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1. Inflammatory imbalance in tracheal aspirate of very preterm newborns is associated with airway obstruction and lung function deficiencies at school age: a cohort study

Author

Cecilia Hagman, Ellen Tufvesson, Ingrid Hansen Pupp, and Lars Björklund

Subjects
Pediatrics, RJ1-570
Abstract

Objective A low expression of club cell secretory protein (CC16) and high levels of proinflammatory cytokines at preterm birth are associated with airway inflammation and more severe neonatal lung disease. The present study aimed to investigate if low levels of CC16, proinflammatory cytokines and vascular endothelial growth factors (VEGF) in tracheal aspirate early after birth were associated with lung function impairment at school age.Patients and methods Participants were 20 children, born very preterm (median gestational age 25+3 weeks+days, IQR: 24+1–27+0 weeks+days), who had tracheal aspirates collected during mechanical ventilation in their first day of life. CC16, cytokines, VEGF and matrix metalloproteinase-9 were measured in the tracheal aspirate and later correlated to results from advanced lung function measurements at 12 years of age.Results Low levels of CC16 and high levels of the proinflammatory cytokines IL-1β and TNF-α in tracheal aspirate were associated with airway obstruction at school age but not with other lung function parameters. The correlation with airway obstruction was even stronger when the ratio between the respective proinflammatory cytokine and CC16 was used. In addition, low levels of VEGF and CC16 were associated with impaired diffusion capacity of the lung.Conclusions An imbalance in inflammatory mediators and growth factors in the lungs at birth may have consequences for airway function and vasculature at school age in preterm born children.

Published
2024
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2. Lung function deficits and bronchodilator reversibility at 12 years of age in children born very preterm compared with controls born at term

Author

Ellen Tufvesson, Cecilia Hagman, Lars Bjorklund, Leif Bjermer, and Ingrid Hansen-Pupp

Abstract

Introduction Very preterm birth is associated with lung function impairment later in life, but several aspects have not been studied. We aimed to comprehensively assess lung function at school age in very preterm infants and term controls, with special emphasis on bronchopulmonary dysplasia (BPD), sex and bronchodilator response. Methods At 12 years of age, 136 children born very preterm (85 with and 51 without BPD), and 56 children born at term performed spirometry, body plethysmography, impulse oscillometry, measurement of diffusion capacity and multiple breath washout, before and after bronchodilator inhalation. Results Airway symptoms and a diagnosis of asthma were more common in children born very preterm. These children had more airflow limitation, seen as lower FEV (pConclusion At 12 years of age, children born very preterm had lower lung function than children born at term in most aspects. Airway obstruction improved markedly after bronchodilator inhalation, and there was only little difference between children with or without BPD.

Published
2022

3. Perinatal inflammation relates to early respiratory morbidity and lung function at 12 years of age in children born very preterm

Author

Ingrid Hansen-Pupp, Cecilia Hagman, Leif Bjermer, Ellen Tufvesson, and Lars J. Björklund

Subjects
medicine.medical_specialty, Vital capacity, medicine.medical_treatment, Gastroenterology, Pulmonary function testing, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, 030225 pediatrics, Internal medicine, medicine, Humans, Very Preterm Birth, Prospective Studies, 030212 general & internal medicine, Child, Prospective cohort study, Lung, Bronchopulmonary Dysplasia, Inflammation, Mechanical ventilation, business.industry, Infant, Newborn, Area under the curve, Infant, Gestational age, General Medicine, medicine.disease, Bronchopulmonary dysplasia, Infant, Extremely Premature, Pediatrics, Perinatology and Child Health, Premature Birth, Female, Morbidity, business
Abstract

Aim: Very preterm birth may be associated with lung function impairment later in life. It is not known if this is caused by prematurity per se or by associated perinatal events, such as maternal–foetal inflammation and severity of early neonatal lung disease. We assessed these factors in a prospective cohort of very preterm infants followed from birth to middle school age. Methods: In 71 infants with a gestational age of median 27.4 (range 23.9–31.7) weeks, pro-inflammatory and modulatory cytokines were measured in umbilical cord blood and in arterial blood sampled at 6, 24 and 72 h after birth, and cumulated cytokine concentrations were calculated as area under the curve (AUC). At median 12.6 (range 12.3–13.5) years of age, pulmonary function testing was done in 53 children. Results: There was a positive correlation between days on mechanical ventilation and AUC for IL-6 (p = 0.001), IL-8 (p = 0.015) and IL-10 (p = 0.006). Infants with bronchopulmonary dysplasia (BPD; n = 32) had higher AUC for the cytokines IL-6, IL-8 and IL-10 than those without BPD (all p < 0.01). Higher levels of AUC for IL-6 at birth correlated with lower forced expiratory volume in 1 s (p = 0.030) and lower mean expiratory flow rate between 25 and 75% of forced vital capacity (p = 0.034). Conclusion: Perinatal inflammation, assessed by circulating cytokines in the first three days of life, was associated with BPD and with airway obstruction at 12 years of age. (Less)

Published
2021

4. Variations in Neonatal Length of Stay of Babies Born Extremely Preterm: An International Comparison Between iNeo Networks

Author

Sarah E. Seaton, Elizabeth S. Draper, Mark Adams, Satoshi Kusuda, Stellan Håkansson, Kjell Helenius, Brian Reichman, Liisa Lehtonen, Dirk Bassler, Shoo K. Lee, Maximo Vento, Brian A. Darlow, Franca Rusconi, Marc Beltempo, Tetsuya Isayama, Kei Lui, Mikael Norman, Junmin Yang, Prakesh S. Shah, Neena Modi, Peter Marshall, Peter Schmidt, Anjali Dhawan, Larissa Korostenski, Javeed Travadi Travadi, Mary Sharp, Andy Gill, Jane Pillow, Jacqueline Stack, Pita Birch, Karen Nothdurft, Lucy Cooke, Dan Casalaz, Jim Holberton, Alice Stewart, Lyn Downe, Michael Stewart, Andrew Berry, Rod Hunt, Peter Morris, Tony De Paoli, Srinivas Bolisetty, Mary Paradisis, Mark Greenhalgh, Pieter Koorts, Carl Kuschel, Sue Jacobs, Lex Doyle, John Craven, Andrew Numa, Hazel Carlisle, Nadia Badawi, Himanshu Popat, Guan Koh, Jonathan Davis, Melissa Luig, Bevan Headley, Chad Andersen, Linda Ng, Georgina Chambers, Nicola Austin, Adrienne Lynn, Brian Darlow, Liza Edmonds, Lindsay Mildenhall, Mariam Buksh, Malcolm Battin, Jutta van den Boom, Vaughan Richardson, David Barker, Barbara Hammond, Victor Samuel Rajadurai, Simon Lam, Genevieve Fung, Jaideep Kanungo, Joseph Ting, Zenon Cieslak, Rebecca Sherlock, Ayman Abou Mehrem, Jennifer Toye, Khalid Aziz, Carlos Fajardo, Jaya Bodani, Lannae Strueby, Mary Seshia, Deepak Louis, Ruben Alvaro, Amit Mukerji, Orlando Da Silva, Mohammad Adie, Kyong-Soon Lee, Eugene Ng, Brigitte Lemyre, Thierry Daboval, Faiza Khurshid, Ermelinda Pelausa, Keith Barrington, Anie Lapoint, Guillaume Ethier, Christine Drolet, Bruno Piedboeuf, Martine Claveau, Marie St-Hilaire, Valerie Bertelle, Edith Masse, Roderick Canning, Hala Makary, Cecil Ojah, Luis Monterrosa, Julie Emberley, Jehier Afifi, Andrzej Kajetanowicz, Marjo Metsäranta, Outi Tammela, Ulla Sankilampi, Timo Saarela, Iris Morag, Shmuel Zangen, Tatyana Smolkin, Francis Mimouni, David Bader, Avi Rothschild, Zipora Strauss, Clari Felszer, Hussam Omari, Smadar Even Tov-Friedman, Benjamin Bar-Oz, Michael Feldman, Nizar Saad, Orna Flidel-Rimon, Meir Weisbrod, Daniel Lubin, Ita Litmanovitz, Amir Kugelman, Eric Shinwell, Gil Klinger, Yousif Nijim, Alona Bin-Nun, Agneta Golan, Dror Mandel, Vered Fleisher-Sheffer, Anat Oron, Lev Bakhrakh, Satoshi Hattori, Masaru Shirai, Toru Ishioka, Toshihiko Mori, Takasuke Amizuka, Toru Huchimukai, Hiroshi Yoshida, Ayako Sasaki, Junichi Shimizu, Toshihiko Nakamura, Mami Maruyama, Hiroshi Matsumoto, Shinichi Hosokawa, Atsuko Taki, Machiko Nakagawa, Kyone Ko, Azusa Uozumi, Setsuko Nakata, Akira Shimazaki, Tatsuya Yoda, Osamu Numata, Hiroaki Imamura, Azusa Kobayashi, Shuko Tokuriki, Yasushi Uchida, Takahiro Arai, Mitsuhiro Ito, Kuniko Ieda, Toshiyuki Ono, Masashi Hayashi, Kanemasa Maki, MieToru Yamakawa, Masahiko Kawai, Noriko Fujii, Kozue Shiomi, Koji Nozaki, Hiroshi Wada, Taho Kim, Yasuyuki Tokunaga, Akihiro Takatera, Toshio Oshima, Hiroshi Sumida, Yae Michinomae, Yoshio Kusumoto, Seiji Yoshimoto, Takeshi Morisawa, Tamaki Ohashi, Yukihiro Takahashi, Moriharu Sugimoto, Noriaki Ono, Shinichiro Miyagawa, Takahiko Saijo, Takashi Yamagami, Kosuke Koyano, Shoko Kobayashi, Takeshi Kanda, Yoshihiro Sakemi, Mikio Aoki, Koichi Iida, Mitsushi Goshi, Yuko Maruyama, Alejandro Avila-Alvarez, José Luis Fernandez-Trisac, Ma Luz Couce Pico, María José Fernández Seara, Andrés Martínez Gutiérrez, Carolina Vizcaíno, Miriam Salvador Iglesias, Honorio Sánchez Zaplana, Belén Fernández Colomer, José Enrique García López, Rafael García Mozo, M. Teresa González Martínez, Ma Dolores Muro Sebastián, Marta Balart Carbonell, Joan Badia Barnusell, Mònica Domingo Puiggròs, Josep Figueras Aloy, Francesc Botet Mussons, Israel Anquela Sanz, Gemma Ginovart Galiana, W. Coroleu, Martin Iriondo, Laura Castells Vilella, Roser Porta, Xavier Demestre, Silvia Martínez Nadal, Cristina de Frutos Martínez, María Jesús López Cuesta, Dolores Esquivel Mora, Joaquín Ortiz Tardío, Isabel Benavente, Almudena Alonso, Ramón Aguilera Olmos, Miguel A. García Cabezas, Ma Dolores Martínez Jiménez, Ma Pilar Jaraba Caballero, Ma Dolores Ordoñez Díaz, Alberto Trujillo Fagundo, Lluis Mayol Canals, Fermín García-Muñoz Rodrigo, Lourdes Urquía Martí, María Fernanda Moreno Galdo, José Antonio Hurtado Suazo, Eduardo Narbona López, José Uberos Fernández, Miguel A. Cortajarena Altuna, Oihana Muga Zuriarrain, David Mora Navarro, María Teresa Domínguez, Ma Yolanda Ruiz del Prado, Inés Esteban Díez, María Teresa Palau Benavides, Santiago Lapeña, Teresa Prada, Eduard Soler Mir, Araceli Corredera Sánchez, Enrique Criado Vega, Náyade del Prado, Cristina Fernández, Lucía Cabanillas Vilaplana, Irene Cuadrado Pérez, Luisa López Gómez, Laura Domingo Comeche, Isabel Llana Martín, Carmen González Armengod, Carmen Muñoz Labián, Ma José Santos Muñoz, Dorotea Blanco Bravo, Vicente Pérez, Ma Dolores Elorza Fernández, Celia Díaz González, Susana Ares Segura, Manuela López Azorín, Ana Belén Jimenez, Tomás Sánchez-Tamayo, Elías Tapia Moreno, María González, José Enrique Sánchez Martínez, José María Lloreda García, Concepción Goñi Orayen, Javier Vilas González, María Suárez Albo, Eva González Colmenero, Elena Pilar Gutiérrez González, Beatriz Vacas del Arco, Josefina Márquez Fernández, Laura Acosta Gordillo, Mercedes Granero Asensio, Carmen Macías Díaz, Mar Albújar, Pedro Fuster Jorge, Sabina Romero, Mónica Rivero Falero, Ana Belén Escobar Izquierdo, Javier Estañ Capell, Ma Isabel Izquierdo Macián, Ma Mar Montejo Vicente, Raquel Izquierdo Caballero, Ma Mercedes Martínez, Aintzane Euba, Amaya Rodríguez Serna, Juan María López de Heredia Goya, Alberto Pérez Legorburu, Ana Gutiérrez Amorós, Víctor Manuel Marugán Isabel, Natalio Hernández González, Segundo Rite Gracia, Ma Purificación Ventura Faci, Ma Pilar Samper Villagrasa, Jiri Kofron, Katarina Strand Brodd, Andreas Odlind, Lars Alberg, Sofia Arwehed, Ola Hafström, Anna Kasemo, Karin Nederman, Lars Åhman, Fredrik Ingemarsson, Henrik Petersson, Pernilla Thurn, Eva Albinsson, Bo Selander, Thomas Abrahamsson, Ingela Heimdahl, Kristbjorg Sveinsdottir, Erik Wejryd, Anna Hedlund, Maria Katarina Söderberg, Lars Navér, Thomas Brune, Jens Bäckström, Johan Robinson, Aijaz Farooqi, Erik Normann, Magnus Fredriksson, Anders Palm, Urban Rosenqvist, Bengt Walde, Cecilia Hagman, Andreas Ohlin, Rein Florell, Agneta Smedsaas-Löfvenberg, Philipp Meyer, Rachel Kusche, Sven Schulzke, Mathias Nelle, Bendicht Wagner, Thomas Riedel, Grégoire Kaczala, Riccardo E. Pfister, Jean-François Tolsa, Matthias Roth, Martin Stocker, Bernhard Laubscher, Andreas Malzacher, John P. Micallef, Lukas Hegi, Romaine Arlettaz, Vera Bernet, Carlo Dani, Patrizio Fiorini, Paolo Ghirri, Barbara Tomasini, Anita Mittal, Jonathan Kefas, Anand Kamalanathan, Michael Grosdenier, Christopher Dewhurst, Andreea Bontea, Delyth Webb, Ross Garr, Ahmed Hassan, Priyadarshan Ambadkar, Mark Dyke, Katharine McDevitt, Glynis Rewitzky, Angela D'Amore, P. Kamath, Paul Settle, Natasha Maddock, Ngozi Edi-Osagie, Christos Zipitis, Carrie Heal, Jacqeline Birch, Abdul Hasib, Aung Soe, Bushra Abdul-Malik, Hamudi Kisat, Vimal Vasu, Savi Sivashankar, Richa Gupta, Chris Rawlingson, Tim Wickham, Marice Theron, Giles Kendall, Aashish Gupta, Narendra Aladangady, Imdad Ali, Neeraj Jain, Khalid Mannan, Vadivelam Murthy, Caroline Sullivan, Shu-Ling Chuang, Tristan Bate, Lidia Tyszcuzk, Geraint Lee, Ozioma Obi, John Chang, Vinay Pai, Charlotte Huddy, Salim Yasin, Richard Nicholl, Poornima Pandey, Jonathan Cusack, Venkatesh Kairamkonda, Dominic Muogbo, Liza Harry, Pinki Surana, Penny Broggio, Tilly Pillay, Sanjeev Deshpande, null Mahadevan, Alison Moore, Porus Bastani, Mehdi Garbash, Mithilesh Lal, Majd Abu-Harb, Alex Allwood, Michael Selter, Paul Munyard, David Bartle, Siba Paul, Graham Whincup, Sanghavi Rekha, Philip Amess, Ben Obi, Peter Reynolds, Indranil Misra, Peter De Halpert, Sanjay Salgia, Rekha Sanghavi, Nicola Paul, Abby Deketelaere, Minesh Khashu, Mark Johnson, Charlotte Groves, Jim Baird, Nick Brennan, Katia Vamvakiti, John McIntyre, Jennifer Holman, Stephen Jones, Alison Pike, Pamela Cairns, Megan Eaton, Karin Schwarz, David Gibson, Lawrence Miall, Dr Krishnamurthy, and Sankara Narayanan

Subjects
Male, medicine.medical_specialty, Birth weight, Standard score, Care provision, 03 medical and health sciences, 0302 clinical medicine, Sex Factors, Pregnancy, 030225 pediatrics, Intensive Care Units, Neonatal, Infant Mortality, Medicine, Humans, 030212 general & internal medicine, International network, business.industry, Obstetrics, Extremely preterm, Infant, Newborn, Gestational age, Infant, Length of Stay, medicine.disease, Infant mortality, Infant, Extremely Premature, Pediatrics, Perinatology and Child Health, Linear Models, Female, Pregnancy, Multiple, business
Abstract

Objective To compare length of stay (LOS) in neonatal care for babies born extremely preterm admitted to networks participating in the International Network for Evaluating Outcomes of Neonates (iNeo). Study design Data were extracted for babies admitted from 2014 to 2016 and born at 24 to 28 weeks of gestational age (n = 28 204). Median LOS was calculated for each network for babies who survived and those who died while in neonatal care. A linear regression model was used to investigate differences in LOS between networks after adjusting for gestational age, birth weight z score, sex, and multiplicity. A sensitivity analysis was conducted for babies who were discharged home directly. Results Observed median LOS for babies who survived was longest in Japan (107 days); this result persisted after adjustment (20.7 days more than reference, 95% CI 19.3-22.1). Finland had the shortest adjusted LOS (−4.8 days less than reference, 95% CI –7.3 to −2.3). For each week's increase in gestational age at birth, LOS decreased by 12.1 days (95% CI –12.3 to −11.9). Multiplicity and male sex predicted mean increases in LOS of 2.6 (95% CI 2.0-3.2) and 2.1 (95% CI 1.6-2.6) days, respectively. Conclusions We identified between-network differences in LOS of up to 3 weeks for babies born extremely preterm. Some of these may be partly explained by differences in mortality, but unexplained variations also may be related to differences in clinical care practices and healthcare systems between countries.

Published
2020

5. Neonatal Outcomes in Very Preterm Infants With Severe Congenital Heart Defects : An International Cohort Study

Author

Mikael Norman, Stellan Håkansson, Satoshi Kusuda, Maximo Vento, Liisa Lehtonen, Brian Reichman, Brian A. Darlow, Mark Adams, Dirk Bassler, Tetsuya Isayama, Franca Rusconi, Shoo Lee, Kei Lui, Junmin Yang, Prakesh S. Shah, Peter Marshall, Peter Schmidt, Anjali Dhawan, Paul Craven, Koert de Waal, Karen Simmer, Andy Gill, Jane Pillow, Jacqueline Stack, Pita Birch, Lucy Cooke, Dan Casalaz, Jim Holberton, Alice Stewart, Lyn Downe, Michael Stewart, Barbara Bajuk, Andrew Berry, Rod Hunt, Charles Kilburn, Tony De Paoli, Srinivas Bolisetty, Mary Paradisis, Ingrid Rieger, Pieter Koorts, Carl Kuschel, Lex Doyle, Andrew Numa, Hazel Carlisle, Nadia Badawi, Alison Loughran‐Fowlds, Guan Koh, Jonathan Davis, Melissa Luig, Chad Andersen, Georgina Chambers, Nicola Austin, Adrienne Lynn, Brian Darlow, Liza Edmonds, Lindsay Mildenhall, Mariam Buksh, Malcolm Battin, Jutta van den Boom, David Bourchier, Vaughan Richardson, Fiona Dineen, Victor Samuel Rajadurai, Simon Lam, Genevieve Fung, Adele Harrison, Anne Synnes, Joseph Ting, Zenon Cieslak, Rebecca Sherlock, Wendy Yee, Khalid Aziz, Jennifer Toye, Carlos Fajardo, Zarin Kalapesi, Koravangattu Sankaran, Sibasis Daspal, Mary Seshia, Ruben Alvaro, Amit Mukerji, Orlando Da Silva, Chuks Nwaesei, Kyong‐Soon Lee, Michael Dunn, Brigitte Lemyre, Kimberly Dow, Ermelinda Pelausa, Keith Barrington, Christine Drolet, Bruno Piedboeuf, Martine Claveau, Marc Beltempo, Valerie Bertelle, Edith Masse, Roderick Canning, Hala Makary, Cecil Ojah, Luis Monterrosa, Akhil Deshpandey, Jehier Afifi, Andrzej Kajetanowicz, Shoo K. Lee, Sture Andersson, Outi Tammela, Ulla Sankilampi, Timo Saarela, Eli Heymann, Shmuel Zangen, Tatyana Smolkin, Francis Mimouni, David Bader, Avi Rothschild, Zipora Strauss, Clari Felszer, Hussam Omari, Smadar Even Tov‐Friedman, Benjamin Bar‐Oz, Michael Feldman, Nizar Saad, Orna Flidel‐Rimon, Meir Weisbrod, Daniel Lubin, Ita Litmanovitz, Amir Kugelman, Eric Shinwell, Gil Klinger, Yousif Nijim, Alona Bin‐Nun, Agneta Golan, Dror Mandel, Vered Fleisher‐Sheffer, David Kohelet, Lev Bakhrakh, Satoshi Hattori, Masaru Shirai, Toru Ishioka, Toshihiko Mori, Takasuke Amizuka, Toru Huchimukai, Hiroshi Yoshida, Ayako Sasaki, Junichi Shimizu, Toshihiko Nakamura, Mami Maruyama, Hiroshi Matsumoto, Shinichi Hosokawa, Atsuko Taki, Machiko Nakagawa, Kyone Ko, Azusa Uozumi, Setsuko Nakata, Akira Shimazaki, Tatsuya Yoda, Osamu Numata, Hiroaki Imamura, Azusa Kobayashi, Shuko Tokuriki, Yasushi Uchida, Takahiro Arai, Mitsuhiro Ito, Kuniko Ieda, Toshiyuki Ono, Masashi Hayashi, Kanemasa Maki, MieToru Yamakawa, Masahiko Kawai, Noriko Fujii, Kozue Shiomi, Koji Nozaki, Hiroshi Wada, Taho Kim, Yasuyuki Tokunaga, Akihiro Takatera, Toshio Oshima, Hiroshi Sumida, Yae Michinomae, Yoshio Kusumoto, Seiji Yoshimoto, Takeshi Morisawa, Tamaki Ohashi, Yukihiro Takahashi, Moriharu Sugimoto, Noriaki Ono, Shinichiro Miyagawa, Takahiko Saijo, Takashi Yamagami, Kosuke Koyano, Shoko Kobayashi, Takeshi Kanda, Yoshihiro Sakemi, Mikio Aoki, Koichi Iida, Mitsushi Goshi, Yuko Maruyama, Alejandro Avila‐Alvarez, José Luis Fernandez‐Trisac, Mª Luz Couce Pico, María José Fernández Seara, Andrés Martínez Gutiérrez, Carolina Vizcaíno, Miriam Salvador Iglesias, Honorio Sánchez Zaplana, Belén Fernández Colomer, José Enrique García López, Rafael García Mozo, M. Teresa González Martínez, Mª Dolores Muro Sebastián, Marta Balart Carbonell, Joan Badia Barnusell, Mònica Domingo Puiggròs, Corporacio Parc Taulí, Josep Figueras Aloy, Francesc Botet Mussons, Israel Anquela Sanz, Gemma Ginovart Galiana, H. De La Santa, W. Coroleu, Martin Iriondo, Laura Castells Vilella, Roser Porta, Xavier Demestre, Silvia Martínez Nadal, Cristina de Frutos Martínez, María Jesús López Cuesta, Dolores Esquivel Mora, Joaquín Ortiz Tardío, Isabel Benavente, Almudena Alonso, Ramón Aguilera Olmos, Miguel A. García Cabezas, Mª Dolores Martínez Jiménez, Mª Pilar Jaraba Caballero, Mª Dolores Ordoñez Díaz, Alberto Trujillo Fagundo, Lluis Mayol Canals, Fermín García‐Muñoz Rodrigo, Lourdes Urquía Martí, María Fernanda Moreno Galdo, José Antonio Hurtado Suazo, Eduardo Narbona López, José Uberos Fernández, Miguel A. Cortajarena Altuna, Oihana Muga Zuriarrain, David Mora Navarro, María Teresa Domínguez, Mª Yolanda Ruiz del Prado, Inés Esteban Díez, María Teresa Palau Benavides, Santiago Lapeña, Teresa Prada, Eduard Soler Mir, Araceli Corredera Sánchez, Enrique Criado Vega, Náyade del Prado, Cristina Fernández, Lucía Cabanillas Vilaplana, Irene Cuadrado Pérez, Luisa López Gómez, Laura Domingo Comeche, Isabel Llana Martín, Carmen González Armengod, Carmen Muñoz Labián, Mª José Santos Muñoz, Dorotea Blanco Bravo, Vicente Pérez, Mª Dolores Elorza Fernández, Celia Díaz González, Susana Ares Segura, Manuela López Azorín, Ana Belén Jimenez MD, Tomás Sánchez‐Tamayo, Elías Tapia Moreno, María González, José Enrique Sánchez Martínez, José María Lloreda García, Concepción Goñi Orayen, Javier Vilas González, María Suárez Albo, Eva González Colmenero, Elena Pilar Gutiérrez González, Beatriz Vacas del Arco, Josefina Márquez Fernández, Laura Acosta Gordillo, Mercedes Granero Asensio, Carmen Macías Díaz, Mar Albújar, Pedro Fuster Jorge, Sabina Romero, Mónica Rivero Falero, Ana Belén Escobar Izquierdo, Javier Estañ Capell, Mª Isabel Izquierdo Macián, Mª Mar Montejo Vicente, Raquel Izquierdo Caballero, Mª Mercedes Martínez, Aintzane Euba, Amaya Rodríguez Serna, Juan María López de Heredia Goya, Alberto Pérez Legorburu, Ana Gutiérrez Amorós, Víctor Manuel Marugán Isabel, Natalio Hernández González, Segundo Rite Gracia, Mª Purificación Ventura Faci, Mª Pilar Samper Villagrasa, Jiri Kofron, Katarina Strand Brodd, Andreas Odlind, Lars Alberg, Sofia Arwehed, Ola Hafström, Anna Kasemo, Karin Nederman, Lars Åhman, Fredrik Ingemarsson, Henrik Petersson, Pernilla Thurn, Eva Albinsson, Bo Selander, Thomas Abrahamsson, Ingela Heimdahl, Kristbjorg Sveinsdottir, Erik Wejryd, Anna Hedlund, Maria Katarina Söderberg, Lars Navér, Thomas Brune, Jens Bäckström, Johan Robinson, Aijaz Farooqi, Erik Normann, Magnus Fredriksson, Anders Palm, Urban Rosenqvist, Bengt Walde, Cecilia Hagman, Andreas Ohlin, Rein Florell, Agneta Smedsaas‐Löfvenberg, Philipp Meyer, Rachel Kusche, Sven Schulzke, Mathias Nelle, Bendicht Wagner, Thomas Riedel, Grégoire Kaczala, Riccardo E. Pfister, Jean‐François Tolsa, Matthias Roth, Martin Stocker, Bernhard Laubscher, Andreas Malzacher, John P. Micallef, Lukas Hegi, Romaine Arlettaz, Vera Bernet, Carlo Dani, Patrizio Fiorini, Paolo Ghirri, Barbara Tomasini, Tampere University, Department of Paediatrics, and Clinical Medicine

Subjects
Heart Defects, Congenital, Male, Pediatrics, medicine.medical_specialty, Epidemiology, Birth weight, Gestational Age, Infant, Premature, Diseases, 030204 cardiovascular system & hematology, 3121 Internal medicine, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Developmental biology, Infant Mortality, cardiac malformation, Medicine, Humans, Hospital Mortality, Original Research, business.industry, Mortality rate, Congenital Heart Disease, Infant, Newborn, Gestational age, Pediatrik, preterm birth, Infant, Retinopathy of prematurity, Odds ratio, medicine.disease, mortality, Bronchopulmonary dysplasia, newborn infant, Infant, Extremely Premature, Necrotizing enterocolitis, Female, Mortality/Survival, Cardiology and Cardiovascular Medicine, business, Cohort study
Abstract

Background Very preterm infants are at high risk of death or severe morbidity. The objective was to determine the significance of severe congenital heart defects ( CHDs ) for these risks. Methods and Results This cohort study included infants from 10 countries born from 2007–2015 at 24 to 31 weeks’ gestation with birth weights CHDs were defined by International Classification of Diseases, Ninth Revision ( ICD‐9 ) and Tenth ( ICD‐10 ) codes and categorized as those compromising systemic output, causing sustained cyanosis, or resulting in congestive heart failure. The primary outcome was in‐hospital mortality. Secondary outcomes were neonatal brain injury, necrotizing enterocolitis, bronchopulmonary dysplasia, and retinopathy of prematurity. Adjusted and propensity score–matched odds ratios ( ORs ) were calculated. Analyses were stratified by type of CHD , gestational age, and network. A total of 609 (0.77%) infants had severe CHD and 76 371 without any malformation served as controls. The mean gestational age and birth weight were 27.8 weeks and 1018 g, respectively. The mortality rate was 18.6% in infants with CHD and 8.9% in controls (propensity score–matched OR , 2.30; 95% CI , 1.61–3.27). Severe CHD was not associated with neonatal brain injury, necrotizing enterocolitis, or retinopathy of prematurity, whereas the OR for bronchopulmonary dysplasia increased. Mortality was higher in all types, with the highest propensity score–matched OR (4.96; 95% CI, 2.11–11.7) for CHD causing congestive heart failure. While mortality did not differ between groups at OR for mortality in infants with CHD increased to 10.9 (95% CI, 5.76–20.70) at 31 weeks’ gestational age. Rates of CHD and mortality differed significantly between networks. Conclusions Severe CHD is associated with significantly increased mortality in very preterm infants.

Published
2020

6. Club cell secretory protein (CC16) in gastric fluid at birth and subsequent lung disease in preterm infants

Author

Lars J. Björklund, Gunnel Hellgren, Ellen Tufvesson, Cecilia Hagman, and Ingrid Hansen-Pupp

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, medicine.medical_treatment, Gestational Age, Inflammation, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Internal medicine, medicine, Humans, Uteroglobin, Bronchopulmonary Dysplasia, Mechanical ventilation, Gastric Juice, Lung, business.industry, Infant, Newborn, Postmenstrual Age, Infant, Gestational age, Respiration, Artificial, Trachea, Secretory protein, Club cell, medicine.anatomical_structure, Matrix Metalloproteinase 9, 030228 respiratory system, Pediatrics, Perinatology and Child Health, Cytokines, Female, Tumor necrosis factor alpha, medicine.symptom, business, Biomarkers, Infant, Premature
Abstract

Background: Club cell secretory protein (CC16) probably has a role in protecting the lung from inflammation. Aim: To evaluate if low levels of CC16 in gastric fluid at birth, reflecting low levels of CC16 in the lung, would be associated with lung inflammation and respiratory morbidity. Methods: A study of 64 infants with mean gestational age 26.1 weeks. CC16 was analyzed in gastric fluid at birth. CC16, pro-inflammatory cytokines, and MMP-9 were analyzed in tracheal aspirate within 24 h from birth. Results: CC16 in gastric fluid increased with gestational age (P = 0.033). Lower concentrations of CC16 in gastric fluid at birth were associated with higher concentrations of IL-1β (P = 0.028), TNF-α (P = 0.034), and MMP-9 (P = 0.015) in tracheal aspirate. Infants who needed mechanical ventilation at 24 and 72 h of age had lower CC16 in gastric fluid than those not ventilated at these ages (P = 0.011 and P = 0.024, respectively). Lower CC16 in gastric fluid was associated with higher FiO2 at 6 h (P = 0.009), higher PaCO2 at 24 h (P = 0.03), more ventilator days (P = 0.012) and more days with supplemental oxygen (P = 0.03). Infants who had either died or were still treated with supplemental oxygen at 36 weeks postmenstrual age had lower CC16 in gastric fluid than infants with none of these outcomes (P = 0.049). Conclusion: A low CC16 concentration in gastric fluid at birth was associated with increased inflammation in the trachea within the first 24 h of life and with more need for respiratory support in the neonatal period. (Less)

Published
2018

7. Development of lung function in children born preterm with and without bronchopulmonary dysplasia - a follow-up study at 12 years of age

Author

Leif Bjermer, Lars J. Björklund, Cecilia Hagman, Ingrid Hansen-Pupp, and Ellen Tufvesson

Subjects
Spirometry, Pediatrics, medicine.medical_specialty, Lung, medicine.diagnostic_test, business.industry, Birth weight, Postmenstrual Age, Gestational age, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030228 respiratory system, Bronchopulmonary dysplasia, Diffusing capacity, Medicine, Very Preterm Birth, 030212 general & internal medicine, business
Abstract

Introduction: Pulmonary disease after very preterm birth may cause permanent lung damage and as a consequence, lung function impairment in long-term survivors, bronchopulmonary dysplasia being one of the earliest manifestation. Aims: The aim of this study was to assess lung function in children 12 years of age, born very preterm and compare with children born at term. In addition we determined the impact of BPD and prematurity during childhood. Methods: Spirometry, impulse oscillometry, body plethysmograhy and diffusing capacity was performed at 12 years of age in 98 children, born at gestational age of 22-31 weeks (median 27 weeks and birth weight 950g). Age-matched children born at term were included as controls (n=17). BPD was defined as need for supplemental oxygen at 36 weeks postmenstrual age. Results: Prematurity was associated with lower forced expiratory flow (FEF25-75), p=0.05, higher total (R5) and peripheral (R5-20) resistance, p=0.01 resp p Prematurity was also associated with lower diffusion capacity, p=0.01 and higher residual volume, p=0.02. Preterm children with BPD showed no significant lung function impairment at the age of 12 compared to preterm children without BPD. Conclusion: Preterm birth is associated with an increased risk of significant obstructive airway disease and lung function impairment at the age of 12, regardless of BPD diagnosis. Children born preterm would benefit from regular assessment of lung function to give an insight regarding long-term sequele and respiratory health throughout adolescence and adulthood.

Published
2019

8. Neonatal Intensive Care Unit-Level Patent Ductus Arteriosus Treatment Rates and Outcomes in Infants Born Extremely Preterm

Author

Mikael Norman, Anne Synnes, Toshihiko Mori, Mitsuhiro Ito, David Kohelet, Hiroshi Matsumoto, Luis Monterrosa, Philipp Meyer, Akhil Deshpandey, Pernilla Thurn, Hiroaki Imamura, Edith Masse, Yuko Maruyama, Toru Ishioka, Satoshi Hattori, Ola Hafström, Wendy Yee, Koravangattu Sankaran, Rachel Kusche, Jehier Afifi, Zipora Strauss, Shmuel Zangen, Takeshi Kanda, Mie Toru Yamakawa, Takashi Yamagami, Sven M. Schulzke, Daniel Lubin, Gil Klinger, Mark Raymond Adams, Maria Katarina Söderberg, Fredrik Ingemarsson, Jennifer Toye, Yukihiro Takahashi, Junichi Shimizu, Michael Feldman, Vera Bernet, Marc Beltempo, Adele Harrison, Joseph Ting, Takeshi Morisawa, Kimberly Dow, Atsuko Taki, Meir Weisbrod, Prakesh S. Shah, Keith J. Barrington, Brian Reichman, Ulla Sankilampi, Benjamin Bar-Oz, Mary Seshia, John P. Micallef, Lev Bakhrakh, Hussam Omari, Liisa Lehtonen, Amit Mukerji, Kozue Shiomi, Bernhard Laubscher, Mikio Aoki, Hiroshi Wada, Cecil Ojah, Dror Mandel, Martin Stocker, Ingela Heimdahl, Toshio Oshima, Bo Selander, Rebecca Sherlock, Yousif Nijim, Ita Litmanovitz, Yoshihiro Sakemi, Yoshio Kusumoto, Henrik Petersson, Alona Bin-Nun, Christine Drolet, Shoko Kobayashi, Shinichiro Miyagawa, Kyong-Soon Lee, Urban Rosenqvist, Takasuke Amizuka, Jean-François Tolsa, Hiroshi Yoshida, Martine Claveau, Andreas Malzacher, Akihiro Takatera, Hiroshi Sumida, Agneta Golan, Jens Bäckström, Thomas Riedel, Rein Florell, Masahiko Kawai, Thomas Brune, Osamu Numata, Lars Åhman, Stellan Håkansson, Outi Tammela, Thomas Abrahamsson, Brigitte Lemyre, Michael Dunn, Clari Felszer, Shuko Tokuriki, Valerie Bertelle, Cecilia Hagman, Takahiko Saijo, Eli Heymann, Akira Shimazaki, Andreas Odlind, Sibasis Daspal, Kosuke Koyano, Roderick Canning, Kjell Helenius, Machiko Nakagawa, Yasushi Uchida, Tamaki Ohashi, Kanemasa Maki, Carlos Fajardo, Orlando da Silva, Matthias Roth, Romaine Arlettaz, Yasuyuki Tokunaga, Toshihiko Nakamura, Azusa Uozumi, Azusa Kobayashi, Avi Rothschild, Karin Nederman, Chuks Nwaesei, Anna Hedlund, Setsuko Nakata, Andreas Ohlin, Katarina Strand Brodd, Erik Normann, Amir Kugelman, Bengt Walde, Dirk Bassler, Tatyana Smolkin, Bruno Piedboeuf, Ermelinda Pelausa, Shoo K. Lee, Noriko Fujii, Orna Flidel-Rimon, Hala Makary, Jiri Kofron, Aijaz Farooqi, Taho Kim, Lars Navér, Khalid Aziz, Toru Huchimukai, Vered Fleisher-Sheffer, Tatsuya Yoda, Agneta Smedsaas Löfvenberg, Tetsuya Isayama, Noriaki Ono, Eva Albinsson, Ruben Alvaro, Kristbjorg Sveinsdottir, Anna Kasemo, Grégoire Kaczala, Junmin Yang, Kyone Ko, Zenon Cieslak, Timo Saarela, Sofia Arwehed, Bendicht Peter Wagner, Mami Maruyama, Eric S. Shinwell, Lars Alberg, Mitsushi Goshi, Zarin Kalapesi, Amish Jain, Moriharu Sugimoto, Mathias Nelle, Koji Nozaki, Kuniko Ieda, Shinichi Hosokawa, Smadar Even Tov-Friedman, Masashi Hayashi, Magnus Fredriksson, Lukas Hegi, Nizar Saad, Seiji Yoshimoto, Francis B. Mimouni, David Bader, Yae Michinomae, Johan Robinson, Erik Wejryd, Toshiyuki Ono, Sture Andersson, Satoshi Kusuda, Ayako Sasaki, Takahiro Arai, Koichi Iida, Masaru Shirai, Andrzej Kajetanowicz, Riccardo Pfister, Anders Palm, and Pfister, Riccardo

Subjects
Male, Pediatrics, Neonatal intensive care unit, health care facilities, manpower, and services, Indomethacin, Anti-Inflammatory Agents, Ibuprofen, Ibuprofen/therapeutic use, Cohort Studies, 0302 clinical medicine, Japan, Periventricular/epidemiology, Neonatal, Ductus arteriosus, 030212 general & internal medicine, Israel, Ductus Arteriosus, Patent, ddc:618, Anti-Inflammatory Agents, Non-Steroidal, Composite outcomes, 3. Good health, Japan/epidemiology, Europe, Intensive Care Units, medicine.anatomical_structure, Echocardiography, Infant, Extremely Premature, Cohort, cardiovascular system, Necrotizing/epidemiology, Gestation, Female, Cohort study, Adult, Non-Steroidal/therapeutic use, Canada, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Leukomalacia, Periventricular, Birth weight, education, Canada/epidemiology, Extremely Premature, Europe/epidemiology, 03 medical and health sciences, Indomethacin/therapeutic use, Enterocolitis, Necrotizing, Intensive Care Units, Neonatal, 030225 pediatrics, medicine, Humans, cardiovascular diseases, Israel/epidemiology, Cerebral Intraventricular Hemorrhage, Retrospective Studies, Cerebral Intraventricular Hemorrhage/epidemiology, Cardiovascular Surgical Procedures/statistics & numerical data, Enterocolitis, business.industry, Cardiovascular Surgical Procedures, Extremely preterm, Infant, Newborn, Infant, Ductus Arteriosus, Newborn, Pediatrics, Perinatology and Child Health, Linear Models, Patent/diagnostic imaging/epidemiology/therapy, business, Leukomalacia
Abstract

To assess associations between neonatal intensive care unit (NICU)-level patent ductus arteriosus (PDA) treatment rates (pharmacologic or surgical) and neonatal outcomes.This cohort study included infants born at 24-28 weeks of gestation and birth weight1500 g in 2007-2015 in NICUs caring for ≥100 eligible infants in 6 countries. The ratio of observed/expected (O/E) PDA treatment rates was derived for each NICU by estimating the expected rate using a logistic regression model adjusted for potential confounders and network. The primary composite outcome was death or severe neurologic injury (grades III-IV intraventricular hemorrhage or periventricular leukomalacia). The associations between the NICU-level O/E PDA treatment ratio and neonatal outcomes were assessed using linear regression analyses including a quadratic effect (a square term) of the O/E PDA treatment ratio.From 139 NICUs, 39 096 infants were included. The overall PDA treatment rate was 45% in the cohort (13%-77% by NICU) and the O/E PDA treatment ratio ranged from 0.30 to 2.14. The relationship between the O/E PDA treatment ratio and primary composite outcome was U-shaped, with the nadir at a ratio of 1.13 and a significant quadratic effect (P.001). U-shaped relationships were also identified with death, severe neurologic injury, and necrotizing enterocolitis.Both low and high PDA treatment rates were associated with death or severe neurologic injury, whereas a moderate approach was associated with optimal outcomes.

Published
2020

9. PERINATAL INFLAMMATION AND INTRAUTERINE GROWTH RETARDATION ARE BOTH ASSOCIATED WITH LUNG FUNCTION IMPAIRMENT AT 12 YEARS OF AGE IN VERY PRETERM INFANTS

Author

Cecilia Hagman, Lars J. Björklund, Ellen Tufvesson, and Ingrid Pupp-Hansen

Subjects
Spirometry, Pediatrics, medicine.medical_specialty, Lung, medicine.diagnostic_test, business.industry, Gestational age, Systemic inflammation, Pulmonary function testing, medicine.anatomical_structure, Diffusing capacity, Cord blood, medicine, Very Preterm Birth, medicine.symptom, business
Abstract

PERINATAL INFLAMMATION AND INTRAUTERINE GROWTH RETARDATION ARE BOTH ASSOCIATED WITH LUNG FUNCTION IMPAIRMENT AT 12 YEARS OF AGE IN VERY PRETERM INFANTS Introduction: Pulmonary disease after very preterm birth may cause permanent lung damage and as a consequence, lung function impairment in long-term survivors. Perinatal inflammation is one of several identified risk factors. Aim and objectives The aim of this study was to evaluate if systemic inflammation early after birth in very preterm infants was related to lung function at preadolescent age. Methods: Spirometry and diffusing capacity was done at 12 years of age in 54 children, born at gestational age of 27.8 weeks. Lung function parameters were compared with inflammatory biomarkers (IL-6, IL-8 and IL-10) previously analyzed from cord blood and at 6, 24 and 72 h after birth. Mean cytokine levels were calculated by area under curve (AUC). BPD was defined as need for supplemental oxygen at 36 weeks PMA. Results: Weight deviation at birth was associated with a lower diffusing capacity (p=0,005) and a lower alveolar volume (p=0,009) at 12-13 years of age. Infants diagnosed with BPD had higher AUC for IL-6, IL-8 and IL-10 in the first 72 h after birth (p=0.009, p There were a significant inverse correlation between AUC for IL-6 in the first days of life and FEV1 (p=0,006) and MMEF25-75 (p=0,019) at 12-13 years of age. Conclusion: The presence of growth retardation at birth as well as perinatal inflammation were risk factors for later impaired lung function at the age of 12. Long term follow up with lung function tests might be useful in infants with specific risk factors.

Published
2018

10. Novel FOXF1 Mutations in Sporadic and Familial Cases of Alveolar Capillary Dysplasia with Misaligned Pulmonary Veins Imply a Role for its DNA Binding Domain

Author

Jane E. Brumbaugh, Michael L. Baker, Jennifer A. Wambach, Nicolas Chassaing, Katayoun Afshar, Deborah Schady, David Mowat, Lawrence S. Prince, Marie T. McDonald, F. Sessions Cole, Kathleen Gibson, Romana Gerychová, Iris Silva, Merrissa Whitt, John B. Cahill, Daniel T. Swarr, Pawel Stankiewicz, Lananh Nguyen, Luk Ho-ming, Thierry Detaille, Csaba Galambos, Yaping Yang, Lakshmi Srinivasan, Harry P.W. Kozakewich, Catherine Barrea, Avinash V. Dharmadhikari, Florence Fellmann, Stephen E. Welty, Robert M. Verdijk, Aaron Hamvas, Irene Valenzuela Palafoll, Patrick E. Lantz, Christine Galant, Adeline Vigouroux, Vincent Muhlethaler, Janet Lioy, John K. Petty, Philippe Friedlich, Charles Shaw-Smith, Colby Navarro, Ivan F M Lo, Partha Sen, Adrian Charles, Kari D Roberts, Przemyslaw Szafranski, Marta Jezova, Melissa M. Riley, Jacques S. Beckmann, Susana Fernandes, Cecilia Hagman, Karin E. M. Diderich, Linda R. Margraf, Stacey L. Peterson-Carmichael, Hari Ravindranathan, A. Julian Garvin, Gustavo Rocha, Jack Goldblatt, Laura S. Finn, Debra L. Kearney, Jane T. Gaede, Axel Bohring, Eric Giannoni, Joseph R. Siebert, Hasnaa Mostafa, Craig W. Zuppan, Melissa Sloman, Stephen Lam, Rosa L. E. van Loon, Allyn McConkie-Rosell, Ulrike Siebers-Renelt, Katarzyna E. Kolodziejska, Claire Langston, Yves Sznajer, Iveta Valášková, Alice S. Brooks, Hitesh Deshmukh, Ella Sugo, Binoy Shivanna, Zeina N. Kiblawi, Masha Bilic, Stephen R. Hays, Jinlong Liang, Pharmacy, Clinical Genetics, Pathology, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - SSS/IREC/MORF - Pôle de Morphologie, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de cardiologie pédiatrique, and UCL - (SLuc) Service de soins intensifs

Subjects
Male, Alveolar capillary dysplasia, Nonsynonymous substitution, Non-Mendelian inheritance, Molecular Sequence Data, Gene Dosage, Biology, Persistent Fetal Circulation Syndrome, Article, Frameshift mutation, Open Reading Frames, 03 medical and health sciences, Exon, 0302 clinical medicine, Databases, Genetic, Gene Order, Genetics, medicine, Humans, Missense mutation, Protein Interaction Domains and Motifs, Amino Acid Sequence, Gene, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Point mutation, Infant, Newborn, Chromosome Mapping, Infant, Forkhead Transcription Factors, medicine.disease, 3. Good health, Mutation, Female, Sequence Alignment, 030217 neurology & neurosurgery
Abstract

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Non-pulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and ten deletions, we have identified an additional thirty eight novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, twenty missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic whereas four familial cases with three showing maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA binding domain, indicating its plausible role in gene regulation. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis.

Published
2013

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