Risk factors associated with adverse fetal outcomes in pregnancies affected by Coronavirus disease 2019 (COVID-19): a secondary analysis of the WAPM study on COVID-19
Authors: Di Mascio Daniele , Sen Cihat , Saccone Gabriele , Galindo Alberto , Grünebaum Amos , Yoshimatsu Jun , Stanojevic Milan , Kurjak Asım , Chervenak Frank , Rodríguez Suárez María José , Gambacorti-Passerini Zita Maria , Baz María de los Angeles Anaya , Aguilar Galán Esther Vanessa , López Yolanda Cuñarro , De León Luis Juan Antonio , Hernández Ignacio Cueto , Herraiz Ignacio , Villalain Cecilia , Venturella Roberta , Rizzo Giuseppe , Mappa Ilenia , Gerosolima Giovanni , Hellmeyer Lars , Königbauer Josefine , Ameli Giada , Frusca Tiziana , Volpe Nicola , Luca Schera Giovanni Battista , Fieni Stefania , Esposito Eutalia , Simonazzi Giuliana , Di Donna Gaetana , Youssef Aly , Della Gatta Anna Nunzia , Di Donna Mariano Catello , Chiantera Vito , Buono Natalina , Sozzi Giulio , Greco Pantaleo , Morano Danila , Bianchi Beatrice , Lombana Marino Maria Giulia , Laraud Federica , Ramone Arianna , Cagnacci Angelo , Barra Fabio , Gustavino Claudio , Ferrero Simone , Ghezzi Fabio , Cromi Antonella , Laganà Antonio Simone , Laurita Longo Valentina , Stollagli Francesca , Sirico Angelo , Lanzone Antonio , Driul Lorenza , Cecchini D Fabiana , Xodo Serena , Rodriguez Brian , Mercado-Olivares Felipe , Elkafrawi Deena , Sisti Giovanni , Esposito Rosanna , Coviello Antonio , Cerbone Marco , Morlando Maddalena , Schiattarella Antonio , Colacurci Nicola , De Franciscis Pasquale , Cataneo Ilaria , Lenzi Marinella , Sandri Fabrizio , Buscemi Riccardo , Gattei Giorgia , Sala Francesca della , Valori Eleonora , Rovellotti Maria Cristina , Done Elisa , Faron Gilles , Gucciardo Leonardo , Esposito Valentina , Vena Flaminia , Giancotti Antonella , Brunelli Roberto , Muzii Ludovico , Nappi Luigi , Sorrentino Felice , Vasciaveo Lorenzo , Liberati Marco , Buca Danilo , Leombroni Martina , Di Sebastiano Francesca , Di Tizio Luciano , Gazzolo Diego , Franchi Massimo , Ianniciello Quintino Cesare , Garzon Simone , Petriglia Giuliano , Borrello Leonardo , Nieto-Calvache Albaro Josè , Burgos-Luna Juan Manuel , Kadji Caroline , Carlin Andrew , Bevilacqua Elisa , Moucho Marina , Pinto Pedro Viana , Figueiredo Rita , Morales Roselló José , Loscalzo Gabriela , Martinez-Varea Alicia , Diago Vincente , Jimenez Lopez Jesús S , Aykanat Alicia Yeliz , Cosma Stefano , Carosso Andrea , Benedetto Chiara , Bermejo Amanda , May Feuerschuette Otto Henrique , Uyaniklar Ozlem , Ocakouglu Sakine Rahimli , Atak Zeliha , Gündüz Reyhan , Haberal Esra Tustas , Froessler Bernd , Parange Anupam , Palm Peter , Samardjiski Igor , Taccaliti Chiara , Okuyan Erhan , Daskalakis George , Moreira de Sa Renato Augusto , Pittaro Alejandro , Gonzalez-Duran Maria Luisa , Guisan Ana Concheiro , Genç Şerife Özlem , Zlatohlávková Blanka , Piqueras Anna Luengo , Oliva Dolores Esteban , Cil Aylin Pelin , Api Olus , Antsaklis Panos , Ples Liana , Kyvernitakis Ioannis , Maul Holger , Malan Marcel , Lila Albert , Granese Roberta , Ercoli Alfredo , Zoccali Giuseppe , Villasco Andrea , Biglia Nicoletta , Madalina Ciuhodaru , Costa Elena , Daelemans Caroline , Pintiaux Axelle , Cueto Elisa , Hadar Eran , Dollinger Sarah , Brzezinski Sinai Noa A. , Huertas Erasmo , Arango Pedro , Sanchez Amadeo , Schvartzman Javier Alfonso , Cojocaru Liviu , Turan Sifa , Turan Ozhan , Di Dedda Maria Carmela , Molpeceres Rebeca Garrote , Zdjelar Snezana , Premru-Srsen Tanja , Cerar Lilijana Kornhauser , Druškovič Mirjam , De Robertis Valentina , Stefanovic Vedran , Nupponen Irmeli , Nelskylä Kaisa , Khodjaeva Zulfiya , Gorina Ksenia A. , Sukhikh Gennady T. , Maruotti Giuseppe Maria , Visentin Silvia , Cosmi Erich , Ferrari Jacopo , Gatti Alessandra , Luvero Daniela , Angioli Roberto , Puri Ludovica , Palumbo Marco , D’Urso Giusella , Colaleo Francesco , Chiara Rapisarda Agnese Maria , Carbone Ilma Floriana , Mollo Antonio , Nazzaro Giovanni , Locci Mariavittoria , Guida Maurizio , Di Spiezio Sardo Attilio , Panici Pierluigi Benedetti , Berghella Vincenzo , Flacco Maria Elena , Manzoli Lamberto , Bifulco Giuseppe , Scambia Giovanni , Zullo Fulvio , D’Antonio Francesco 
Published: September 2020

Abstract

Objectives
To evaluate the strength of association between maternal and pregnancy characteristics and the risk of adverse perinatal outcomes in pregnancies with laboratory confirmed COVID-19.

Methods
Secondary analysis of a multinational, cohort study on all consecutive pregnant women with laboratory-confirmed COVID-19 from February 1, 2020 to April 30, 2020 from 73 centers from 22 different countries. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite adverse fetal outcome, defined as the presence of either abortion (pregnancy loss before 22 weeks of gestations), stillbirth (intrauterine fetal death after 22 weeks of gestation), neonatal death (death of a live-born infant within the first 28 days of life), and perinatal death (either stillbirth or neonatal death). Logistic regression analysis was performed to evaluate parameters independently associated with the primary outcome. Logistic regression was reported as odds ratio (OR) with 95% confidence interval (CI).

Results
Mean gestational age at diagnosis was 30.6±9.5 weeks, with 8.0% of women being diagnosed in the first, 22.2% in the second and 69.8% in the third trimester of pregnancy. There were six miscarriage (2.3%), six intrauterine device (IUD) (2.3) and 5 (2.0%) neonatal deaths, with an overall rate of perinatal death of 4.2% (11/265), thus resulting into 17 cases experiencing and 226 not experiencing composite adverse fetal outcome. Neither stillbirths nor neonatal deaths had congenital anomalies found at antenatal or postnatal evaluation. Furthermore, none of the cases experiencing IUD had signs of impending demise at arterial or venous Doppler. Neonatal deaths were all considered as prematurity-related adverse events. Of the 250 live-born neonates, one (0.4%) was found positive at RT-PCR pharyngeal swabs performed after delivery. The mother was tested positive during the third trimester of pregnancy. The newborn was asymptomatic and had negative RT-PCR test after 14 days of life. At logistic regression analysis, gestational age at diagnosis (OR: 0.85, 95% CI 0.8–0.9 per week increase; p<0.001), birthweight (OR: 1.17, 95% CI 1.09–1.12.7 per 100 g decrease; p=0.012) and maternal ventilatory support, including either need for oxygen or CPAP (OR: 4.12, 95% CI 2.3–7.9; p=0.001) were independently associated with composite adverse fetal outcome.

Conclusions
Early gestational age at infection, maternal ventilatory supports and low birthweight are the main determinants of adverse perinatal outcomes in fetuses with maternal COVID-19 infection. Conversely, the risk of vertical transmission seems negligible.