addition, fetal hypoxia resulted in enlarged distal airspaces and decreased septal wall volume. Moreover, there was a reduction in mature SFTPB (surfactant protein B) and processed SFTPC protein expression concomitant with a decrease in alveolar type 2 cell number. These findings demonstrate that maternally independent fetal hypoxia predominantly affects distal airway development, alveolar type 2 cell number, and surfactant production, with mild effects on the vasculature.
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Affiliation(s)
| | - Mallory Hunt
- Division of Cardiovascular Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | | | - Tiffany L Vincent
- Division of Pulmonology and Sleep Medicine, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania
| | | | | | | | | | - Arthur Colson
- Pôle de Recherche en Physiopathologie de la Reproduction, Institut de Recherche Expérimentale et Clinique, and
- Service d'Obstétrique, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
| | | | | | - Sylvia N Michki
- Division of Cardiology
- Division of Pulmonology and Sleep Medicine, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania
| | | | - Fréderic Debiève
- Pôle de Recherche en Physiopathologie de la Reproduction, Institut de Recherche Expérimentale et Clinique, and
- Service d'Obstétrique, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Jeremy Katzen
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and
| | - Lisa R Young
- Division of Pulmonology and Sleep Medicine, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania
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Zhong J, Pankratova S, Doughty R, Flyger CK, Sangild PT, Skovgaard K, Jensen HE, Nguyen DN, Thymann T. Postnatal enteral plasma supplementation following birth asphyxia increases fluid retention and kidney health in newborn pigs. Physiol Rep 2025; 13:e70238. [PMID: 39910739 PMCID: PMC11798866 DOI: 10.14814/phy2.70238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 01/14/2025] [Accepted: 01/27/2025] [Indexed: 02/07/2025] Open
Abstract
Birth asphyxia can result in kidney dysfunction, disturbances in systemic electrolytes and fluid balance in newborns. Currently, there is no proven dietary approach to support asphyxiated newborns. This study investigates whether oral plasma supplementation improves kidney function and overall health in asphyxiated newborns. Cesarean-delivered near-term pigs with or without an 8 min intrauterine clamping of the umbilical cord were fed a milk replacer dissolved in water for 24 h in Experiment 1. Pigs were fed 72 h with milk replacers dissolved in either maternal plasma or water in Experiment 2. Blood, urine, and kidney tissue were collected for further analyses. Asphyxia disrupted blood electrolyte balance. And plasma feeding led to higher fluid retention for both asphyxiated and control pigs. Additionally, plasma feeding may also affect kidney development and protect kidneys from asphyxia induced impairments. Birth asphyxia in pigs led to immediate disturbance of electrolyte balance, impaired fluid retention, and kidney impairments. Plasma feeding may improve postnatal newborn hydration and may also improve the condition of kidneys following asphyxia.
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Affiliation(s)
- Jingren Zhong
- Section for Comparative Pediatrics and Nutrition, Department of Veterinary and Animal SciencesUniversity of CopenhagenFrederiksbergDenmark
| | - Stanislava Pankratova
- Section for Comparative Pediatrics and Nutrition, Department of Veterinary and Animal SciencesUniversity of CopenhagenFrederiksbergDenmark
| | - Richard Doughty
- Department of PathologyAkershus University HospitalLørenskogNorway
| | - Christoffer Kirkelund Flyger
- Section for Pathobiological Sciences, Department of Veterinary and Animal SciencesUniversity of CopenhagenFrederiksbergDenmark
| | - Per Torp Sangild
- Section for Comparative Pediatrics and Nutrition, Department of Veterinary and Animal SciencesUniversity of CopenhagenFrederiksbergDenmark
- Department of PediatricsOdense University HospitalOdenseDenmark
- Department of NeonatologyRigshospitaletCopenhagenDenmark
| | - Kerstin Skovgaard
- Department of Biotechnology and BiomedicineTechnical University of DenmarkLyngbyDenmark
| | - Henrik Elvang Jensen
- Section for Pathobiological Sciences, Department of Veterinary and Animal SciencesUniversity of CopenhagenFrederiksbergDenmark
| | - Duc Ninh Nguyen
- Section for Comparative Pediatrics and Nutrition, Department of Veterinary and Animal SciencesUniversity of CopenhagenFrederiksbergDenmark
| | - Thomas Thymann
- Section for Comparative Pediatrics and Nutrition, Department of Veterinary and Animal SciencesUniversity of CopenhagenFrederiksbergDenmark
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Lock MC, Patey OV, Smith KLM, Niu Y, Jaggs B, Trafford AW, Giussani DA, Galli GLJ. Maladaptive cardiomyocyte calcium handling in adult offspring of hypoxic pregnancy: protection by antenatal maternal melatonin. J Physiol 2024; 602:6683-6703. [PMID: 39572933 DOI: 10.1113/jp287325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 10/10/2024] [Indexed: 12/18/2024] Open
Abstract
Chronic fetal hypoxia is one of the most common complications of pregnancy and can programme cardiac abnormalities in adult offspring including ventricular remodelling, diastolic dysfunction and sympathetic dominance. However, the underlying mechanisms at the level of the cardiomyocyte are unknown, preventing the identification of targets for therapeutic intervention. Therefore, we aimed to link echocardiographic data with cardiomyocyte function to reveal cellular mechanism for cardiac dysfunction in rat offspring from hypoxic pregnancy. Further, we investigated the potential of maternal treatment with melatonin as antenatal antioxidant therapy. Wistar rats were randomly allocated into normoxic (21% O2) or hypoxic (13% O2) pregnancy with or without melatonin treatment (5 µg/ml; normoxic melatonin in the maternal drinking water from gestational day 6 to 20 (term = 22 days). After delivery, male and female offspring were maintained to adulthood (16 weeks). Cardiomyocytes were isolated from the left and right ventricles, and calcium (Ca2+) handling was investigated in field-stimulated myocytes. Systolic and diastolic function was negatively impacted in male and female offspring of hypoxic pregnancy demonstrating biventricular systolic and diastolic dysfunction and compensatory increases in cardiac output. Ca2+ transients from isolated cardiomyocytes in offspring of both sexes in hypoxic pregnancy displayed diastolic dysfunction with a reduced rate of [Ca2+]i recovery. Cardiac and cardiomyocyte dysfunction in male and female adult offspring was ameliorated by maternal antenatal treatment with melatonin in hypoxic pregnancy. Therefore, cardiomyocyte Ca2+ mishandling provides a cellular mechanism explaining functional deficits in hearts of male and female offspring in pregnancies complicated by chronic fetal hypoxia. KEY POINTS: This study identified significant changes in Ca2+ handling within cardiomyocytes isolated from offspring of hypoxic pregnancy including reduced systolic Ca2+ transients, impaired diastolic recovery of [Ca2+]i and a greater increase in systolic [Ca2+]i amplitude to β-adrenergic stimulation. These changes in cardiomyocyte Ca2+ handling help to explain dysregulation of biventricular systolic and diastolic dysfunction determined by echocardiography. The data show protection against maladaptive cardiomyocyte calcium handling and thereby improvement in cardiac function in adult offspring of hypoxic pregnancy treated with melatonin with doses lower than those recommended for overcoming jet lag in humans. Melatonin treatment alone in healthy pregnancy did cause some alterations in cardiac structure. Therefore, maternal treatment with melatonin should only be given to pregnancies affected by chronic fetal hypoxia.
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Affiliation(s)
- Mitchell C Lock
- Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, UK
| | - Olga V Patey
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Kerri L M Smith
- Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, UK
| | - Youguo Niu
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Ben Jaggs
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Andrew W Trafford
- Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, UK
| | - Dino A Giussani
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Gina L J Galli
- Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, UK
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Ramsie M, Cheung PY, O'Reilly M, Lee TF, Schmölzer GM. Pharmacokinetic and pharmacodynamic evaluation of various vasopressin doses and routes of administration in a neonatal piglet model. Sci Rep 2024; 14:23096. [PMID: 39367115 PMCID: PMC11452715 DOI: 10.1038/s41598-024-74188-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 09/24/2024] [Indexed: 10/06/2024] Open
Abstract
Epinephrine is the only recommended vasopressor during neonatal cardiopulmonary resuscitation. However, there are concerns about the potential adverse effects of epinephrine, which might hamper efficacy during cardiopulmonary resuscitation. An alternative might be vasopressin, which has a preferable adverse effect profile, however, its optimal dose and route of administration is unknown. We aimed to compare the pharmacodynamics and pharmacokinetics of various vasopressin doses administered via intravenous (IV), intraosseous (IO), endotracheal (ETT), and intranasal (IN) routes in healthy neonatal piglets. Forty-four post-transitional piglets (1-3 days of age) were anesthetized, intubated via a tracheostomy, and randomized to receive vasopressin via intravenous (control), IO, ETT, or IN route. Heart rate (HR), arterial blood pressure, carotid blood flow, and cardiac function (e.g., stroke volume, ejection fraction) were continuously recorded throughout the experiment. Blood was collected prior to drug administration and throughout the observation period for pharmacodynamics and pharmacokinetic analysis. Significant changes in hemodynamic parameters were observed following IO administration of vasopressin while pharmacokinetic parameters were not different between IV and IO vasopressin. Administration of vasopressin via ETT or IN did not change hemodynamic parameters and had significantly lower maximum plasma concentrations and systemic absorption compared to piglets administered IV vasopressin (p < 0.05). The IV and IO routes appear the most effective for vasopressin administration in neonatal piglets, while the ETT and IN routes appear unsuitable for vasopressin administration.
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Affiliation(s)
- Marwa Ramsie
- Centre for the Studies of Asphyxia and Resuscitation, Neonatal Research Unit, Royal Alexandra Hospital, 10240 Kingsway Avenue NW, Edmonton, AB, T5H 3V9, Canada
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
| | - Po-Yin Cheung
- Centre for the Studies of Asphyxia and Resuscitation, Neonatal Research Unit, Royal Alexandra Hospital, 10240 Kingsway Avenue NW, Edmonton, AB, T5H 3V9, Canada
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
| | - Megan O'Reilly
- Centre for the Studies of Asphyxia and Resuscitation, Neonatal Research Unit, Royal Alexandra Hospital, 10240 Kingsway Avenue NW, Edmonton, AB, T5H 3V9, Canada
| | - Tze-Fun Lee
- Centre for the Studies of Asphyxia and Resuscitation, Neonatal Research Unit, Royal Alexandra Hospital, 10240 Kingsway Avenue NW, Edmonton, AB, T5H 3V9, Canada
| | - Georg M Schmölzer
- Centre for the Studies of Asphyxia and Resuscitation, Neonatal Research Unit, Royal Alexandra Hospital, 10240 Kingsway Avenue NW, Edmonton, AB, T5H 3V9, Canada.
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.
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Hashim L, Vari D, Bhat AM, Tsuda T. Adaptive Growth of the Ductus Arteriosus and Aortic Isthmus in Various Ductus-Dependent Complex Congenital Heart Diseases. Pediatr Cardiol 2024; 45:1588-1595. [PMID: 37477699 DOI: 10.1007/s00246-023-03236-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 07/06/2023] [Indexed: 07/22/2023]
Abstract
BACKGROUND The ductus arteriosus (DA) is critical in maintaining postnatal circulation in neonates with obstructed systemic circulation (OSC) and pulmonary circulation (OPC). We hypothesized that the size of the DA and aortic isthmus (AoI) undergoes adaptive growth in utero to counteract the hemodynamic challenges in these congenital heart diseases (CHD). METHODS Postnatal echocardiograms of neonates diagnosed prenatally with ductal-dependent CHD who were started on prostaglandins within 24 h of birth were reviewed. We assessed the cross-sectional area of the aortic valve opening, pulmonary valve opening, AoI, and DA by calculating (diameter)2/body surface area. Neonates were classified into OSC or OPC then subgrouped depending upon the patency of semilunar valves: OSC with and without aortic atresia (OSC-AA and OSC-nAA, respectively) and OPC with and without pulmonary atresia (OPC-PA and OPC-nPA, respectively). RESULTS Ninety-four cases were studied. The DA in OSC was significantly larger than OPC, and the DA in OSC-AA was significantly larger than OSC-nAA. The size of the AoI was significantly larger in OPC than OSC and larger in OSC-AA than OSC-nAA. Within the OSC-nAA group, there was no significant difference in the size of the DA, AoI, or pulmonary valve opening between those with retrograde flow (RF) at the AoI and without (nRF) except the aortic valve opening was significantly larger in nRF. All groups had comparable cross-sectional areas of systemic output. CONCLUSIONS Our findings suggest that DA and AoI show compensatory growth to maintain critical blood flow to vital organs against primary anatomical abnormalities in ductus-dependent CHD. (249 words).
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Affiliation(s)
- Liza Hashim
- Nemours Cardiac Center, Nemours Children's Health, 1600 Rockland Rd, Wilmington, DE, 19803, USA
- Department of Pediatrics, Division of Pediatric Cardiology, University of Virginia Children's Hospital, 1204 W. Main St, Charlottesville, VA, 22903, USA
| | - Daniel Vari
- Nemours Cardiac Center, Nemours Children's Health, 1600 Rockland Rd, Wilmington, DE, 19803, USA
- Cincinnati Children's Hospital Medical Center, The Heart Institute, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
| | - Abdul M Bhat
- Nemours Cardiac Center, Nemours Children's Health, 1600 Rockland Rd, Wilmington, DE, 19803, USA
- Department of Pediatrics, Sidney Kimmel Medical College at Thomas Jefferson University, 1025 Walnut St. #100, Philadelphia, PA, 19107, USA
| | - Takeshi Tsuda
- Nemours Cardiac Center, Nemours Children's Health, 1600 Rockland Rd, Wilmington, DE, 19803, USA.
- Department of Pediatrics, Sidney Kimmel Medical College at Thomas Jefferson University, 1025 Walnut St. #100, Philadelphia, PA, 19107, USA.
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Martinelli S, Rolfo A, Pace C, Canu L, Nuzzo AM, Giuffrida D, Gaglioti P, Todros T. Anatomical and functional changes of the fetal adrenal gland in intrauterine growth restriction. Int J Gynaecol Obstet 2024; 166:1100-1107. [PMID: 38532440 DOI: 10.1002/ijgo.15491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 02/26/2024] [Accepted: 03/10/2024] [Indexed: 03/28/2024]
Abstract
OBJECTIVE The aim of this study was to demonstrate the establishment of adrenal sparing in intrauterine growth restricted (IUGR) human fetuses. IUGR fetuses are a subgroup of small for gestational age (SGA) fetuses that are unable to reach their own growth potential because of chronic hypoxia and undernutrition. We hypothesized that in IUGR fetuses the adrenal gland is relatively larger and secretion of noradrenaline (NA), adrenaline (A), and cortisol is increased. STUDY DESIGN This is a prospective observational study including 65 singleton pregnancies (42 IUGR and 23 controls). Using two-dimensional ultrasound, we measured fetal adrenal diameters and adrenal/abdominal circumference (AD/AC) ratio between 25 and 37 weeks. We considered only one measurement per fetus. In 21 pregnancies we also measured NA, A, and cortisol levels in arterial and venous fetal cord blood collected at the time of delivery. RESULTS The AD/AC ratio was significantly higher in IUGR fetuses than in controls. Cord NA and A levels were significantly higher in IUGR fetuses than in controls. An increase in cortisol secretion in IUGR fetuses was observed but the difference was not statistically significant. CONCLUSIONS Adrenal sparing correlates with a relative increase in adrenal measurements and function.
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Affiliation(s)
- Serena Martinelli
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
- Centro di Ricerca e Innovazione sulle Patologie Surrenaliche, AOU Careggi, Florence, Italy
- European Network for the Study of Adrenal Tumors, (ENS@T) Center of Excellence, Florence, Italy
| | - Alessandro Rolfo
- Department of Surgical Sciences, University of Turin, Turin, Italy
| | - Carlotta Pace
- AOU Città della Salute e della Scienza, Sant' Anna Hospital, Turin, Italy
| | - Letizia Canu
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
- Centro di Ricerca e Innovazione sulle Patologie Surrenaliche, AOU Careggi, Florence, Italy
- European Network for the Study of Adrenal Tumors, (ENS@T) Center of Excellence, Florence, Italy
| | - Anna Maria Nuzzo
- Department of Surgical Sciences, University of Turin, Turin, Italy
| | | | - Pietro Gaglioti
- AOU Città della Salute e della Scienza, Sant' Anna Hospital, Turin, Italy
| | - Tullia Todros
- Department of Surgical Sciences, University of Turin, Turin, Italy
- AOU Città della Salute e della Scienza, Sant' Anna Hospital, Turin, Italy
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Pattamathamakul S, Duangkum C, Chaiyarach S, Kongwattanakul K, Saksiriwuttho P, Komwilaisak R, Chantanavilai S, Pongsamakthai M, Sirikarn P. The Impact of Fetal Growth Restriction on Prenatal 2D Ultrasound and Doppler Study of the Fetal Adrenal Gland. J Pregnancy 2024; 2024:9968509. [PMID: 39238897 PMCID: PMC11377111 DOI: 10.1155/2024/9968509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 05/31/2024] [Accepted: 08/12/2024] [Indexed: 09/07/2024] Open
Abstract
Background: Uteroplacental insufficiency in fetuses with growth restriction (FGR) leads to chronic hypoxia and stress, predominantly affecting the adrenal glands. However, the mechanisms of impact remain unclear. Objectives: This study is aimed at comparing the Doppler indices of the adrenal artery and the adrenal gland sizes between FGR and those with normal growth. Materials and Methods: A multicenter, cross-sectional study was conducted from February to December 2023. We compared 34 FGR to 34 with normal growth in terms of inferior adrenal artery (IAA) Doppler indices and adrenal gland volumes. Results: The IAA peak systolic velocity (PSV) in the FGR group was 14.9 ± 2.9 cm/s compared to 13.5 ± 2.0 cm/s in the normal group, with a mean difference of 1.4 cm/s (95% confidence interval [CI]: 0.27-2.65; p value = 0.017). There were no significant differences between groups in terms of IAA pulsatility index (PI), resistance index (RI), or systolic/diastolic (S/D), with p values of 0.438, 0.441, and 0.658, respectively. The volumes of the corrected whole adrenal gland and the corrected neocortex were significantly larger in the FGR group, with p values of 0.031 and 0.020, respectively. Conclusion: Both increased IAA PSV and enlarged volumes of the corrected whole adrenal gland and neocortex were found in fetuses with FGR, suggesting significant adrenal gland adaptation in response to chronic intrauterine stress.
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Affiliation(s)
- Suphawan Pattamathamakul
- Department of Obstetrics and GynecologyFaculty of MedicineKhon Kaen University, Khon Kaen, Thailand
| | - Chatuporn Duangkum
- Department of Obstetrics and GynecologyFaculty of MedicineKhon Kaen University, Khon Kaen, Thailand
| | - Sukanya Chaiyarach
- Department of Obstetrics and GynecologyFaculty of MedicineKhon Kaen University, Khon Kaen, Thailand
| | - Kiattisak Kongwattanakul
- Department of Obstetrics and GynecologyFaculty of MedicineKhon Kaen University, Khon Kaen, Thailand
| | - Piyamas Saksiriwuttho
- Department of Obstetrics and GynecologyFaculty of MedicineKhon Kaen University, Khon Kaen, Thailand
| | - Ratana Komwilaisak
- Department of Obstetrics and GynecologyFaculty of MedicineKhon Kaen University, Khon Kaen, Thailand
| | | | | | - Prapassara Sirikarn
- Department of Epidemiology and BiostatisticsFaculty of Public HealthKhon Kaen University, Khon Kaen, Thailand
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Ramsie M, Cheung PY, Lee TF, O'Reilly M, Schmölzer GM. Comparison of various vasopressin doses to epinephrine during cardiopulmonary resuscitation in asphyxiated neonatal piglets. Pediatr Res 2024; 95:1265-1272. [PMID: 37940664 PMCID: PMC11035119 DOI: 10.1038/s41390-023-02858-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 09/22/2023] [Accepted: 09/24/2023] [Indexed: 11/10/2023]
Abstract
BACKGROUND Current neonatal resuscitation guidelines recommend epinephrine for cardiac arrest. Vasopressin might be an alternative during asphyxial cardiac arrest. We aimed to compare vasopressin and epinephrine on incidence and time to return of spontaneous circulation (ROSC) in asphyxiated newborn piglets. DESIGN/METHODS Newborn piglets (n = 8/group) were anesthetized, intubated, instrumented, and exposed to 30 min of normocapnic hypoxia, followed by asphyxia and asystolic cardiac arrest. Piglets were randomized to 0.2, 0.4, or 0.8IU/kg vasopressin, or 0.02 mg/kg epinephrine. Hemodynamic parameters were continuously measured. RESULTS Median (IQR) time to ROSC was 172(103-418)s, 157(100-413)s, 122(93-289)s, and 276(117-480)s for 0.2, 0.4, 0.8IU/kg vasopressin, and 0.02 mg/kg epinephrine groups, respectively (p = 0.59). The number of piglets that achieved ROSC was 6(75%), 6(75%), 7(88%), and 5(63%) for 0.2, 0.4, 0.8IU/kg vasopressin, and 0.02 mg/kg epinephrine, respectively (p = 0.94). The epinephrine group had a 60% (3/5) rate of post-ROSC survival compared to 83% (5/6), 83% (5/6), and 57% (4/7) in the 0.2, 0.4, and 0.8IU/kg vasopressin groups, respectively (p = 0.61). CONCLUSION Time to and incidence of ROSC were not different between all vasopressin dosages and epinephrine. However, non-significantly lower time to ROSC and higher post-ROSC survival in vasopressin groups warrant further investigation. IMPACT Time to and incidence of ROSC were not statistically different between all vasopressin dosages and epinephrine. Non-significantly lower time to ROSC and higher post-ROSC survival in vasopressin-treated piglets. Overall poorer hemodynamic recovery following ROSC in epinephrine piglets compared to vasopressin groups. Human neonatal clinical trials examining the efficacy of vasopressin during asphyxial cardiac arrest will begin recruitment soon.
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Affiliation(s)
- Marwa Ramsie
- Centre for the Studies of Asphyxia and Resuscitation, Neonatal Research Unit, Royal Alexandra Hospital, Edmonton, AB, Canada
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
| | - Po-Yin Cheung
- Centre for the Studies of Asphyxia and Resuscitation, Neonatal Research Unit, Royal Alexandra Hospital, Edmonton, AB, Canada
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
| | - Tze-Fun Lee
- Centre for the Studies of Asphyxia and Resuscitation, Neonatal Research Unit, Royal Alexandra Hospital, Edmonton, AB, Canada
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
| | - Megan O'Reilly
- Centre for the Studies of Asphyxia and Resuscitation, Neonatal Research Unit, Royal Alexandra Hospital, Edmonton, AB, Canada
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
| | - Georg M Schmölzer
- Centre for the Studies of Asphyxia and Resuscitation, Neonatal Research Unit, Royal Alexandra Hospital, Edmonton, AB, Canada.
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.
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9
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Holmes H, Saini BS, Moir OJ, Darby JRT, Morrison JL, Sun L, Seed M. Pulmonary Vascular Regulation in the Fetal and Transitional Lung. Clin Perinatol 2024; 51:1-19. [PMID: 38325936 DOI: 10.1016/j.clp.2023.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Fetal lungs have fewer and smaller arteries with higher pulmonary vascular resistance (PVR) than a newborn. As gestation advances, the pulmonary circulation becomes more sensitive to changes in pulmonary arterial oxygen tension, which prepares them for the dramatic drop in PVR and increase in pulmonary blood flow (PBF) that occur when the baby takes its first few breaths of air, thus driving the transition from fetal to postnatal circulation. Dynamic and intricate regulatory mechanisms control PBF throughout development and are essential in supporting gas exchange after birth. Understanding these concepts is crucial given the role the pulmonary vasculature plays in the development of complications with transition, such as in the setting of persistent pulmonary hypertension of the newborn and congenital heart disease. An improved understanding of pulmonary vascular regulation may reveal opportunities for better clinical management.
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Affiliation(s)
- Hannah Holmes
- Division of Cardiology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, M5G 1X8, Canada
| | - Brahmdeep S Saini
- Division of Cardiology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, M5G 1X8, Canada
| | - Olivia J Moir
- Division of Cardiology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, M5G 1X8, Canada
| | - Jack R T Darby
- Early Origins of Adult Health Research Group, University of South Australia, Adelaide, South Australia, 5001, Australia
| | - Janna L Morrison
- Early Origins of Adult Health Research Group, University of South Australia, Adelaide, South Australia, 5001, Australia; Department of Physiology, Faculty of Medicine, University of Toronto, 555 University Avenue, Toronto, Ontario, M5G 1X8 Canada; Translational Medicine Program, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario, M5G 1X8 Canada
| | - Liqun Sun
- Division of Cardiology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, M5G 1X8, Canada
| | - Mike Seed
- Division of Cardiology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, M5G 1X8, Canada; Department of Physiology, Faculty of Medicine, University of Toronto, 555 University Avenue, Toronto, Ontario, M5G 1X8 Canada; Translational Medicine Program, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario, M5G 1X8 Canada; Research Institute, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario, M5G 1X8 Canada; Department of Diagnostic Imaging, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario, M5G 1X8 Canada.
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10
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Dixit S, Dixit NA, Rawat A, Bajpai A, Alelyani M, Sabah ZU, Raghuwanshi S. Color Doppler ultrasound in high-low risk pregnancies and its relationship to fetal outcomes: a cross-sectional study. Front Pediatr 2024; 11:1221766. [PMID: 38444769 PMCID: PMC10912586 DOI: 10.3389/fped.2023.1221766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 12/26/2023] [Indexed: 03/07/2024] Open
Abstract
Objective To calculate the multivessel color Doppler indices in high-risk and low-risk pregnancies and relate these to fetal outcomes. Methods The investigation involved 60 patients who were pregnant. The patients were separated into groups according to assessment of low and high risk. The patients underwent color Doppler ultrasonography to detect the maternal and fetal blood vessels, and the measured Doppler indices were then analyzed for any association with fetal outcomes. Results The gestational stages (in weeks) of the participants at the respective times of investigation and delivery were 32.06 ± 2.98 and 36.2 ± 1.78 in the low-risk group and 29.21 ± 1.95 and 29.83 ± 1.86 in the high-risk group. The pulsatility index (PI), resistive index (RI), and systolic/diastolic ratio (SD) decreased with gestation length in the low-risk group, whereas in the high-risk group, these values increased in the uterine and umbilical arteries. With increased gestational stage, MCA-PSV (peak systolic velocity) in the middle cerebral artery (MCA) increased, while PI decreased. Pulsatile and reversal flow of the uterine vein, the vein of Galen, and the umbilical vein were noted in high-risk pregnancies, and these negatively affected the fetal outcome. The fetal venous parameters were more specific and sensitive for predicting an unfavorable fetal outcome than the arterial factors, with a greater negative predictive value. Conclusion The results of our study indicate that abnormal Doppler indices of the blood vessels in high-risk pregnant patients will result in adverse clinical outcomes. Therefore, the patients can be monitored and managed accordingly using Doppler ultrasonography.
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Affiliation(s)
- Snehil Dixit
- Department of Medical Rehabilitation Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Nitin Arun Dixit
- Department of Radiodiagnosis, King George Medical University, Lucknow, India
| | - Anil Rawat
- Department of Radiodiagnosis, King George Medical University, Lucknow, India
| | - Akanksha Bajpai
- Department of Radiodiagnosis, Career Institute of Medical Sciences, Lucknow, India
| | - Magbool Alelyani
- Department of Radiological Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Zia Ul Sabah
- Department of Medicine, College of Medicine, King Khalid University, Abha, Saudi Arabia
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11
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Dibbon KC, Mercer GV, Maekawa AS, Hanrahan J, Steeves KL, Ringer LCM, Simpson AJ, Simpson MJ, Baschat AA, Kingdom JC, Macgowan CK, Sled JG, Jobst KJ, Cahill LS. Polystyrene micro- and nanoplastics cause placental dysfunction in mice†. Biol Reprod 2024; 110:211-218. [PMID: 37724921 DOI: 10.1093/biolre/ioad126] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 08/22/2023] [Accepted: 09/13/2023] [Indexed: 09/21/2023] Open
Abstract
Maternal exposure to microplastics and nanoplastics has been shown to result in fetal growth restriction in mice. In this study, we investigated the placental and fetal hemodynamic responses to plastics exposure in mice using high-frequency ultrasound. Healthy, pregnant CD-1 dams were given either 106 ng/L of 5 μm polystyrene microplastics or 106 ng/L of 50 nm polystyrene nanoplastics in drinking water throughout gestation and were compared with controls. Maternal exposure to both microplastics and nanoplastics resulted in evidence of placental dysfunction that was highly dependent on the particle size. The umbilical artery blood flow increased by 48% in the microplastic-exposed group and decreased by 25% in the nanoplastic-exposed group compared to controls (p < 0.05). The microplastic- and nanoplastic-exposed fetuses showed a significant decrease in the middle cerebral artery pulsatility index of 10% and 13%, respectively, compared to controls (p < 0.05), indicating vasodilation of the cerebral circulation, a fetal adaptation that is part of the brain sparing response to preserve oxygen delivery. Hemodynamic markers of placental dysfunction and fetal hypoxia were more pronounced in the group exposed to polystyrene nanoplastics, suggesting nanoplastic exposure during human pregnancy has the potential to disrupt fetal brain development, which in turn may cause suboptimal neurodevelopmental outcomes.
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Affiliation(s)
- Katherine C Dibbon
- Department of Chemistry, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada
| | - Grace V Mercer
- Department of Chemistry, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada
| | - Alexandre S Maekawa
- Department of Chemistry, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada
| | - Jenna Hanrahan
- Department of Chemistry, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada
| | - Katherine L Steeves
- Department of Chemistry, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada
| | - Lauren C M Ringer
- Department of Chemistry, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada
| | - André J Simpson
- Environmental NMR Centre and Department of Physical and Environmental Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Myrna J Simpson
- Environmental NMR Centre and Department of Physical and Environmental Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Ahmet A Baschat
- Department of Gynecology & Obstetrics, Johns Hopkins Center for Fetal Therapy, Johns Hopkins University, Baltimore, MD, USA
| | - John C Kingdom
- Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada
- Maternal-Fetal Medicine Division, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Christopher K Macgowan
- Translational Medicine, Hospital for Sick Children , Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - John G Sled
- Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada
- Translational Medicine, Hospital for Sick Children , Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- Mouse Imaging Centre, Hospital for Sick Children , Toronto, Ontario, Canada
| | - Karl J Jobst
- Department of Chemistry, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada
| | - Lindsay S Cahill
- Department of Chemistry, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada
- Discipline of Radiology, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada
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12
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Arnautovic T, Sinha S, Laptook AR. Neonatal Hypoxic-Ischemic Encephalopathy and Hypothermia Treatment. Obstet Gynecol 2024; 143:67-81. [PMID: 37797337 PMCID: PMC10841232 DOI: 10.1097/aog.0000000000005392] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 07/27/2023] [Indexed: 10/07/2023]
Abstract
Neonatal hypoxic-ischemic encephalopathy (HIE) is an important clinical entity because it is associated with death and long-term disability, including cognitive impairment, cerebral palsy, seizures, and neurosensory deficits. Over the past 40 years, there has been an intensive search to identify therapies to improve the prognosis of neonates with HIE. Hypothermia treatment represents the culmination of laboratory investigations including small and large animal studies, followed by pilot human studies, and, finally, randomized controlled trials to establish efficacy and safety. Clinical trials have demonstrated that hypothermia treatment reduces mortality and improves early childhood outcome among survivors. Hypoxic-ischemic encephalopathy is a multi-system disease process that requires intensive medical support for brain monitoring and monitoring of non-central nervous system organ dysfunction. Treatment must be conducted in a level III or IV neonatal intensive care unit with infrastructure for an integrated approach to care for critically ill neonates. Hypothermia treatment is the first and currently the only therapy to improve outcomes for neonates with HIE and indicates that HIE is modifiable. However, outcomes likely can be improved further. Hypothermia treatment has accelerated investigation of other therapies to combine with hypothermia. It has also stimulated a more intensive approach to brain monitoring, which allows earlier intervention for complications. Finally, HIE and hypothermia treatment negatively influences the psychological state of affected families, and there is growing recognition of the importance of trauma-informed principles to guide medical professionals.
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Affiliation(s)
- Tamara Arnautovic
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, and Warren Alpert Medical School of Brown University, Providence, Rhode Island
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13
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Sergi CM, Spencer D, Al-Jishi T. Stillbirth Investigations: An Iconographic and Concise Diagnostic Workup in Perinatal Pathology. J Lab Physicians 2023; 15:475-487. [PMID: 37780873 PMCID: PMC10539070 DOI: 10.1055/s-0043-1764485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 01/23/2023] [Indexed: 10/03/2023] Open
Abstract
Introduction Stillbirth is a dramatic event for the parents, health care team, and anyone close to the expectant parents. Multidisciplinary team (MDT) meetings are essential to improve communication in health care. We review the most frequent findings discussed at MDT meetings. Methods A PubMed search was conducted through December 2021 since the inception (1965) using clinical queries with the key terms "stillbirth" AND "investigation" AND "pathology" AND "human." The search strategy included reviews, meta-analyses, randomized controlled trials, clinical trials, and observational studies. This systematic review is based on, but not limited to, the search results. It is the experience of more than 30 years of pediatrics, obstetrics, and pathology staff. Results Two hundred and six articles were screened and complemented through the perusal of congressional activities and personal communications. Pathological findings following perinatal death can be divided into macroscopic, histologic, and placental findings. The placenta is crucial in fetal medicine and is key in determining the cause of stillbirth in a substantial number of events. Perinatal lung disease is essential to evaluate the response of newborns to extrauterine life and address newborns' outcomes appropriately. Conclusions Stillbirth remains one of the less explored areas of medicine, and we can determine the cause in a limited number of cases. Nevertheless, placental pathology is critical in the etiology discovery pathway. Accurate investigations and discussion of photography-supported findings are vital in promoting communication at MDT meetings.
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Affiliation(s)
- Consolato M. Sergi
- Department of Anatomic Pathology, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
| | - Deborah Spencer
- Department of Pathology, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina, United States
| | - Taher Al-Jishi
- Department of Obstetrics and Gynecology University of Ottawa, Ottawa, Ontario, Canada
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14
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Ahmadzadeh E, Polglase GR, Stojanovska V, Herlenius E, Walker DW, Miller SL, Allison BJ. Does fetal growth restriction induce neuropathology within the developing brainstem? J Physiol 2023; 601:4667-4689. [PMID: 37589339 PMCID: PMC10953350 DOI: 10.1113/jp284191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Accepted: 08/04/2023] [Indexed: 08/18/2023] Open
Abstract
Fetal growth restriction (FGR) is a complex obstetric issue describing a fetus that does not reach its genetic growth potential. The primary cause of FGR is placental dysfunction resulting in chronic fetal hypoxaemia, which in turn causes altered neurological, cardiovascular and respiratory development, some of which may be pathophysiological, particularly for neonatal life. The brainstem is the critical site of cardiovascular, respiratory and autonomic control, but there is little information describing how chronic hypoxaemia and the resulting FGR may affect brainstem neurodevelopment. This review provides an overview of the brainstem-specific consequences of acute and chronic hypoxia, and what is known in FGR. In addition, we discuss how brainstem structural alterations may impair functional control of the cardiovascular and respiratory systems. Finally, we highlight the clinical and translational findings of the potential roles of the brainstem in maintaining cardiorespiratory adaptation in the transition from fetal to neonatal life under normal conditions and in response to the pathological environment that arises during development in growth-restricted infants. This review emphasises the crucial role that the brainstem plays in mediating cardiovascular and respiratory responses during fetal and neonatal life. We assess whether chronic fetal hypoxaemia might alter structure and function of the brainstem, but this also serves to highlight knowledge gaps regarding FGR and brainstem development.
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Affiliation(s)
- Elham Ahmadzadeh
- The Ritchie CentreHudson Institute of Medical ResearchClaytonVictoriaAustralia
- Department of Obstetrics and GynaecologyMonash UniversityClaytonVictoriaAustralia
| | - Graeme R. Polglase
- The Ritchie CentreHudson Institute of Medical ResearchClaytonVictoriaAustralia
- Department of Obstetrics and GynaecologyMonash UniversityClaytonVictoriaAustralia
| | - Vanesa Stojanovska
- The Ritchie CentreHudson Institute of Medical ResearchClaytonVictoriaAustralia
- Department of Obstetrics and GynaecologyMonash UniversityClaytonVictoriaAustralia
| | - Eric Herlenius
- Department of Women's and Children's HealthKarolinska InstitutetSolnaSweden
- Astrid Lindgren Children´s HospitalKarolinska University Hospital StockholmSolnaSweden
| | - David W. Walker
- The Ritchie CentreHudson Institute of Medical ResearchClaytonVictoriaAustralia
- Neurodevelopment in Health and Disease Research Program, School of Health and Biomedical SciencesRoyal Melbourne Institute of Technology (RMIT)MelbourneVictoriaAustralia
| | - Suzanne L. Miller
- The Ritchie CentreHudson Institute of Medical ResearchClaytonVictoriaAustralia
- Department of Obstetrics and GynaecologyMonash UniversityClaytonVictoriaAustralia
| | - Beth J. Allison
- The Ritchie CentreHudson Institute of Medical ResearchClaytonVictoriaAustralia
- Department of Obstetrics and GynaecologyMonash UniversityClaytonVictoriaAustralia
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15
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Desoye G, Carter AM. Fetoplacental oxygen homeostasis in pregnancies with maternal diabetes mellitus and obesity. Nat Rev Endocrinol 2022; 18:593-607. [PMID: 35902735 DOI: 10.1038/s41574-022-00717-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/22/2022] [Indexed: 11/09/2022]
Abstract
Despite improvements in clinical management, pregnancies complicated by pre-existing diabetes mellitus, gestational diabetes mellitus or obesity carry substantial risks for parent and offspring. Some of the endocrine and metabolic changes in parent and fetus in diabetes mellitus and obesity lead to fetal oxygen deficit, mostly due to insulin-induced accelerated fetal metabolism. The human fetus deals with reduced oxygenation through a wide range of adaptive responses that act at various levels in the placenta as well as the fetus. These responses ensure adequate oxygen delivery to the fetus, increase the oxygen transport capacity of fetal blood and redistribute oxygen-rich blood to vital organs such as the brain and heart. The liver has a central role in adapting to reduced oxygenation by increasing its oxygen extraction and stimulating erythropoietin synthesis to increase haematocrit. The type of adaptive response depends on the onset and duration of hypoxia and the severity of the metabolic disturbance. In pregnancies characterized by diabetes mellitus or obesity, these adaptive systems come under additional strain owing to the increased maternal supply of glucose and resultant fetal hyperinsulinaemia, both of which stimulate oxidative metabolism. In the rare situation that the adaptive responses are overwhelmed, stillbirth can ensue.
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Affiliation(s)
- Gernot Desoye
- Department of Obstetrics and Gynaecology, Medical University of Graz, Graz, Austria.
- Center for Pregnant Women with Diabetes, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
| | - Anthony M Carter
- Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
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16
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Indrio F, Marchese F, Rinaldi M, Maffei G, Dargenio V, Cinquepalmi R, Mantovani MP, Aceti A. Is acidemia at birth a risk factor for functional gastrointestinal disorders? Eur J Pediatr 2022; 181:3625-3633. [PMID: 35927380 PMCID: PMC9508039 DOI: 10.1007/s00431-022-04565-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 06/15/2022] [Accepted: 07/11/2022] [Indexed: 11/25/2022]
Abstract
Functional gastrointestinal disorders (FGIDs) are common in early childhood. It has been demonstrated that neonatal acidemia at delivery can lead to significant neonatal morbidity. The primary aim of this study was to evaluate the relationship between acidemia at birth and the development of FGIDs, as regurgitation, colic, and constipation, in term infants. Term newborns born at the Foggia University Hospital, Italy during the year 2020 were included in the study. As per routine clinical practice, a cord blood gas analysis on a blood sample drawn from the umbilical artery (UA) of each infant immediately after birth was performed, and Apgar score was recorded. One year after birth, each infant's parents were interviewed through a phone call to investigate development of FGIDs, feeding practices, and morbidities. During the study period, 1574 term newborns met the inclusion criteria. The prevalence of infantile colic, regurgitation, and constipation was higher in infants with low UA pH (colic 51.5% vs. 25.4%, p < 0.001; regurgitation 30.6% vs. 15.2%, p < 0.001; constipation 24.6% vs. 16.0%, p = 0.015), with infants having moderate-severe acidemia facing the highest risk for all the examined FGIDs. In binary logistic regression analyses, UA pH and perinatal antibiotic exposure proved to be independently associated with the later diagnosis of each FGID. CONCLUSION Newborns with acidemia at birth appear to face a higher risk of FGIDs in infancy. Avoiding low cord blood pH should continue to be the goal for obstetricians, while enhanced long-term surveillance for infants who experienced birth acidemia should be required. WHAT IS KNOWN • Cord blood gas analysis is recommended in all high-risk deliveries, and in some centers, it is performed after all deliveries. • Neonatal acidemia at birth has been linked to adverse outcomes, mainly neurological. Recently, perinatal asphyxia has been reported to increase the risk of developing necrotizing enterocolitis in term infants. WHAT IS NEW • An association between acidemia at birth and risk of developing FGIDs such as regurgitation and colic during the first year of life had never been described so far. • An increased surveillance of infants with low UA pH at birth may be beneficial and could allow for early detection of any of the reported FGIDs.
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Affiliation(s)
- Flavia Indrio
- Department of Medical and Surgical Science, Pediatric Section, University of Foggia, Viale Pinto 1, 71122 Foggia, Italy
| | - Flavia Marchese
- Department of Medical and Surgical Science, Pediatric Section, University of Foggia, Viale Pinto 1, 71122 Foggia, Italy
| | - Matteo Rinaldi
- Department of Neonatology and NICU, Ospedali Riuniti Foggia, Viale Pinto 1, 71122 Foggia, Italy
| | - Gianfranco Maffei
- Department of Neonatology and NICU, Ospedali Riuniti Foggia, Viale Pinto 1, 71122 Foggia, Italy
| | - Vanessa Dargenio
- Department of Medical and Surgical Science, Pediatric Section, University of Foggia, Viale Pinto 1, 71122 Foggia, Italy
| | - Roberta Cinquepalmi
- Department of Medical and Surgical Science, Pediatric Section, University of Foggia, Viale Pinto 1, 71122 Foggia, Italy
| | - Massimo Pettoello Mantovani
- European Pediatric Association, Union of National European Pediatric Societies and Associations, Berlin, Germany
- Association Pour L’Activité Et La Recherche Scìentifiques, Nouchatel, Switzerland
- University of Foggia, Foggia, Italy
- Italian Society of Pediatrics, Rome, Italy
- Italian Academy of Pediatrics, Milan, Italy
| | - Arianna Aceti
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Neonatal Intensive Care Unit, IRCCS AOUBO, Via Massarenti 9, 40138 Bologna, Italy
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17
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Baschat AA, Galan HL, Lee W, DeVore GR, Mari G, Hobbins J, Vintzileos A, Platt LD, Manning FA. The role of the fetal biophysical profile in the management of fetal growth restriction. Am J Obstet Gynecol 2022; 226:475-486. [PMID: 35369904 DOI: 10.1016/j.ajog.2022.01.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 01/17/2022] [Accepted: 01/21/2022] [Indexed: 11/01/2022]
Abstract
Growth-restricted fetuses are at risk of hypoxemia, acidemia, and stillbirth because of progressive placental dysfunction. Current fetal well-being, neonatal risks following delivery, and the anticipated rate of fetal deterioration are the major management considerations in fetal growth restriction. Surveillance has to quantify the fetal risks accurately to determine the delivery threshold and identify the testing frequency most likely to capture future deterioration and prevent stillbirth. From the second trimester onward, the biophysical profile score correlates over 90% with the current fetal pH, and a normal score predicts a pH >7.25 with a 100% positive predictive value; an abnormal score on the other hand predicts current fetal acidemia with similar certainty. Between 30% and 70% of growth-restricted fetuses with a nonreactive heart rate require biophysical profile scoring to verify fetal well-being, and an abnormal score in 8% to 27% identifies the need for delivery, which is not suspected by Doppler findings. Future fetal well-being is not predicted by the biophysical profile score, which emphasizes the importance of umbilical artery Doppler and amniotic fluid volume to determine surveillance frequency. Studies with integrated surveillance strategies that combine frequent heart rate monitoring with biophysical profile scoring and Doppler report better outcomes and stillbirth rates of between 0% and 4%, compared with those between 8% and 11% with empirically determined surveillance frequency. The variations in clinical behavior and management challenges across gestational age are better addressed when biophysical profile scoring is integrated into the surveillance of fetal growth restriction. This review aims to provide guidance on biophysical profile scoring in the in- and outpatient management of fetal growth restriction.
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18
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Crosstalk between foetal vasoactive peptide hormones and placental aminopeptidases regulates placental blood flow: Its significance in preeclampsia. Placenta 2022; 121:32-39. [DOI: 10.1016/j.placenta.2022.02.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 02/20/2022] [Indexed: 11/18/2022]
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Drake RR, Louey S, Thornburg KL. Intrauterine growth restriction elevates circulating acylcarnitines and suppresses fatty acid metabolism genes in the fetal sheep heart. J Physiol 2022; 600:655-670. [PMID: 34802149 PMCID: PMC9075772 DOI: 10.1113/jp281415] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 11/17/2021] [Indexed: 02/03/2023] Open
Abstract
At birth, the mammalian myocardium switches from using carbohydrates as the primary energy substrate to free fatty acids as the primary fuel. Thus, a compromised switch could jeopardize normal heart function in the neonate. Placental embolization in sheep is a reliable model of intrauterine growth restriction (IUGR). It leads to suppression of both proliferation and terminal differentiation of cardiomyocytes. We hypothesized that the expression of genes regulating cardiac fatty acid metabolism would be similarly suppressed in IUGR, leading to compromised processing of lipids. Following 10 days of umbilicoplacental embolization in fetal sheep, IUGR fetuses had elevated circulating long-chain fatty acylcarnitines compared with controls (C14: CTRL 0.012 ± 0.005 nmol/ml vs. IUGR 0.018 ± 0.005 nmol/ml, P < 0.05; C18: CTRL 0.027 ± 0.009 nmol/mol vs. IUGR 0.043 ± 0.024 nmol/mol, P < 0.05, n = 12 control, n = 12 IUGR) indicative of impaired fatty acid metabolism. Uptake studies using fluorescently tagged BODIPY-C12-saturated free fatty acid in live, isolated cardiomyocytes showed lipid droplet area and number were not different between control and IUGR cells. mRNA levels of sarcolemmal fatty acid transporters (CD36, FATP6), acylation enzymes (ACSL1, ACSL3), mitochondrial transporter (CPT1), β-oxidation enzymes (LCAD, HADH, ACAT1), tricarboxylic acid cycle enzyme (IDH), esterification enzymes (PAP, DGAT) and regulator of the lipid droplet formation (BSCL2) gene were all suppressed in IUGR myocardium (P < 0.05). However, protein levels for these regulatory genes were not different between groups. This discordance between mRNA and protein levels in the stressed myocardium suggests an adaptive protection of key myocardial enzymes under conditions of placental insufficiency. KEY POINTS: The fetal heart relies on carbohydrates in utero and must be prepared to metabolize fatty acids after birth but the effects of compromised fetal growth on the maturation of this metabolic system are unknown. Plasma fatty acylcarnitines are elevated in intrauterine growth-restricted (IUGR) fetuses compared with control fetuses, indicative of impaired fatty acid metabolism in fetal organs. Fatty acid uptake and storage are not different in IUGR cardiomyocytes compared with controls. mRNA levels of genes regulating fatty acid transporter and metabolic enzymes are suppressed in the IUGR myocardium compared with controls, while protein levels remain unchanged. Mismatches in gene and protein expression, and increased circulating fatty acylcarnitines may have long-term implications for offspring heart metabolism and adult health in IUGR individuals. This requires further investigation.
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Affiliation(s)
- Rachel R Drake
- Center for Developmental Health, Knight Cardiovascular Institute, School of Medicine, Oregon Health and Science University, Portland, Oregon, USA
- Department of Chemical Physiology and Biochemistry, School of Medicine, Oregon Health and Science University, Portland, Oregon, USA
| | - Samantha Louey
- Center for Developmental Health, Knight Cardiovascular Institute, School of Medicine, Oregon Health and Science University, Portland, Oregon, USA
| | - Kent L Thornburg
- Center for Developmental Health, Knight Cardiovascular Institute, School of Medicine, Oregon Health and Science University, Portland, Oregon, USA
- Department of Chemical Physiology and Biochemistry, School of Medicine, Oregon Health and Science University, Portland, Oregon, USA
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20
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Salvi S, D'Emidio L, Roughton M, De Carolis S, Lanzone A, Bhide A, Carvalho JS. Is Cardiomegaly an Indication of "Heart-Sparing Effect" in Small Fetuses? Fetal Diagn Ther 2021; 48:701-707. [PMID: 34818224 DOI: 10.1159/000519059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 08/16/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION This study aimed to test the hypothesis that cardiac size is maintained in small fetuses presenting with cardiomegaly. MATERIALS AND METHODS We identified singleton fetuses with estimated fetal weight <10th centile and with cardiomegaly without another more likely cardiac or extra-cardiac cause. We used Z-scores for cardiac and thoracic circumferences normalized for gestational age (GA), biparietal diameter (BPD), head circumference (HC), and femur length (FL), obtained from 188 normally grown fetuses. RESULTS When comparing chest size, small fetuses had significantly lower thoracic circumferences median Z-scores (IQR) for GA = -4.82 (-6.15 to -3.51), BPD = -2.42 (-4.04 to -1.48), HC = -2.72 (-4.53 to -1.90), and FL = -1.60 (-2.87 to -0.71); p < 0.001 for all. When comparing heart size, small fetuses showed lower cardiac circumferences median Z-scores (IQR) for GA = -1.59 (-2.79 to -0.16); p < 0.001, similar cardiac circumferences Z-scores for BPD = 0.29 (-0.65 to 1.28); p = 0.284 and HC = 0.11 (-1.13 to 0.96); p = 0.953, and higher cardiac circumferences Z-scores for FL = 0.94 (-0.05 to 2.13); p < 0.001. CONCLUSIONS Our results show that in small fetuses with cardiomegaly, the heart maintains normal dimensions when normalized to cranial diameters and higher dimensions when normalized to long bones. This provides insight into cardiac adaptation to adverse intrauterine environment.
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Affiliation(s)
- Silvia Salvi
- Fetal Medicine Unit, St. George's University Hospitals NHS Foundation Trust, London, United Kingdom.,UOC Patologia Ostetrica, Dipartimento Scienze Della Salute Della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Laura D'Emidio
- Fetal Medicine Unit, St. George's University Hospitals NHS Foundation Trust, London, United Kingdom
| | - Michael Roughton
- Medical Statistics, Royal Brompton Hospital, London, United Kingdom
| | - Sara De Carolis
- Medical Statistics, Royal Brompton Hospital, London, United Kingdom.,Istituto di Clinica Ostetrica e Ginecologica, Università Cattolica Del Sacro Cuore, Rome, Italy
| | - Antonio Lanzone
- Medical Statistics, Royal Brompton Hospital, London, United Kingdom.,Istituto di Clinica Ostetrica e Ginecologica, Università Cattolica Del Sacro Cuore, Rome, Italy
| | - Amar Bhide
- Fetal Medicine Unit, St. George's University Hospitals NHS Foundation Trust, London, United Kingdom.,Vascular Biology Research Centre, Molecular and Clinical Sciences Research Institute, St George's University of London, London, United Kingdom
| | - Julene S Carvalho
- Fetal Medicine Unit, St. George's University Hospitals NHS Foundation Trust, London, United Kingdom.,Brompton Centre for Fetal Cardiology, Royal Brompton Hospital NHS Foundation Trust, London, United Kingdom.,Cardiology Clinical Academic Group, Molecular and Clinical Sciences Research Institute, St. George's University of London, London, United Kingdom
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21
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Lantto J, Erkinaro T, Haapsamo M, Huhta H, Alanne L, Kokki M, Ohtonen P, Bhide A, Acharya G, Räsänen J. Peripheral chemoreflex activation and cardiac function during hypoxemia in near-term fetal sheep without placental compromise. J Appl Physiol (1985) 2021; 131:1486-1495. [PMID: 34590908 DOI: 10.1152/japplphysiol.01111.2020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
A drop in arterial oxygen content activates fetal chemoreflex including an increase in sympathetic activity leading to peripheral vasoconstriction and redistribution of blood flow to protect the brain, myocardium, and adrenal glands. By using a chronically instrumented fetal sheep model with intact placental circulation at near-term gestation, we investigated the relationship between peripheral chemoreflex activation induced by hypoxemia and central hemodynamics. A total of 17 Åland landrace sheep fetuses at 115-128/145 gestational days were instrumented. Carotid artery was catheterized in 10 fetuses and descending aorta in 7 fetuses. After a 4-day recovery, baseline measurements of fetal arterial blood pressures, blood gas values, and fetal cardiovascular hemodynamics by pulsed Doppler ultrasonography were obtained under isoflurane anesthesia. Comparable data to baseline were collected 10 min (acute hypoxemia) and 60 min (prolonged hypoxemia) after maternal hypo-oxygenation to saturation level of 70%-80% was achieved. During prolonged hypoxemia, pH and base excess (BE) were lower and lactate levels were higher in the descending aorta than in the carotid artery. During hypoxemia mean arterial blood pressure (MAP) in the descending aorta increased, whereas in the carotid artery, MAP decreased. In addition, right pulmonary artery pulsatility index values increased, and the diastolic component in the aortic isthmus blood flow velocity waveform became more retrograde, thus decreasing the aortic isthmus antegrade/retrograde blood flow (AoI Net Flow) ratio. Both fetal ventricular cardiac outputs were maintained even during prolonged hypoxemia when significant fetal metabolic acidemia developed. Fetal chemoreflex activation induced by hypoxemia decreased the perfusion pressure in the cerebral circulation. Fetal weight-indexed left ventricular cardiac output (LVCO) or AoI Net Flow ratio did not correlate with a drop in carotid artery blood pressure.NEW & NOTEWORTHY During fetal hypoxemia with intact placental circulation, peripheral chemoreflex was activated, as demonstrated by an increase in the descending aorta blood pressure, pulmonary vasoconstriction, and an increase in retrograde diastolic AoI blood flow, while both ventricular cardiac outputs remained stable. However, perfusion pressure in the cerebral circulation decreased. These changes were seen even during prolonged hypoxemia when significant metabolic acidosis developed. Weight-indexed LVCO or AoI Net Flow ratio did not correlate with a drop in carotid artery blood pressure.
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Affiliation(s)
- Juulia Lantto
- Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland
| | - Tiina Erkinaro
- Department of Anesthesiology, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Mervi Haapsamo
- Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland
| | - Heikki Huhta
- Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Leena Alanne
- Department of Obstetrics and Gynecology, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland.,Faculty of Health Sciences, School of Medicine, Institute of Clinical Medicine Kuopio, Kuopio, Finland
| | - Merja Kokki
- Department of Anesthesiology, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland
| | - Pasi Ohtonen
- Division of Operative Care, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Amarnath Bhide
- Department of Obstetrics and Gynecology, St. George's Hospital, London, United Kingdom.,Women's Health & Perinatal Research Group, Department of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Ganesh Acharya
- Women's Health & Perinatal Research Group, Department of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway.,Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm, Sweden
| | - Juha Räsänen
- Department of Obstetrics and Gynecology, Fetal Medicine Center, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
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22
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The newborn sheep translational model for pulmonary arterial hypertension of the neonate at high altitude. J Dev Orig Health Dis 2021; 11:452-463. [PMID: 32705972 DOI: 10.1017/s2040174420000616] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Chronic hypoxia during gestation induces greater occurrence of perinatal complications such as intrauterine growth restriction, fetal hypoxia, newborn asphyxia, and respiratory distress, among others. This condition may also cause a failure in the transition of the fetal to neonatal circulation, inducing pulmonary arterial hypertension of the neonate (PAHN), a syndrome that involves pulmonary vascular dysfunction, increased vasoconstrictor tone and pathological remodeling. As this syndrome has a relatively low prevalence in lowlands (~7 per 1000 live births) and very little is known about its prevalence and clinical evolution in highlands (above 2500 meters), our understanding is very limited. Therefore, studies on appropriate animal models have been crucial to comprehend the mechanisms underlying this pathology. Considering the strengths and weaknesses of any animal model of human disease is fundamental to achieve an effective and meaningful translation to clinical practice. The sheep model has been used to study the normal and abnormal cardiovascular development of the fetus and the neonate for almost a century. The aim of this review is to highlight the advances in our knowledge on the programming of cardiopulmonary function with the use of high-altitude newborn sheep as a translational model of PAHN.
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23
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Issa A, Abdulkadir MB, Adesiyun OO, Owolabi B, Suberu H, Alabi KO, Bakare RR. Relationships between cardiovascular signs and neurological signs in asphyxiated neonates in Ilorin, North Central Nigeria. Afr Health Sci 2021; 21:743-752. [PMID: 34795731 PMCID: PMC8568228 DOI: 10.4314/ahs.v21i2.33] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Background Perinatal asphyxia is a condition associated with multiple organ dysfunctions inclusive of cardiovascular dysfunction. Neurologic predictors of survival have been studied, but little has been reported regarding cardiovascular signs and their role in determining outcome in asphyxia. Objective The study aimed to determine the relationship between cardiovascular signs and outcomes in asphyxiated newborns with hypoxic ischaemic encephalopathy. Methods This was a cross sectional study involving asphyxiated new-born babies recruited within the first 24 hours of life. Hypoxic ischaemic encephalopathy staging was done using Sarnat and Sarnat staging. All patients had a detailed cardiovascular examination on admission, after initial resuscitation (30 – 60 minutes) into admission, and were followed till final outcome: discharge or death. Results Eighty-five asphyxiated new-borns with HIE were studied over seven months. Abnormal cardiovascular-related signs identified in the patients included respiratory distress (64.7%), small volume pulse (57.6%), hypotension (52.9%), hypoxemia (48.2%) and shock (32.9%). Five babies died. None of the clinical signs had a significant relationship with mortality. Conclusion Abnormal cardiovascular signs increased with the progression of HIE staging but had no relationship with mortality.
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Affiliation(s)
| | - Mohammed Baba Abdulkadir
- Department of Paediatrics and Child Health, University of Ilorin Teaching Hospital
- Department of Paediatrics and Child Health, University of Ilorin, Nigeria
| | - Omotayo Olukemi Adesiyun
- Department of Paediatrics and Child Health, University of Ilorin Teaching Hospital
- Department of Paediatrics and Child Health, University of Ilorin, Nigeria
| | | | - Habibat Suberu
- Department of Paediatrics and Child Health, University of Ilorin Teaching Hospital
| | | | - Ruqayat Ronke Bakare
- Department of Paediatrics and Child Health, University of Ilorin Teaching Hospital
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24
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Clarke GD, Li J, Kuo AH, Moody AJ, Nathanielsz PW. Cardiac magnetic resonance imaging: insights into developmental programming and its consequences for aging. J Dev Orig Health Dis 2021; 12:203-219. [PMID: 33349289 PMCID: PMC7987688 DOI: 10.1017/s2040174420001233] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Cardiovascular diseases (CVD) are important consequences of adverse perinatal conditions such as fetal hypoxia and maternal malnutrition. Cardiac magnetic resonance imaging (CMR) can produce a wealth of physiological information related to the development of the heart. This review outlines the current state of CMR technologies and describes the physiological biomarkers that can be measured. These phenotypes include impaired ventricular and atrial function, maladaptive ventricular remodeling, and the proliferation of myocardial steatosis and fibrosis. The discussion outlines the applications of CMR to understanding the developmental pathways leading to impaired cardiac function. The use of CMR, both in animal models of developmental programming and in human studies, is described. Specific examples are given in a baboon model of intrauterine growth restriction (IUGR). CMR offers great potential as a tool for understanding the sequence of dysfunctional adaptations of developmental origin that can affect the human cardiovascular system.
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Affiliation(s)
- G D Clarke
- Department of Radiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - J Li
- Department of Radiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - A H Kuo
- Department of Radiology, Massachusetts General Hospital, Boston, MA, USA
| | - A J Moody
- Department of Radiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - P W Nathanielsz
- Department of Animal Science, University of Wyoming, Laramie, WY, USA
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25
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Lorenzi T, Sagrati A, Montanari E, Senzacqua M, Morroni M, Fabri M. Hypoxia-induced expression of neuronal nitric oxide synthase in astrocytes of human corpus callosum. Brain Struct Funct 2021; 226:1353-1361. [PMID: 33709161 DOI: 10.1007/s00429-021-02244-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 02/22/2021] [Indexed: 10/22/2022]
Abstract
Nitric oxide (NO) is a gaseous neurotransmitter largely diffused in the brain; among other functions, it regulates the cerebral blood flow in response to hypoxia. NO can be synthetized by three different isoforms of the enzyme NO synthase: neuronal (nNOS), typical of neurons, endothelial and inducible. The aim of this study was to assess nNOS expression in human corpus callosum (CC) astrocytes, and its relationship with the hypoxia duration. Autoptic samples of CC from adult human subjects have been processed with immunohistochemistry and immunofluorescence using antibodies anti-nNOS and anti-glial fibrillary acidic protein (GFAP), the astrocyte marker. Results demonstrated for the first time the presence of nNOS-immunopositive astrocytes in the human CC. In particular, nNOS-positive astrocytes were absent in subjects deceased after a short hypoxia; their number and labeling intensity, however, increased with hypoxia prolongation. Neuronal NOS immunopositivity of CC astrocytes seems thus related to the hypoxia duration and the consequent brain damage.
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Affiliation(s)
- Teresa Lorenzi
- Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, School of Medicine, Università Politecnica delle Marche, Via Tronto 10/A, 60126, Ancona, Italy
| | - Andrea Sagrati
- Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, School of Medicine, Università Politecnica delle Marche, Via Tronto 10/A, 60126, Ancona, Italy
| | - Eva Montanari
- Department of Biomedical Sciences and Public Health, Section of Legal Medicine, Università Politecnica delle Marche, Via Tronto 10/A, 60126, Ancona, Italy
| | - Martina Senzacqua
- Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, School of Medicine, Università Politecnica delle Marche, Via Tronto 10/A, 60126, Ancona, Italy
| | - Manrico Morroni
- Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, School of Medicine, Università Politecnica delle Marche, Via Tronto 10/A, 60126, Ancona, Italy.,Electron Microscopy Unit, United Hospitals, Via Conca 71, 60020, Ancona, Italy
| | - Mara Fabri
- Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, School of Medicine, Università Politecnica delle Marche, Via Tronto 10/A, 60126, Ancona, Italy.
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26
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Jagota D, George H, Walker M, Ravi Chandran A, Milligan N, Shinar S, Whitehead CL, Hobson SR, Serghides L, Parks WT, Baschat AA, Macgowan CK, Sled JG, Kingdom JC, Cahill LS. Sex differences in fetal Doppler parameters during gestation. Biol Sex Differ 2021; 12:26. [PMID: 33691774 PMCID: PMC7944891 DOI: 10.1186/s13293-021-00370-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 03/01/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Fetal sex is known to affect pregnancy outcomes. In current clinical practice, monitoring of fetal well-being is based on Doppler ultrasound measurements of major placental and fetal vessels. The objective of this study was to investigate the effect of fetal sex on Doppler parameters throughout gestation in healthy pregnancy. METHODS A prospective study was conducted in 240 pregnant women with ultrasound examinations at a 4-weekly interval between 12 and 38 weeks of gestation. Pulsed Doppler spectra were collected for the umbilical arteries (UAs), middle cerebral artery (MCA), descending abdominal aorta (DAo), and ductus venosus (DV). Linear mixed effects models were used to determine if the pulsatility indices (PIs) of these vessels depended on gestational age and fetal sex. RESULTS While there were no differences in the MCA PI and DV PIV over gestation between female and male fetuses, the trajectory of the UA and DAo PIs differed by fetal sex (p = 0.02 and p = 0.01, respectively). CONCLUSIONS Doppler ultrasound parameters were found to be dependent on fetal sex for some vessels and not for others in healthy pregnancies. Further investigations are needed to understand the physiological mechanisms for these sex differences and the relevance for disease processes in pregnancy.
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Affiliation(s)
- Dakshita Jagota
- Department of Chemistry, Memorial University of Newfoundland, 283 Prince Philip Drive, St. John's, NL, A1B 3X7, Canada
| | - Hannah George
- Department of Chemistry, Memorial University of Newfoundland, 283 Prince Philip Drive, St. John's, NL, A1B 3X7, Canada
| | - Melissa Walker
- Mount Sinai Hospital, Toronto, Ontario, Canada
- Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada
| | | | - Natasha Milligan
- Division of Cardiology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada
| | | | - Clare L Whitehead
- Pregnancy Research Centre, Department of Obstetrics and Gynaecology, Royal Women's Hospital, Parkville, Australia
| | | | - Lena Serghides
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Department of Immunology and Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
- Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada
| | - W Tony Parks
- Department of Pathology, Mount Sinai Hospital, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Ahmet A Baschat
- Centre for Fetal Therapy, Johns Hopkins Medicine, Baltimore, MD, USA
| | - Christopher K Macgowan
- Translational Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - John G Sled
- Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada
- Translational Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - John C Kingdom
- Mount Sinai Hospital, Toronto, Ontario, Canada
- Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada
| | - Lindsay S Cahill
- Department of Chemistry, Memorial University of Newfoundland, 283 Prince Philip Drive, St. John's, NL, A1B 3X7, Canada.
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27
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Hellgren KT, Premanandhan H, Quinn CJ, Trafford AW, Galli GLJ. Sex-dependent effects of developmental hypoxia on cardiac mitochondria from adult murine offspring. Free Radic Biol Med 2021; 162:490-499. [PMID: 33186741 DOI: 10.1016/j.freeradbiomed.2020.11.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 10/29/2020] [Accepted: 11/04/2020] [Indexed: 12/12/2022]
Abstract
Insufficient oxygen supply (hypoxia) during fetal and embryonic development can lead to latent phenotypical changes in the adult cardiovascular system, including altered cardiac function and increased susceptibility to ischemia reperfusion injury. While the cellular mechanisms underlying this phenomenon are largely unknown, several studies have pointed towards metabolic disturbances in the heart of offspring from hypoxic pregnancies. To this end, we investigated mitochondrial function in the offspring of a mouse model of prenatal hypoxia. Pregnant C57 mice were subjected to either normoxia (21%) or hypoxia (14%) during gestational days 6-18. Offspring were reared in normoxia for up to 8 months and mitochondrial biology was assessed with electron microscopy (ultrastructure), spectrophotometry (enzymatic activity of electron transport chain complexes), microrespirometry (oxidative phosphorylation and H202 production) and Western Blot (protein expression). Our data showed that male adult offspring from hypoxic pregnancies possessed mitochondria with increased H202 production and lower respiratory capacity that was associated with reduced protein expression of complex I, II and IV. In contrast, females from hypoxic pregnancies had a higher respiratory capacity and lower H202 production that was associated with increased enzymatic activity of complex IV. From these results, we speculate that early exposure to hypoxia has long term, sex-dependent effects on cardiac metabolic function, which may have implications for cardiovascular health and disease in adulthood.
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Affiliation(s)
- Kim T Hellgren
- Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester M13 9NT, UK
| | - Hajani Premanandhan
- Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester M13 9NT, UK
| | - Callum J Quinn
- Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester M13 9NT, UK
| | - Andrew W Trafford
- Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester M13 9NT, UK
| | - Gina L J Galli
- Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester M13 9NT, UK.
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28
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Darby JRT, Varcoe TJ, Holman SL, McMillen IC, Morrison JL. The reliance on α-adrenergic receptor stimuli for blood pressure regulation in the chronically hypoxaemic fetus is not dependent on post-ganglionic activation. J Physiol 2020; 599:1307-1318. [PMID: 33347615 DOI: 10.1113/jp280693] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 11/30/2020] [Indexed: 11/08/2022] Open
Abstract
KEY POINTS Chronic hypoxaemia is associated with intrauterine growth restriction (IUGR) and a predisposition to the development of hypertension in adult life. IUGR fetuses exhibit a greater reliance on α-adrenergic activation for blood pressure regulation. The fetal blood pressure response to post-ganglionic blockade is not different between control and IUGR fetuses. The decrease in mean arterial pressure is greater in the IUGR sheep fetus after α-adrenergic receptor blockade at the level of the vasculature and this is inversely related to fetal P O 2 . The increased reliance that the IUGR fetus has on α-adrenergic activation for maintenance of mean arterial pressure is not a result of increased post-ganglionic sympathetic activation. ABSTRACT Intrauterine growth restriction (IUGR) is associated with an increased risk of cardiovascular disease in adult life. Placental restriction (PR) in sheep results in chronic hypoxaemia and early onset IUGR with increased circulating plasma noradrenaline concentrations. These IUGR fetuses exhibit a greater decrease in mean arterial pressure (MAP) during α-adrenergic blockade. We aimed to determine the role of post-ganglionic sympathetic activation with respect to regulating MAP in IUGR fetal sheep. PR was induced by carunclectomy surgery prior to conception. Fetal vascular catheterization was performed at 110-126 days gestational age (GA) (term, 150 days) in nine control and seven PR-IUGR fetuses. The fetal blood pressure response to both a post-ganglionic and an α-adrenergic receptor blocker was assessed at 116-120 days GA and/or 129-131 days GA. The effect of both post ganglionic and α-adrenergic blockade on fetal blood pressure was then compared between control and IUGR fetuses at both GAs. There was no difference in the effect of post-ganglionic blockade on MAP in control and IUGR fetal sheep at either 116-120 days GA or 129-131 days GA. α-adrenergic receptor blockade decreased MAP to the same extent in both control and IUGR fetuses at 116-120 days GA. At 129-131 days GA, the drop in MAP in response to α-adrenergic receptor blockade was greater in IUGR fetuses than controls. There was a significant inverse relationship between the drop in MAP in response to α-adrenergic receptor blockade at both GAs with fetal P O 2 . Thus, the increased dependence on α-adrenergic activation for blood pressure regulation in the chronically hypoxaemic IUGR fetus is not a result of increased post-ganglionic sympathetic activation.
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Affiliation(s)
- Jack R T Darby
- Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
| | - Tamara J Varcoe
- Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
| | - Stacey L Holman
- Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
| | - I Caroline McMillen
- Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
| | - Janna L Morrison
- Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
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29
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The application of in utero magnetic resonance imaging in the study of the metabolic and cardiovascular consequences of the developmental origins of health and disease. J Dev Orig Health Dis 2020; 12:193-202. [PMID: 33308364 PMCID: PMC8162788 DOI: 10.1017/s2040174420001154] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Observing fetal development in utero is vital to further the understanding of later-life diseases. Magnetic resonance imaging (MRI) offers a tool for obtaining a wealth of information about fetal growth, development, and programming not previously available using other methods. This review provides an overview of MRI techniques used to investigate the metabolic and cardiovascular consequences of the developmental origins of health and disease (DOHaD) hypothesis. These methods add to the understanding of the developing fetus by examining fetal growth and organ development, adipose tissue and body composition, fetal oximetry, placental microstructure, diffusion, perfusion, flow, and metabolism. MRI assessment of fetal growth, organ development, metabolism, and the amount of fetal adipose tissue could give early indicators of abnormal fetal development. Noninvasive fetal oximetry can accurately measure placental and fetal oxygenation, which improves current knowledge on placental function. Additionally, measuring deficiencies in the placenta’s transport of nutrients and oxygen is critical for optimizing treatment. Overall, the detailed structural and functional information provided by MRI is valuable in guiding future investigations of DOHaD.
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30
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Fetal cardiovascular magnetic resonance imaging. Pediatr Radiol 2020; 50:1881-1894. [PMID: 33252756 DOI: 10.1007/s00247-020-04902-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 09/23/2020] [Accepted: 11/02/2020] [Indexed: 12/11/2022]
Abstract
Fetal cardiovascular MRI is showing promise as a clinical diagnostic tool in the setting of congenital heart disease when the cardiac anatomy is unresolved by US or when complementary quantitative data on blood flow, oxygen saturation and hematocrit are required to aid in management. Compared with postnatal cardiovascular MRI, prenatal cardiovascular MRI still has some technical limitations. However, ongoing technical advances continue to improve the robustness and usability of fetal cardiovascular MRI. In this review, we provide an overview of the state of the art of fetal cardiovascular MRI and summarize the current focus of clinical application for this versatile technique.
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31
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Jia X, Ma XH, Liang JW. Application of voxel-based morphometric method to detect brain changes in children with non-cyanotic congenital heart disease. World J Radiol 2020; 12:204-212. [PMID: 33033575 PMCID: PMC7523084 DOI: 10.4329/wjr.v12.i9.204] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 06/07/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Congenital heart disease (CHD) is a cardiovascular malformation caused by abnormal heart and/or vascular development in the fetus. In children with CHD, abnormalities in the development and function of the nervous system are common. At present, there is a lack of research on the preoperative neurological development and injury in young children with non-cyanotic CHD. AIM To determine the changes in white matter, gray matter, and cerebrospinal fluid (CSF) by magnetic resonance imaging (MRI) in children with non-cyanotic CHD as compared with healthy controls. METHODS Children diagnosed with non-cyanotic CHD on ultrasonography (n = 54) and healthy control subjects (n = 35) were included in the study. All the subjects were aged 1-3 years. Brain MRI was performed prior to surgery for CHD. The SPM v12 software was used to calculate the volumes of the gray matter, white matter, CSF, and the whole brain (sum of the gray matter, white matter, and CSF volumes). Volume differences between the two groups were analyzed. Voxel-based morphometry was used to compare specific brain regions with statistically significant atrophy. RESULTS Compared with the control group, the study group had significantly reduced whole-brain white matter volume (P < 0.05), but similar whole-brain gray matter, CSF, and whole-brain volumes (P > 0.05). As compared with the healthy controls, children with non-cyanotic CHD had mild underdevelopment in the white matter of the anterior central gyrus, the posterior central gyrus, and the pulvinar. CONCLUSION Children with non-cyanotic CHD show decreased white matter volume before surgery, and this volume reduction is mainly concentrated in the somatosensory and somatic motor nerve regions.
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Affiliation(s)
- Xuan Jia
- Department of Radiology, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Xiao-Hui Ma
- Department of Radiology, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Jia-Wei Liang
- Department of Radiology, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
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32
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Acharya G, Ebbing C, Karlsen HO, Kiserud T, Rasmussen S. Sex-specific reference ranges of cerebroplacental and umbilicocerebral ratios: longitudinal study. ULTRASOUND IN OBSTETRICS & GYNECOLOGY : THE OFFICIAL JOURNAL OF THE INTERNATIONAL SOCIETY OF ULTRASOUND IN OBSTETRICS AND GYNECOLOGY 2020; 56:187-195. [PMID: 31503378 DOI: 10.1002/uog.21870] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 08/21/2019] [Accepted: 08/23/2019] [Indexed: 06/10/2023]
Abstract
OBJECTIVES Observational studies have shown that low cerebroplacental ratio (CPR) values predict an increased risk of adverse perinatal outcome. The inverse ratio, i.e. the umbilicocerebral ratio (UCR), has been suggested to be a better predictor as it rises with increasing degree of fetal compromise. However, longitudinal reference ranges for UCR have not been established, and whether gestational-age-dependent changes in CPR or UCR differ between male and female fetuses has not been studied. Thus, the aims of this study were to investigate sex-specific, gestational-age-associated serial changes in CPR and UCR during the second half of pregnancy and to establish longitudinal reference ranges. METHODS This was a secondary analysis of prospectively collected data from a dual-center longitudinal observational cohort study of low-risk singleton pregnancies. Doppler blood-flow velocity waveforms were obtained serially from the umbilical artery (UA) and fetal middle cerebral artery (MCA) from 19-41 weeks' gestation, and pulsatility indices (PIs) were determined. CPR and UCR were calculated as the ratios MCA-PI/UA-PI and UA-PI/MCA-PI, respectively. The course and outcome of pregnancies were recorded, and the sex of the fetus was determined after delivery. Reference intervals for CPR and UCR were constructed using multilevel modeling, and gestational-age-specific Z-scores in male and female fetuses were compared. RESULTS Of a total of 299 pregnancies enrolled, 284 (148 male and 136 female fetuses) were included in the final analysis, and 979 paired measurements of UA-PI and MCA-PI were used to construct sex-specific longitudinal reference intervals. The relationship of both CPR and UCR with gestational age was U-shaped, but in opposite directions. There was a small but significant difference in Z-scores of CPR and UCR between male and female fetuses throughout the second half of pregnancy (P = 0.007). CONCLUSIONS We have established longitudinal reference ranges for CPR and UCR suitable for serial monitoring, with the possibility of refining assessment by using fetal sex-specific ranges and conditioning by a previous measurement. The clinical significance of such refinements needs further evaluation. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.
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Affiliation(s)
- G Acharya
- Women's Health and Perinatology Research Group, Department of Clinical Medicine, Faculty of Health Sciences, University of Tromsø and Department of Obstetrics and Gynecology, University Hospital of North Norway, Tromsø, Norway
- Department of Clinical Science, Intervention & Technology, Karolinska Institutet and Center for Fetal Medicine Karolinska, University Hospital, Stockholm, Sweden
| | - C Ebbing
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
| | - H O Karlsen
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
| | - T Kiserud
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - S Rasmussen
- Department of Clinical Science, University of Bergen, Bergen, Norway
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Stefopoulou M, Johnson J, Wilsgaard T, Lindgren P, Herling L, Kiserud T, Acharya G. Volume blood flow-based indices of fetal brain sparing in the second half of pregnancy: A longitudinal study. Acta Obstet Gynecol Scand 2020; 99:1717-1727. [PMID: 32776322 DOI: 10.1111/aogs.13950] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 06/24/2020] [Accepted: 06/30/2020] [Indexed: 11/29/2022]
Abstract
INTRODUCTION Cerebroplacental ratio (CPR) and umbilicocerebral ratio (UCR) are clinically used as a measure of fetal brain sparing. These are calculated as the ratios between the pulsatility indices (PIs) of middle cerebral (MCA) and umbilical (UA) arteries, and are an indirect representation of the balance between cerebral and placental perfusion. Volume blood flow (Q)-based ratios, ie Q-CPR or Q-UCR, would directly reflect the distribution of fetal cardiac output to the placenta and brain. Thus, we aimed to determine the development pattern of Q-CPR and Q-UCR during the second half of pregnancy, construct reference intervals, and evaluate their association with CPR and UCR. MATERIAL AND METHODS In a longitudinal cohort study of low-risk pregnancies, the inner diameter of the fetal superior vena cava (SVC) and umbilical vein (UV) was measured and velocity waveforms were obtained from the MCA, UA, UV and SVC using ultrasound at approximately 4-weekly intervals from 20 to 41 weeks. The CPR was calculated as PIMCA /PIUA and the inverse ratio was the UCR. Cerebral and placental blood flows were estimated as the product of mean velocity and cross-sectional area of the SVC and UV, respectively. Q-CPR was calculated as QSVC /QUV and the inverse as the Q-UCR. Gestational age-specific reference intervals were calculated and associations between variables were tested using multilevel regression modeling. RESULTS Longitudinal reference intervals of Q-CPR and Q-UCR were established based on 471 paired measurements of QSVC and QUV obtained serially from 134 singleton pregnancies. The mean Q-CPR increased from 0.4 to 0.8 during the second half of pregnancy and Q-UCR declined from 2.5 to 1.3, while the CPR and UCR had U-shaped curves but in opposite directions. No significant correlation was found between CPR and Q-CPR (R = 0.10; P = .051), or UCR and Q-UCR (R = 0.09; P = .11), and the agreement between PI-based and Q-based indices of fetal brain sparing was poor. CONCLUSIONS Indices of fetal brain sparing based on placental and cerebral volume blood flow differ from those calculated from UA and MCA PIs. They correlated poorly with conventional CPR and UCR, indicating that they may provide additional/different physiological information. Reference values of Q-CPR and Q-UCR established here can be useful to investigate their clinical value further.
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Affiliation(s)
- Maria Stefopoulou
- Department of Clinical Science, Division of Obstetrics and Gynecology, Intervention & Technology, Karolinska Institutet and Center for Fetal Medicine Karolinska, University Hospital, Stockholm, Sweden.,Department of Clinical Medicine, Faculty of Health Sciences, Women's Health and Perinatology Research Group, UiT-The Arctic University of Norway, Tromsø, Norway.,Department of Obstetrics and Gynecology, University Hospital of North Norway, Tromsø, Norway
| | - Jonas Johnson
- Department of Clinical Science, Division of Obstetrics and Gynecology, Intervention & Technology, Karolinska Institutet and Center for Fetal Medicine Karolinska, University Hospital, Stockholm, Sweden
| | - Tom Wilsgaard
- Department of Community Medicine, UiT, The Arctic University of Norway, Tromsø, Norway
| | - Peter Lindgren
- Department of Clinical Science, Division of Obstetrics and Gynecology, Intervention & Technology, Karolinska Institutet and Center for Fetal Medicine Karolinska, University Hospital, Stockholm, Sweden
| | - Lotta Herling
- Department of Clinical Science, Division of Obstetrics and Gynecology, Intervention & Technology, Karolinska Institutet and Center for Fetal Medicine Karolinska, University Hospital, Stockholm, Sweden.,Department of Clinical Medicine, Faculty of Health Sciences, Women's Health and Perinatology Research Group, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Torvid Kiserud
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.,Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Ganesh Acharya
- Department of Clinical Science, Division of Obstetrics and Gynecology, Intervention & Technology, Karolinska Institutet and Center for Fetal Medicine Karolinska, University Hospital, Stockholm, Sweden.,Department of Clinical Medicine, Faculty of Health Sciences, Women's Health and Perinatology Research Group, UiT-The Arctic University of Norway, Tromsø, Norway.,Department of Obstetrics and Gynecology, University Hospital of North Norway, Tromsø, Norway
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Shaw CJ, Botting KJ, Niu Y, Lees CC, Giussani DA. Maternal and fetal cardiovascular and metabolic effects of intra-operative uterine handling under general anesthesia during pregnancy in sheep. Sci Rep 2020; 10:10867. [PMID: 32616745 PMCID: PMC7331497 DOI: 10.1038/s41598-020-67714-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 06/05/2020] [Indexed: 11/25/2022] Open
Abstract
A cohort study of 6,500,000 human pregnancies showed an increased risk of adverse fetal outcomes following abdominal but not non-abdominal surgery under general anesthesia. This may be the consequence of uterine handling during abdominal surgery. However, there are no data on any effects on the cardiometabolic physiology of the fetus or mother in response to uterine manipulation in otherwise healthy pregnancy. Consequently, 9 sheep in late gestation were anesthetized with isofluorane and maternal and fetal catheters and flow probes were implanted to determine cardiovascular and metabolic changes during uterine handling. Uterine handling led to an acute increase in uterine artery vascular resistance, fetal peripheral vasoconstriction, a reduction in oxygen delivery to the femoral circulation, worsening fetal acidosis. There was no evidence of systemic fetal hypoxia, or changes in fetal heart rate, carotid blood flow or carotid oxygen delivery. Therefore, the data support that uterine handling during abdominal surgery under general anesthesia can impact adversely on fetal cardiometabolic health. This may provide a potential explanation linking adverse fetal outcomes in abdominal compared with non-abdominal surgery during pregnancy. The data have important implications for human fetal surgery where the uterus is handled, as operative procedures during late gestation under general maternal anesthesia become more prevalent.
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Affiliation(s)
- Caroline J Shaw
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK.,Institute of Reproductive and Developmental Biology, Imperial College London, London, UK
| | - Kimberley J Botting
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK.,Cambridge Cardiovascular Research Initiative, Cambridge, UK
| | - Youguo Niu
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK.,Cambridge Cardiovascular Research Initiative, Cambridge, UK
| | - Christoph C Lees
- Institute of Reproductive and Developmental Biology, Imperial College London, London, UK.,Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium
| | - Dino A Giussani
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK. .,Cambridge Cardiovascular Research Initiative, Cambridge, UK.
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Reyes RV, Herrera EA, Ebensperger G, Sanhueza EM, Giussani DA, Llanos AJ. Perinatal cardiopulmonary adaptation to the thin air of the Alto Andino by a native Altiplano dweller, the llama. J Appl Physiol (1985) 2020; 129:152-161. [PMID: 32584666 DOI: 10.1152/japplphysiol.00800.2019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Most mammals have a poor tolerance to hypoxia, and prolonged O2 restriction can lead to organ injury, particularly during fetal and early postnatal life. Nevertheless, the llama (Lama Glama) has evolved efficient mechanisms to adapt to acute and chronic perinatal hypoxia. One striking adaptation is the marked peripheral vasoconstriction measured in the llama fetus in response to acute hypoxia, which allows efficient redistribution of cardiac output toward the fetal heart and adrenal glands. This strong peripheral vasoconstrictor tone is triggered by a carotid body reflex and critically depends on α-adrenergic signaling. A second adaptation is the ability of the llama fetus to protect its brain against hypoxic damage. During hypoxia, in the llama fetus there is no significant increase in brain blood flow. Instead, there is a fall in brain O2 consumption and temperature, together with a decrease of Na+-K+-ATPase activity and Na+ channels expression, protecting against seizures and neuronal death. Finally, the newborn llama does not develop pulmonary hypertension in response to chronic hypoxia. In addition to maintaining basal pulmonary arterial pressure at normal levels the pulmonary arterial pressor response to acute hypoxia is lower in highland than in lowland llamas. The protection against hypoxic pulmonary arterial hypertension and pulmonary contractile hyperreactivity is partly due to increased hemoxygenase-carbon monoxide signaling and decreased Ca2+ sensitization in the newborn llama pulmonary vasculature. These three striking physiological adaptations of the llama allow this species to live and thrive under the chronic influence of the hypobaric hypoxia of life at high altitude.
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Affiliation(s)
- R V Reyes
- Programa de Fisiopatología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,International Center for Andean Studies (INCAS), Universidad de Chile, Santiago, Chile
| | - E A Herrera
- Programa de Fisiopatología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,International Center for Andean Studies (INCAS), Universidad de Chile, Santiago, Chile
| | - G Ebensperger
- Programa de Fisiopatología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,International Center for Andean Studies (INCAS), Universidad de Chile, Santiago, Chile
| | - E M Sanhueza
- Programa de Fisiopatología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - D A Giussani
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - A J Llanos
- Programa de Fisiopatología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,International Center for Andean Studies (INCAS), Universidad de Chile, Santiago, Chile
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36
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Maternal hyperoxygenation for the human fetus: should studies be curtailed? Pediatr Res 2020; 87:630-633. [PMID: 31600768 DOI: 10.1038/s41390-019-0604-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 03/25/2019] [Accepted: 06/27/2019] [Indexed: 11/08/2022]
Abstract
Congenital hypoplasia of left heart structures in fetuses frequently progresses with gestational development. Interference with cerebral development is common in these fetuses. Chronic maternal hyperoxygenation (MHO) has been recommended to increase left ventricular size and to limit cerebral damage. The effects of MHO on cerebral blood flow and metabolism have been studied in normal fetuses and fetuses with left heart hypoplasia. Maternal hyperoxygenation increases fetal pulmonary blood flow. This is associated with reduction of foramen ovale flow, thus limiting the increase in left ventricular output. Modest increase in the size of left heart structures has been reported, but in another study, no significant improvement occurred. In sheep fetuses increased oxygenation results in marked reduction of cerebral blood flow, with no change in oxygen delivery or consumption by the brain, but significant reduction in cerebral glucose delivery and consumption. In one study of fetuses with left heart hypoplasia, chronic MHO was associated with decrease in head size. The effectiveness of MHO in improving left ventricular development is controversial. MHO is, however, associated with reduction of cerebral blood flow and possible interference with cerebral development. In view of this it is recommended that all studies of chronic maternal hyperoxygenation be curtailed.
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Sun L, Marini D, Saini B, Schrauben E, Macgowan CK, Seed M. Understanding Fetal Hemodynamics Using Cardiovascular Magnetic Resonance Imaging. Fetal Diagn Ther 2020; 47:354-362. [PMID: 32062652 DOI: 10.1159/000505091] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 11/25/2019] [Indexed: 11/19/2022]
Abstract
Human fetal circulatory physiology has been investigated extensively using grey-scale ultrasound, which provides excellent visualization of cardiac anatomy and function, while velocity profiles in the heart and vessels can be interrogated using Doppler. Measures of cerebral and placental vascular resistance, as well as indirect measures of intracardiac pressure obtained from the velocity waveform in the ductus venosus are routinely used to guide the management of fetal cardiovascular and placental disease. However, the characterization of some key elements of cardiovascular physiology such as vessel blood flow and the oxygen content of blood in the arteries and veins, as well as fetal oxygen delivery and consumption are not readily measured using ultrasound. To study these parameters, we have historically relied on data obtained using invasive measurements made in animal models, which are not equivalent to the human in every respect. Over recent years, a number of technical advances have been made that have allowed us to examine the human fetal circulatory system using cardiovascular magnetic resonance (CMR). The combination of vessel blood flow measurements made using cine phase contrast magnetic resonance imaging and vessel blood oxygen saturation and hematocrit measurements made using T1 and T2 mapping have enabled us to emulate those classic fetal sheep experiments defining the distribution of blood flow and oxygen transport across the fetal circulation in the human fetus. In addition, we have applied these techniques to study the relationship between abnormal fetal cardiovascular physiology and fetal development in the setting of congenital heart disease and placental insufficiency. CMR has become an important diagnostic tool in the assessment of cardiovascular physiology in the setting of postnatal cardiovascular disease, and is now being applied to the fetus to enhance our understanding of normal and abnormal fetal circulatory physiology and its impact on fetal well-being.
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Affiliation(s)
- Liqun Sun
- Division of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Davide Marini
- Division of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Brahmdeep Saini
- Division of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Eric Schrauben
- Division of Translational Medicine, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Christopher K Macgowan
- Division of Translational Medicine, Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Mike Seed
- Division of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada, .,Department of Paediatrics and Medical Imaging, University of Toronto, Toronto, Ontario, Canada,
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38
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Jellyman JK, Fletcher AJW, Fowden AL, Giussani DA. Glucocorticoid Maturation of Fetal Cardiovascular Function. Trends Mol Med 2020; 26:170-184. [PMID: 31718939 DOI: 10.1016/j.molmed.2019.09.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 09/17/2019] [Accepted: 09/30/2019] [Indexed: 12/27/2022]
Abstract
The last decade has seen rapid advances in the understanding of the central role of glucocorticoids in preparing the fetus for life after birth. However, relative to other organ systems, maturation by glucocorticoids of the fetal cardiovascular system has been ignored. Here, we review the effects of glucocorticoids on fetal basal cardiovascular function and on the fetal cardiovascular defense responses to acute stress. This is important because glucocorticoid-driven maturational changes in fetal cardiovascular function under basal and stressful conditions are central to the successful transition from intra- to extrauterine life. The cost-benefit balance for the cardiovascular health of the preterm baby of antenatal glucocorticoid therapy administered to pregnant women threatened with preterm birth is also discussed.
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Affiliation(s)
- Juanita K Jellyman
- Department of Biological Sciences, California State Polytechnic University, Pomona, CA, USA.
| | | | - Abigail L Fowden
- Department of Physiology Development and Neuroscience, University of Cambridge, Cambridge, UK; Cambridge Cardiovascular Strategic Research Initiative, Cambridge, UK; Cambridge Strategic Research Initiative in Reproduction, Cambridge, UK
| | - Dino A Giussani
- Department of Physiology Development and Neuroscience, University of Cambridge, Cambridge, UK; Cambridge Cardiovascular Strategic Research Initiative, Cambridge, UK; Cambridge Strategic Research Initiative in Reproduction, Cambridge, UK.
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39
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Varcoe TJ, Darby JRT, Holman SL, Bradshaw EL, Kuchel T, Vaughan L, Seed M, Wiese MD, Morrison JL. Fetal cardiovascular response to acute hypoxia during maternal anesthesia. Physiol Rep 2020; 8:e14365. [PMID: 32026576 PMCID: PMC7002532 DOI: 10.14814/phy2.14365] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 01/03/2020] [Indexed: 12/23/2022] Open
Abstract
Preclinical imaging studies of fetal hemodynamics require anesthesia to immobilize the animal. This may induce cardiovascular depression and confound measures under investigation. We compared the impact of four anesthetic regimes upon maternal and fetal blood gas and hemodynamics during baseline periods of normoxia, and in response to an acute hypoxic challenge in pregnant sheep. Merino ewes were surgically prepared with maternal and fetal vascular catheters and a fetal femoral artery flow probe at 105-109 days gestation. At 110-120 days gestation, ewes were anesthetized with either isoflurane (1.6%), isoflurane (0.8%) plus ketamine (3.6 mg·kg-1 ·h-1 ), ketamine (12.6 mg·kg-1 ·h-1 ) plus midazolam (0.78 mg·kg-1 ·h-1 ), propofol (30 mg·kg-1 ·h-1 ), or remained conscious. Following 60 min of baseline recording, nitrogen was administered directly into the maternal trachea to displace oxygen and induce maternal and thus fetal hypoxemia. During normoxia, maternal PaO2 was ~30 mmHg lower in anesthetized ewes compared to conscious controls, regardless of the type of anesthesia (p < .001). There was no effect of anesthesia on fetal mean arterial blood pressure (MAP; p > .05), but heart rate was 32 ± 8 bpm lower in fetuses from ewes administered isoflurane (p = .044). During maternal hypoxia, fetal MAP increased, and peripheral blood flow decreased in all fetuses except those administered propofol (p < .05). Unexpectedly, hypoxemia also induced fetal tachycardia regardless of the anesthetic regime (p < .05). These results indicate that despite maternal anesthesia, the fetus can mount a cardiovascular response to acute hypoxia by increasing blood pressure and reducing peripheral blood flow, although the heart rate response may differ from when no anesthesia is present.
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Affiliation(s)
- Tamara J. Varcoe
- Early Origins of Adult Health Research GroupUniversity of South AustraliaAdelaideAustralia
- School of Pharmacy and Medical SciencesUniversity of South AustraliaAdelaideAustralia
| | - Jack R. T. Darby
- Early Origins of Adult Health Research GroupUniversity of South AustraliaAdelaideAustralia
- School of Pharmacy and Medical SciencesUniversity of South AustraliaAdelaideAustralia
| | - Stacey L. Holman
- Early Origins of Adult Health Research GroupUniversity of South AustraliaAdelaideAustralia
- School of Pharmacy and Medical SciencesUniversity of South AustraliaAdelaideAustralia
| | - Emma L. Bradshaw
- Early Origins of Adult Health Research GroupUniversity of South AustraliaAdelaideAustralia
- School of Pharmacy and Medical SciencesUniversity of South AustraliaAdelaideAustralia
| | - Tim Kuchel
- South Australian Health and Medical Research InstituteAdelaideAustralia
| | - Lewis Vaughan
- South Australian Health and Medical Research InstituteAdelaideAustralia
| | | | - Michael D. Wiese
- School of Pharmacy and Medical SciencesUniversity of South AustraliaAdelaideAustralia
| | - Janna L. Morrison
- Early Origins of Adult Health Research GroupUniversity of South AustraliaAdelaideAustralia
- School of Pharmacy and Medical SciencesUniversity of South AustraliaAdelaideAustralia
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40
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Smolich JJ, Kenna KR, Cheung MMH, Mynard JP. Brief asphyxial state following immediate cord clamping accelerates onset of left-to-right shunting across the ductus arteriosus after birth in preterm lambs. J Appl Physiol (1985) 2020; 128:429-439. [PMID: 31971471 DOI: 10.1152/japplphysiol.00559.2019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Reversal of shunting across the ductus arteriosus from right-to-left to left-to-right is a characteristic feature of the birth transition. Given that immediate cord clamping (ICC) followed by an asphyxial cord clamp-to-ventilation (CC-V) interval may augment left ventricular (LV) output and central blood flows after birth, we tested the hypothesis that an asphyxial CC-V interval accelerates the onset of postnatal left-to-right ductal shunting. High-fidelity central blood flow signals were obtained in anesthetized preterm lambs (gestation 128 ± 2 days) after ICC followed by a nonasphyxial (∼40 s, n = 9) or asphyxial (∼90 s, n = 9) CC-V interval before mechanical ventilation for 30 min after birth. Left-to-right ductal flow segments were related to aortic isthmus and descending aortic flow profiles to quantify sources of ductal shunting. In the nonasphyxial group, phasic left-to-right ductal shunting was initially minor after birth, but then rose progressively to 437 ± 164 ml/min by 15 min (P < 0.001). However, in the asphyxial group, this shunting increased from 24 ± 21 to 199 ± 93 ml/min by 15 s after birth (P < 0.001) and rose further to 471 ± 190 ml/min by 2 min (P < 0.001). This earlier onset of left-to-right ductal shunting was supported by larger contributions (P < 0.001) from direct systolic LV flow and retrograde diastolic discharge from an arterial reservoir/windkessel located in the descending aorta and its major branches, and associated with increased pulmonary arterial blood flow having a larger ductal component. These findings suggest that the duration of the CC-V interval after ICC is an important modulator of left-to-right ductal shunting, LV output and pulmonary perfusion at birth.NEW & NOTEWORTHY This birth transition study in preterm lambs demonstrated that a brief (∼90 s) asphyxial interval between umbilical cord clamping and ventilation onset resulted in earlier and greater left-to-right shunting across the ductus arteriosus after birth. This greater shunting 1) resulted from an increased left ventricular output associated with a higher systolic left-to-right ductal flow and increased retrograde diastolic discharge from a lower body arterial reservoir/windkessel, and 2) was accompanied by greater lung perfusion after birth.
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Affiliation(s)
- Joseph J Smolich
- Heart Research, Murdoch Children's Research Institute, Melbourne, Australia.,Department of Paediatrics, University of Melbourne, Melbourne, Australia
| | - Kelly R Kenna
- Heart Research, Murdoch Children's Research Institute, Melbourne, Australia
| | - Michael M H Cheung
- Heart Research, Murdoch Children's Research Institute, Melbourne, Australia.,Department of Paediatrics, University of Melbourne, Melbourne, Australia.,Department of Cardiology, Royal Children's Hospital, Parkville, Victoria, Australia
| | - Jonathan P Mynard
- Heart Research, Murdoch Children's Research Institute, Melbourne, Australia.,Department of Paediatrics, University of Melbourne, Melbourne, Australia.,Department of Biomedical Engineering, University of Melbourne, Melbourne, Australia.,Department of Cardiology, Royal Children's Hospital, Parkville, Victoria, Australia
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Evaluation of Vascular Endothelial Function in Young and Middle-Aged Women with Respect to a History of Pregnancy, Pregnancy-Related Complications, Classical Cardiovascular Risk Factors, and Epigenetics. Int J Mol Sci 2020; 21:ijms21020430. [PMID: 31936594 PMCID: PMC7013677 DOI: 10.3390/ijms21020430] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 01/06/2020] [Accepted: 01/07/2020] [Indexed: 12/12/2022] Open
Abstract
The aim of the study was to examine the effect of previous pregnancies and classical cardiovascular risk factors on vascular endothelial function in a group of 264 young and middle-aged women 3 to 11 years postpartum. We examined microvascular functions by peripheral arterial tonometry and EndoPAT 2000 device with respect to a history of gestational hypertension, preeclampsia, fetal growth restriction, the severity of the disease with regard to the degree of clinical signs and delivery date. Besides, we compared Reactive Hyperemia Index (RHI) values and the prevalence of vascular endothelial dysfunction among the groups of women with normal and abnormal values of BMI, waist circumference, systolic and diastolic blood pressures, heart rate, total serum cholesterol levels, serum high-density lipoprotein cholesterol levels, serum low-density lipoprotein cholesterol levels, serum triglycerides levels, serum lipoprotein A levels, serum C-reactive protein levels, serum uric acid levels, and plasma homocysteine levels. Furthermore, we determined the effect of total number of pregnancies and total parity per woman, infertility and blood pressure treatment, presence of trombophilic gene mutations, current smoking of cigarettes, and current hormonal contraceptive use on the vascular endothelial function. We also examined the association between the vascular endothelial function and postpartum whole peripheral blood expression of microRNAs involved in pathogenesis of cardiovascular/cerebrovascular diseases (miR-1-3p, miR-16-5p, miR-17-5p, miR-20a-5p, miR-20b-5p, miR-21-5p, miR-23a-3p, miR-24-3p, miR-26a-5p, miR-29a-3p, miR-92a-3p, miR-100-5p, miR-103a-3p, miR-125b-5p, miR-126-3p, miR-130b-3p, miR-133a-3p, miR-143-3p, miR-145-5p, miR-146a-5p, miR-155-5p, miR-181a-5p, miR-195-5p, miR-199a-5p, miR-210-3p, miR-221-3p, miR-342-3p, miR-499a-5p, and miR-574-3p). A proportion of overweight women (17.94% and 20.59%) and women with central obesity (18.64% and 21.19%) had significantly lower RHI values at 10.0% false positive rate (FPR) both before and after adjustment of the data for the age of patients. At 10.0% FPR, a proportion of women with vascular endothelial dysfunction (RHI ≤ 1.67) was identified to have up-regulated expression profile of miR-1-3p (11.76%), miR-23a-3p (17.65%), and miR-499a-5p (18.82%) in whole peripheral blood. RHI values also negatively correlated with expression of miR-1-3p, miR-23a-3p, and miR-499a-5p in whole peripheral blood. Otherwise, no significant impact of other studied factors on vascular endothelial function was found. We suppose that screening of these particular microRNAs associated with vascular endothelial dysfunction may help to stratify a highly risky group of young and middle-aged women that would benefit from early implementation of primary prevention strategies. Nevertheless, it is obvious, that vascular endothelial dysfunction is just one out of multiple cardiovascular risk factors which has only a partial impact on abnormal expression of cardiovascular and cerebrovascular disease associated microRNAs in whole peripheral blood of young and middle-aged women.
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Agrawal V, Lakshminrusimha S, Chandrasekharan P. Chest Compressions for Bradycardia during Neonatal Resuscitation-Do We Have Evidence? CHILDREN-BASEL 2019; 6:children6110119. [PMID: 31671867 PMCID: PMC6915497 DOI: 10.3390/children6110119] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Revised: 10/16/2019] [Accepted: 10/17/2019] [Indexed: 02/06/2023]
Abstract
The International Liaison Committee on Resuscitation (ILCOR) recommends the initiation of chest compressions (CC) during neonatal resuscitation after 30 s of effective ventilation if the infant remains bradycardic (defined as a heart rate less than 60 bpm). The CC are performed during bradycardia to optimize organ perfusion, especially to the heart and brain. Among adults and children undergoing cardiopulmonary resuscitation (CPR), CC is indicated only for pulselessness or poor perfusion. Neonates have a healthy heart that attempts to preserve coronary and cerebral perfusion during bradycardia secondary to asphyxia. Ventilation of the lungs is the key step during neonatal resuscitation, improving gas exchange and enhancing cerebral and cardiac blood flow by changes in intrathoracic pressure. Compressing the chest 90 times per minute without synchrony with innate cardiac activity during neonatal bradycardia is not based on evidence and could potentially be harmful. Although there are no studies evaluating outcomes in neonates, a recent pediatric study in a hospital setting showed that when CC were initiated during pulseless bradycardia, a third of the patients went into complete arrest, with poor survival at discharge. Ventilation-only protocols such as helping babies breathe are effective in reducing mortality and stillbirths in low-resource settings. In a situation of complete cardiac arrest, CC reinitiates pulmonary flow and supports gas exchange. However, the benefit/harm of performing asynchronous CC during bradycardia as part of neonatal resuscitation remains unknown.
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Affiliation(s)
- Vikash Agrawal
- Division of Neonatology, Department of Pediatrics, University at Buffalo, Buffalo, NY 14260, USA.
| | - Satyan Lakshminrusimha
- Division of Neonatology, Department of Pediatrics, University of California Davis, Davis, CA 95616, USA.
| | - Praveen Chandrasekharan
- Division of Neonatology, Department of Pediatrics, University at Buffalo, Buffalo, NY 14260, USA.
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No. 197a-Fetal Health Surveillance: Antepartum Consensus Guideline. JOURNAL OF OBSTETRICS AND GYNAECOLOGY CANADA 2019; 40:e251-e271. [PMID: 29680082 DOI: 10.1016/j.jogc.2018.02.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
OBJECTIVE This guideline provides new recommendations pertaining to the application and documentation of fetal surveillance in the antepartum period that will decrease the incidence of birth asphyxia while maintaining the lowest possible rate of obstetrical intervention. Pregnancies with and without risk factors for adverse perinatal outcomes are considered. This guideline presents an alternative classification system for antenatal fetal non-stress testing to what has been used previously. This guideline is intended for use by all health professionals who provide antepartum care in Canada. OPTIONS Consideration has been given to all methods of fetal surveillance currently available in Canada. OUTCOMES Short- and long-term outcomes that may indicate the presence of birth asphyxia were considered. The associated rates of operative and other labour interventions were also considered. EVIDENCE A comprehensive review of randomized controlled trials published between January 1996 and March 2007 was undertaken, and MEDLINE and the Cochrane Database were used to search the literature for all new studies on fetal surveillance antepartum. The level of evidence has been determined using the criteria and classifications of the Canadian Task Force on Preventive Health Care (Table 1). SPONSOR This consensus guideline was jointly developed by the Society of Obstetricians and Gynaecologists of Canada and the British Columbia Perinatal Health Program (formerly the British Columbia Reproductive Care Program or BCRCP) and was partly supported by an unrestricted educational grant from the British Columbia Perinatal Health Program. RECOMMENDATION 1: FETAL MOVEMENT COUNTING: RECOMMENDATION 2: NON-STRESS TEST: RECOMMENDATION 3: CONTRACTION STRESS TEST: RECOMMENDATION 4: BIOPHYSICAL PROFILE: RECOMMENDATION 5: UTERINE ARTERY DOPPLER: RECOMMENDATION 6: UMBILICAL ARTERY DOPPLER.
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Liston R, Sawchuck D, Young D. N° 197a-Surveillance du bien-être fœtal : Directive consensus d'antepartum. JOURNAL OF OBSTETRICS AND GYNAECOLOGY CANADA 2019; 40:e272-e297. [PMID: 29680083 DOI: 10.1016/j.jogc.2018.02.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
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Sussman D, Saini BS, Schneiderman JE, Spitzer R, Seed M, Lye SJ, Wells GD. Uterine artery and umbilical vein blood flow are unaffected by moderate habitual physical activity during pregnancy. Prenat Diagn 2019; 39:976-985. [PMID: 31254464 DOI: 10.1002/pd.5517] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 06/10/2019] [Accepted: 06/13/2019] [Indexed: 12/16/2022]
Abstract
OBJECTIVE This study aims to noninvasively quantify blood flow in the uterine arteries (UTAs) and umbilical vein (UV) using phase-contrast magnetic resonance imaging (PC-MRI) and test whether these correlate with maternal fitness parameters. METHOD Resting UTA and UV flows were measured in 23 healthy 30 ± 3-year-old women who engaged in moderate-intensity physical activity during pregnancy. Participant fitness was characterized in the second and third trimesters using the submaximal oxygen uptake (VO2 ) test measuring heart rate (HR), VO2 , ventilation (ventilatory equivalent [VE]/VO2 ), and the Borg rating of perceived exertion (respiratory quotient [RQ]). Linear regression models were used to determine the associations between blood flow and maternal fitness measures. RESULTS Blood flows in the UTA (957 ± 241 mL/min) and UV (132 ± 38 mL/min/kg) were successfully measured in 20 (87%) participants. Neither was associated with any physical fitness parameters (HR, VO2 , VE/VO2 , and RQ) nor with any second-to-third trimester change in these parameters. CONCLUSION PC-MRI can be used to noninvasively measure blood flow in the UTA and UV. Neither resting UTA nor UV flow is associated with maternal fitness parameters. This is the first MRI-based study to provide novel hemodynamic data suggesting decoupling between maternal moderate fitness level and the maternal-placental-fetal hemodynamic system in healthy, normal body mass index (BMI) pregnancies.
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Affiliation(s)
- Dafna Sussman
- Translational Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.,Kinesiology and Physical Education, University of Toronto, Toronto, Ontario, Canada
| | - Brahmdeep S Saini
- Heart Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.,Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Jane E Schneiderman
- Kinesiology and Physical Education, University of Toronto, Toronto, Ontario, Canada.,Clinical Research Services, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Rachel Spitzer
- Department of Obstetrics and Gynecology, Mount Sinai Hospital, Toronto, Ontario, Canada.,Heart Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Mike Seed
- Department of Obstetrics and Gynecology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.,Heart Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.,Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Stephen J Lye
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Greg D Wells
- Translational Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.,Kinesiology and Physical Education, University of Toronto, Toronto, Ontario, Canada
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Budunoglu MD, Yapca OE, Yldildiz GA, Atakan Al R. Fetal renal blood flow velocimetry and cerebro-placental ratio in patients with isolated oligohydramnios. J Gynecol Obstet Hum Reprod 2019; 48:495-499. [PMID: 31176048 DOI: 10.1016/j.jogoh.2019.06.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 05/20/2019] [Accepted: 06/04/2019] [Indexed: 10/26/2022]
Abstract
OBJECTIVE It's proposed that oligohydramnios is caused by decreased renal perfusion due to redistribution of fetal blood at fetal growth restriction. Isolated oligohydramnios refers to the presence of oligohydramnios without fetal structural and chromosomal abnormalities, without fetal growth restriction, without intrauterine infection, and in the absence of known maternal disease. It's unknown whether the redistribution or decreased renal perfusion cause isolated oligohydramnios. The aim of the study was to evaluate fetal renal artery Doppler blood velocimetry and cerebro-placental ratio (CPR) among women with isolated oligohydramnios between 25-40 weeks of gestational age. STUDY DESIGN The middle cerebral artery, umbilical artery and, renal artery pulsatility index (PI) values were measured in 45 fetuses with isolated oligohydramnios and 65 fetuses with normal amniotic fluid. Oligohydramnios was defined as deepest vertical amniotic fluid being measured lower than 1cm. The CPR (middle cerebral artery PI/umbilical artery PI) and renal artery PI values were expressed as multiples of the normal median (MoM) and were compared between the two groups. RESULTS There was no difference in MoM of CPR PI (p=0.167) and MoM of renal artery PI values (right p=0.253, left p=0.353) between the groups. CONCLUSION The renal artery Doppler velocimetry and CPR were not significantly different in the women with isolated oligohydramnios, compared to the women with normal amniotic fluid.
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Affiliation(s)
| | - Omer Erkan Yapca
- Department of Obstetrics and Gynecology, Ataturk University, Faculty of Medicine, Turkey
| | | | - Ragip Atakan Al
- Department of Obstetrics and Gynecology, Ataturk University, Faculty of Medicine, Turkey.
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Cahill LS, Hoggarth J, Lerch JP, Seed M, Macgowan CK, Sled JG. Fetal brain sparing in a mouse model of chronic maternal hypoxia. J Cereb Blood Flow Metab 2019; 39:1172-1184. [PMID: 29271304 PMCID: PMC6547196 DOI: 10.1177/0271678x17750324] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Hypoxic stress is a common occurrence during human pregnancy, yet little is known about its effects on the fetal brain. This study examined the fetal hemodynamic responses to chronic hypoxia in an experimental mouse model of chronic maternal hypoxia (11% O2 from E14.5 to E17.5). Using high-frequency Doppler ultrasound, we found fetal cerebral and ductus venosus blood flow were both elevated by 69% and pulmonary blood flow was decreased by 62% in the fetuses exposed to chronic hypoxia compared to controls. This demonstrates that brain sparing persists during chronic fetal hypoxia and is mediated by "streaming," where highly oxygenated blood preferentially flows through the ductus venosus towards the cerebral circulation, bypassing the liver and the lungs. Consistent with these changes in blood flow, the fetal brain volume measured by MRI is preserved, while the liver and lung volumes decreased compared to controls. However, hypoxia exposed fetuses were rendered vulnerable to an acute hypoxic challenge (8% O2 for 3 min), demonstrating global blood flow decreases consistent with imminent fetal demise rather than elevated cerebral blood flow. Despite this vulnerability, there were no differences in adult brain morphology in the mice exposed to chronic maternal hypoxia compared to controls.
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Affiliation(s)
- Lindsay S Cahill
- 1 Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Johnathan Hoggarth
- 1 Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Jason P Lerch
- 1 Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.,2 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.,3 Program in Neuroscience and Mental Health, The Hospital for Sick Children, Toronto, Ontario Canada
| | - Mike Seed
- 4 Division of Cardiology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.,5 Translational Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Christopher K Macgowan
- 2 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.,5 Translational Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - John G Sled
- 1 Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.,2 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.,5 Translational Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
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Wood CE, Keller-Wood M. Current paradigms and new perspectives on fetal hypoxia: implications for fetal brain development in late gestation. Am J Physiol Regul Integr Comp Physiol 2019; 317:R1-R13. [PMID: 31017808 DOI: 10.1152/ajpregu.00008.2019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The availability of oxygen to the fetus is limited by the route taken by oxygen from the atmosphere to fetal tissues, aided or diminished by pregnancy-associated changes in maternal physiology and, ultimately, a function of atmospheric pressure and composition of the mother's inspired gas. Much of our understanding of the fetal physiological response to hypoxia comes from experiments designed to elucidate the cardiovascular and endocrine responses to transient hypoxia. Complementing this work is equally impactful research into the origins of intrauterine growth restriction in which animal models designed to restrict the transfer of oxygen from the maternal to the fetal circulation were used. A common assumption has been that outcomes measured after a period of hypoxia are related to cellular deprivation of oxygen and reoxygenation: an assumption based on a focus on what we can see "under the streetlights." Recent studies demonstrate that availability of oxygen may not tell the whole story. Transient hypoxia in the fetal sheep stimulates transcriptomics responses that mirror inflammation. This response is accompanied by the appearance of bacteria in the fetal brain and other tissues, likely resulting from a hypoxia-stimulated release of bacteria from the placenta. The appearance of bacteria in the fetus after transient hypoxia complements the recent discovery of bacterial DNA in the normal human placenta and in the tissues of fetal sheep. An understanding of the mechanism of the physiological, cellular, and molecular responses to hypoxia requires an appreciation of stimuli other than cellular oxygen deprivation: stimuli that we would have never known about without looking "between the streetlights," illuminating direct responses to the manipulated variables.
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Affiliation(s)
- Charles E Wood
- Department of Physiology and Functional Genomics, University of Florida College of Medicine , Gainesville, Florida
| | - Maureen Keller-Wood
- Department of Pharmacodynamics, University of Florida College of Pharmacy , Gainesville, Florida
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Hromadnikova I, Kotlabova K, Dvorakova L, Krofta L. Maternal Cardiovascular Risk Assessment 3-to-11 Years Postpartum in Relation to Previous Occurrence of Pregnancy-Related Complications. J Clin Med 2019; 8:jcm8040544. [PMID: 31010048 PMCID: PMC6517910 DOI: 10.3390/jcm8040544] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 04/04/2019] [Accepted: 04/16/2019] [Indexed: 02/07/2023] Open
Abstract
The aim of the present study was to assess the long-term outcomes of women 3-to-11 years postpartum in relation to the previous occurrence of pregnancy-related complications such as gestational hypertension (GH), preeclampsia (PE) and fetal growth restriction (FGR). Body mass index (BMI), waist circumference values, the average values of systolic (SBP) and diastolic (DBP) blood pressures and heart rate, total serum cholesterol levels, serum HDL (high-density lipoprotein) cholesterol levels, serum LDL (low-density lipoprotein) cholesterol levels, serum triglycerides levels, serum lipoprotein A levels, serum CRP (C-reactive protein) levels, plasma homocysteine levels, serum uric acid levels, individual and relative risks of having a heart attack or stroke over the next ten years were compared between groups (50 GH, 102 PE, 34 FGR and 90 normal pregnancies) and correlated with the severity of the disease with regard to clinical signs (25 PE without severe features, 77 PE with severe features), and delivery date (36 early PE, 66 late PE). The adjustment for potential covariates was made, where appropriate. At 3–11 years follow-up women with a history of GH, PE regardless of the severity of the disease and the delivery date, PE without severe features, PE with severe features, early PE, and late PE had higher BMI, waist circumferences, SBP, DBP, and predicted 10-year cardiovascular event risk when compared with women with a history of normotensive term pregnancy. In addition, increased serum levels of uric acid were found in patients previously affected with GH, PE regardless of the severity of the disease and the delivery date, PE with severe features, early PE, and late PE. Higher serum levels of lipoprotein A were found in patients previously affected with early PE. The receiver operating characteristic (ROC) curve analyses were able to identify a substantial proportion of women previously affected with GH or PE with a predisposition to later onset of cardiovascular diseases. Women with a history of GH and PE represent a risky group of patients that may benefit from implementation of early primary prevention strategies.
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Affiliation(s)
- Ilona Hromadnikova
- Department of Molecular Biology and Cell Pathology, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic.
| | - Katerina Kotlabova
- Department of Molecular Biology and Cell Pathology, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic.
| | - Lenka Dvorakova
- Department of Molecular Biology and Cell Pathology, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic.
| | - Ladislav Krofta
- Institute for the Care of the Mother and Child, Third Faculty of Medicine, Charles University, 14700 Prague, Czech Republic.
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50
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Hromadnikova I, Kotlabova K, Dvorakova L, Krofta L, Sirc J. Postnatal Expression Profile of microRNAs Associated with Cardiovascular and Cerebrovascular Diseases in Children at the Age of 3 to 11 Years in Relation to Previous Occurrence of Pregnancy-Related Complications. Int J Mol Sci 2019; 20:ijms20030654. [PMID: 30717412 PMCID: PMC6387366 DOI: 10.3390/ijms20030654] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 01/29/2019] [Accepted: 01/30/2019] [Indexed: 02/07/2023] Open
Abstract
Children descending from pregnancies complicated by gestational hypertension (GH), preeclampsia (PE) or fetal growth restriction (FGR) have a lifelong cardiovascular risk. The aim of the study was to verify if pregnancy complications induce postnatal alterations in gene expression of microRNAs associated with cardiovascular/cerebrovascular diseases. Twenty-nine microRNAs were assessed in peripheral blood, compared between groups, and analyzed in relation to both aspects, the current presence of cardiovascular risk factors and cardiovascular complications and the previous occurrence of pregnancy complications with regard to the clinical signs, dates of delivery, and Doppler ultrasound examination. The expression profile of miR-21-5p differed between controls and children with a history of uncomplicated pregnancies with abnormal clinical findings. Abnormal expression profile of multiple microRNAs was found in children affected with GH (miR-1-3p, miR-17-5p, miR-20a-5p, miR-21-5p, miR-23a-3p, miR-26a-5p, miR-29a-3p, miR-103a-3p, miR-125b-5p, miR-126-3p, miR-133a-3p, miR-146a-5p, miR-181a-5p, miR-195-5p, and miR-342-3p), PE (miR-1-3p, miR-20a-5p, miR-20b-5p, miR-103a-3p, miR-133a-3p, miR-342-3p), and FGR (miR-17-5p, miR-126-3p, miR-133a-3p). The index of pulsatility in the ductus venosus showed a strong positive correlation with miR-210-3p gene expression in children exposed to PE and/or FGR. Any of changes in epigenome (up-regulation of miR-1-3p and miR-133a-3p) that were induced by pregnancy complications are long-acting and may predispose children affected with GH, PE, or FGR to later development of cardiovascular/cerebrovascular diseases. Novel epigenetic changes (aberrant expression profile of microRNAs) appeared in a proportion of children that were exposed to GH, PE, or FGR. Screening of particular microRNAs may stratify a highly risky group of children that might benefit from implementation of early primary prevention strategies.
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Affiliation(s)
- Ilona Hromadnikova
- Department of Molecular Biology and Cell Pathology, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic.
| | - Katerina Kotlabova
- Department of Molecular Biology and Cell Pathology, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic.
| | - Lenka Dvorakova
- Department of Molecular Biology and Cell Pathology, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic.
| | - Ladislav Krofta
- Institute for the Care of the Mother and Child, Third Faculty of Medicine, Charles University, 14700 Prague, Czech Republic.
| | - Jan Sirc
- Institute for the Care of the Mother and Child, Third Faculty of Medicine, Charles University, 14700 Prague, Czech Republic.
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