RBGO Cover 1.Indd

ISSN 0100-7203 RBGO eISSN 1806-9339 Gynecology & Obstetrics

Revista Brasileira de Ginecologia e Obstetrícia Number 3 • Volume 43 • Pages 155–246 • March 2021 ISSN 0100-7203

RBGO Gynecology and Obstetrics Revista Brasileira de Ginecologia e Obstetrícia

Editor in Chief

Marcos Felipe Silva de Sá Universidade de São Paulo, Ribeirão Preto, SP, Brazil

Former Editors

Jean Claude Nahoum Sérgio Pereira da Cunha Rio de Janeiro, RJ (1979–1989) Ribeirão Preto, SP (1994–1997) Clarice do Amaral Ferreira Jurandyr Moreira de Andrade Rio de Janeiro, RJ (1989–1994) Ribeirão Preto, SP, Brazil (1997–2015)

Associated Editors

Agnaldo Lopes da Silva Filho Fabrício da Silva Costa Luiz Gustavo Oliveira Brito Universidade Federal de Minas Gerais, Monash University, Melbourne, Universidade de São Paulo, Campinas, SP, Brazil Belo Horizonte, MG, Brazil Victoria, Australia Marcos Nakamura Pereira Alessandra Cristina Marcolin Fernanda Garanhani de Castro Surita Instituto Fernandes Figueira, Universidade de São Paulo, Universidade Estadual de Campinas, Rio de Janeiro, RJ, Brazil Ribeirão Preto, SP, Brazil Campinas, SP, Brazil Maria Celeste Osório Wender Ana Katherine da Silveira Gonçalves Fernando Marcos dos Reis Universidade Federal do Rio Grande do Sul, Universidade Federal do Rio Grande do Universidade Federal de Minas Gerais, Porto Alegre, RS, Brazil Norte, Natal, RN, Brazil Belo Horizonte, MG, Brazil Maria Laura Costa do Nascimento Universidade Estadual de Campinas, Andréa da Rocha Tristão Gabriel Costa Osanan Campinas, SP, Brazil Universidade Estadual Paulista Universidade Federal de Minas Gerais, Melânia Maria Ramos de Amorim “Júlio de Mesquite Filho”, Botucatu, SP, Brazil Belo Horizonte, MG, Brazil Angélica Nogueira Rodrigues Universidade Federal de Campina Grande, Gustavo Salata Romão Campina Grande, PB, Brazil Universidade Federal de Minas Gerais, Universidade de Ribeirão Preto, Mila de Moura Behar Pontremoli Salcedo Belo Horizonte, MG, Brazil Ribeirão Preto, SP, Brazil Universidade Federal de Ciências da Saúde Antonio Rodrigues Braga Neto Helena von Eye Corleta de Porto Alegre, Porto Alegre, RS, Brazil Universidade Federal do Rio de Janeiro, Universidade Federal do Rio Grande do Sul, Omero Benedicto Poli Neto Rio de Janeiro, RJ, Brazil Porto Alegre, RS, Brazil Universidade de São Paulo, Ribeirão Preto, Conrado Milani Coutinho Ilza Maria Urbano Monteiro SP, Brazil Universidade de São Paulo, Universidade Estadual de Campinas, Patrícia El Beitune Ribeirão Preto, SP, Brazil Campinas, SP, Brazil Universidade Federal de Ciências da Saúde Corintio Mariani Neto João Paulo Souza de Porto Alegre, RS, Brazil Universidade Cidade de São Paulo, Universidade de São Paulo, Ribeirão Preto, Paula Andrea de Albuquerque Salles Navarro São Paulo, SP, Brazil SP, Brazil Universidade de São Paulo, Cristina Laguna Benetti Pinto José Carlos Peraçoli Ribeirão Preto, SP, Brazil Universidade Estadual de Campinas, Universidade Estadual Paulista “Júlio de Renato Moretti-Marques Campinas, SP, Brazil Mesquita Filho”, Botucatu, SP, Brazil Hospital Israelita Albert Einstein, Daniel Guimarães Tiezzi José Geraldo Lopes Ramos São Paulo, SP, Brazil Universidade de São Paulo,Ribeirão Preto, Universidade Federal do Rio Grande do Ricardo Carvalho Cavalli Universidade de São Paulo, SP, Brazil Sul, Porto Alegre, RS, Brazil Ribeirão Preto, SP, Brazil Diama Bhadra Andrade Peixoto do Vale José Guilherme Cecatti Ricardo Mello Marinho Universidade Estadual de Campinas, Universidade de São Paulo, Campinas, SP, Brazil Faculdade Ciências Médicas de Minas Campinas, SP, Brazil José Maria Soares Júnior Gerais, Belo Horizonte, MG, Brazil Eddie Fernando Candido Murta Universidade de São Paulo, São Paulo, SP, Brazil Rosana Maria dos Reis Universidade Federal do Triângulo Mineiro, Julio Cesar Rosa e Silva Universidade de São Paulo, Ribeirão Preto, Uberaba, MG, Brazil Universidade de São Paulo, Ribeirão Preto, SP, Brazil SP, Brazil Edward Araujo Júnior Lucia Alves da Silva Lara Rosiane Mattar Universidade Federal de São Paulo, Universidade de São Paulo, Ribeirão Preto, Universidade Federal de São Paulo, São Paulo, SP, Brazil SP, Brazil São Paulo, SP, Brazil Elaine Christine Dantas Moisés Lucia Helena Simões da Costa Paiva Rodrigo de Aquino Castro Universidade de São Paulo, Universidade Estadual de Campinas, Universidade Federal de São Paulo, Ribeirão Preto, SP, Brazil Campinas, SP, Brazil São Paulo, SP, Brazil Eliana Aguiar Petri Nahas Luiz Carlos Zeferino Silvana Maria Quintana Universidade Estadual Paulista Universidade Estadual de Campinas, Universidade de São Paulo, “Júlio de Mesquita Filho”, Botucatu, SP, Brazil Campinas, SP, Brazil Ribeirão Preto, SP, Brazil Editorial Board

Sophie Françoise Mauricette Derchain Iracema de Mattos Paranhos Calderon Newton Sergio de Carvalho Universidade Estadual de Campinas, Universidade Estadual Paulista Universidade Federal do Paraná, Campinas, SP, Brazil “Júlio de Mesquita Filho”, Botucatu, SP, Brazil Curitiba, PR, Brazil Alex Sandro Rolland de Souza João Luiz Pinto e Silva Nuno Henrique Malhoa Migueis Clode Instituto de Medicina Integral Universidade Estadual de Campinas, Faculdade de Medicina de Lisboa, Lisboa, Prof. Fernando Figueira, Recife, PE, Brazil Campinas, SP, Brazil Portugal Ana Carolina Japur de Sá Rosa e Silva João Paulo Dias de Souza Olímpio Barbosa Moraes Filho Universidade de São Paulo, Universidade de São Paulo, Universidade de Pernambuco, Recife, Ribeirão Preto, SP, Brazil Ribeirão Preto, SP, Brazil PE, Brazil Aurélio Antônio Ribeiro da Costa João Sabino Lahorgue da Cunha Filho Paulo Roberto Nassar de Carvalho Universidade de Pernambuco, Universidade Federal do Rio Grande do Sul, Instituto Fernandes Figueira-Fiocruz, Recife, PE, Brazil Porto Alegre, RS, Brazil Rio de Janeiro, RJ, Brazil Belmiro Gonçalves Pereira José Carlos Peraçoli Renato Augusto Moreira de Sá Universidade Estadual de Campinas, Universidade Estadual Paulista Universidade Federal Fluminense, Campinas, SP, Brazil “Júlio de Mesquita Filho”, Botucatu, SP, Brazil Niterói, RJ, Brazil Carlos Augusto Alencar Junior José Juvenal Linhares Rintaro Mori Universidade Federal do Ceará, Universidade Federal do Ceará, National Center for Child Health Fortaleza, CE, Brazil Campus de Sobral, Fortaleza, CE, Brazil and Development, Tokyo, Japan Carlos Grandi Joshua Vogel Roberto Eduardo Bittar Universidad de Buenos Aires, Department of Reproductive Health and Universidade de São Paulo, Buenos Aires, Argentina Research, World Health Organization, São Paulo, SP, Brazil Cesar Cabello dos Santos Geneva, Switzerland Rosane Ribeiro Figueiredo Alves Universidade Estadual de Campinas, Juvenal Soares Dias-da-Costa Universidade Federal de Goiás, Goiânia, Campinas, SP, Brazil Universidade Federal de Pelotas, GO, Brazil Délio Marques Conde Pelotas, RS, Brazil Roseli Mieko Yamamoto Nomura Universidade Federal de São Paulo, Hospital Materno Infantil de Goiânia, Laudelino Marques Lopes São Paulo, SP, Brazil Goiânia, GO, Brazil University of Western Ontario, Rossana Pulcinelli Vieira Francisco Dick Oepkes London, Ontario, Canada Universidade de São Paulo, University of Leiden, Leiden, Luciano Marcondes Machado Nardozza São Paulo, SP, Brazil The Netherlands Universidade Federal de São Paulo, Ruﬀ o de Freitas Junior Dino Roberto Soares de Lorenzi São Paulo, SP, Brazil Universidade Federal de Goiás, Universidade de Caxias do Sul, Luis Otávio Zanatta Sarian Goiânia, GO, Brazil Caxias do Sul, RS, Brazil Universidade Estadual de Campinas, Sabas Carlos Vieira Diogo de Matos Graça Ayres de Campos Campinas, SP, Brazil Universidade Federal do Piauí, Teresina, Universidade do Porto, Porto, Portugal Luiz Claudio Santos Thuler PI, Brazil Eduardo Pandolﬁ Passos Instituto Nacional do Câncer, Sebastião Freitas de Medeiros Universidade Federal do Rio Grande do Sul, Rio de Janeiro, RJ, Brazil Universidade Federal do Mato Grosso, Porto Alegre, RS, Brazil Luiz Henrique Gebrim Cuiabá, MT, Brazil Edmund Chada Baracat Universidade Federal de São Paulo, Selmo Geber Universidade de São Paulo, São Paulo, SP, Brazil Universidade Federal de Minas Gerais, São Paulo, SP, Brazil Manoel J. B. Castello Girão, Belo Horizonte, MG, Brazil Eliana Martorano Amaral Universidade Federal de São Paulo, Silvia Daher Universidade Estadual de Campinas, São Paulo, SP, Brazil Universidade Federal de São Paulo, Campinas, SP, Brazil Marcelo Zugaib São Paulo, SP, Brazil Francisco Edson Lucena Feitosa Universidade de São Paulo, Shaun Patrick Brennecke Universidade Federal do Ceará, Fortaleza, São Paulo, SP, Brazil University of Melbourne Parkville, CE, Brazil Marcos Desidério Ricci Victoria, Australia George Condous Universidade de São Paulo, Técia Maria de Oliveira Maranhão Nepean Hospital in West Sydney, Sidney, São Paulo, SP, Brazil Universidade Federal do Rio Grande do Australia Maria de Lourdes Brizot Norte, Natal, RN, Brazil Giuseppe Rizzo Universidade de São Paulo, Toshiyuki Hata Università degli Studi di Roma São Paulo, SP, Brazil University Graduate School of Medicine, “Tor Vergata”, Roma, Italy Marilza Vieira Cunha Rudge Kagawa, Japan Gutemberg Leão de Almeida Filho Universidade Estadual Paulista Wellington de Paula Martins Universidade Federal do Rio de Janeiro, “Júlio de Mesquita Filho”, Universidade de São Paulo, Rio de Janeiro, RJ, Brazil Botucatu, SP, Brazil Ribeirão Preto, SP, Brazil

Editorial Oﬃ ce

Bruno Henrique Sena Ferreira

Editorial Production

Thieme Medical Publishers ISSN 0100-7203

Federação Brasileira das Associações de Ginecologia e Obstetrícia Brazilian Federation of Gynecology and Obstetrics Associations

Society Board (2020–2024) Presidency and Executive Staﬀ

President Av. Brigadeiro Luís Antônio, 3421 - Sala 903 - Agnaldo Lopes da Silva Filho (MG) Jardim Paulista, São Paulo, SP, Brazil CEP: 01401-001 Administrative Director Phone.: (+55 11) 5573-4919 Sérgio Podgaec (SP) www.febrasgo.org.br Scientifi c Director [email protected] César Eduardo Fernandes (SP) Financial Director RBGO Editorial Offi ce Olímpio B. de Moraes Filho (PE) Professional Status Defence editorial.offi [email protected] Maria Celeste Osório Wender (RS) Vice-president of North Region Ricardo de Almeida Quintairos (PA) Vice-president of Northeast Region Carlos Augusto Pires C. Lino (BA) Vice-president of Middle West Region Marta Franco Finotti (GO) Vice-president of Southeast Region Marcelo Zugaib (SP) Vice-president of South Region Almir Antônio Urbanetz (PR) Volume 43, Number 3/2021 RBGO Gynecology and Obstetrics Revista Brasileira de Ginecologia e Obstetrícia

Editorial

155 Shortcomings in the training program of medical residency during the COVID-19 pandemic in Brazil. How will they be repaired? Marcos Felipe Silva de Sá

Original Articles

Obstetrics

158 History of Maternal Mortality in the City of Ribeirão Preto, in its Regional Health Department, and in the State of São Paulo after the Establishment of the Maternal Committees from 1998 to 2017 Aderson Tadeu Berezowski and Antonio Luiz Rodrigues Júnior

High Risk Pregnancy

165 Disease Progression and Obstetric Outcomes of Women with Multiple Sclerosis at a Reference Center in Northeastern Brazil Gabrielle Maria Carvalho de Barros, Bianca Etelvina Santos de Oliveira, Gabriela Januário Oliveira, Rômulo Kunrath Pinto Silva, Thiago Nóbrega Cardoso, and Sabina Bastos Maia

Contraception

172 Postplacental Placement of Intrauterine Devices: Acceptability, Reasons for Refusal and Proposals to Increase its Use Maria Beatriz de Paula Leite Kraft, Mariana Miadaira, Marcos Marangoni Júnior, Cássia Raquel Teatin Juliato, and Fernanda Garanhani Surita

Lower Genital Tract Diseases

178 Awareness about Vulvovaginal Aesthetics Procedures among Medical Students and Health Professionals in Saudi Arabia Shazia Iqbal, Khalid Akkour, Bushra Bano, Ghaiath Hussain, Manal Khalid Kamal Ali Elhelow, Atheer Mansour Al-Mutairi, and Balqees Sami Khaza’l Aljasim

Mastology

185 Switching of Hormone Therapies in Breast Cancer Women Luana Moreira de Medeiros, Rebeca Stahlschmidt, Amanda Canato Ferracini, Cinthia Madeira de Souza, Cassia Raquel Teatin Juliato, and Priscila Gava Mazzola

190 Comparison of Automated Breast Ultrasound and Hand-Held Breast Ultrasound in the Screening of Dense Breasts Fernanda Philadelpho, Maria Julia Gregorio Calas, Gracy de Almeida Coutinho Carneiro, Isabela Cunha Silveira, Andréia Brandão Ribeiro Vaz, Adriana Maria Coelho Nogueira, Anke Bergmann, and Flávia Paiva Proença Lobo Lopes

Thieme Revinter Publicações Ltda online www.thieme-connect.com/products RBGO Gynecology and Obstetrics Volume 43, Number 3/2021

Covid-19

200 Comparison of Laboratory and Radiological Findings of Pregnant and Non-Pregnant Women with Covid-19 Kadir Burak Ozer, Onder Sakin, Kazibe Koyuncu, Berk Cimenoglu, and Recep Demirhan

Systematic Review

207 Vertical Transmission of SARS-CoV-2: A Systematic Review Ionara Diniz Evangelista Santos Barcelos, Ivan Andrade de Araújo Penna, Adriana de Góes Soligo, Zelma Bernardes Costa, and Wellington Paula Martins

Short Communication

216 Evaluation of the Seroprevalence of Infectious Diseases in 2,445 in vitro Fertilization Cycles João Guilherme Grassi dos Anjos, Newton Sergio de Carvalho, Karam Abou Saab, Edward Araujo Júnior, and Jaime Kulak Junior

Case Reports

220 Familial Chylomicronemia Syndrome-Induced Acute Necrotizing Pancreatitis during Pregnancy Julia Cristina Coronado Arroyo, Marcio José Concepción Zavaleta, Eilhart Jorge García Villasante, Mikaela Kcomt Lam, Luis Alberto Concepción Urteaga, and Francisca Elena Zavaleta Gutiérrez

225 Ex vivo Retrieval of Mature Oocytes for Fertility Preservation in a Patient with Bilateral Borderline Ovarian Tumor Bruno Ramalho de Carvalho, Geórgia Fontes Cintra, Taise Moura Franceschi, Íris de Oliveira Cabral, Leandro Santos de Araújo Resende, Brenda Pires Gumz, and Thiago David Alves Pinto

Letters to the Editor

232 Are Endocan Plasma Levels Altered in Preeclampsia? Ana Cristina dos Santos Lopes, Suellen Rodrigues Martins, Luci Maria SantAna Dusse, Melina de Barros Pinheiro, and Patrícia Nessralla Alpoim

235 Advanced Cervical Cancer: Leveraging the Historical Threshold of Overall Survival Eduardo Paulino and Andreia Cristina de Melo

238 COVID-19 in Brazil: A Message to the World Bruno Ramalho de Carvalho

Febrasgo Statement

240 HPV infection - Screening, diagnosis and management of HPV-induced lesions Ana Katherine da Silveira Gonçalves de Oliveira, Claudia Marcia de Azevedo Jacyntho, Fernanda Kesselring Tso, Neide Aparecida Tosato Boldrini, Neila Maria de Góis Speck, Raquel Autran Coelho Peixoto, Rita Maira Zanine, Yara Lucia Mendes Furtado de Melo Complementary material is available online at www.rbgo.org.br.

Cover design: © Thieme Cover image source: © Thieme

© 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights Revista Brasileiro de Ginecologia e Obstetrícia is an official publication of the reserved. RBGO Gynecology and Obstetrics/Revista Brasileiro de Ginecologia e Federação Brasileira das Associações de Ginecologia e Obstetrícia (Brazilian Obstetrícia is published monthly by Thieme-Revinter Publicações Ltda., Rua Federation of Association of Gynecology and Obstetrics, Febrasgo), It is do Matoso, 170, Rio de Janeiro 20270-135, Brazil. listed in Isi - Web of Science, Web of Knowledge (Emerging), MEDLINE / Editorial comments should be sent to [email protected]. Articles may PubMed, Index Medicus, Scopus (Sci Verse), SCImago, SciELO (Scientific be submitted to this journal on an open-access basis. For further informa- Electronic Library Online), LILACS (Literatura Latino-Americana e do Caribe tion, please send an e-mail to [email protected]. The content of this em Ciências da Saúde, Index Medicus Latino Americano), and Portal de journal is available online at www.thieme-connect.com/products. Visit our Periódicos Capes (Coordenação de Aperfeiçoamento de Pessoal de Nível Web site at www.thieme.com and the direct link to this journal at www. Superior). Thieme Medical Publishers is a member of the CrossRef initiative. rbgo.com.br. ISSN 0100-7203

Some of the product names, patents, and registered designs referred to in this medical knowledge, neither the authors, editors, or publisher, nor any other publication are in fact registered trade marks or proprietary names even though party who has been involved in the preparation of this work, warrants that speciﬁ c reference to this fact is not always made in the text. Therefore, the the information contained here in is in every respect accurate or complete, appearance of a name without designation as proprietary is not to be construed and they are not responsible for any errors or omissions or for the results as a representation by the Publisher that it is in the public domain. obtained from use of such information. Because of rapid advances in the All rights, including the rights of publication, distribution, and sales, as well medical sciences, independent verification of diagnoses and drug dosages as the right to translation, are reserved. No part of this work covered by the should be made. Readers are encouraged to confirm the information con- copyrights hereon may be reproduced or copied in any form or by any means— tained herein with other sources. For example, readers are advised to check graphic, electronic, or mechanical, including photocopying, recording, taping, or the product information sheet included in the package of each drug they information and retrieval systems—without written permission of the Publisher. plan to administer to be certain that the information contained in this publi- Important Note: Medical knowledge is ever-changing. As new research cation is accurate and that changes have not been made in the recommended and clinical experience broaden our knowledge, changes in treatment and dose or in the contraindications for administration. This recommendation is drug therapy may be required. The authors and editors of the material here- of particular importance in connection with new or infrequently used drugs. in have consulted sources believed to be reliable in their efforts to provide Although all advertising material is expected to conform to ethical information that is complete and in accord with the standards accepted at (medical) standards, inclusion in this journal does not constitute a guar- the time of publication. However, in view of the possibility of human er- antee or endorsement of the quality or value of such product or of claims ror by the authors, editors, or publisher of the work herein, or changes in made by its manufacturer. THIEME Editorial 155

Editorial Shortcomings in the training program of medical residency during the COVID-19 pandemic in Brazil. How will they be repaired? Marcos Felipe Silva de Sá1

1 Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil

Rev Bras Ginecol Obstet 2021;43(3):155–157.

Medical Residency Programs (MRPs) have been presented as Video classes and applications that allow interactivity the dominant model for postgraduate medical training world- through messages or oral communication were suggested. wide. They are considered the gold standard by the medical Regarding the maintenance or suspension of the activities of community and give different status to doctors who hold these the medical resident, each MRP should analyze it in a titles. The success of this model resides in the link established particular way, justifying the decision to the local Medical between theoretical learning and the practice experienced in Residency Commission (Portuguese acronym: Coreme). health services, which has made this pattern of specialization After the resumption of normality, the replacement of an almost mandatory target for the vast majority of medical MRP activities not developed during the pandemic would students, not only for their specialization, but also as a way of be the object of analysis and subsequent decision by the correcting eventual deficiencies in undergraduate training. National Medical Residency Commission. 1 Thus, professional competence in the practice of medicine Guidelines were generic and many decisions were delegated has become synonymous with specialization that can only be to program coordinators themselves, as long as the workload obtained in well-structured programs with a balanced foreseen for residents was respected. However, the pandemic planning between theoretical and practical activities taught felllike anavalancheoverhospital institutionsand therewas no by qualified professionals dedicated to these activities. uniformity of actions to meet the National Medical Residency The COVID-19 pandemic has caused major losses for MRPs. Commission guidelines. Most services were unprepared for In order to adapt to the negative impacts of the pandemic, distance learning activities, and the lack of adequate infrastruc- MRPs were compulsorily led to a significant reorganization in ture for the transmission of video classes, teleconferences and their schedules. These changes included reductions or cancel- patient care (telemedicine) was an important factor for non- lations of activities in the operating room and outpatient compliance with some of these recommendations. clinics, visits to wards, simulation sessions, among others. In Several times, this deficiency was solved in an improvised addition, hospitals have undergone adaptations in their care waywithmanydifficulties. Despite these facts, there was routines that directly impacted the training of residents in progress in many services that considerably improved the both clinical and surgical areas, since a large part of the teaching system, installed new equipment and invested in program activities were transferred to the care of COVID-19 the training of teachers/preceptors and coordinators. They also patients. adapted to patient care with the use of telemedicine, reserving On May 8th 2020, the National Medical Residency Com- face-to-face appointments to cases considered essential due to mission (Portuguese acronym: CNRM), linked to the Ministry the severity of the morbidity and/or clinical conditions. 2 of Education, responsible for the evaluation and accredita- Appointments were not scheduled for patients with low- tion of MRPs throughout Brazil, released a draft Technical severity morbidities or they were seen via telemedicine Note of recommendations to MRPs for the development of consultations. activities during the pandemic. According to the document, However, as a resultof the worsening of the pandemic across each MRP should make its pedagogical project more flexible the country, hospitals and outpatient services faced an alarm- in order to adapt to the current health reality. Face-to-face ing increase in COVID-19 cases. Frequently clinical directors of classes should be suspended and theoretical activities should hospitals demanded from their local Medical Residency Com- be developed on technology-mediated virtual platforms. mission that doctors attending their programs were allocated

Address for correspondence DOI https://doi.org/ © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights Marcos Felipe Silva de Sá, PhD, Av. 10.1055/s-0041-1728694. reserved. Bandeirantes, 3.900, Vila Monte ISSN 0100-7203. This is an open access article published by Thieme under the terms of the Alegre, 14049-900, Ribeirão Creative Commons Attribution License, permitting unrestricted use, Preto, SP, Brazil distribution, and reproduction so long as the original work is properly cited. (e-mail: [email protected]). (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda., Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil 156 Shortcomings in the training program of medical residency during the COVID-19 pandemic in Brazil Silva de Sá

to supply the human resources shortage to face the pandemic. training? Will they be properly prepared for the exercise of In addition, in order to protect health professionals, part of the specialties? Will they be entitled to the specialist title hospital team that presented risk factors was removed from awarded at the end of the Medical Residency Program? face-to-face activities, generating an important shortage in Apparently, there are no answers to these questions and, the teaching and support teams for residents. Therefore, the although so many doubts and uncertainties exist about the adaptation process of hospitals to the new situation became future of these residents, the topic has not been debated in quite complicated, which reflected negatively in MRPs and depth, as it should. made it impossible to comply with the specific programming What are the perspectives for residents to complement for each area. their specialized training today? There is also no answer to Considering that surgery is a high-risk situation for the this question neither prospects for a solution to this dramatic transmission of respiratory infections and following global situation formed around a generation that had the misfor- guidance, both the National Health Agency (ANS) and the tune to attend the Medical Residency Program in the period National Health Surveillance Agency (Anvisa) advised the of the worst pandemic that has plagued humanity in the last postponement of elective and non-essential surgeries, having 100 years. a considerable impact on the number of surgical procedures. In view of the current situation of the pandemic in Brazil, Hundreds of thousands of surgeries were postponed or the horizon for the training of current residents is abso- canceled as a result of this pandemic, causing delay in the lutely bleak in most specialties. The correction of the route diagnosis and treatment of thousands of surgical/oncological will be difficult to execute for economic reasons and the cases in this period. 3-6 impossibility to postpone the entry of new residents this Despite the negative impact on the training of residents, by year, a decision that was taken prematurely already in the mid-2020, a reduction in the course of the pandemic was middle of 2020. expected, with progressive return of clinical and surgical But, what about 2022? It is time to start preparing for next activities to normal in the second half of that year. In year and find a way to minimize all the damage done to the July 2020, the National Medical Residency Commission made training of residents who attended 2020 and 2021 programs. a consultation through a specific questionnaire applied to more Who should lead this debate? Undoubtedly, the National than 10,000 medical residents from all Brazilian states and Medical Residency Commission, as the controller and regions. For 73.9% of respondents, it would be possible to regain responsible for the accreditation of programs, should initiate skills during the period planned for the residency. A similar this debate. It must involve representatives of Universities result was found in the perception of 278 consultants from Hospitals which account for the vast majority of programs, Medical Residency Commissions. Thus, based on results of the the Brazilian Medical Association (Portuguese acronym: survey, the National Medical Residency Commission decided to AMB) which is official institutions that regulate the activities maintain the regular start and end dates of Medical Residency of specialty societies and the Federal Council of Medicine Programs for the year 2021, as well as dates foreseen for the (Portuguese acronym: CFM), that regulate the activities selection processes. Exceptional cases related to Medical related to the professional practice of medicine. These last Residency Programs should be evaluated by the respective two entities already have a permanent seat on the National supervisors and if an extension of residents’ training was Medical Residency Commission. necessary, the justification should beforwarded to the National A study group formed by these four instances on an Medical Residency Commission plenary for analysis after egalitarian basis would be ideal. This is the most opportune approval by the local Medical Residency Commission and the time for any deliberations on the part of the CNRM since we respective State Medical Residency Commission - Cerem) and are still in the first quarter of the year 2021 and there would the guarantee of the scholarship payment by the program itself. be time for rearrangements in the calendar, particularly with Furthermore, even in this condition, the dates of selection regard to the termination of the current programs, as well as processes for the entry of new residents in 2021 would be for the entry of new ones classes in 2022. maintained. 7 The idea with this resolution was the possibility Obviously, this is a difficult task that no one country in the of recovering the competence training during the remaining world has ever experienced it. Therefore, the exchange of period planned for the residency. In fact, the programs officially information between similar institutions from different ended on March 1st, 2021 and new classes were admitted to countries may be crucial to generate a solution to this start on that same date. 8 impasse. Probably many of these countries are presently As much as services have endeavored to mitigate the discussing and preparing measures to mitigate this problem negative impact of the pandemic on Medical Residency in the coming months or years and they could share all the Programs, practical activities have been far from the quali- knowledge learned during the pandemic. tatively and quantitatively ideal. Given this situation, many If none of this happens in Brazil, it may signs that this doubts remain about the final outcome of the training of country does not seem to be caring about the quality of the these residents. medical professionals placed in the job market to develop What can be done to recover the training losses of such a noble and relevant mission and whose performance residents enrolled in Medical Residency Programs during should have a direct impact on the preservation of health the pandemic? Are they going to be put on the job market and treatment of diseases. In other words, on people’sown after finishing a Medical Residency Program with incomplete lives.

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. Shortcomings in the training program of medical residency during the COVID-19 pandemic in Brazil Silva de Sá 157

References Ginecol Obstet. 2020;42(07):411–414. Doi: 10.1055/s-0040- 1 Ministério da Educação. Secretaria de Educação Superior. Comissão 1715147 Nacional de Residência Médica. Nota Técnica No. 1/2020/ 6 Rosa-e-Silva JC, Ribeiro PA, Brito LGO, Gomes MTV, Podgaec S, CNRM/CGRS/DDES/SESU/SESU. Recomendações quanto ao desenvol- Ribeiro HSAA, et al. Gynecological surgery and COVID-19: what is vimento das atividades dos Programas de Residência Médica (PRMs) the impact and how should I manage it? Rev Bras Ginecol Obstet. durante enfrentamento a pandemia por COVID-19. 2020 [Internet] 2020;42(07):415–419. Doi: 10.1055/s-0040-1715146 2020 [cited 2021 Mar 14]. Available from: http://portal.mec.gov.br/ 7 Ministério da Educação. Secretaria de Educação Superior. Diretoria de index.php?option=com_docman&view=download&alias=145481- Desenvolvimento de Educação em Saúde. Comissão Nacional de sei-23000&category_slug=2020&Itemid=30192 Residência Médica. Ata da 7ª Sessão Ordinária da Comissão Nacional 2 Sun SY, Guazzelli CAF, Santos JFK, Novoa DG, Mattar R. Telemedi- de Residência Médica realizada nos dias 23 e 24 de julho de 2020 cine in obstetrics: new era, new attitudes. Rev Bras Ginecol [Internet]. 2020 [cited 2021 Mar 14]. Available from: http://portal. Obstet. 2020;42(07):371–372. Doi: 10.1055/s-0040-1715145 mec.gov.br/index.php?option=com_docman&view=download&alias 3 Brindle ME, Gawande A. Managing COVID-19 in surgical systems. Ann =154291-ata-7reuniao-ordinaria-1&category_slug=2020&Itemid= Surg. 2020;272(01):e1–e2. Doi: 10.1097/SLA.0000000000003923 30192 4 Carvalho BR, Rosa-e-Silva ACJS, Ferriani RA, Reis RM, Silva de Sá 8 Ministério da Educação. Secretaria de Educação Superior. Diretoria MF. COVID-19 and assisted reproduction: a point of view on the de Desenvolvimento de Educação em Saúde. Comissão Nacional de Brazilian scenario. Rev Bras Ginecol Obstet. 2020;42(06): Residência Médica. Ata da 1ª Sessão Ordinária da Comissão Nacional 305–309. Doi: 10.1055/s-0040-1713795 de Residência Médica dos dias 21 e 22 de janeiro de 2021 [Internet]. 5 Romão GS, Schreiner L, Laranjeiras CLS, Di Bella ZIKJ, Coelho RA, 2021 [cited 2021 Mar 14]. Available from: http://portal.mec.gov.br/ Simões MCR, et al. Medical residency in gynecology and obstetrics index.php?option=com_docman&view=download&alias=170731- in times of COVID-19: recommendations of the National Special- ata-janeiro-2021&category_slug=2020&Itemid=30192 ized Comission on Medical Residency of Febrasgo. Rev Bras

History of Maternal Mortality in the City of Ribeirão Preto, in its Regional Health Department, and in the State of São Paulo after the Establishment of the Maternal Committees from 1998 to 2017 Recorte histórico da mortalidade materna no município de Ribeirão Preto, no seu Departamento Regional de Saúde,enoestadodeSãoPauloapósainstituiçãodos comitês de mortalidade materna de 1998 a 2017

Aderson Tadeu Berezowski1 Antonio Luiz Rodrigues Júnior1

1 Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Address for correspondence Antonio Luiz Rodrigues-Júnior, PhD, Ribeirão Preto, SP, Brazil Av. Bandeirantes 3.900, Ribeirão Preto, SP, 14049-900, Brazil (e-mail: [email protected]). Rev Bras Ginecol Obstet 2021;43(3):158–164.

Abstract Objective To describe the evolution of maternal mortality right after the establishment of maternal death committees in the region of the city of Ribeirão Preto, state of São Paulo, Brazil. Methods The present study describes the spatial and temporal distribution of maternal mortality frequencies and rates, using data from the state of São Paulo, the municipality of Ribeirão Preto, and its Regional Health Department (DRS-XIII) from 1998 to 2017. The present ecological study considered the maternal mortality and live birth frequencies made available by the Computer Science Department of the Brazilian Uniﬁed Health System (Departamento de Informática do Sistema Único de Saúde, DATASUS, in the Portuguese acronym)/Ministry of Health, which were grouped by year and political-administrative division (the state of São Paulo, the DRS-XIII, and the city of Ribeirão Preto). The maternal mortality rate (MMR) was calculated and presented through descriptive measures, graphs, and cartograms. Results The overall MMR observed for the city of Ribeirão Preto was of 39.1; for the DRS-XIII, it was of of 40.4; and for the state of São Paulo, it was of 43.8 for every 100 thousand live birhts. During this period, the MMR for the city of Ribeirão Preto ranged Keywords from 0% to 80% of the total maternal mortalities, and from 40.7% to 47.2% of live births ► maternal mortality in the DRS-XIII. The city of Ribeirao Preto had an MMR of 76.5 in 1998and 1999, which ► health regionalization decreased progressively to 12.1 until the years of 2012 and 2013, and increased to 54.3 ► mother and child for every 100 thousand live births over the past 4 years. The state of São Paulo State had healthcare an MMR of 54.0 in 1998–1999, which varied throughout the study period, with values

received DOI https://doi.org/ © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights June 5, 2020 10.1055/s-0040-1719143. reserved. accepted ISSN 0100-7203. This is an open access article published by Thieme under the terms of the September 15, 2020 Creative Commons Attribution License, permitting unrestricted use, published online distribution, and reproduction so long as the original work is properly cited. January 28, 2021 (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda., Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil Maternal Mortality in the City of Ribeirão Preto Berezowski, Rodrigues-Júnior 159

of 48.0 in 2008–2009, and 54.1 for every 100 thousand live births in 2016–2017. Several times before 2015, the city of Ribeirão Preto and the DRS-XIII reached the Millennium Goals. Recently, however, the MMR increased, which can be explained by the improvement in the surveillance of maternal mortality. Conclusion The present study describes a sharp decline in maternal death in the region of Ribeirão Preto by the end of 2012–2013, and a subsequent and distressing increase in recent years that needs to be fully faced.

Resumo Objetivo Descrever a evolução da mortalidade materna após a instituição dos comitês de morte materna na região de Ribeirão Preto. Métodos Este estudo descreveu a distribuição espacial e temporal das frequências e da razão de mortalidade materna, utilizando dados do estado de São Paulo, do Departamento Regional de Saúde de Ribeirão Preto (DRS-XIII), e do município de Ribeirão Preto, no período de 1998 a 2017. O estudo ecológico considerou frequências de mortes maternas e de nascidos vivos disponibilizadas pelo Departamento de Informática do Sistema Único de Saúde (DATASUS)/Ministério da Saúde, que foram agrupadas por ano e pela referida divisão político-administrativa. A taxa de mortalidade materna (TMM) foi calculada e apresentada por medidas descritivas, gráficos e cartogramas. Resultados O total observado para o município de Ribeirão Preto foi uma TMM de 39,1; para o DRS-XIII, TMM de 40,4; e, para o estado de São Paulo, uma TMM de 43,8 por 100 mil habitantes. No período do estudo, a RMM do município de Ribeirão Preto variou de 0% até 80,0% do total de mortes maternas, e de 40,7% a 47,2% dos nascidos vivosnoDRS-XIII.OmunicípiodeRibeirãoPretoapresentouTMMde76,5nobiênio 1998–1999, que progressivamente diminuiu para 12,1 em 2012–2013, e aumentou para 54,3 por 100 mil habitantes nos últimos 4 anos. O estado de São Paulo apresentou TMM de 54,0 em 1998–1999, tendo variado ao longo do período com valores de 48,0 no período 2008–2009, e 54,1 no período 2016–2017. Várias vezes antes de 2015, o Palavras-chave município de Ribeirão Preto e o DRS-XIII atingiram as Metas do milênio. Recentemente, ► morte materna porém, a TMM aumentou, o que pode ser explicado pela melhoria da vigilância da ► regionalização da mortalidade materna. saúde Conclusão Oestudodescreveuumacentuadodeclíniodamortematernanaregião ► atenção materno- de Ribeirão Preto até o finaldobiênio2012–2013, e um subsequente e aflitivo infantil aumento em anos recentes, que precisa ser enfrentado.

Introduction created in 1987, was a precursor of the Maternal Mortality Committees, established in 1988 with the creation of the Maternal mortality is an important public health problem that Botucatu, Campinas, Marília, Ribeirão Preto, and São Paulo must be addressed with effective and permanent measures, committees. Initially, the committees were located in the and its determinants are directly associated with the organi- medical schools of those regions, and, based on their initial zation of the healthcare service and the increased value of experience, the program was later disseminated throughout – women in society.1 Maternal mortality has long been the Brazil.3 5 A progressive structuring of committees throughout subject of international discussions and of the Brazilian health the country then occurred, institutionalizing the program at reform in the mid-1980s, highlighting the efforts of Anibal the national, state, regional, municipal and local levels.6 Faúndes, a Chilean working in Brazil who helped create the In 1997, the report of maternal mortalities became com- Comprehensive Women’s Health Care Program (Programa de pulsory, and groups were established to study the subject in Assistência Integral à Saúde da Mulher, PAISM, in the Portu- depth, identify causality, understand avoidability, and guide guese acronym). The program broke the traditional view that the regional structuring of comprehensive healthcare for women’s care should be centered on reproductive issues, women, especially maternal healthcare, aimed at tackling which contributed to the creation of the Maternal Mortality the problem and ﬁnding solutions.7 The objective was to Committees.2 The Maternal Mortality Prevention Program of support specialized groups to discuss on a case-by-case basis the Department of Health of the State of São Paulo, which was women’s deaths due to pregnancy and the pregnancy-

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. 160 Maternal Mortality in the City of Ribeirão Preto Berezowski, Rodrigues-Júnior

puerperal cycle, and provide managers with the information the state of São Paulo. Throughout the period, Ribeirão Preto needed for decision-making toward a reduction in maternal represented 1.1% of the total maternal mortalities and 1.3% of mortality. In the Ribeirão Preto region, where one of the first the total live births in the state of São Paulo; the DRS-XIII committees was created and where the headquarters of the represented 2.6% and 2.9% of that total respectively. Ribeirão Regional Health Department (DRS-XIII) are located, maternal Preto had an MMR of 39.1, the DRS-XIII, of 40.4, and the state mortality is a serious public health issue, similar to the of São Paulo State, of 43.8 for every 100 thousand live births. situation in the rest of the country. Among the data reported for the DRS-XIII, in the period, The present study aimed to produce a spatial and tempo- 43.1% of maternal mortalities and 44.5% of live births oc- ral distribution of maternal mortality, describing the epide- curred in Ribeirão Preto; the percentage of maternal mortal- miological phenomena by considering as ecologic unities the ity for this municipality ranged from 0% to 80.0%, and the state of São Paulo, the DRS-XIII, and the city of Ribeirão Preto, percentage of live births, from 40.7% to 47.2%. and using official data from 1998 to 2017. The ►Fig. 1 shows the number of cases of maternal mortality recorded by year in Ribeirão Preto and the other Methods municipalities of the DRS-XIII. As one can see in the figure, Ribeirão Preto registers an expressive fraction of maternal The present is an ecological study on maternal mortality mortality when compared with the other 25 municipalities from 1998 and 2017, which used public and official data of the DRS-XIII, which influenced similarities between the provided by the Computer Science Department of the Brazil- epidemiological patterns of Ribeirão Preto and the DRS-XIII. ain Unified Health System (Departamento de Informática do The ►Fig. 2 shows biennial time series of MMRs which Sistema Único de Saúde, DATASUS, in the Portuguese acro- allowed a more clear observation than that of yearly rates, nym)/Ministry of Health. Maternal mortality and live birth because of the aforementioned variation control. An expres- frequencies were grouped by year (time) and by the political sive drop in MMRs was observed from 1998 on in Ribeirão division of state of São Paulo’s Administrative Office into Preto and in the DRS-XII. In 1998, Ribeirão Preto had an MMR Regional Departments of Health (spatial). Maternal mortali- of 76.5 for every 100 thousand live births, and this rate ty and live birth frequencies were collected and organized by started to drop until 2012–2013, when the MMR was of 12.1, year from 1998 to 2017; the ecological unities were defined but unfortunately it begun to increase, reaching 54.2 over the as the state of São Paulo (645 municipalities), the DRS-XIII, past 4 years. The state of São Paulo did not show an expres- and the city of Ribeirão Preto. The data were collected in sive decrease in the maternal mortality: in 1998, the MMR September 2019. The maternal frequencies were rearranged was of 54.0; it increased and decreased until reaching 48.0 in by biennium because the yearly frequencies were too small, 2008–2009; and it rose again to 54.1 in 2016–2017. and data variation was great. The maternal mortality rates The ►Fig. 3 shows the spatial distribution of frequencies (MMRs) were obtained by taking the counts of deaths of of maternal mortality using empirical cut points to create pregnant women plus the counts of deaths of women that captions, because the quantile classification led to very happened up to the 42nd day after delivery by causes related confusing divisions. The current division enables the obser- to pregnancy or not, with the exception of accidental deaths; vation of municipalities without maternal mortality in the theses sums were divided by the total live births according to period, and the outlier influence of maternal counts from temporal and spatial strata, and their results were expressed Ribeirão Preto. This illustration shows those municipalities for every 100 thousand live births.8,9 that did not report maternal mortalities in the period, like Tables, charts, and cartograms were used to produce spatial Altinópolis (ALTPL), Santo Antonio da Alegria (SAALG), Cássia and temporal information using the R software (R Foundation dos Coqueiros (CCOQR), Dumont (DUMNT), Guatapará for Statistical Computing, Vienna, Austria). Data from 2018 on (GTPRA), and Santa Cruz da Esperança (SCESP); in addition, were not included due to the delay in data verification and the municipalities who registered few maternal deaths were formalization by the DATASUS. The cartograms helped in the Barrinha (BARR), Pradópolis (PRADP), Luis Antonio (LSANT), geographical interpretation of different municipalities in the São Simão (SSIMA), Santa Rosa de Viterbo (SRVIT), Cravinhos DRS-XII, by considering the existence of any structure related (CRVNH), Serra Azul (SAZUL), Serrana (SERRN), Brodowski to mother and child healthcare in each municipality of the (DBWSK), and Jardinópolis (JRDNP). DRS-XIII, according to the Brazilian National Registry of The ►Fig. 4 shows the frequencies of live births in the 26 Healthcare Establishments (Cadastro Nacional de Estabeleci- municipalities of the DRS-XIII that were divided by quintile mentos de Saúde, CNES, in the Portuguese acronym). class; in this case, the caption division did not produce mis- The present study used public secondary data and was interpretations on risk. By overlaying the existence of mother conducted according to the ethics criteria establish by Reso- and children healthcare services registered by the CNES, the lution No. 510/16, Article 1, sole paragraph, items II, III, IV, illustration highlights those places with expressive maternal and V of the Brazilian National Health Council. deaths where there was no proper assistance for pregnant women. The illustration also shows that several municipalities Results are far from Ribeirão Preto, and sometimes are located near the border of the DRS-XIII. Among all municipalities of the DRS- The ►Table 1 presents the annual maternal mortality from XIII, sixteen did not offer specialized mother and child health- 1998 to 2017 for the city of Ribeirão Preto, the DRS-XIII, and care services. The figure also shows that the municipalities

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. Maternal Mortality in the City of Ribeirão Preto Berezowski, Rodrigues-Júnior 161

Table 1 Temporal and spatial frequency distribution of maternal mortality and live births from 1998 to 2017 in the city of Ribeirão Preto, the Regional Department of Health (DRS-XIII), and the state of São Paulo

Year Ribeirão Preto DRS-XIII State of São Paulo Maternal mortality Live births Maternal mortality Live births Maternal mortality Live births 1998 6 7,660 10 18,802 386 693,413 1999 6 8,033 12 19,089 374 714,428 2000 3 7,880 4 18,836 275 687,779 2001 5 7,407 16 17,312 257 632,483 2002 5 7,646 9 17,096 248 623,302 2003 0 7,462 6 17,494 208 610,555 2004 1 7,600 6 17,763 214 618,080 2005 4 7,691 7 17,926 219 618,880 2006 1 7,395 4 16,743 246 603,368 2007 3 7,297 7 15,965 252 595,408 2008 4 7,668 8 16,966 246 601,795 2009 2 7,870 8 17,241 339 598,473 2010 2 8,141 3 17,971 271 601,352 2011 4 8,353 5 18,225 249 610,222 2012 0 8,272 3 17,840 227 616,608 2013 2 8,210 3 17,925 240 610,896 2014 2 8,628 4 18,669 263 625,687 2015 3 8,834 12 18,939 311 634,026 2016 5 8,271 9 17,539 308 601,437 2017 4 8,322 8 17,858 348 611,803 Total 62 158,640 144 356,199 5,481 12,509,995 with the largest number of live births are located in the north reduction of 4.3 unities per year.12 In 2015, the MMR in Brazil of the DRS-XIII, and the municipalities located in the south and was of 62.0.13 By using the data of the present study, the state east of the DRS-XIII have lower live birth rates; among these, of São Paulo State had an MMR of 49.1, which is in line with only Cajuru (CJURU) and Santa Rita do Passa Quatro (STRP4) the study by Morse et al;11 the DRS-XIII had an MMR of 63.4; offered specialized mother and child healthcares. Both ﬁgures and Ribeirão Preto, an MMR of 34.0. According to the data in are complementary, as the indicator is calculated by the ►Table 1, Ribeirão Preto reached the MDG for the MMR in number of maternal mortalities and the total live births. The 2004 (13.2), in 2006 (13.5), in 2009 (25.4), in 2010 (24.6), in cartogram of maternal mortality shows the municipalities 2012 (0.0), in 2013 (24.4), in 2014 (23.2), and in 2015 (34.0). where pregnant women get exposed to the determining The DRS-XIII reached the MDG for the MMR in 2000 (21.2), in environmental factors, where they develop their lifestyles, 2003 (34.3), in 2004 (33.8), in 2006 (23.9), in 2010 (16.7), in and where they access mother and child healthcare services, 2011 (27.4), in 2012 (16.8), in 2013 (16.7), and in 2014 (21.4). when they exist. Finally, the state of São Paulo reached the MDG for the MMR in 2003 (34.1), in 2004 (34.6), and in 2005 (35.4). Discussion Thinking about the range of frequencies throughout the study period (►Fig. 1), the prevention for maternal mortality The United Nations (UN) sponsored the Millennium Summit would not get the effectiveness and it would argue politics out in 2000, which was attended by 191 correspondents of the about pregnancy protection programs and actions. The esti- member states, and the signatory countries agreed to eight mates should be taken by facing the precision of binary goals to be achieved until 2015, aiming the 21st century variables (poisson, binomial or logistic) for rare events into human development; they became known as Millennium small populations (overdispersion) while the epidemiological Development Goals (MDGs).10 The ﬁfth MDG involves the analysis is to be performed. If maternal deaths in Ribeirão Preto reduction of maternal mortality by 75.0%, based on 1990 were observed as absolute counts (poisson random variable), indicators.11 Brazil presented 143 maternal mortalities per in the years 2003 and 2012, this ecologic unity showed none, 100 thousand live births in 1990; by considering the known while in the corresponding years right before they were high, underreporting at that time and the need for adjusted and this instability arose the burden of random effect along the estimates, the MDG stated that the achievement of an period of study; if such variable was to be observed as MMR of 35.8 in 2015 would demand an annual hypothetical proportion in regard total counts into DRS-XIII (binomial or

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. 162 Maternal Mortality in the City of Ribeirão Preto Berezowski, Rodrigues-Júnior

Fig. 1 Stacked bar chart showing the yearly frequency of maternal mortalityies according to the place of residence: the city of Ribeirão Fig. 3 Spatial distribution of maternal mortality frequencies among Preto and the other municipalities of the Regional Department of the municipalities of the DRS-XIII from 1998 to 2017 by empirical Health (DRS-XIII). classiﬁcation legend.

logistic random variable), the overdispersion would also be in the technical standardization of protocol detection arose presented as well as source of confounding because statistical the likelihood of maternal mortality reality. These conjec- estimation property. tures would be applicable alone or combined. After 1998, the MMR in Ribeirão Preto decreased until its The ►Fig. 3 shows 6 municipalities with no maternal lowest estimate in 2012–2013 (12.1), and then it increased mortality reports, a low rate of live births, and no mother and again. By coincidence, the decrease in the MMR occurred child healthcare services. The absence of specialized health- before the implementation of the Regional Maternal Mortal- care may be explained by economic reasons, as the costs of ity Committee, so there is no association between them. As a maintaining it are high, while the demand for it is low. The matter of fact, the MMR had been decreasing over the ►Fig. 4 shows that the municipalities located to the south previous decades through the control of the environmental and east of the DRS-XIII had the lowest absolute birth rates conditions on broad public health programs and actions, and did not have mother and child specialized care, except specially in primary care, despite the fact that the imple- for two municipalities (Cajuru and Santa Rita do Passa mentation of the Maternal Mortality Committee meant an Quatro). Thus, these municipalities are more vulnerable to important strategy to boost that decrease. The ►Fig. 2 also maternal mortality and, because of their small populations, shows a conservative trend in the epidemiologic curve for the difficulties to establish and maintain specialized mother the state of São Paulo for the past 20 years. There was no and child healthcare services are great. The alternative for significant decrease, but a stable fluctuation, as the MMRs at those municipalities, therefore, is the improvement of pri- the beginning and at the end of the period were similar. mary healthcare by focusing on assistance, communication, Nevertheless, recent increases in MMRs were observed, and transportation systems, as a result of intermunicipality and they can be explained by two conjectures: 1) the planning and acts for sharing healthcare resources. organization of mother and child healthcare is a very mean- By the times of economic crisis, it must concern the costs ingful environmental determinant, and 2) the improvement to maintain maternity ward because scarce resources in municipalities, and Regional Intermanager Commission (RIC: “Comissão Intergestora Regional” in Portuguese), public or public-private partnerships, or even by management contracts with private institutions on a complementary basis, may contribute to the mother and child healthcare. If the establishment and maintenance of mother and child healthcare institutions is unfeasible due to economic reasons, emergency transportation and communication systems by telemedicine should be prioritized, so that women at high risk will be rapidly identified, and the regional assistance can react promptly. The professional training must be prevention-based and the Maternal Mortality Com- mittee should contribute to the treatment protocols and specific clinical guidelines for the risk of maternal mortality. Maternal mortality surveillance is the set of actions that Fig. 2 Biennial distribution of maternal mortalities rates (100 fi thousand live births) for Ribeirão Preto, the DRS-XIII, and the state of enables the identi cation, detection, and prevention of the São Paulo. outcome. However, the Maternal Mortality Committee

Fig. 4 Spatial distribution of live births for each municipality of the DRS-XIII from 1998 to 2017, overlaid by places where there were mother and child healthcare services registered at the CNES. responsibility is not mandatory, but assessorial, including identification. As an important environmental determinant, the case investigation, the establishment of critical learning, mother and child healthcare services play a crucial role in the determination of avoidability, the assessment of quality the control of maternal mortality. indicators, the strategy for the identification and the implementation, as well as the contribution to the sensitization of Contributors managers.14 All authors contributed to the concept and design of the The Maternal Mortality Committees are supported by study; analysis and interpretation of data; draft or revi- government institutions and the civil society, and have sion of the manuscript; and they have approved the educational, non-coercive, and non-punitive attributions, manuscript as submitted. All authors are responsible for keeping the confidentiality of issues discussed internally. the reported research. In addition, while its membership is legally constituted, the RIC representatives should be concerned, as they play exec- Conflict of Interests utive contracts and they may contribute for these issues The authors have no conflicts of interests to declare. involving mother and child healthcare.

References Conclusion 1 Berezowski AT, Silva JCNCE, Megid MC, Rudge MVC. Mortalidade materna: índices da região de Botucatu. In: Faúndes A, Cecatti JG. The present study provided a historical overview of mater- Morte materna: uma tragédia evitável. Campinas: Editora da nal mortality in the state of São Paulo, the DRS-XIII, and the Unicamp; 1991:151–169 city of Ribeirão Preto after the implementation of the 2 Ramos L. O homem que aprendeu a enxergar as mulheres. Pesqui Maternal Mortality Committees in 1998. The positive im- FAPESP. 2016;245:22–29 pact on the ﬁght against maternal mortality on the part of 3 Rodrigues AV, de Siqueira AASão Paulo State Committee. Uma Ribeirão Preto and the DRS-XIII can be clearly observed, análise da implementação dos comitês de estudos de morte materna no Brasil: um estudo de caso do Comitê do Estado de since, throughout the study period, they presented low São Paulo. Cad Saude Publica. 2003;19(01):183–189. Doi: MMRs and achieved the MDGs several times. However, in 10.1590/S0102-311X2003000100020 recent years, an increase in MMRs has been observed, 4 Faúndes A, Cecatti JG. Morte materna: uma tragédia evitável. which would be explained by an improvement in case Campinas: Editora da Unicamp; 1991

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. 164 Maternal Mortality in the City of Ribeirão Preto Berezowski, Rodrigues-Júnior

5 Troncon JK, de Quadros Netto DL, Rehder PM, Cecatti JG, Surita FG. 9 Rothman KJ, Greenland S, Lash TL. Modern epidemiology. 3rd ed. [Maternal mortality in a reference center in the Brazilian South- Philadelphia: Lippincott Williams & Wilkins; 2008 east]. Rev Bras Ginecol Obstet. 2013;35(09):388–393. Doi: 10 United Nations. Department of Economic and Social Affairs. The 10.1590/S0100-72032013000900002 millennium development goals - report 2010 New York: UN; 2010 6 Rodrigues AV. Comitê de mortalidade materna do Estado de São 11 Morse ML, Fonseca SC, Barbosa MD, Calil MB, Eyer FPC. Mortal- Paulo: trajetórias e vicissitudes [dissertação]. Universidade de São idade materna no Brasil: o que mostra a produção científica nos Paulo; 2000 últimos 30 anos? Cad Saude Publica. 2011;27(04):623–638. Doi: 7 Ministério da Saúde Conselho Nacional de Saúde. Resolução no. 10.1590/S0102-311X2011000400002 256, de 01 de outubro de 1997 [Internet]. Que defina o Óbito 12 Ministério da Saúde. Secretaria de Vigilância em Saúde. Mortal- Materno nos Estados e Municípios, como evento de Notificação idade materna no Brasil. Bol Epidemiol. 2012;43(01):1–7 Compulsória para a Vigilância Epidemiológica 1997 [cited 2020 13 Mendes JDV. Mortalidade materna no Estado de São Paulo - Jan 12]. Available from: http://bvsms.saude.gov.br/bvs/saudele- atualização até 2015. BEPA. 2018;15(173):3–9 gis/cns/1997/res0256_01_10_1997.html 14 Ministério da Saúde Secretaria de Vigilância em Saúde Departa- 8 Rouquayrol MZ, Almeida Filho N. Epidemiologia e saúde. 5a ed. mento de Análise de Situação em Saúde. Guia de vigilância do Rio de Janeiro: MEDSI; 1999 óbito materno. Brasília (DF): Ministério da Saúde; 2009

Disease Progression and Obstetric Outcomes of Women with Multiple Sclerosis at a Reference Center in Northeastern Brazil Progressão da doença e desfechos obstétricos em mulheres portadoras de esclerose múltipla em um centro de referência no Nordeste brasileiro

Gabrielle Maria Carvalho de Barros1 Bianca Etelvina Santos de Oliveira2 Gabriela Januário Oliveira1 Rômulo Kunrath Pinto Silva1 Thiago Nóbrega Cardoso3 Sabina Bastos Maia1

1 Department of Obstetrics and Gynecology, Centro de Ciências Address for correspondence Sabina Bastos Maia, PhD, Departamento Médicas, Universidade Federal da Paraíba, João Pessoa, PB, Brazil de Obstetrícia e Ginecologia, Centro de Ciências Médicas, 2 Centro de Referência em Esclerose Múltipla da Paraíba, Fundação Universidade Federal da Paraíba, Jardim Universitário s/n, Campus I, Centro Integrado de Apoio ao Portador de Deﬁciência, João Pessoa, João Pessoa, PB, Brazil (e-mail: [email protected]). PB, Brazil 3 Departamento de Obstetrícia e Ginecologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil

Rev Bras Ginecol Obstet 2021;43(3):165–171.

Abstract Objective To describe the obstetric outcomes of patients with multiple sclerosis (MS) and the impact of pregnancy and the postpartum period on the progression of the disease. Methods A case series study performed between December 2019 and February 2020, reporting pregnancies occurred between 1996 and 2019. The subjects included were women with MS undergoing follow-up at an MS referral center in Northeastern Brazil, and who had at least one pregnancy after the onset of MS symptoms, or who had their first relapse in the first year after delivery. Results In total, 26 women and 38 pregnancies were analyzed – 32 of them resulted in delivery, and the remaining 6, in miscarriages. There was a significant increase in the prevalence of relapse during the postpartum period when compared with the gestational period. In 16 (42.1%) of the pregnancies, there was exposure to disease- Keywords modifying therapies (DMTs) – 14 (36.8%), to interferon β, and 2 (5.3%), to fingolimod. ► multiple sclerosis Higher rates of abortion, prematurity and low birth weight were reported in the group ► pregnancy was exposed to DMT when compared with the one who was not. fi ► postpartum period Conclusion In the sample of the present study, there was a signi cant increase in the ► infant rate of MS relapse during the postpartum period when compared with the gestational ► newborn period. Additionally, it seems that exposure to DMTs during pregnancy may affect the ► abortion obstetric outcomes of the patients.

received DOI https://doi.org/ © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights July 9, 2020 10.1055/s-0040-1722157. reserved. accepted ISSN 0100-7203. This is an open access article published by Thieme under the terms of the October 6, 2020 Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda., Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil 166 Disease Progression and Obstetric Outcomes of Women with Multiple Sclerosis Barros et al.

Resumo Objetivo Descrever os desfechos obstétricos de pacientes com esclerose múltipla (EM) e o impacto da gravidez e do período pós-parto na progressão da doença. Métodos Uma série de casos realizada entre dezembro de 2019 e fevereiro de 2020, que retrata gestações ocorridas entre 1996 e 2019. As pacientes incluídas neste estudo foram mulheres com EM, que realizam acompanhamento em um centro de referência em EM no Nordeste do Brasil, e que tiveram ao menos uma gestação após o início dos sintomas da EM, ou tiveram o primeiro surto da doença no ano posterior ao parto. Resultados No total, 26 mulheres e 38 gestações foram avaliadas – dentre as quais, 32 resultaram em partos, e 6, em abortamentos. Houve um aumento significativo na prevalência de surtos durante o pós-parto quando comparado com o período gestacional. Em 16 (42,1%) das gravidezes, houve exposição a terapias modificadoras da doença (TMDs) – 14 (36,8%) a β-interferona, e 2 (5,3%) a fingolimode. As taxas de Palavras-chave abortamento, prematuridade e baixo peso ao nascer foram mais elevadas no grupo ► esclerose múltipla exposto às TMDs quando comparado com o não exposto. ► gravidez Conclusão Na amostra deste estudo, houve um aumento significativo na taxa de ► período pós-parto surtos da EM durante o período pós-parto quando comparado com o período ► bebê gestacional. Além disso, a exposição às TMDs durante a gestação pode afetar os ► recém-nascido desfechos obstétricos das pacientes. ► aborto

– Introduction Regarding the obstetric outcomes, studies6,15 17 suggest that the neonates of patients with MS may have their Multiple sclerosis (MS) is an inflammatory chronic disease development affected, especially if exposed to a DMT in that affects the central nervous system.1,2 Due to a complex the initial weeks of pregnancy, since some medications immune response, varying degrees of demyelination, axonal may impair fetal development. In Brazil, 55% of pregnan- loss and metabolic changes occur, often progressing to cies are unplanned, so the exposure may be even higher than neurological disability.2,3 The course of the disease is usually in other locations.18 characterized by periods of acute neurological affection (MS There aren’t many publications available about the rela- relapses, attacks or exacerbations) interspersed with periods tionship between MS and pregnancy in Brazil.14,19 Thus, the of stability, since the relapsing-remitting MS (RRMS) clinical present study aims to evaluate the changes in MS during and course is the most common form of the disease. Despite this, after pregnancy, and to describe the obstetric outcomes of other clinical courses – such as primary progressive MS patients followed up at an MS reference center in Northeast- (PPMS) and secondary progressive MS (SPMS) – do present ern Brazil. themselves with continuous progression of the disability, 4 regardless of the occurrence of relapses. Methods Multiple sclerosis mainly affects young women aged between 20 and 40 years, but it does not seem to have a The present work consists of a retrospective and descriptive negative impact on their fertility.3,5 However, in previous case series, with cross-sectional and quantitative design. decades, the little variety and effectiveness of the available The necessary data were obtained through a review of disease-modifying therapies (DMTs) led many patients to medical records and telephone interviews with the disregard motherhood due to the fear of disability. Never- patients. Data collection took place between December 2019 theless, in the past few years there has been a substantial and February 2020, and the pregnancies occurred between improvement in the development of DMTs, which brought 1996 and 2019. about a better opportunity for disease control and an in- The sample was composed of female patients, with con- crease in the desire for motherhood.6 firmed diagnosis of MS, according to the revised McDonald During pregnancy, hormonal and immunological altera- criteria, who consult with a MS specialist at Centro de tions promote significant changes in the behavior of MS.7,8 Referência de Esclerose Múltipla da Paraíba (CREMPB), The rate of relapses during pregnancy tends to decrease located at Fundação Centro Integrado de Apoio ao Portador continuously over the three trimesters. In the postpartum de Deficiência (FUNAD), in the city of João Pessoa, state of period, however, the rate generally increases above prepreg- Paraíba, Brazil.4 All patients had at least one pregnancy after nancy levels, until, within a few months, it returns to regular the onset of symptoms, or had the first attack of the disease in – levels.9 14 The course of the disease does not seem to be the first year after delivery. The exclusion criteria were: affected in the long term.14 patients under 18 years of age; patients who were still

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. Disease Progression and Obstetric Outcomes of Women with Multiple Sclerosis Barros et al. 167 pregnant; and women who had not yet completed 1 year of ison between the numerical variables, the Student t-test with postpartum. We performed convenience sampling, thus all equal variances was used. The margin of error used was 5%. patients who met the criteria of the research were included, The research project was approved by the Ethics in Human since MS is still considered a rare disease. Research Committee of Centro de Ciências Médicas (CCM) at The data collected included: the patient’s age; number of Universidade Federal da Paraíba (UFPB) (under CAAE: pregnancies and when they happened; the number of abor- 24244819.3.0000.8069, opinion 3.718.929), and it respects tions and trimester of loss; the type of delivery and type of the ethical principles set forth in resolution 466/2012 of the anesthesia used; specifics regarding the newborn (weight Brazilian National Health Council (Conselho Nacional de and gestational age at birth); and the period during which Saúde, CNS, in Portuguese), which is part of the Ministry of exclusive and complementary breastfeeding occurred. Fur- Health. thermore, worsening of the chronic MS symptoms; exacerbations of MS during pregnancy; gestational exposure to a Results DMT; and MS relapses that took place up to one year after delivery were also evaluated. Overall, 30 women and 44 pregnancies were initially The definition of MS relapse used in the present study recruited. However, four women and six pregnancies were consists of the appearance or reappearance of one or more later excluded, since they did not meet the established MS symptoms, associated with a deterioration of the neuro- criteria. Thus, 26 women and 38 pregnancies – 32 (84.2%) logical examination. The condition must last at least 24 hours resulting in delivery and 6 (15.8%), in miscarriages – were in the absence of fever or infection.4 finally included (►Fig. 1). Following the definition of the World Health Organization The median age at the onset of symptoms was 24.5 years, (WHO), we considered as breastfed the infants who solely and the median age at diagnosis was 27 years. Most women ingested breast milk (exclusive breastfeeding), and those who (17; 654%), had only 1 pregnancy assessed in the present had their breast milk diet supplemented with other liquids and study; 8 (30.8%) had 2 gestations included; and 1 (3,.8%) had solids, including non-human milk (complementary breast- 5 pregnancies analyzed. In total, 24 (92.3%) patients had feeding). Children who did not receive any amount of breast RRMS, whereas 2 (7.7%) had SPMS; 6 (23.1%) of the assessed milk were perceived as not breastfed.20 women had their first MS relapse postpartum (►Table 1). As for abortion, we herein define it as an expulsion or Only 1 (2.6%) of the assessed pregnancies used artificial extraction of a conception product without signs of life with reproduction methods. The patient was using hormonal less than 20 weeks of gestation. Newborns with low birth therapy, in preparation for in vitro fertilization, when she weight are those who weighed less than 2,500 g at birth, became pregnant naturally. Such pregnancy lasted until due while newborns with high birth weight are those who date and there were no relapses during the gestation. How- weighed more than 4,000 g at birth, regardless of the gesta- ever, an exacerbation happened four months after delivery. tional age. All newborns delivered before reaching 37 full Out of the 6 abortions – all reported by different patients – weeks of gestational age were considered premature.21 5 (83.3%) happened during the first trimester, and only 1 All data were analyzed using the the Statistical Package for (16.7%) took place during the second trimester. In 3 (50%) of Social Sciences (SPSS, IBM Corp., Armonk, NY, US) software, these gestations, there was exposure to a DMT (interferon β- version 23. For the association between the categorical 1a – 2 at a dosage of 44 µg and 1 at a dosage of 30 µg). When variables, we used the Fisher exact test; and for the compar- assessing the 38 pregnancies, the percentage of miscarriages

Fig. 1 Consolidated Standards of Reporting Trails (CONSORT) ﬂowchart of the study sample.

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. 168 Disease Progression and Obstetric Outcomes of Women with Multiple Sclerosis Barros et al.

Table 1 General data regarding the 26 patients and 38 Table 2 Multiple sclerosis relapses during pregnancy versus pregnancies during the postpartum period

Median n(%) Relapse(s) Pregnancy Relapse(s) Postpartum (P25; P75) n(%) n(%) Age(years)attheonset 24.5 Yes 5(15.6) Yes 18(56.3) of symptoms (20.5; 28.75) 1st trimester 1(3.1) 0 to 90 days 11 (57.9) Age (years) at diagnosis 27 (23.25; 29) 2nd trimester 2(6.3) 90 to 180 days 4 (21.1) Number of pregnancies 3rd trimester 2(6.3) 180 to 360 days 4 (21.1) assessed per patient No 27(84.4) No 14(43.8) 1pregnancy 17(65.4) Total 32 (100%) Total 32 (100) 2pregnancies 8(30.8) 5pregnancies 1(3.8) Note: Onewomanhadtworelapsesintheyearafterdelivery. Clinical course of the multiple sclerosis Table 3 Data on the possible effects of disease-modifying Relapsing-remitting 24(92.3) therapies on obstetric outcomes multiple sclerosis Exposed to Not exposed p-value Secondary progressive 2(7.7) multiple sclerosis disease- to disease- modifying modifying Women whose first exacerbation 6(23.1) therapies therapies of multiple sclerosis happened n ¼ 13 n ¼ 19 during the first year n(%) n(%) postpartum Low birth 2(15.4) 1(5.3) p ¼ 0.552 Gestational exposure 16(42.1) weight to disease-modifying p ¼ therapies Prematurity 3(23.1) 3(15.8) 0.666 Interferon β 14(36.8) Neonatal 0 death Fingolimod 2(5.3) Birth defects 0 Birth weight (grams) 3,160 (2,912.5; 3,412.5) Note: According to the Student t-test with equal variances. Low birth weight 3(9.4) High birth weight 0(0) birth; 4 (21.1%), between 90 and 180 days after the delivery; Prematurity 6(18.8) and 4 (21.1%), between 180 and 360 days. In 29 (90.6%) pregnancies, the chosen type of delivery was Period of exclusive 75 (5.25; 150) breastfeeding (days) cesarean section, while the remaining 3 (9.4%) were delivered via vaginal birth. Spinal anesthesia was used in 23 Breastfed infants 27(84.4) (71.9%) deliveries; epidural was used in other 6 (18.8%) Type of delivery women; 2 (6.3%) women did not receive any kind of anes- Cesarean section 29(90.6) thesia; and 1 (3.1%) woman could not recall which kind of Vaginal 3(9.4) anesthesia had been used. There were no statistically significant associations between the occurrence of relapses during among women who were undergoing a DMT at conception the postpartum period and the different types of delivery was 18.8% (3 out of 16) and 13,6% (3 out of 22) amongst those (p ¼ 1.000) and anesthesia (p ¼ 0.480). who were not; however, p ¼ 0.682. Altogether, 27 (84.4%) infants were breastfed, with 24 Considering only the pregnancies that resulted in delivery, (75%) having undergone some period of exclusive breast- in 13 (40.6%) of them there was exposure to a DMT – 11 (34.4%) feeding. When comparing the group of patients who pre- to interferon β,and2(6.3%)tofingolimod. As shown sented postpartum relapses with the group who did not, the in ►Table 2, gestational relapses occurred in 5 of these 32 median of days spent on exclusive breastfeeding was higher pregnancies (15.6%), all in different patients – 1 (3.1%) during in the group with no exacerbations; however, p ¼ 0.612. the first trimester; 2 (6.3%) in the second; and 2 (6.3%) during When assessing the relationship between gestational the third. In the first year following delivery, 19 relapses took exposure to a DMT and the outcomes of low birth weight place after 18 (56.3%) of these births: 1 woman presented with and prematurity, the group of patients who were exposed 2 episodes of MS exacerbation in that period. In all, 21 of the 32 had higher percentages for both events – 2 (15.4%) versus 1 pregnancies (65.6%) had a related episode of exacerbation, (5.3%) regarding low birth weight (p ¼ 0.552); and 3 (23.1%) either during the gestation itself or during the postpartum versus 3 (15.8%) for prematurity (p ¼ 0.666); however, period. Out of the relapses that occurred in the first year p > 0.05. There were no reports of neonatal deaths or birth postpartum, 11 (57.9%) happened up to 90 days after the defects (►Table 3).

Discussion Among the analyzed pregnancies, exposure to DMTs reached 42.1% of the sample, which is similar to the rate Overall, there was a significant increase in the rate of observed in other studies.17,28 All patients discontinued such postpartum MS relapses when compared with the gestation- therapies after the pregnancy was diagnosed. The outcomes al period. Artificial reproductive techniques were only used of abortion, low birth weight and prematurity were more in 1 (2.6%) pregnancy. Exposure to a DMT occurred in 16 frequent in the group of exposed patients; however, p > 0.05. (42.1%) pregnancies, including 2 accidental exposures to In total, 2 (5.3%) pregnancies developed with exposure to fingolimod. A high rate (90.6% [29]%) of cesarean sections fingolimod, which is in fact rare, since there currently are was reported. The group of patients who did not have 500 reports of said event in the literature.6 Both pregnancies postpartum MS relapses presented a higher median of were successful, with no gestational exacerbations. Neither exclusive breastfeeding days when compared with the group of the newborns was premature, nor did any present with that had postpartum relapses. birth weight alterations. However, both women reported a Despite current scientific evidence that MS has no signif- relapse in the first 90 days postpartum. icant influence on fertility, it is possible for some patients to Currently, there are no class-A DMTs for use during preg- present an association of MS and infertility, which may lead nancy according to the Food and Drug Administration.6,29 some couples to resort to artificial reproduction methods. However, when it comes to older medications such as inter- However, studies show that the rate of relapse increases after feron β, it is recommended to interrupt treatment right when using such techniques. Said increment is possibly due to the the pregnancy is diagnosed, in light of a tendency this medi- association of different factors: the suspension of the DMT; cation to increase the rate of prematurity.6 Nevertheless, some the stress associated with the process; and immunological specialists still consider maintaining its use during pregnancy – changes induced by hormone therapy.5,22 24 in selected cases.6,29 As for fingolimod, a washout period of at The only gestation evaluated in the present study that least two to three months is recommended, since some studies happened with the help of some kind of reproduction suggest30,31 that it might be associated with fetal malforma- technique turned out to result in a relapse four months after tions. Despite this, there is a considerable risk of disease the delivery – although no exacerbations occurred during reactivation due to sudden DMT withdrawal.6 In the present pregnancy. Still, we cannot undoubtedly connect these study, there were no cases of malformations among the events, as the hormonal therapy was not followed through, exposed fetuses, and there is a possibility that the postpartum and the relapse happened after the birth – aperiodof relapses may have occurred due to a natural tendency toward predisposition for this occurrence. exacerbation often verified during that period. Still, further During pregnancy, there is an increase in the humoral studies are necessary to assess the effects of the exposure to immune response, which, when associated to the change in fingolimod during pregnancy, as well as the consequences of the immunological pattern of reaction of Th1 to Th2 and its suspension. hormonal alterations, may promote significant changes in In regards to prenatal care, pregnancies in women with – the clinical behavior of MS.6 8 Thus, the rate of relapse MS are not, at first sight, considered high-risk – unless there continuously decreases during the three gestational is an important disability status or other comorbidities. trimesters, and especially during the last one, in which the When it comes to the type of delivery, it follows an obstetric rate reaches its lowest numbers. After delivery, however, indication.6,29 Although MS has been recognized as a risk there is an important increase in said rate, which then factor for cesarean section, because of fatigue, spasticity of declines and returns to its prepregnancy levels within four the lower limbs, slower progression of labor and/or pelvic – to six months.9 14 dysfunction (possible features of MS), it has been suggested The sample assessed in the present research behaved that cultural characteristics also play a role in this similarly to what has just been described, since there was a context.6,32 The rate of cesarean sections in our sample remarkable difference between the prevalence of relapse was considered overly elevated (90.6%), since most studies during pregnancy and in the year following delivery. present rates around 40% or lower.9,10,13,32 This probably Despitethis,twopatientsreportedanexacerbationduring happened due to the disability caused by MS, but also due to their third trimester, which is rather unusual. However, a Brazilian cultural tendency to opt for surgical births – the one of these women, who had both sensory and motor national rate was around 56% in 2018–, in addition to symptoms in the left lower limb, did present with a Zika possible fear among both obstetricians and neurologists of virusinfectionjustdaysbeforetherelapse.Therewasno putting these women through the stress of vaginal birth.33 evidence of congenital syndrome related to the viral Therefore, it is important to restate that, after an obstetric infection, but the patient went into premature labor at evaluation, if no deterrent factors are identified, vaginal 34weeksofgestationalage.Therewerenopostpartum delivery is considered safe for these patients.6,29 exacerbations. The gestational relapse was probably due to Furthermore, breastfeeding has been pointed out as a the virus, since other infections have been identified as possible protective factor regarding postpartum relapses, triggers for MS activity.25 As to the Zika virus itself, so far since some studies show a significant difference between there are few studies linking it to MS, but some the rate of relapse in women who breastfed exclusively and reports26,27 suggestthatitmightinducedeteriorationof those who did not breastfeed or did so as part of a comple- the neurological condition. mentary diet.34,35 Among the pregnancies that resulted in

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. 170 Disease Progression and Obstetric Outcomes of Women with Multiple Sclerosis Barros et al.

birth, a considerable percentage of the newborns (75%) went 6 Fragoso YD, Adoni T, Brooks JBB, Finkelsztejn A, da Gama PD, through some period of exclusive breastfeeding, and the Grzesiuk AK, et al. Practical evidence-based recommendations for group of patients who did not present postpartum relapses patients with multiple sclerosis who want to have children. Neurol Ther. 2018;7(02):207–232. Doi: 10.1007/s40120-018-0110-3 had a higher median of exclusive breastfeeding days when 7 Gold SM, Voskuhl RR. Estrogen treatment in multiple sclerosis. J p > compared with the group with relapses, but 0.05. This Neurol Sci. 2009;286(1-2):99–103. Doi: 10.1016/j.jns.2009.05.028 discussion still needs to be clarified, since it is difficult to 8 Al-Shammri S, Rawoot P,Azizieh F, AbuQoora A, Hanna M, Saminathan establish whether women who breastfeed for a longer period TR, Raghupathy R. Th1/Th2 cytokine patterns and clinical profiles have fewer postpartum relapses or if they already have a during and after pregnancy inwomen with multiple sclerosis. J Neurol – lower relapse rate, thus enabling them to postpone the Sci. 2004;222(1-2):21 27. Doi: 10.1016/j.jns.2004.03.027 9 Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, return to the use of DMT and hence making it possible for Moreau TPregnancy in Multiple Sclerosis Group. Rate of pregnan- them to breastfeed for longer periods. cy-related relapse in multiple sclerosis. N Engl J Med. 1998;339 When it comes to the limitations of the present study, we (05):285–291. Doi: 10.1056/NEJM199807303390501 would like to highlight its small sample, which is due to the 10 Bsteh G, Algrang L, Hegen H, Auer M, Wurth S, Di Pauli F, et al. low prevalence of MS, as it is a rare condition. The present Pregnancy and multiple sclerosis in the DMT era: A cohort study in Western Austria. Mult Scler. 2020;26(01):69–78. Doi: 10.1177/ work also has an observational and retrospective design, 1352458518816614 which makes it vulnerable to a greater number of biases 11 Fernández Liguori N, Klajn D, Acion L, Cáceres F, Calle A, Carrá A, et when compared with other types of studies. However, this al. Epidemiological characteristics of pregnancy, delivery, and format is adequate and should be used for rare diseases such birth outcome in women with multiple sclerosis in Argentina as MS. (EMEMAR study). Mult Scler. 2009;15(05):555–562. Doi: 10.1177/1352458509102366 12 Hellwig K. Pregnancy in multiple sclerosis. Eur Neurol. 2014;72 Conclusion (Suppl 1):39–42. Doi: 10.1159/000367640 13 Jesus-Ribeiro J, Correia I, Martins AI, Fonseca M, Marques I, Batista S, et In the present study, there was a significant reduction in the al. Pregnancy in multiple sclerosis: a Portuguese cohort study. Mult rate of MS relapses in the gestational period when Scler Relat Disord. 2017;17:63–68. Doi: 10.1016/j.msard.2017.07.002 compared with the postpartum period. The rate of DMT 14 Finkelsztejn A, Fragoso YD, Ferreira MLB, Lana-Peixoto MA, Alves- exposure during conception was similar to what has been Leon SV, Gomes S, et al. The Brazilian database on pregnancy in multiple sclerosis. Clin Neurol Neurosurg. 2011;113(04): reported by other studies: most women were on interferon 277–280. Doi: 10.1016/j.clineuro.2010.11.016 β fi ,althoughtwocasesof ngolimod exposure were also 15 Dahl J, Myhr KM, Daltveit AK, Gilhus NE. Pregnancy, delivery and identified. We encourage the performance of new studies to birth outcome in different stages of maternal multiple sclerosis. J assess the evolution of multiple sclerosis during the gesta- Neurol. 2008;255(05):623–627. Doi: 10.1007/s00415-008-0757-2 tional and puerperal cycles, to provide more tangible scien- 16 Chen YH, Lin HL, Lin HC. Does multiple sclerosis increase risk of tific evidence. adverse pregnancy outcomes? A population-based study. Mult Scler. 2009;15(05):606–612. Doi: 10.1177/1352458508101937 17 Nguyen AL, Havrdova EK, Horakova D, Izquierdo G, Kalincik T, van Contributors der Walt A, et al;MSBase Study Group. Incidence of pregnancy and All authors contributed to the concept and design of the disease-modifying therapy exposure trends in women with mul- present study; analysis and interpretation of data; draft or tiple sclerosis: A contemporary cohort study. Mult Scler Relat – revision of the manuscript; and they have approved the Disord. 2019;28:235 243. Doi: 10.1016/j.msard.2019.01.003 18 Viellas EF, Domingues RMSM, Dias MAB, da Gama SGN, Theme Filha manuscript as submitted. All authors are responsible for MM, da Costa JV, et al. Prenatal care in Brazil. Cad Saude Publica. the reported research. 2014;30(Suppl 1):S1–S15. Doi: 10.1590/0102-311X00126013 19 Fragoso YD, Finkelsztejn A, Comini-Frota ER, da Gama PD, Grzesiuk fl Con ict of Interests AK, Khouri JMN, et al. Pregnancy and multiple sclerosis: the initial The authors have no conflict of interests to declare. results from a Brazilian database. Arq Neuropsiquiatr. 2009;67 (3A):657–660. Doi: 10.1590/S0004-282X2009000400015 20 World Health Organization. Infant and young child feeding: References model chapter for textbooks for medical students and allied 1 Dobson R, Giovannoni G. Multiple sclerosis - a review. Eur J Neurol. health professionals. Geneva: WHO; 2009 2019;26(01):27–40. Doi: 10.1111/ene.13819 21 World Health Organization. International Classification of Dis- 2 Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372 eases and Mortality and Morbidity Statistics. Geneva: WHO; 2019 (9648):1502–1517. Doi: 10.1016/S0140-6736(08)61620-7 22 Hellwig K, Beste C, Brune N, Haghikia A, Muller T, Schimrigk S, et al. 3 Martin R, Sospedra M, Rosito M, Engelhardt B. Current multiple Increased MS relapse rate during assisted reproduction technique. J sclerosis treatments have improved our understanding of MS auto- Neurol. 2008;255(04):592–593. Doi: 10.1007/s00415-008-0607-2 immune pathogenesis. Eur J Immunol. 2016;46(09):2078–2090. 23 Hellwig K, Schimrigk S, Beste C, Muller T, Gold R. Increase in Relapse Doi: 10.1002/eji.201646485 Rate during Assisted Reproduction Technique in Patients with Mul- 4 Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi tiple Sclerosis. Eur Neurol. 2009;61:65–68. Doi: 10.1159/000177937 G, et al. Diagnosis of multiple sclerosis: 2017 revisions of the 24 Correale J, Farez MF, Ysrraelit MC. Increase in multiple sclerosis McDonald criteria. Lancet Neurol. 2018;17(02):162–173. Doi: activity after assisted reproduction technology. Ann Neurol. 10.1016/S1474-4422(17)30470-2 2012;72(05):682–694. Doi: 10.1002/ana.23745 5 Hellwig K, Correale J. Artificial reproductive techniques in multiple 25 Marrodan M, Alessandro L, Farez MF, Correale J. The role of sclerosis. Clin Immunol. 2013;149(02):219–224. Doi: 10.1016/j. infections in multiple sclerosis. Mult Scler. 2019;25(07):891–901. clim.2013.02.001 Doi: 10.1177/1352458518823940

26 Benjamin LA. A tale of two demyelinating diseases and Zika virus. 31 Lu E, Wang BW, Alwan S, Synnes A, Dahlgren L, Sadovnick AD, et al. Mult Scler. 2019;25(03):430–431. Doi: 10.1177/1352458518799584 A Review of Safety-Related Pregnancy Data Surrounding the Oral 27 Alves-Leon SV, Lima MDR, Nunes PCG, Chimelli LMC, Rabelo K, Disease-Modifying Drugs for Multiple Sclerosis. CNS Drugs. 2014; Nogueira RMR, et al. Zika virus found in brain tissue of a multiple 28(02):89–94. Doi:10.1007/s40263-013-0131-5 sclerosis patient undergoing an acute disseminated encephalomy- 32 Finkelsztejn A, Brooks JBB, Paschoal FM Jr, Fragoso YD. What can we elitis-like episode. Mult Scler. 2019;25(03):427–430. Doi: 10.1177/ really tell women with multiple sclerosis regarding pregnancy? A 1352458518781992 systematic review and meta-analysis of the literature. BJOG. 2011; 28 Hellwig K, Haghikia A, Rockhoff M, Gold R. Multiple sclerosis and 118(07):790–797. Doi: 10.1111/j.1471-0528.2011.02931.x pregnancy: experience from a nationwide database in Germany. 33 Ministério da Saúde. DATASUS [Internet]. Estatísticas vitais. 2018 Ther Adv Neurol Disorder. 2012;5(05):247–253. Doi: 10.1177/ [cited 2020 Jun 6]. Available from: http://www2.datasus.gov.br/ 1756285612453192 DATASUS/index.php?area¼0205 29 Dobson R, Dassan P, Roberts M, Giovannoni G, Nelson-Piercy C, 34 Hellwig K, Rockhoff M, Herbstritt S, Borisow N, Haghikia A, Elias- Brex PA. UK consensus on pregnancy in multiple sclerosis: Hamp B, et al. Exclusive breastfeeding and the effect on postpartum ‘Association of British Neurologists’ guidelines. Pract Neurol. multiple sclerosis relapses. JAMA Neurol. 2015;72(10):1132–1138. 2019;19(02):106–114. Doi: 10.1136/practneurol-2018-002060 Doi: 10.1001/jamaneurol.2015.1806 30 Karlsson G, Francis G, Koren G, Heining P, Zhang X, Cohen JA, et al. 35 Pakpoor J, Disanto G, Lacey MV, Hellwig K, Giovannoni G, Ramago- Pregnancy outcomes in the clinical development program of palan SV. Breastfeeding and multiple sclerosis relapses: a meta- ﬁngolimod in multiple sclerosis. Neurology. 2014;82:674–680. analysis. J Neurol. 2012;259(10):2246–2248. Doi: 10.1007/s00415- Doi: 10.1212/WNL.0000000000000137 012-6553-z

Postplacental Placement of Intrauterine Devices: Acceptability, Reasons for Refusal and Proposals to Increase its Use Dispositivo intrauterino pós-placentário: Aceitação, motivosderecusasepropostasdeaçõesqueampliem sua prática

Maria Beatriz de Paula Leite Kraft1 Mariana Miadaira1 Marcos Marangoni Júnior1 Cássia Raquel Teatin Juliato1 Fernanda Garanhani Surita1

1 Department of Obstetrics and Gynecology, School of Medical Address for correspondence Fernanda Garanhani Surita, MD, Science, Universidade Estadual de Campinas, Campinas, SP, Brazil Associate Professor, R. Alexander Fleming, 101, 13083-881, Campinas, SP, Brazil (e-mail: [email protected]). Rev Bras Ginecol Obstet 2021;43(3):172–177.

Abstract Objective To evaluate the acceptability of postplacental placement of intrauterine devices (PPIUD), reasons for refusal and suggested policies to increase its use. Methods Cross-sectional study conducted at the Women Hospital of the Universi- dade de Campinas, Campinas, SP, Brazil. Postplacental placement of intrauterine devices was offered to women admitted in labor who did not present infections, uterine malformation, twin pregnancy, preterm birth, and were at least 18 years old. In case of refusal, the parturient was asked to give their reasons and the answers were classiﬁed as misinformation about contraception or other reasons. The following were considered misinformation: fear of pain, bleeding, contraception failure and future infertility. Bivariate analysis was performed. Results Amongst 241 invited women, the refusal rate was of 41.9%. Misinformation corresponded to 50.5% of all refusals, and the reasons were: fear of pain (39.9%); fear of contraception failure (4.9%); fear of bleeding (3.9%); fear of future infertility (1.9%); other reasons for refusal were 49.5%. Parturients aged between 18 and 27 years old refused the PPIUD more frequently due to misinformation (67.4%), and older parturients (between 28 and 43 years old) refused frequently due to other reasons (63.6%) (p ¼ 0.002). The mean age of those who declined the PPIUD due to misinformation was 27.3 6.4 years old, while those who declined for other reasons had a mean age of 29.9 5.9 years old (p ¼ 0.017). Keywords Conclusion The refusal of the PPIUD was high, especially amongst young women and ► postpartum due to misinformation. It is necessary to develop educative measures during antenatal ► contraception care to counsel women about contraception, reproductive health and consequences of ► intrauterine device unintended pregnancy. ► health education

received DOI https://doi.org/ © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights February 13, 2020 10.1055/s-0041-1725053. reserved. accepted ISSN 0100-7203. This is an open access article published by Thieme under the terms of the January 6, 2021 Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda., Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil Postplacental Placement of Intrauterine Devices Kraft et al. 173

Resumo Objetivo Avaliar a taxa de aceitação do dispositivo intrauterino pós-placentário (DIUPP); os motivos de recusa e propor medidas que aumentem sua aceitação. Métodos Estudo de corte transversal realizado no Hospital da Mulher da Universidade Estadual de Campinas, Campinas, SP, Brasil. O DIUPP foi oferecido a mulheres admitidas em trabalho de parto que não apresentavam: infecções, malformação uterina, gravidez gemelar,partoprematuroecomidademínimade18anos.Emcasoderecusa, perguntou-se o motivo, e as respostas foram agrupadas em informações equivocadas sobre contracepção ou outros motivos. Considerou-se informação equivocada: medo de dor, sangramentos, falha da contracepção e prejuízo da fertilidade. Análises bivariadas foram realizadas. Resultados Entre 241 mulheres, a taxa de recusa foi de 41,9%. A desinformação correspondeu a 50,5% de todos os motivos de recusa, que foram: medo da dor (39,9%); medo da falha da contracepção (4,9%); medo de sangramento (3,9%), medo de o dispositivo intrauterino (DIU) prejudicar a fertilidade (1,9%). Outros motivos de recusa atingem 49,5%. Parturientes com idade entre 18 e 27 anos recusaram o PPIUD com mais frequência devido a desinformação (67,4%), e as mais velhas (com idade entre 28 e 43 anos) recusaram com frequência devido a outros motivos (63,6%) (p ¼ 0,002). Houve diferença entre a idade média de quem recusou o PPIUD por desinformação (27,3 6,4 anos) em comparação com outras razões (29,9 5,9 anos), (p ¼ 0,017). Palavras-chave Alémdisso,ambososgruposapresentaramaltastaxasderecusapordesinformação, ► pós-parto de 67,4 e 36,4%, respectivamente. ► contracepção Conclusão A recusa do DIUPP foi alta, principalmente entre as mulheres jovens e por ► dispositivo desinformação. Diante disso, é necessário o desenvolvimento de medidas educativas intrauterino durante o pré-natal e aconselhar as mulheres sobre contracepção, saúde reprodutiva e ► educação em saúde gravidez indesejada.

Introduction at the time of a cesarean delivery. In the USA, a study has Contraception is important to women as it allows them to shown that 35% of all pregnancies were accounted within decide whether it is the right time to conceive. In 2012, the 18 months after a previous pregnancy. Those pregnancies occurrence rate of unintended pregnancies worldwide was are more common among adolescent girls and are more of 53 for every 1,000 women aged between 15 and 44 years likely to have been unplanned.9 The postpartum period is an old, and its prevalence was of 40%.1 In the United States of opportunity to counsel women about contraception America (USA), 50% of all pregnancies were unplanned2 and, because, at that time, women often do not plan to conceive in Brazil, the rate is 55.4%.3 Also, in some Brazilian regions, again in the near future. However, it is known that 40% of this figure rises to 65% (such as in the South).4 Amongst women do not attend medical appointments in the post- Brazilian women in the postpartum period, 25.5% reported partum period and that of all women after childbirth that feeling embarrassed to have conceived.3 These statistics are nursing, 20% will ovulate again as early as in the 3rd reflect the importance of assuring contraception to all month after parturition and, therefore, will be at risk of women.5 The postpartum period is a great opportunity to conceiving again.10 address contraceptive needs. The period immediately after childbirth is a great Nowadays, the most efficient contraceptive methods are opportunity to provide contraceptive methods, including – long-acting reversible contraceptives (LARCs), including intra- LARCs.11 13 Therefore, it is important to evaluate the accept- uterine devices (IUD) (copper and levonorgestrel [LNG] intra- ability and refusal rates for these kinds of contraceptives, as uterine systems) and subdermal progestin implants. They well as the reasons for refusals, to create policies that demand no changes in habit, are well tolerated, and are stimulate women to adhere to contraception immediately more effective than other methods with < 2pregnanciesin after childbirth. The present study aims to evaluate the 1,000 users.6 Also, LARC methods have the lowest discontinua- acceptance of PPIUD. Also, it is necessary to examine the tion rates.6 Still, short-term reversible methods are highly refusal rate, the motives for refusal and the age of the patient prescribed,7 even though studies show lowcontinuation rates.8 at the time. These data are important to help in the creation Intrauterine devices must be offered to all women in of policies that could increase the acceptance of contracep- reproductive age, especially after delivery, both vaginal and tion immediately after childbirth.

Methods reasons) among these groups (a χ2 test was performed). Also, the mean age of the patients who refused PPIUD due to The present study was approved by the Ethical Committee of misinformation was compared with the mean age of the the Universidade de Campinas’ (under number 80620717. women who refused for other reasons, and a Mann-Whitney 6.0000.5404) and is part of a large group of studies that analyze test was performed to evaluate if there was statistical signifi- the insertion of IUDs immediately after childbirth. cance. All information was analyzed by SAS Statistical Analysis The data presented in this cross-sectional study are from System for Windows, version 9.2 (SAS Institute, Inc., Cary, the recruitment of a large study, a clinical trial that compared NC, USA). expulsion of postplacental copper IUD and the LNG 52mg 14 intrauterine system (IUS). Thus, the sample is intentional Results because it includes the necessary number of women invited to reach the sample size of the clinical trial. Postplacental placement of intrauterine devices was offered The insertion of PPIUD was offered to women that would to 241 women, of whom 140 accepted PPIUD insertion go through a cesarean delivery or were admitted in labor at (58.1%). Of all the patients involved, 74 were < 24 years old the Women Hospital of the Universidade de Campinas. The (30.7%), while 167 were between 25 and 43 years old (69.3%). exclusion criteria were the presence of any maternal infec- There was no significance in the mean age of the patients tion or anemia, rupture of membranes for > 18 hours, uterine who refused or accepted PPIUD insertion (►Table 1). malformation, or twin pregnancy. Also, the pregnancy had to The motives to refuse the PPIUD are described in ►Fig. 1.To have been 37 weeks long and the parturient age had to be correlate the refusal motives with theknowledge of the patient between 18 and 43 years old. If the parturient was classified as a candidate, PPIUD was offered. The present study was Table 1 Postplacental intrauterine device placement conducted between May 2018 and January 2019. acceptance and refusal according to women age In case of acceptance, the patient was randomized to receive a TCu380A IUD or an LNG IUS, and a total of 70 units Acceptance Refusal of each was inserted. In case of refusal, the woman was asked Women age n ¼ 140 % n ¼ 101 % p-value why she did not want PPIUD insertion. Subsequently, the (years old) refusal reasons were grouped according to misinformation 18–24 46 32.9 28 27.7 0.825 or other reasons. Fear of pain, bleeding, contraception failure, 25–29 41 29.3 31 30.7 and IUD impairing fertility were considered misinformation. 30–34 30 21.4 22 21.8 To evaluate if there was a statistical difference between the – mean age of acceptance and refusal, the Mann-Whitney test 35 43 23 16.4 20 19.8 was performed. Besides that, women who refused PPIUD were Mean age/SD 27.9 5.8 28.05 6.2 0.506 categorized in 2 age groups (between 18 and 27 years old Abbreviation: SD, standard deviation. versus between 28 and 43 years old) to analyze if the refusal Chi-squared test motives showed any tendency (misinformation versus other Mann-Whitney test

Fig. 1 Motives for refusal of postplacental intrauterine device placement

Table 2 Refusal of post placental intrauterine device by misinformation and women age

Misinformation Other reasons n ¼ 51 (50.5%) n ¼ 50 (49.5%) Mean age SD Mean age SD p-value 27.3 6.4 29.9 5.4 0.017 Age groups n % n % (years old) 18–27 31 60,78 15 30 0.002 28–43 20 39,21 35 70

Mann-Whitney test Chi-squared test about contraception methods, fear of pain, bleeding, contra- care. Also, it is common for women after childbirth to think less ception failure and IUD impairing fertility (in black) were about contraception,15 and any period with no protection considered examples of misinformation. All other motives could result in an unintended pregnancy.16 Since the antenatal (in gray) were considered as not being correlated with misin- visits will be the period when a woman has most frequent formation (desire for nonreversible contraception methods contact with a healthcare provider, it is also the duty of the such as sterilization or vasectomy; desire to use another type healthcare provider to discuss the reproductive future of the of contraception; desire to not use any contraception method woman. The period immediately after childbirth is a good at all; previous maladjustment to IUDs; fear of developing opportunity to initiate contraception, including IUDs, because ovarian cysts; desire to insert the IUD at the postpuerperal the patient is not pregnant, probably does not want to conceive medical consultation; and desire to not be randomized). in the near future, and will not feel pain during its insertion. It Therefore, 50.5% of all refusals were due to a lack of knowledge is important to study the acceptance rates of the use of of contraception methods, that is, misinformation. contraception immediately after childbirth, as well as the It was also observed that patients aged between 18 and motives for its refusal, in order to promote this type of family 27 years old were more likely to refuse PPIUD insertion due planning. to misinformation (67.4%) when compared with those aged The present study showed that slightly more than half of the between 28 and 43 years old (36.47%), who usually refused patients accepted PPIUD, and their mean age was 28 years old. this type of contraception because of other reasons (63.6%), The refusal rate was high (41.9%), and the most frequent refusal (chi-squared test; p ¼ 0.002). There was difference between motives were misinformation about IUD, such as: fear of pain, the mean age of the patients who did not want the PPIUD bleeding, contraception failure and IUD impairing fertility. insertion due to lack of knowledge (27.3 6yearsold)andof Intrauterine devices do not cause pelvic pain, prejudicefertility, those who did not want it due to other reasons (29.8 5.8 or have a high failure risk.6,17,18 As for bleeding, although years old), with statistical relevance (Mann-Whitney test; copper IUDs may increase menstrual blood flow, this can be p ¼ 0.017). In all ages, the refusal rate due to misinformation easily controlled with medication. These refusal motives can, was high (67.4 and 36.47%, respectively). These data are therefore, be easily demystified, but only by properly counsel- summarized in ►Table 2. ing the patients about this method. Patients aged between 18 and 27 years old and between 28 and 43 years old refused Discussion PPIUD insertion frequently due to lack of information and, amongst the younger patients, the chances of refusing this Our study showed that the rate of refusal of IUDs immedi- contraception due to misinformation are higher. ately after childbirth was high (41.9%), mainly due to lack of The present study has some limitations. The sample size is information about IUD by the patients, especially amongst intentional, based on the sample calculated for a randomized younger women. study.14 Epidemiological data, such as race and education, The practice of PPIUD insertion has gained attention were not collected. However, we consider the results recently and is recommended by the World Health Organiza- obtained in this simple analysis very strong. Recognizing tion (WHO). It should be considered an excellent contraceptive misinformation as a barrier to PPIUD use, especially amongst method, because women are rarely in such frequent and those of a young age, is the first step in the development of intense contact with health professionals as they are during public policies on contraception that should be added to pregnancy and the immediate postpartum period. Therefore, others such as training of healthcare professionals. Other this period is a good opportunity to promote education and studies performed in developing countries have also shown provide counseling in reproductive health. that the lack of IUD awareness impacts on low acceptance of After childbirth, it is common for recent mothers to develop this type of contraception and encourage policies to educate many concerns about the newborn and often forget about their women about contraception and IUDs.19 These studies agree own health. The fact that 40% of all women who give birth do that educating couples about contraception and antenatal not attend puerperal appointments9 reflects this loss of self- care increases PPIUD usage.20

As other studies, the present study shows that misinforma- Survey, 2011/2012. Reprod Health. 2016;13(Suppl 3):118. Doi: tion about contraception is frequent amongst women, and that 10.1186/s12978-016-0227-8 this failure facilitates the occurrence of unintended pregnan- 4 Prietsch SOM, González-Chica DA, Cesar JA, Mendoza-Sassi RA. 21,22 Gravidez não planejada no extremo Sul do Brasil: prevalência e cies. Also, basic interventions such as counseling increase – 23 fatores associados. Cad Saude Publica. 2011;27(10):1906 1916. IUD acceptance, andmultipleapproachesonthismatter Doi: 10.1590/S0102-311 2011001000004 enhance the rate of acceptance by women immediately after 5 Ministério da Saúde Pesquisa Nacional de Demografia e Saúde da parturition.24 A recent study showed that with PPIUD, almost Criança e da Mulher – PNDS 2006: dimensões do processo all the expulsions occurred within 42 days after childbirth, and reprodutivo e da saúde da criança Brasília (DF): Ministério da suggests special attention during this period to identify prema- Saúde;. 2009 6 Trussell J. Contraceptive efficacy. In: Hatcher RA, Trussel J, Nelson ture expulsions.14 Postplacental placement of IUD or intrauter- AL, Cates W, Stewart RH, Kowal D, et al., eds. Contraceptive ine system (IUS) is associated with less discomfort during the technology. 20th ed. New York: Ardent Media; 2011:779–863 procedure; however, it is associatedwith higher expulsion rates 7 Mosher WD, Jones JNational Center for Health Statistics. Use of than other interval placements.25 contraception in the United States: 1982-2008. Vital Health Stat The period of gestation is, therefore, an excellent moment 23. 2010;(29):1–44 8 Hall KS, Castaño PM, Westhoff CL. The influence of oral contracep- to clarify with women the importance of contraceptive tive knowledge on oral contraceptive continuation among young fi methods, the preference for long-term methods, the bene ts women. J Womens Health (Larchmt). 2014;23(07):596–601. Doi: of IUD, and the advantages of its insertion immediately after 10.1089/jwh.2013.4574 childbirth. Obstetricians and gynecologists and other health 9 Gemmill A, Lindberg LD. Short interpregnancy intervals in the care agents should frequently talk to pregnant women about United States. Obstet Gynecol. 2013;122(01):64–71. Doi: 10.1097/ family planning. Other important information that should be AOG.0b013e3182955e58 10 Ogburn JA, Espey E, Stonehocker J. Barriers to intrauterine device shared with pregnant women is that contraception immedi- insertion in postpartum women. Contraception. 2005;72(06): ately after delivery improves perinatal outcomes for the 426–429. Doi: 10.1016/j.contraception.2005.05.016 woman herself and for the newborn – studies show an 11 Celen S, Möröy P,Sucak A, Aktulay A, Danişman N. Clinical outcomes increase in child survival rates, a decrease in unintended of early postplacental insertion of intrauterine contraceptive devi- pregnancies and maternal mortality, and a reduction in ces. Contraception. 2004;69(04):279–282. Doi: 10.1016/j.contra- – maternal depression.26 28 ception.2003.12.004 12 Tocce KM, Sheeder JL, Teal SB. Rapid repeat pregnancy in adolescents: do immediate postpartum contraceptive implants make a Conclusion difference? Am J Obstet Gynecol. 2012;206(06):481.e1–481.e7. Doi: 10.1016/j.ajog.2012.04.015 The present study has showed that the rate of refusal of 13 Washington CI, Jamshidi R, Thung SF, Nayeri UA, Caughey AB, IUDs after childbirth was high, mainly due to lack of Werner EF. Timing of postpartum intrauterine device placement: – information about the devices by the patients, especially a cost-effectiveness analysis. Fertil Steril. 2015;103(01):131 137. Doi: 10.1016/j.fertnstert.2014.09.032 amongst younger women. Policies need to be revised to 14 Laporte M, Marangoni M Jr, Surita F, Juliato CT, Miadaira M, increase contraception awareness after childbirth, through Bahamondes L. Postplacental placement of intrauterine devices: measures such as family planning groups with pregnant A randomized clinical trial. Contraception. 2020;101(03): women, information sheets and counseling during prenatal 153–158. Doi: 10.1016/j.contraception.2019.12.006 care appointments. 15 Teal SB. Postpartum contraception: optimizing interpregnancy intervals. Contraception. 2014;89(06):487–488. Doi: 10.1016/j. contraception.2014.04.013 Contributions 16 Allen RH, Goldberg AB, Grimes DA. Expanding access to intra- Surita F. G. and Juliato C. R. T. designed the research; data uterine contraception. Am J Obstet Gynecol. 2009;201(05):456. e1–456.e5. Doi: 10.1016/j.ajog.2009.04.027 collection was performed by Kraft M. B. P. L.. Miadaira M., 17 Anpalagan A, Condous G. Is there a role for use of levonorgestrel Marangoni M. Jr.,Kraft M. B. P. L. and Surita F. G. performed intrauterine system in women with chronic pelvic pain? the statistical analysis. Kraft M. B. P. L.wrote the paper; all J Minim Invasive Gynecol. 2008;15(06):663–666. Doi: authors revised this version. Kraft M. B. P. L. and Surita F. G. 10.1016/j.jmig.2008.07.008 had primary responsibility for the final content. 18 Andersson K, Batar I, Rybo G. Return to fertility after removal of a levonorgestrel-releasing intrauterine device and Nova-T.Contracep- tion. 1992;46(06):575–584. Doi: 10.1016/0010-7824(92)90122-a fl Con ict of Interests 19 Ezugwu EC, Achara JI, Ezugwu OC, Ezegwui HU. Acceptance of The authors have no conflict of interests to declare. postpartum intrauterine contraceptive device among women attending antenatal care in a low-resource setting in Nigeria. Int J Gynaecol Obstet. 2020;148(02):181–186. Doi: 10.1002/ References ijgo.13027 1 Sedgh G, Singh S, Hussain R. Intended and unintended pregnan- 20 Da Costa V,Ingabire R, Sinabamenye R, Karita E, Umutoni V, Hoagland cies worldwide in 2012 and recent trends. Stud Fam Plann. 2014; A, et al. An exploratory analysis of factors associated with interest in 45(03):301–314. Doi: 10.1111/j.1728-4465.2014.00393.x postpartum intrauterine device uptake among pregnant women and 2 Henshaw SK. Unintended pregnancy in the United States. Fam couples in Kigali, Rwanda. Clin Med Insights Reprod Health. 2019; Plann Perspect. 1998;30(01):24–29, 46 13:1179558119886843. Doi: 10.1177/1179558119886843 3 Theme-Filha MM, Baldisserotto ML, Fraga ACSA, Ayers S, da Gama 21 Rosenberg MJ, Waugh MS, Long S. Unintended pregnancies and SG, Leal MD. Factors associated with unintended pregnancy in use, misuse and discontinuation of oral contraceptives. J Reprod Brazil: cross-sectional results from the Birth in Brazil National Med. 1995;40(05):355–360

22 Castaño PM, Bynum JY, Andrés R, Lara M, Westhoff C. Effect of placement: a systematic review and meta-analysis. Obstet Gynecol. daily text messages on oral contraceptive continuation: a ran- 2018;132(04):895–905. Doi: 10.1097/AOG.0000000000002822 domized controlled trial. Obstet Gynecol. 2012;119(01):14–20. 26 Kozuki N, Lee AC, Silveira MF, Victora CG, Adair L, Humphrey J, Doi: 10.1097/AOG.0b013e31823d4167 et al; Child Health Epidemiology Reference Group Small-for- 23 Arrowsmith ME, Aicken CRH, Saxena S, Majeed A. Strategies for Gestational-Age-Preterm Birth Working Group. The associations improving the acceptability and acceptance of the copper intra- of birth intervals with small-for-gestational-age, preterm, and uterine device. Cochrane Database Syst Rev. 2012;(03): neonatal and infant mortality: a meta-analysis. BMC Public CD008896. Doi: 10.1002/14651858.CD008896.pub2 Health. 2013;13(Suppl 3):S3. Doi: 10.1186/1471-2458-13-S3-S3 24 Makins A, Taghinejadi N, Sethi M, et al. Factors inﬂuencing the 27 Cleland J, Conde-Agudelo A, Peterson H, Ross J, Tsui A. Contracep- likelihood of acceptance of postpartum intrauterine devices across tion and health. Lancet. 2012;380(9837):149–156. Doi: 10.1016/ four countries: India, Nepal, Sri Lanka, and Tanzania. Int J Gynaecol S0140-6736(12)60609-6 Obstet. 2018;143(Suppl 1):13–19. Doi: 10.1002/ijgo.12599 28 Brito CNO, Alves SV, Ludermir AB, Araújo TVB. Depressão pós- 25 Jatlaoui TC, Whiteman MK, Jeng G, Tepper NK, Berry-Bibee E, parto entre mulheres com gravidez não pretendida. Rev Saude Jamieson DJ, et al. Intrauterine device expulsion after postpartum Publica. 2015;49:33. Doi: 10.1590/S0034-8910.2015049005257

Awareness about Vulvovaginal Aesthetics Procedures among Medical Students and Health Professionals in Saudi Arabia

Shazia Iqbal1 Khalid Akkour2 Bushra Bano3 Ghaiath Hussain4 ManalKhalidKamalAliElhelow5 Atheer Mansour Al-Mutairi5 Balqees Sami Khaza’l Aljasim5

1 Alfarabi College of Medicine Riyadh, Alfarabi, Kingdom of Saudi Arabia Address for correspondence Shazia Iqbal, FCPS, 3830 Al Bahar Al 2 King Saud University, Saudi Arabia Arabi, Ishbiliyah, 7211, Riyadh 13226, Arábia Saudita 3 Allama Iqbal Medical College, Lahore, Pakistan (e-mail: [email protected]). 4 Birmingham University, Birmingham, United Kingdom 5 Department of Clinical Sciences, Alfarabi College of Medicine, Alfarabi, Kingdom of Saudi Arabia

Rev Bras Ginecol Obstet 2021;43(3):178–184.

Abstract Objective The present study aimed to explore the opinion and ethical consideration of vulvovaginal aesthetics procedures (VVAPs) among health professionals and medical students in Saudi Arabia. Methods This is a cross-sectional study performed between January 2020 and April 2020. Data was collected through electronic media, WhatsApp, and emails. The results were analyzed by applying the Students t-test, and correlations were considered significant if they presented a p-value < 0.05. Results There is significant demand to educate doctors, health professionals, medical students, and gynecologists for the VVAPs to have a solid foundation, justified indications, and knowledge about various aesthetic options. Although female doctors, medical students, young doctors, and gynecologists have more knowledge about VVAPs, all health Keywords professionals ought to be aware of recent trends in vulvovaginal aesthetics (VVA). The ► vulvovaginal present analysis determined that VVA should be under the domain of gynecologists, rather cosmetic procedures than under that of plastic surgeons, general surgeons, and cosmetologists. The majority of ► vulvovaginal the participants considered that vaginal rejuvenation, “G-spot” augmentation, clitoral aesthetics procedures surgery, and hymenoplasty are not justifiable on medical grounds. ► awareness about Conclusion The decision to opt for different techniques for vaginal tightening and aesthetic surgery revitalization should be taken very carefully, utilizing the shared decision-making among health approach. Ethical aspects and moral considerations are important key factors before professionals embarking in the VVAPs purely for cosmetic reasons. Further research is required to ► aesthetic gynecology determine the sexual, psychological, and body image outcomes for women who ► sexual and underwent elective VVAPs. Moreover, medical educators must consider VVAPs as part reproductive health of the undergraduate and postgraduate medical curriculum.

received DOI https://doi.org/ © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights May 27, 2020 10.1055/s-0041-1725050. reserved. accepted ISSN 0100-7203. This is an open access article published by Thieme under the terms of the December 3, 2020 Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda., Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil Awareness about Vulvovaginal Aesthetics Procedures Iqbal et al. 179

Introduction about the perceptions of healthcare professionals and medical students in a geographical region. It will help to analyze the Presently, vulvovaginal aesthetics procedures (VVAPs) diverse cultural context about familiarity and the impact of are being marketed and promoted by surgeons, while the VVAPs procedures in a medical and ethical context. The present evidence of their safety and efﬁcacy is still questionable. There study aimed to explore the awareness of VVAPs among health are serious concerns regarding medical ethics, morals, and professionals and medical students in Saudi Arabia. principles about aesthetic procedures in gynecology. Evidence- based recommendations for these aesthetic procedures are Methods scarce. There are no clear guidelines nor convincing pieces of evidence to consider the implications of this practice. There are We conducted a cross-sectional study by designing a compre- only a few studies that addressed the concerns of perimen- hensive Google Docs survey, and descriptive analysis was opausal women regarding reproductive health and sexual performed. We conducted the present study between January health.1,2 Additionally, there is a lack of research that mentions 2020 and April 2020, in Saudi Arabia. The internal reviewer the concerns of women in postoperative vulvovaginal oncology board of the research unit approved the study at the Alfarabi cases to preserve the quality of sexual well-being.3 College of Medicine Riyadh. We distributed the survey through Recently, there is a dramatic change in trends of genital electronic media, WhatsApp, and emails. All participants were aesthetics in a different part of the word.4 In a fewcountries, the informed about the aim of the study, and we explained a brief use of laser treatment for vaginal rejuvenation and tightening is description of the purpose of the study. The participants trendy and effective.5 A variety of procedures has emerged, declared consent for contribution before ﬁlling the survey. A including reduction labiaplasty, hymenoplasty, G-spot augmentation, and vaginal laxity. Moreover, many nonsurgical Table 1 Sociodemographic characteristics of 260 participants procedures are being promoted as simple, safe, and as improving sexual pleasure worldwide. In the middle east, little is Characteristics of Frequency Percentage researched regarding awareness of vulvovaginal aesthetic participants (n ¼ 260) (VVA) procedures among health professionals. Moreover, Gender time demands to examine the indications and the standardization of training for gynecologists regarding the awareness of Male 53 21% different indications and a vast range of VVAPs. Female 207 79.6% In the perimenopausal age group, genitourinary problems Age (years old) are common in the form of vaginal atrophy, laxity, vulvovaginal 20–25 165 63.4% prolapse, vulval burning pain, urinary incontinence, etc. These 26–40 75 28.8% changes lead to low self-esteem and reduce the quality of sexual 41–50 15 5.7% health among some women. We have observed the various nonsurgical and surgical treatment options in the practice; for > 50 5 1.9% example, the use of polycarbophil-based cream in postmeno- Working in Region pausal women, vaginal tightening by lasers, and surgical pro- Central area 161 61.9% cedures.6 To treat lichen sclerosis and lichen planus, some Southern area 65 25.0% studies suggested the use of autologous platelet-rich plasma Western area 27 10.3% intradermal injections to treat vulval lichen sclerosis.7 Various therapeutic options have been adopted by health care providers Eastern area 4 1.5% for treating vaginal atrophy to improve the quality of sexual Northern area 3 1.1% health; for example, injectable hyaluronic acid plus calcium Educational level – hydroxyapatite along with different surgical options.8 10 Medical students 117 45% There is a considerable gap in research to assess the MBBS Graduates 48 18.4% readiness of health care professionals before embarking in the aesthetic procedures and in the practice on patients. The Postgraduate 35 13.4% trainee gynecology present article explored the responsiveness of health professionals and medical students about VVA procedures in Postgraduate 30 11.5% trainee surgery Saudi Arabia. The authors will recommend a model for the enhancement of knowledge and awareness about VVAPs Consultant 20 7.6% gynecology among health providers. There is hardlyany data that support the awareness of VVAPs Other specialties 10 3.8% procedures in the Middle East and Saudi Arabia. Regarding Duration of ethical concerns related to VVAPs, it is important to inquire in employment (years) their own culture and Islamic region.11 Cultural beliefs play a 1–517165.7% great impact in the adoption of recent trends in aesthetic 5–10 69 26.5% gynecology and implement evidence-based practice. Along > 10 20 7.6% with awareness of the patients, it isequally important to inquire

descriptive analysis of the results was performed, and • fi we presented statistics in graphs and charts. To determine It is not justi able • fi correlations, the results were analyzed by applying the It is rarely justi able • fi Students t-test, and we considered correlations as being It is justi able • fi significant if they presented a p-value < 0.05. The internal It is highly justi able reviewer board of the research unit approved the study at The authors questioned the participants about the possible Alfarabi College of Medicine Riyadh. benefits of VVAPs, and we assessed general proclamations and All practicing Saudi medical licensed (SML) medical doc- guidance on this topic in the third section. Regarding practical tors, Saudi registered health professionals, consultants of all issues about the VVAPs (minimum age of performance, whether specialties, residents, registrars, and medical students in it should be performed in public hospitals, etc.), an evaluation Saudi Arabia in the public and private sectors. We included was made using a four-point Likert scale with the following medical students of public and private medical schools. Any options: nonpracticing doctor out of practice for > five years was • Agree excluded from the study, considering their lack of knowledge • Partially agree regarding the health updates on reproductive and sexual • Neither agree nor disagree (neutral) health. We also excluded paramedical staff and allied health • Disagree professionals. The authors of the present study prepared a research questionnaire, and a pilot study established the Concerning the sample collection, we collected data from validity of this questionnaire on 70 participants to establish 260 participants among the 350 expected participants. After significant findings. We divided the questionnaire into three the third reminder, the response rate was of 74%, which was sections, and each section had an elaborated description considered acceptable to establish results. mentioning the facts and purpose of the study. The first section regarded demographic details including age, gender, Results level of qualification, employability status, years of working experiences as a health professional, specialty type, and the Regarding the demographic data, 72.9% were < 25 years old category of health sectors (public or private). (freshmen residents, medical students). More than half of The opinions of the participants about any medical justifi- them (65.7%) had < 5 years ofexperience working in thehealth cation and ethical objections against VVAPswere mentioned in profession. Among the 260 participants of the study, most of the second section. Some details and clarifications about the them were female (79.6%) and worked in public hospitals procedures were explained to the participants. The four-point (60.31%). Most of them were medical students (45%), followed Likert scale was used in the survey. We asked the participants by gynecology trainees (13.4%), and gynecology consultants to answer whether several VVAPs were medically justifiable, (7.6%). ►Table 1 summarizes the sociodemographic character- with the following answer options: istics of the participants.

Fig. 1 Percentage of participant’sopinionaboutthejustiﬁcation of various vulvovaginal aesthetics procedures on medical grounds (n ¼ 260).

Fig. 2 Percentage of participant’s opinion about the justiﬁcation of various vulvovaginal aesthetics procedures on an ethical basis (n ¼ 260).

About 68.7% of the participants did not have much considered that vaginal rejuvenation, “G-spot” augmenta- knowledge about VVAPs. More than half of the participants tion, clitoral surgery, and hymenoplasty are not justiﬁable on agreed that VVAPs on medical grounds is justiﬁed for vaginal medical grounds, as shown in ►Fig. 1. tightening (by laser), vaginal atrophy (by laser) and whiten- Regarding ethical considerations, more than half of the ing of the vulva. However, the majority of the participants participants considered that vaginal rejuvenation, “G-spot”

Table 2 Percentage of participants who considered that vulvovaginal aesthetics procedures should be performed by gynecologists (n ¼ 260)

VVAPs Private practice Specialty % Yes No p-value ObGyn Plastic surgery Other surgical p-value Hymenoplasty 56.6% 43.1% 0.051 29.6% 8.3% 22.0% 0.025 Augmentation of the labia minora 73.2% 36.9% 0.030 41.3% 12.5% 25.0% 0.021 “G-spot” augmentation 60.1% 39.2% 0.051 49.3% 12.5% 21.3% 0.011 Clitoral surgery 48.3% 41.0% 0.041 44.9% 16.7% 22.9% 0.014 Vaginal rejuvenation 42.8% 14.9% 0.022 54.3% 16.7% 24.1% 0.021 Augmentation of the labia majora 45.3% 41.9% 0.052 51.5% 13.6% 28.4% 0.025 Mons pubis liposuction 42.5% 50.0% 0.059 56.5% 17.4% 37.0% 0.025 Laser Vaginal tightening 52.1% 35.1% 0.041 57.8% 26.1% 21.0% 0.001 Whitening 49.2% 47.3% 0.057 68.0% 30.4% 12.9% 0.001 Vaginal laser (atrophy) 38.5% 60.7% 0.560 65.0% 37.5% 18.1% 0.003

Abbreviation: VVAPs, vulvovaginal aesthetic procedures.

Table 3 Percentage of participants’ opinion about vulvovaginal aesthetics procedures enhancing the quality of life and correlation between difference of opinion among different health professionals (n ¼ 260)

VVAPs Considering plastic surgery % Health professionals opinion about VVAPs enhancing quality of life Yes Medical students Residents Specialists p-value Hymenoplasty 24.6% 55.8% 34.6% 21.1% 0.048 Augmentation of the labia minora 38,2% 53.8% 31.3% 21.1% 0.001 “G-spot” augmentation 39.1% 37.7% 22.7% 30.6% 0.001 Clitoral surgery 26.3% 45.1% 35.0% 24.2% 0.015 (Continued)

Table 3 (Continued)

VVAPs Considering plastic surgery % Health professionals opinion about VVAPs enhancing quality of life Yes Medical students Residents Specialists p-value Vaginal rejuvenation 31.4% 45.6% 27.6% 24.2% 0.005 Augmentation of the labia majora 66.1% 56.8% 30.5% 21.4% 0.043 Mons pubis Liposuction 66.5% 60.8% 30.1% 31.8% 0.051 Laser Vaginal tightening 69.5% 62.9% 26.1% 36.0% 0.013 Whitening 74.2% 64.9% 23.7% 17.0% 0.057 Vaginal laser (atrophy) 84.9% 71.8% 20.7% 26.7% 0.013

Abbreviation: VVAPs, vulvovaginal aesthetic procedures.

augmentation, clitoral surgery, and hymenoplasty are not The present study determined that health professionals ethically accepted, as shown in ►Fig. 2. It was determined perceived that VVAPs improve the quality of sexual health and that aesthetic procedures should be performed by gynecolo- reduce female sexual dysfunctions.16 Therefore, they would gists rather than by plastic surgeons or general surgeons recommend these procedures to indicated patients. Addition- (p < 0.025), as shown in ►Table 2. According to the opinion ally, the results revealed that, in our conservative culture, of the participants, VVAPs related to vaginal tightening and aesthetic deprivation was observed in general among health vaginal atrophy are associated with enhanced self-esteem and providers.17 Therefore, health providers need to enhance quality of reproductive/sexual life (p < 0.013), as shown awareness about the variety of procedures and improve their in ►Table 3. However, almost all specialty consultants consid- counseling skills to determine the impact of the decision to ered that VVAPs are overpriced procedures. However, there submit patents to surgery on the psychological and sexual was no significant difference in the opinions of private and well-being of the patients.18 Particularly, VVAPs recommen- public health professionals regarding the pricing of different dations for uterovaginal prolapse and postoperative oncology VVAPs (p ¼ 0.05). cases should be justified to boost the self-esteem of the patients.19,20 Discussion The present analysis determined that VVAought to be under the domain of gynecologists rather than under those of plastic Currently, women are facing a dilemma regarding freedom of surgeons and cosmetologists.21,22 Moreover, the decision to choice related to a long list of VVAPs and female genital opt for different techniques for vaginal tightening and revitali- cosmetic surgery. Some procedures are indicated on medical zation should be taken very carefully, utilizing the shared grounds but are not ethically accepted in the region. Our decision-making approach.15 Ethical aspects and moral research found that there is a significant demand to educate considerations arekey pointsto keep inmind before embarking doctors, health professionals, medical students, and gynecol- in the VVAPs purely for cosmetic reasons.23 The decision about ogists regarding VVAPs in order to have a solid foundation, VVAPs in menopausal women needs special considerations, justified indications, and knowledge about various aesthetic and one must give priority to conservative management rather options. Skilled health professionals should have optimal than to surgery.24,25 There should be evidence-based guide- expertise to test signs and symptoms of the patients and lines and algorithms to be followed by practitioners to help in involve a multidisciplinary health team for management.12 decisions regarding VVAPs.14,26,27 Although medical students, young doctors, and gynecologists The authors have suggested the step-by-step approach for have more knowledge about VVAPs, all health professionals the enhancement of awareness about VVAPs in medical must know recent trends in VVA.13,14 education. It would be better to incorporate VVAPs in the Regarding the ethical aspects of VVAPs, our results medical curriculum and postgraduate training, since many are consistent with the Royal College of Obstetrics and courses are spreading medical knowledge of marketing and Gynecology.15 This analysis recommends that ethical conflict of interests. In medical schools, there is a need to opinion for patients opting for female genital cosmetic integrate the course about aesthetics surgery, especially at procedures needs to be discussed carefully with microscopic the clerkship phase, as shown in ►Fig. 3. details and should be opted only for indicated patients; for Furthermore, during the clinical rotations for medical example, if sexual health is compromised physically (atrophy students, there must be an option for rotation to aesthetic or laxity) and psychologically. Although the health profes- gynecology clinics. During postgraduate training, there sionals had below-average knowledge about different types should be the choice of attachments at VVA clinics for of procedures, the majority had a positive attitude toward gynecology trainees. Besides, the arrangements of multidis- female genital cosmetic surgery if the concerns of the patient ciplinary meetings (gynecology, cosmetology, plastic sur- are associated with sexual and psychological satisfaction. gery) can help the postgraduate trainee to develop the

Fig. 3 Step by step integration of awareness and knowledge about vulvovaginal aesthetics procedures in medical education. skills of decision making about different procedures based on Conclusion the signs and symptoms of the patients. The arrangements of workshops and conferences on VVAPs can enhance knowl- Vulvovaginal aesthetics procedures have gained significant edge and provide opportunities for health professionals to popularity among health professionals, different media exchange their views. Clinical training in the VVAPs subspe- platforms, and patients. In the reproductive age group, this cialty in the form of VVAPs courses, medical ethics VVAPs topic has appeared as a fascinating area for discussion to courses, and regular awareness campaigns can enhance increase self-esteem, and to rejuvenate genitals for the education among health professionals. improvement of sexual function. The present study aimed to explore the awareness of VVAPs among health professionals Challenges and medical students in Saudi Arabia. There is a significant demand to educate doctors, health professionals, medical Currently, the biggest challenge for health professionals is the students, and gynecologists for the VVAPs to have a solid business model approach to VVAPs. The business of pursuing foundation, justified indications, and knowledge about various beauty for a perfect body can go further than the body- aesthetic options. Skilled health professionals should have improving productsand practices. For somewomen, modifying optimal expertise to evaluate the clinical picture of the their bodies has become normalized, and “designer vagina” has patients and involve multidisciplinary health teams for man- become a public word, increasing the trend for female genital agement. Although female doctors, medical students, young cosmetic surgery.25 Mostly, women are being misled about the doctors, andgynecologists have moreknowledge about VVAPs, normal appearance of genitalia and its normal variations, all health professionals ought to be aware of recent trends in desiring a pre-pubertal, doll-like look, with nonapparent labia VVA. This analysis determined that VVA should be under the minora (not having it projected beyond the labia majora), no domain of gynecologists domain rather than under those of excess skin on the clitoris head, not much fat over the mons plastic surgeons, general surgeons, and cosmetologists. Most pubis, etc. This misleading is eventually showing the lack of of the participants considered that vaginal rejuvenation, awareness of treating physicians and healthcare providers “G-spot” augmentation, clitoral surgery, and hymenoplasty rather than of patients. Being medical educators, we must are not justifiable on medical grounds. Regarding ethical opt for an evidence-based approach to create awareness among considerations, more than half of the participants considered health providers and the public rather than support the that vaginal rejuvenation, “G-spot” augmentation, clitoral business model. Further research is required in order to surgery, and hymenoplasty are not ethically accepted. Addi- determine the sexual, psychological, and body image outcomes tionally, the decision to opt for different techniques for vaginal for women who underwent elective VVAPs. It is imperative to tightening and revitalization should be taken very carefully, determine the benefits and impacts on sexual satisfaction, and utilizing the shared decision-making approach. Ethical aspects the need for assessment of functional disorders before surgery. and moral considerations are important key factors before There is a requirement to conduct a qualitative and in-depth embarking in VVAPs purely for cosmetic reasons. Further analysis to inquire about the reasons for ethical and medical research is required to determine the sexual, psychological, justifications based on personal and cultural beliefs and body image outcomes for women who underwent elective regarding VVAPs. VVAPs. It is imperative to determine the benefits and impacts

on sexual satisfaction postoperatively. Medical educators must 12 Hodžić S Ascertaining deadly harms: aesthetics and politics of consider VVAPs as part of the undergraduate and postgraduate global evidence. Cult Anthropol. 2013;28(01):86–109. Doi: curriculum in order to enhance awareness among medical 10.1111/j.1548-1360.2012.01174.x 13 Vieira-Baptista P, Lima-Silva J, Fonseca-Moutinho J, Monteiro V, professionals. Águas F. Survey on aesthetic vulvovaginal procedures: what do Portuguese doctors and medical students think? Rev Bras Ginecol Contributors Obstet. 2017;39(08):415–423. Doi: 10.1055/s-0037-1603967 All authors were involved in the design and interpretation 14 Weinberger JM, Houman J, Caron AT, Anger J. Female sexual of the analyses, contributed with the writing of the dysfunction: a systematic review of outcomes across various – manuscript, read and approved the final manuscript. treatment modalities. Sex Med Rev. 2019;7(02):223 250. Doi: 10.1016/j.sxmr.2017.12.004 15 Royal College of Obstetricians and Gynaecologists. Ethical opinion fl Con ict of Interests paper: ethical considerations in relation to female genital cos- The authors have no conflict of interests to declare. metic surgery (FGCS) [Internet]. London:RCOG Ethics Commit- tee;2013 Oct [cited 2020 May 27]. Available from: https://www. Acknowledgments rcog.org.uk/globalassets/documents/guidelines/ethics-issues- and-resources/rcog-fgcs-ethical-opinion-paper.pdf We would like to thank the medical students of the 16 Weinberger JM, Houman J, Caron AT, Patel DN, Baskin AS, Ackerman Alfarabi College of Medicine for their active participation AL, et al. Female sexual dysfunction and the placebo effect: a meta- in the present research. analysis. Obstet Gynecol. 2018;132(02):453–458. Doi: 10.1097/ AOG.0000000000002733 17 Moss H, O’Neill D. Aesthetic deprivation in clinical settings. Lancet. References 2014;383(9922):1032–1033. Doi: 10.1016/s0140-6736(14)60507-9 1 Alvisi S, Gava G, Orsili I, Giacomelli G, Baldassarre M, Seracchioli R, 18 Preti M, Vieira-Baptista P, Digesu GA, Bretschneider CE, Damaser et al. Vaginal health in menopausal women. Medicina (Kaunas). M, Demirkesen O, et al. The clinical role of LASER for vulvar and 2019;55(10):615. Doi: 10.3390/medicina55100615 vaginal treatments in gynecology and female urology: An 2 Caruso S, Cianci S, Fava V, Rapisarda AMC, Cutello S, Cianci A. ICS/ISSVD best practice consensus document. Neurourol Urodyn. Vaginal health of postmenopausal women on nutraceutical con- 2019;38(03):1009–1023. Doi: 10.1002/nau.23931 taining equol. Menopause. 2018;25(04):430–435. Doi: 10.1097/ 19 Peiretti M, Corvetto E, Candotti G, Angioni S, Figus A, Mais V. New GME.0000000000001061 Keystone flap application in vulvo-perineal reconstructive sur- 3 Cox P, Panay N. Vulvovaginal atrophy in women after cancer. Climac- gery: A case series. Gynecol Oncol Rep. 2019;30:100505. Doi: teric. 2019;22(06):565–571. Doi: 10.1080/13697137.2019.1643180 10.1016/j.gore.2019.100505 4 Desai SA, Dixit VV. Audit of female genital aesthetic surgery: 20 Rubinsak LA, Christianson MS, Akers A, Carter J, Kaunitz AM, changing trends in India. J Obstet Gynaecol India. 2018;68(03): Temkin SM. Reproductive health care across the lifecourse of the 214–220. Doi: 10.1007/s13224-018-1115-7 female cancer patient. Support Care Cancer. 2019;27(01):23–32. 5 Benincà G, Bosoni D, Vicariotto F, Raichi M. Efficacy and safety of Doi: 10.1007/s00520-018-4360-5 dynamic quadripolar radiofrequency, a new high-tech, high- 21 Pinto H, Fontdevila J, Eds. Regenerative medicine procedures for safety option for vulvar rejuvenation. Obstet Gynecol Rep. aesthetic physicians. Cham: Springer; 2019 2017;1(03):1–5. Doi: 10.15761/OGR.1000115 22 Placik OJ, Devgan LL. Female genital and vaginal plastic surgery: 6 Yodplob T, Sirisopana K, Jongwannasiri M, Sirisreetreerux P, an overview. Plast Reconstr Surg. 2019;144(02):284e–297e. Doi: Viseshsindh W, Kochakarn W. Local treatment with a polycarbo- 10.1097/PRS.0000000000005883 phil-based cream in postmenopausal women with genitourinary 23 Rabley A, O’Shea T, Terry R, Byun S, Louis Moy M. Laser therapy for syndrome of menopause. Int Urogynecol J Pelvic Floor Dysfunct. genitourinary syndrome of menopause. Curr Urol Rep. 2018;19 2020;•••;. Doi: 10.1007/s00192-020-04282-9 (10):83. Doi: 10.1007/s11934-018-0831-y 7 Goldstein AT, Mitchell L, Govind V, Heller D. A randomized 24 Schiavi MC, Di Tucci C, Colagiovanni V, Faiano P, Giannini A, D’Oria double-blind placebo-controlled trial of autologous platelet- O, et al. A medical device containing purified bovine colostrum rich plasma intradermal injections for the treatment of vulvar (Monurelle Biogel) in the treatment of vulvovaginal atrophy in lichen sclerosus. J Am Acad Dermatol. 2019;80(06):1788–1789. postmenopausal women: Retrospective analysis of urinary symp- Doi: 10.1016/j.jaad.2018.12.060 toms, sexual function, and quality of life. Low Urin Tract Symp- 8 Amori P, Di Nardo V, Vitiello G, Franca K, Hercogova J, Wollina U, toms. 2019;11(02):O11–O15. Doi: 10.1111/luts.12204 et al. Primavera: A new therapeutical approach to vulvo-vaginal 25 Royal Australian College of General Practitioners. Female genital atrophy. Dermatol Ther (Heidelb). 2018;31(06):e12678. Doi: cosmetic surgery - A resource for general practitioners and other 10.1111/dth.12678 health professionals [Internet]. MelbourneRACGP2015 [cited 9 Cohen PR. Genital rejuvenation: the next frontier in medical and 2020 May 5]. Available from: https://www.racgp.org.au/clini- cosmetic dermatology. Dermatol Online J. 2018;24(09):13030 cal-resources/clinical-guidelines/key-racgp-guidelines/view-all- 10 González IP, Leibaschoff G, Esposito C, et al. Genitourinary syn- racgp-guidelines/female-genital-cosmetic-surgery drome of menopause and the role of biostimulation with non- 26 VanderBrink BA, Stock JA, Hanna MK. Aesthetic aspects of recon- cross-linked injectable hyaluronic acid plus calcium hydroxyapa- structive clitoroplasty in females with bladder exstrophy-epis- tite. J Biol Regul Homeost Agents. 2019;33(06):1961–1966. Doi: padias complex. J Plast Reconstr Aesthet Surg. 2010;63(12): 10.23812/19-251-L 2141–2145. Doi: 10.1016/j.bjps.2010.02.005 11 Figo Committee For The Ethical Aspects Of Human Reproduction 27 Reichman O, Margesson LJ, Rasmussen CA, Lev-Sagie A, Sobel JD. And Women’s Health. Ethical considerations regarding requests Algorithms for managing vulvovaginal symptoms-a practical and offering of cosmetic genital surgery. Int J Gynaecol Obstet. primer. Curr Infect Dis Rep. 2019;21(10):40. Doi: 10.1007/ 2015;128(01):85–86. Doi: 10.1016/j.ijgo.2014.10.003 s11908-019-0693-6

Switching of Hormone Therapies in Breast Cancer Women Avaliação da mudança do esquema hormonioterápico em mulheres com câncer de mama

Luana Moreira de Medeiros1 Rebeca Stahlschmidt2 Amanda Canato Ferracini2 Cinthia Madeira de Souza2 Cassia Raquel Teatin Juliato3 Priscila Gava Mazzola1

1 Faculty of Pharmaceutical Sciences, Universidade de Campinas Address for correspondence Amanda Canato Ferracini, Pharmacist, (Unicamp), Campinas, SP, Brazil PhD candidate, Rua Tessália Vieira de Camargo, 126, Cidade 2 Graduate Program in Medical Sciences, Faculty of Medical Sciences, Universitária “Zeferino Vaz,” Campinas, SP, 13083-887, Brazil Universidade de Campinas (Unicamp), Campinas, SP, Brazil (e-mail: [email protected]). 3 Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Universidade de Campinas (Unicamp), Campinas, SP, Brazil

Rev Bras Ginecol Obstet 2021;43(3):185–189.

Abstract Objective The objective of the present study was to analyze the reasons that led to hormone therapies (HTs) regimen changes in women with breast cancer. Methods This was a retrospective cross-sectional study from a single-institution Brazilian cancer center with patient records diagnosed with breast cancer between January 2012 and January 2017. Keywords Results From 1,555 women who were in treatment with HT, 213 (13.7%) women had ► breast cancer HT switched, either tamoxifen to anastrozole or vice-versa. Most women included in ► tamoxifen the present study who switched HT were > 50 years old, postmenopausal, Caucasian, ► hormone therapy and had at least one comorbidity. From the group with therapy change, ‘disease ► aromatase inhibitor progression’ was reason of change in 124 (58.2%) cases, and in 65 (30.5%) patients, ► anastrozole ‘presence of side effects’ was the reason. From those women who suffered with side effects, 24 (36.9%) had comorbidities. Conclusion The present study demonstrated a low rate of HT switch of tamoxifen to anastrozole. Among the reasons for changing therapy, the most common was disease progression, which includes cancer recurrence, metastasis or increased tumor. Side effects were second; furthermore, age and comorbidities are risk factors for side effects.

Resumo Objetivo O objetivo do presente estudo foi analisar os motivos que levaram às mudanças no esquema hormonioterápico (HT) em mulheres com câncer de mama. Métodos Estudo transversal retrospectivo realizado no Hospital da Mulher de Campinas e consequente pesquisa de prontuários de mulheres diagnosticados com câncer de mama entre janeiro de 2012 e janeiro de 2017.

received DOI https://doi.org/ © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights July 4, 2020 10.1055/s-0040-1719149. reserved. accepted ISSN 0100-7203. This is an open access article published by Thieme under the terms of the September 21, 2020 Creative Commons Attribution License, permitting unrestricted use, published online distribution, and reproduction so long as the original work is properly cited. January 19, 2021 (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda., Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil 186 Switching of Hormone Therapies in Breast Cancer Women Medeiros et al.

Resultados De 1.555 mulheres em tratamento com HT, 213 (13,7%) mulheres tiveram HT alterado, tamoxifeno para anastrozol ou vice-versa. A maioria das mulheres incluídas no presente estudo que tiveram mudança de HT tinha > 50 anos, estava na pós-menopausa, era caucasiana e tinha pelo menos uma comorbidade. Os principais motivos de troca de HT foram devido a ’progressão da doença’, ocorrendo em 124 Palavras-chave (58,2%) casos e a ’presença de efeitos colaterais’ (n ¼ 65; 30,5%). Das mulheres que ► câncer de mama sofreram efeitos colaterais, 24 (36,9%) apresentaram comorbidades. ► tamoxifeno Conclusão O presente estudo demonstrou uma baixa taxa na alteração de tamoxi- ► terapia hormonal feno para anastrozol. Entre as razões mais comuns para alterar a HT estava a progressão ► inibidor da da doença, que inclui recorrência do câncer, metástase ou aumento do tumor. Os aromatase efeitos colaterais foram a segunda causa e, além disso, a idade e as comorbidades ► anastrozol foram fatores de risco para efeitos colaterais.

Introduction anastrozole or vice-versa.8 The exclusion criterionwas medical records that did not describe the reason for change in therapy. Breast cancer (BC) is the most common type of gynecological The present study was approved by the Research Ethics cancer, and it is the highest cancer-related cause of death among Committee (CAAE: 54977116.0.0000.5404). All procedures them.1 Oncological therapy includes surgery, radiotherapy and were performed according to the 1946 Helsinki Declaration systemic therapy, as chemotherapy and hormone therapy.2 The patients (or a legal responsible) authorized access to Hormone therapy (HT), such as anastrozole and tamoxifen, is their computed record containing information about pick up used for patients whose tumor is positive for estrogen receptor, of HT. Changes in the dispensation pattern was the trigger to which reaches 70% of BC cases. These tumors grow and prolif- analyze medical records. Researchers did not evaluate or erate as a result of estrogen action on its receptors.3 follow the prescribed change in the treatment. Other data According to international guidelines, HT is an extensive such as age, ethnicity, menopausal state, onset of treatment, treatment with duration of 5 to 10 years, and adherence and date of treatment change, reason(s) for change, presence of adequate treatment duration is crucial to the effectiveness of comorbidities, which change of treatment occurred, and date the treatment. Although these classes of drugs are well tolerat- of death, if it occurred, were obtained from the clinical files. ed, the drug-related side effects are one of the most important Disease progression was considered cancer recurrence, at – causes for non-adherence or treatment discontinuation.4 6 least 20% increase in tumor or more, new lesions and metas- Although there are options to investigate symptoms re- tasis to other locations. Overall survival (OS) was calculated as lated to side effects, for which medication switch is one of the the number of months from cancer diagnosis to death or the strategies, causes of these changes and its relationship with last follow-up.9 patient outcomes in therapy are still poorly studied. Because Side effects were categorized according to the Common HTs are commonly dispensed through pharmacy channels, Terminology Criteria for Adverse Events (CTCAE) Version 5.0: their significant potential adverse events, adherence, and cardiac disorders (ischemic events), eye disorders (cataract, high patient self-management requirements suggest the glaucoma and blurred vision), gastrointestinal disorders (nau- clinical pharmacist to drug therapy management.7 In the sea, vomit, diarrhea, esophageal pain), general disorders and present study, we aimed to access the reasons for changes in administration site conditions (fatigue), musculoskeletal and the HT regimen in patients treating BC. Then, we evaluate its connective tissue disorders (arthralgia, chest wall pain, pain in frequency and its relationship with disease progression, side extremity, myalgia), nervous system disorders (stroke, head- effects and comorbidities. ache, peripheral motor neuropathy), reproductive system and breast disorders (vaginal hemorrhage, vaginal discharge), skin Methods and subcutaneous tissue disorders (pruritus, rash maculopap- ular, dry skin and hyperpigmentation), and vascular disorders This was a cross-sectional study. Data was collected from (thromboembolic events, hot flashes, phlebitis).10 In cases of computed records from January 2012 to January 2017, at the side effects not categorized in this reference (i.e.: criterion of Hospital da Mulher of the Universidade de Campinas (UNI- classification is not specific to tamoxifen or anastrozole), these CAMP, in the Portuguese acronym), Brazil, a public hospital were classified as “without classification.” specialized in women’s health, being a referral center in the After data collection, statistical analysis was performed. The region for the treatment of women with BC. The inclusion chi-squared test was used for categorical variables, and the criteria were medical records from: women > 18 years old Mann-Whitney test for numeric variables. To describe the with a diagnosis of BC (any stage of the disease), treated with sample profile, data was organized in tables to obtain absolute tamoxifen or anastrozole, accompanied at the hospital, and frequency and percentage. Associations were analyzed among who had change of treatment with HT out of the suggested (1) comorbidities with side effects and treatment duration; (2) period of the international protocol, either from tamoxifen to side effects; and (3) disease progression. When two side effects

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. SwitchingofHormoneTherapiesinBreastCancerWomen Medeiros et al. 187 occurred for the same patient and both were decisive factors Table 2 Reasons for change in hormone therapy for the change in therapy, they were amounted as two symptoms. The Cox hazards model was used to identify variables Modification n % that predict OS analysis. Calculations were performed using Reason of change fi hazard ratio (HR) values and 95% con dence intervals (95% Disease progression 124 58.2 CIs). Differences were significant when p < 0.05. Side effect 65 30.5 Risk 11 5.2 Results Non-adherence 5 2.3 From 1,555 women treated with HT, 213 (13.7%) underwent Confirmation of menopause 4 1.9 a HT change. Most of the women included in the present Others 4 1.9 study who switched HT were > 50 years old, the average age Total 213 100 was 61.4 13.7, postmenopausal, Caucasian, and had at least one comorbidity (►Table 1). Forty-nine women died. Risk of patient sufferiing side effects due to her comorbidities. Most of the patients included in the present study, 208 (97.7%), changed tamoxifen to anastrozole therapy, and only Table 3 Characteristics and frequency of side effects, according 5 (2.3%) women changed anastrozole to tamoxifen. The to the Common Terminology Criteria of Adverse Events major reason for treatment changes was disease progression like cancer recurrence, increased tumor or metastasis, 124 Side effects n (%) (58.2%), followed by side effects, 65 (30.5%). The category “confirmation of menopause” aimed to Vascular disorders 19 29.2 confirm menopausal status either because the patient Without classification 14 21.5 reached menopause naturally or caused by ovarian ablation, Skin and subcutaneous tissue disorders 6 9.2 which is one of the reasons for changing therapy from Musculoskeletal and connective 69.2 tamoxifen to anastrozole. tissue disorders “ ” The category risk included patients who presented Gastrointestinal disorders 6 9.2 comorbidities that could increase the risk of some side Nervous system disorders 4 6.2 effects, such as cardiovascular problems, endometrial thick- ening, or osteoporosis. The category “others” included Reproductivesystemandbreastdisorders 4 6.2 women who had changes in therapy, either because they Eye disorders 3 4.6 reached the total time of the treatment protocol, had drug General disorders and administration 34.6 interaction, advanced age or allergies (►Table 2). The main site conditions side effects are described in ►Table 3, the most common Cardiac disorders 2 3.1 fi being vascular disorders, without classi cation, followed by Total to calculate percentage considered 65 patients, since 2 patients skin and cutaneous disorders. had two different types of side effects decisive to change their therapy. The correlation among disease progression, side effects Side effects not classified by Common Terminology Criteria of Adverse and treatment time was analyzed. Patients who suffered Events (CTCAE) version 5.0.

Table 1 Demographic characteristics of the study population

Characteristic n (%) disease progression had an average of duration of treatment Age (years old) until the switch of therapy of 20.5 13.3 months, and 20–49 37 17.4 patients who presented side effects had an average duration of treatment until the switch of therapy of 12.4 10.9 50 176 82.6 months, with p-value ¼ 0.0030. Patients who presented Ethnicity side effects were also older (65.4 13.1 years old) than Caucasian 185 86.9 women who did not present side effects (59.6 13.7 years Non-caucasian 28 13.1 old), with p-value ¼ 0.0001. Menopause status The relationship between comorbidities and side effects also was evaluated. From 65 women, 48 (73.8%) who pre- Premenopausal 49 23 sented side effects had at least one comorbidity, indicating Postmenopausal 154 72.3 that comorbidity might be a risk factor for side effects Ignored 10 4.7 (p ¼ 0.0544). Twenty-four out of 65 (36.9%) women had at Comorbidity least 1 side effect-related comorbidity. Thus, a correlation Yes 137 64.3 between comorbidity related to its side effect and the adverse event was determined (p ¼ 0.0002). No 76 35.7 Women who had side effects were older and had less Comorbidity is all diseases besides breast cancer. treatment time (p ¼ 0.0030). Thus, their age can be a risk

factor for side effects and the side effect itself hinders the comorbidities that increase the risk of side effects, and had women to proceed with the treatment even if it had been their treatment switched preventing severe adverse events. effective. In this group, statistical analysis also demonstrated The retrospective design of the present study is a limita- that it took at least 12 months of treatment to occur a side tion. The routine professional practice, such as HT manage- effect was incompatible with continuing with the therapy. ment by a pharmacist, is essential to evaluate the causes of Furthermore, women who switched HT and presented dis- these changes and its relationship with patient outcomes. In ease progression had more risk of death than women who this context, prospective and clinical studies should be had side (HR: 4.112; 95% CI 1.732–9.761). conducted to analyze other variables. The present study evidences better understanding and Discussion knowledge of changes in HT regimen and that healthcare professionals, including pharmacists, should be more atten- The present study showed that 13 in 100 women switched tive to the comorbidities of their patients and other clinical their HT for BC treatment. These changes were related to factors, since these elements can increase the risk of the disease progression, comorbidities and side effects. A similar occurrence of a serious adverse event that can be avoided. A study performed in Italy, which included 939 women, found cost-effectiveness study should be planned in order to un- that 7.8% had switched from tamoxifen to aromatase derstand the impact on different models of health systems. inhibitor,11 results lower than those of our study. Most of the therapy switches from tamoxifen to anastrozole were Conclusion due to hospital protocol. Although disease progression was found as the most common reason for the switching of HT, it The present study demonstrated a low rate of HT switch in was not related to therapeutic ineffectiveness, since BC can women with BC. Among the causes for therapy changes, progress because of other factors, such as tumor aggres- disease progression, which includes cancer recurrence, me- siveness, stage of the disease in which the treatment was tastasis or increased tumor, was the most common. Side initiated, resistance to treatment, growth factors supplied to effects were second, and age as well as comorbidities indi- cells around the tumor, among others.12,13 cated risk factors of side effects. Besides these factors, there are some comorbidities that are risk factors for cancer progression like diabetes mellitus, Contributors dyslipidemia and smoking, and those comorbidities were All of the authors contributed with the project and data found in some women who suffered disease progres- interpretation, the writing of the article, the critical – sion.14 16 Data of our study also points out that patients review of the intellectual content, and with the final had an average of 20 months until progression of the disease. approval of the version to be published. A study that evaluated hormone therapy found a progression free survival (PFS) of 8.2 to 13.8 months with anastrozole Conflict of Interests treatment, and another study had an average of 15.9 months The authors have no conflict of interests to declare. to the PFS event, also with anastrozole treatment.17,18 Low/medium adherence was associated with systemic side Acknowledgments effects and higher stages of disease.19 The cases of side effect as We gratefully acknowledge the pharmacy staff, the reason for treatment switch affected more than half of the patients, doctors of Caism at Unicamp for their cooperation, women who had comorbidities related to the adverse event: support and collaboration during the research. We also hypertension, dyslipidemia, diabetes mellitus, smoking, and thank the research group in clinical pharmacy and phar- – hypothyroidism, which are risk factors to vascular disorders.20 22 maceutical care of Unicamp, the Statistics Department for Diabetes mellitus, besides inducing predisposition to ischemic performing the statistical analyses, National Council of events, also increases the risk of ophthalmic disorders like Technological and Scientific Development (CNPq), and glaucoma and cataract, peripheral pain, gastrointestinal symp- the São Paulo Research Foundation, FAPESP - Fundação de – toms such as nausea and vomit, and hepatic steatosis.23 26 Amparo à Pesquisa do Estado de São Paulo (Fellowship for Smoking causes predisposition for cutaneous, gastrointestinal undergraduate research opportunity 2017/06130–4) for and gynecological complications such as endometrial thicken- funding for the conduction of the research. – ing.27 29 There are evidences of therapy management in ’ a collaborative group, improving patient s adherence, reducing References adverse events and reducing costs of healthcare system.30 1 World Health Organization. Cancer: diagnosis and treatment ’ Include a pharmacist in team-based to improve patient shealth- [Internet]. 2017 [cited 2020 Apr 15]. Available from: https:// 7–31 care, specialty in oncology, have shown positive results. www.who.int/cancer/treatment/en/ Correlation between side effects and comorbidities analysis 2 World Health Organization. Breast cancer [Internet]. 2018 [cited showed that a third of patients who suffered side effects also 2020 Apr 15]. Available from: https://www.who.int/cancer/pre- had comorbidities that predisposed to those side effects. The vention/diagnosis-screening/breast-cancer/en/ 3 Burstein HJ, Lacchetti C, Anderson H, Buchholz TA, Davidson NE, number of patients presenting side effects could have been Gelmon KA, et al. Adjuvant endocrine therapy for women with fi higher considering the patients who were early identi ed with hormone receptor-positive breast cancer: ASCO clinical practice

guideline focused update. J Clin Oncol. 2019;37(05):423–438. en: subgroup analysis from a phase III randomized trial of Doi: 10.1200/JCO.18.01160 fulvestrant 500 mg vs anastrozole 1 mg for hormone receptor- 4 Güth U, Myrick ME, Schötzau A, Kilic N, Schmid SM. Drug switch positive advanced breast cancer (FALCON). Breast Cancer. 2018; because of treatment-related adverse side effects in endocrine 25(03):356–364. Doi: 10.1007/s12282-018-0838-8 adjuvant breast cancer therapy: how often and how often does it 18 Reinert T, Barrios CH. Overall survival and progression-free work? Breast Cancer Res Treat. 2011;129(03):799–807. Doi: survival with endocrine therapy for hormone receptor-positive, 10.1007/s10549-011-1668-y HER2-negative advanced breast cancer: review. Ther Adv Med 5 Kwan ML, Roh JM, Laurent CA, Lee J, Tang L, Hershman D, et al. Oncol. 2017;9(11):693–709. Doi: 10.1177/1758834017728928 Patterns and reasons for switching classes of hormonal therapy 19 Stahlschmidt R, Ferracini AC, de Souza CM, de Medeiros LM, among women with early-stage breast cancer. Cancer Causes Juliato CRT, Mazzola PG. Adherence and quality of life in women Control. 2017;28(06):557–562. Doi: 10.1007/s10552-017-0888-9 with breast cancer being treated with oral hormone therapy. 6 Moscetti L, Agnese Fabbri M, Sperduti I, Fabrizio N, Frittelli P, Support Care Cancer. 2019;27(10):3799–3804. Doi: 10.1007/ Massari A, et al. Adjuvant aromatase inhibitor therapy in early s00520-019-04671-x breast cancer: what factors lead patients to discontinue treat- 20 Messerli FH, Williams B, Ritz E. Essential hypertension. ment? Tumori. 2015;101(05):469–473. Doi: 10.5301/tj.5000376 Lancet. 2007;370(9587):591–603. Doi: 10.1016/S0140-6736 7 Khandelwal N, Duncan I, Ahmed T, Rubinstein E, Pegus C. Oral (07)61299-9 chemotherapy program improves adherence and reduces medi- 21 Anderson TJ, Grégoire J, Pearson GJ, Barry AR, Couture P, Dawes M, cation wastage and hospital admissions. J Natl Compr Canc Netw. et al. 2016 Canadian Cardiovascular Society guidelines for the 2012;10(05):618–625. Doi: 10.6004/jnccn.2012.0063 management of dyslipidemia for the prevention of cardiovascular 8 Burstein HJ, Temin S, Anderson H, Buchholz TA, Davidson NA, disease in the adult. Can J Cardiol. 2016;32(11):1263–1282. Doi: Gelmon KE, et al. Adjuvant endocrine therapy for women with 10.1016/j.cjca.2016.07.510 hormone receptor-positive breast cancer: american society of 22 Fazio S, Palmieri EA, Lombardi G, Biondi B. Effects of thyroid clinical oncology clinical practice guideline focused update. J Clin hormone on the cardiovascular system. Recent Prog Horm Res. Oncol. 2014;32(21):2255–2269. Doi: 10.1200/JCO.2013.54.2258 2004;59:31–50. Doi: 10.1210/rp.59.1.31 9 Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, 23 Stratton IM, Adler AI, Neil HAW, Matthews DR, Manley SE, Cull CA, Ford R, et al. New response evaluation criteria in solid tumours: et al. Association of glycaemia with macrovascular and microvas- revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(02): cular complications of type 2 diabetes (UKPDS 35): prospective 228–247. Doi: 10.1016/j.ejca.2008.10.026 observational study. BMJ. 2000;321(7258):405–412 10 National Institutes of Health National Cancer Institute U.S. De- 24 Sayin N, Kara N, Pekel G. Ocular complications of diabetes partment of Health and Human Services. Common Terminology mellitus. World J Diabetes. 2015;6(01):92–108. Doi: 10.4239/ Criteria for Adverse Events (CTCAE) v4.0 [Internet]. 2009 [cited wjd.v6.i1.92 2020 Apr 22]. Available from: https://www.eortc.be/services/ 25 Kim JH, Park HS, Ko SY, Hong SN, Sung I-K, Shim CS, et al. Diabetic doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf factors associated with gastrointestinal symptoms in patients 11 Tinari N, Fanizza C, Romero M, Gambale E, Moscetti L, Vaccaro A, with type 2 diabetes. World J Gastroenterol. 2010;16(14):1782- et al. Identiﬁcation of subgroups of early breast cancer patients at –1787. Doi: 10.3748/wjg.v16.i14.1782 high risk of nonadherence to adjuvant hormone therapy: results 26 Richard J, Lingvay I. Hepatic steatosis and Type 2 diabetes: current of an Italian survey. Clin Breast Cancer. 2015;15(02):e131–e137. and future treatment considerations. Expert Rev Cardiovasc Ther. Doi: 10.1016/j.clbc.2014.10.005 2011;9(03):321–328. Doi: 10.1586/erc.11.15 12 Witsch E, Sela M, Yarden Y. Roles for growth factors in cancer 27 Freiman A, Bird G, Metelitsa AI, Barankin B, Lauzon GJ. Cutaneous progression. Physiology (Bethesda). 2010;25(02):85–101. Doi: effects of smoking. J Cutan Med Surg. 2004;8(06):415–423. Doi: 10.1152/physiol.00045.2009 10.1007/s10227-005-0020-8 13 Salkeni MA, Hall SJ. Metastatic breast cancer: Endocrine therapy 28 El-Zayadi AR. Heavy smoking and liver. World J Gastroenterol. landscape reshaped. Avicenna J Med. 2017;7(04):144–152. Doi: 2006;12(38):6098–6101. Doi: 10.3748/wjg.v12.i38.6098 10.4103/ajm.AJM_20_17 29 American College of Obstetricians and Gynecologists (ACOG). 14 Masur K, Vetter C, Hinz A, Thomas N, Henrich H, Niggemann B, Endometrial hyperplasia [Internet]. 2020 [cited 2020 Apr 15]. Zänker KS. Diabetogenic glucose and insulin concentrations Available from: https://www.acog.org/Patients/FAQs/Endometri- modulate transcriptome and protein levels involved in tumour al-Hyperplasia#causes cell migration, adhesion and proliferation. Br J Cancer. 2011;104 30 McBane SE, Dopp AL, Abe A, Benavides S, Chester EA, Dixon (02):345–352. Doi: 10.1038/sj.bjc.6606050 DLAmerican College of Clinical Pharmacy. , et al; . Collaborative 15 Ho CH, Chen YC, Wang JJ, Liao KM. Incidence and relative risk for drug therapy management and comprehensive medication man- developing cancer among patients with COPD: a nationwide agement-2015. Pharmacotherapy. 2015;35(04):e39–e50. Doi: cohort study in Taiwan. BMJ Open. 2017;7(03):e013195. Doi: 10.1002/phar.1563 10.1136/bmjopen-2016-013195 31 Jackson K, Letton C, Maldonado A, Bodiford A, Sion A, Hartwell R, et al. A 16 Nelson ER, Chang CY, McDonnell DP. Cholesterol and breast pilot study to assess the pharmacy impact of implementing a chemo- cancer pathophysiology. Trends Endocrinol Metab. 2014;25 therapy-induced nausea or vomiting collaborative disease therapy (12):649–655. Doi: 10.1016/j.tem.2014.10.001 management in the outpatient oncology clinics. J Oncol Pharm Pract. 17 Noguchi S, Ellis MJ, Robertson JFR, Thirlwell J, Fazal M, Shao Z. 2019;25(04):847–854. Doi: 10.1177/1078155218765629 Progression-free survival results in postmenopausal Asian wom-

Comparison of Automated Breast Ultrasound and Hand-Held Breast Ultrasound in the Screening of Dense Breasts Comparação entre a ultrassonograﬁa automatizada e a ultrassonograﬁa convencional no rastreio de mamas densas

Fernanda Philadelpho1 Maria Julia Gregorio Calas1 Gracy de Almeida Coutinho Carneiro1 Isabela Cunha Silveira1 Andréia Brandão Ribeiro Vaz1 Adriana Maria Coelho Nogueira1 Anke Bergmann1,2 Flávia Paiva Proença Lobo Lopes1,3

1 Radiology Department, Diagnósticos da América (DASA), Barra da Address for correspondence Fernanda Philadelpho, MD, PhD, Av das Tijuca, RJ, Brazil Américas, 4666, sala 301 B, 22640-102, Centro Médico 2 Clinical Epidemiology Program, Instituto Nacional de Cancer (INCA), Barrashopping,BarradaTijuca,RiodeJaneiro,RJ,Brazil Rio de Janeiro, RJ, Brazil (e-mail: [email protected]). 3 Radiology Department, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

Rev Bras Ginecol Obstet 2021;43(3):190–199.

Abstract Objective To compare hand-held breast ultrasound (HHBUS) and automated breast ultrasound (ABUS) as screening tool for cancer. Methods A cross-sectional study in patients with mammographically dense breasts was conducted, and both HHBUS and ABUS were performed. Hand-held breast ultrasound was acquired by radiologists and ABUS by mammography technicians and analyzed by breast radiologists. We evaluated the Breast Imaging Reporting and Data System (BI-RADS) classification of the exam and of the lesion, as well as the amount of time required to perform and read each exam. The statistical analysis employed was measures of central tendency and dispersion, frequencies, Student t test, and a univariate logistic regression, through the odds ratio and its respective 95% confidence interval, and with p < 0.05 considered of statistical significance. Results A total of 440 patients were evaluated. Regarding lesions, HHBUS detected 15 (7.7%) BI-RADS 2, 175 (89.3%) BI-RADS 3, and 6 (3%) BI-RADS 4, with 3 being confirmed by biopsy as Keywords invasive ductal carcinomas (IDCs), and 3 false-positives. Automated breast ultrasound identified ► dense breast 12 (12.9%) BI-RADS 2, 75 (80.7%) BI-RADS 3, and 6 (6.4%) BI-RADS 4, including 3 lesions fi ► screening detected by HHBUS and con rmed as IDCs, in addition to 1 invasive lobular carcinoma and 2 ► hand-held breast high-risk lesions not detected by HHBUS. The amount of time required for the radiologist to ultrasound read the ABUS was statistically inferior compared with the time required to read the HHBUS p < ► automated breast ( 0.001). The overall concordance was 80.9%. A total of 219 lesions were detected, from ultrasound those 70 lesions by both methods, 126 only by HHBUS (84.9% not suspicious by ABUS) and 23 ► breast cancer only by ABUS.

received DOI https://doi.org/ © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights May 25, 2020 10.1055/s-0040-1722156. reserved. accepted ISSN 0100-7203. This is an open access article published by Thieme under the terms of the October 6, 2020 Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda., Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil Comparison of Automated Breast Ultrasound and Hand-Held Breast Ultrasound Philadelpho et al. 191

Conclusion Compared with HHBUS, ABUS allowed adequate sonographic study in supplemental screening for breast cancer in heterogeneously dense and extremely dense breasts. Resumo Objetivo Comparar a ultrassonografia convencional das mamas (US) com a ultrassonografia automatizada das mamas (ABUS) no rastreio do câncer. Métodos Realizamos um estudo transversal com pacientes com mamas mamogra- ficamente densas, sendo avaliadas pela US e pela ABUS. A US foi realizada por radiologistas e a ABUS por técnicos de mamografia e analisada por radiologistas especializados em mama. A classificação Breast Imaging Reporting and Data System (BIRADS) do exame e das lesões o tempo de leitura e de aquisição foram avaliados. A análise estatística foi realizada através de medidas de tendência central, dispersão e frequências, teste t de Student e regressão logística univariada, através do odds ratio, com intervalo de confiança de 95%, e com p < 0,05 sendo considerado estatisticamente significante. Resultados Foram avaliadas 440 pacientes. Em relação às lesões, a US detectou 15 (7,7%) BI-RADS 2, 175 (89,3%) BI-RADS 3 e 6 (3%) BI-RADS 4, das quais 3 foram confirmadas, por biópsia, como carcinomas ductais invasivos e 3 falso-positivos. A ABUS identificou 12 (12,9%) BI-RADS 2, 75 (80,7%) BI-RADS 3 e 6 (6,4%) BI-RADS 4, Palavras-chave incluindo 3 lesões detectadas pela US e confirmadas como carcinomas ductais ► mama densa invasivos, além de 1 carcinoma lobular invasivo e 2 lesões de alto risco não detectadas ► rastreamento pela US. O tempo de leitura dos exames da ABUS foi estatisticamente inferior ao tempo ► ultrassonografia do radiologista para realizar a US (p < 0,001). A concordância foi de 80,9%. Um total de convencional 219lesõesforamdetectadas,dasquais70porambososmétodos,126observadas ► ultrassonografia apenas pela US (84,9% não eram lesões suspeitas no ABUS) e 23 apenas pela ABUS. automatizada Conclusão Comparado à US, a ABUS permitiu adequado estudo complementar no ► câncer de mama rastreio do câncer de mamas heterogeneamente densas e extremamente densas.

Introduction a phenomenon known as “masking.”“Masking” occurs as a consequence of the reduced contrast between dense breast Breast cancer is considered one of the most frequent malig- tissue and a lesion, and a greater superimposition of tissue nancies in women worldwide.1 A key factor for breast cancer that might lead to misdiagnosis.4 The overall sensitivity of patients is the early detection of the disease as it may mammography as a screening method is 85%. However, in improve the outcomes (treatment success and mortality women with dense breast tissue, its sensitivity is reduced to reduction).2 The workflow of breast screening for this pur- between 47.8 and 64.4%.2,7 High density breast tissues tend pose is already known, with mammography being consid- to decrease with age;8 however, in up to 50% of women, this – ered the standard screening method.2 4 There are some may be a life-long issue.2,4,7,9 differences among review boards around the world regard- There are several risk factors associated with breast ing when to start the screening with mammography. The cancer, including genetic factors, age, behavioral factors American College of Radiology Cancer Society and College of (smoke, diet, among others), family history, hormone factors, Surgeons recommend it for women over 40 years old.5 The and mammographic breast density. In some series, it was European guidelines on breast cancer screening and diagno- observed that women with extremely high-density breasts sis suggests mammography screening every 2 or 3 years in have more probability to develop cancer when compared women over 45 years old.6 Brazillian Societies (radiology, with those with low-density breasts.7 mastology and gyneco-obstetritics)3 recommend breast For this reason, alternative screening tools are needed for screening with mammography from the age of 40 and also the correct evaluation of these patients. Breast US is well support the recommendation of complementation of the recognized as a diagnostic tool; however, it is not usually screening with ultrasound (US) in high-density breasts. used for screening purposes in all women. It is specific Even though it is recommended worldwide as the gold valuable in the case of patients with high-density breasts, standard screening method, mammography has several lim- especially when it is performed by an experienced – itations, especially that is not equally effective in all women professional.10 12 due to different patterns of breast density.2 It is well de- When thinking of an algorithm to be stablished in the scribed that the sensitivity of the mammogram to detect screening of patients with high-density breasts, multiple lesions decreases significantly the higher the breast density, observational and retrospective studies support the use of US

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. 192 Comparison of Automated Breast Ultrasound and Hand-Held Breast Ultrasound Philadelpho et al.

as a supplemental screening tool to detect breast Institutional Review Board (CAAE: 58146816.3.0000.5257) lesions.4,10,11,13 In Brazil, there is an increased demand for and written informed consent obtained from all hand-held breast ultrasound (HHBUS) as a screening tool, participants. since its use is recommended by our national guidelines as a Asymptomatic women who had heterogeneously or ex- complementary exam for high-density breasts.3 Due to this tremely dense breast tissue (classified by BI-RADS as C or D) increased demand, there are not enough experienced radi- and who underwent screening digital mammography and ologists specialized in breast imaging to perform the exams. HHBUS examinations were asked to participate in the study. Most of the time, the exam is performed by a general Mammography exams were used to assure dense breast (BI- radiologist, with less experience in breast imaging, resulting RADS as C or D) independently of further BI-RADS classifica- in reduced sensitivity and increased false positives, when tion. After routine exams (mammogram and HHBUS), compared with the specialist in breast exams. This is partial- patients had ABUS examination performed on the same ly because general radiologists are neither experienced in day. Mammography images and reports were available for reading mammography nor familiar with the American the radiologists to make sure about the breast density College of Radiologists Breast Imaging Reporting and Data (heterogeneously or extremely dense breast tissue) when System (ACR BI-RADS).14 interpreting HHBUS or ABUS. When interpreting ABUS or One of the main challenges with HHBUS is to ensure HHBUS, they were blinded to the results of each other. When reproducible and standardized images and interpretation, a suspicious or dubious finding was observed in the ABUS as it is a highly operator-dependent technique and is also evaluation, another HHBUS exam was performed by a radi- dependent on the experience of the performer.10,15 Another ologist not involved in the study (considered a recall) to issue that must be taken into account is that HHBUS can be decide whether or not to proceed with biopsy, guided by the too time consuming for the radiologist, especially when the HHBUS findings as ABUS cannot be used to guide biopsies. demand is high.16 Patients with breast surgery for breast cancer or benign The automated breast ultrasound (ABUS) has been ap- causes (including breast implants) or breast radiotherapy proved by the Food and Drug Administration (FDA) in 2012 in the previous 12 months were excluded from the study. All and has been widely used as a supplemental screening tool images were reported with the current ACR BI-RADS classi- for breast cancer. It was designed to supplement some of the fication.14 We compared and classified each observed lesion issues regarding HHBUS, such as operator dependency, little with BI-RADS classification, regarding its features (morpho- experience with breast exams, and low sensitivity and logic characteritics, size and location). reproductibility. It is supposed to be used as an adjunct to The HHBUS exams were performed by 30 radiologists, mammography for screening asymptomatic women with some were specialized in breast imaging (n ¼ 13), while all dense breasts.15,17,18 others were not. Variable ultrasound systems were used, all One potential advantage of ABUS is also the possibility to equipped with a linear-array transducer with a bandwidth of divide acquisition and interpretation, while still being effec- 7 to 14 MHz. The mean time to perform HHBUS from begin- – tive.17 19 A main advantage of the ABUS is that it may be ning to end, observed in the HHBUS machine, was also performed by a trained person without loss in the perfor- measured. When an ABUS recall was needed for further mance as its automated acquitision provides proper orienta- investigation, this additional time to perform HHBUS was tion, full breast volume images with great reproductibility, not taken into account. and also detectability.4,17 By using ABUS, the breast radiolo- Automated breast ultrasound exams (Invenia ABUS, Au- gist can focus on the interpretation, as the entire process is tomated Breast Ultrasound System, GE Healthcare, Sunny- conducted by other health personnel, thus improving the vale, CA, USA) were performed by one of four trained exam workflow; and the specialized radiologist can dedicate mammography technicians, with a preestablished protocol. his full time to diagnosis. For those who will perform ABUS, it The ABUS system consists of a scanning unit (with a 10–- is a simple method that does not require a lot of training.17,20 15 MHz high-frequency linear transducer) and the image Another advantage point is that the acquired data (includ- review workstation. To be performed, the patient lies in a ing 3D volume) can be evaluated further at anytime and supine position with the arms above the head (►Fig. 1A). The independently by two different radiologists (double-read- technician performing the study is only required to apply gel ing), which is useful in cases of doubt and also for use in to the breast, and to put the scanning plate and transducer clinical trials.15 In several studies, ABUS had results similar to with slight pressure and select the patient’s breast size. The those of HHBUS regarding detection of occult breast breast tissue should be fully covered to avoid air bubble lesions.4,19 formation on the contact surface. The system then sets all The aim of the present study is to compare the perfor- scanning parameters. The transducer slides continuously mance of HHBUS and ABUS in our setting as a supplemental over a membrane, which is kept in contact with the breast screening tool for breast cancer. (►Fig. 1B). The number of required scans to image the whole breast is determined by patient’s breast size and ranges from Methods three to four scans per breast. Anteroposterior, medial, and lateral views are routinely acquired (►Fig. 2). If there are A unicentric cross-sectional study was performed in our additional indications, such as for large breasts, superior and private imaging institution after approval by our national inferior views are also acquired. All views must contain the

Fig. 1 Automatedbreastultrasoundscanningunit(A)andtransducer(B).Patient lies in a supine position with the arms above the head and the technician performs the study, using a 15 cm long transducer with slight pressure.

Fig. 2 Automated breast ultrasound acquires images (A- lateral view, (B) medial view; and (C) anteroposterior view) and schematic drawings (D) of automated breast ultrasound views: Lateral (orange), medial (yellow), and anteroposterior (pink).

nipple as a reference point, which is marked by the operator multiplanar reconstructions, including sagittal and 2-mm- at the end of each scan, to allow correct orientation and thick coronal images, parallel to the chest wall. All ABUS postprocessing reconstructions. In the anteroposterior view, exams were interpreted by one of the six breast radiologists the nipple should be centered on the image. In the medial that participated in the study. The mean acquisition time to and lateral views, the nipple should be at the periphery of the perform ABUS by technicians from the time the scan effec- image. The images are acquired with a 15-cm field of view for tively started and finished, observed in ABUS machine, and review. The participating technicians and radiologists re- mean interpretation time to read ABUS by radiologists, from ceived standardized ABUS training, provided by the system the time the study was opened until the final conclusion, vendor, for 1 month, performing 50 exams during this period were measured. (data not shown). After acquisition, the axial image series is We also assessed the exams limitations and presence of sent to a dedicated workstation and then can be examined in pain during ABUS. We divided the perception of pain, as

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. 194 Comparison of Automated Breast Ultrasound and Hand-Held Breast Ultrasound Philadelpho et al.

described by the patients, in four categories: absent (no The other exams (341/440 [77.5%]) were performed by non- pain), minimal, mild, and severe. specialized radiologists (n ¼ 17), who took an overall of For patients in the BI-RADS 4 category, biopsy results 4 minutes and 15 seconds (range, 1–33 minute). The mean were obtained for comparison. Demographic and clinical exam time was 5 minutes and 3 seconds (p < 0.001). characteristics are presented through measures of central Regarding ABUS, the mean exam acquiring time was tendency and dispersion (quantitative variables) and abso- 14 minutes (range, 6–24 minute), and the breast radiologist lute and relative frequency (qualitative variables). The Stu- (n ¼ 6) mean reading time was 4 minutes and 25 seconds dent t-test was used to evaluate the difference between the (range, 2–20 minute). In 68.4% of the exams, 6 views were means. Association between breast lesion and exam was acquired (3 for each breast); 7 views were acquired in 11.1% performed using a univariate logistic regression, through the of exams (3 for one breast and 4 for the other), and in the odds ratio and its respective 95% confidence interval. Agree- remaining 18.4% of exams, 8 views were performed (4 for ment between the methods was obtained by simple concor- each breast). dance. For all comparisons, a statistically significant The majority of the patients described no pain (66.4%) or difference was considered when p < 0.05. minimal pain (18.9%) during ABUS exam (►Table 1). When pain was present, the medial view was the main site (9.5%). Results When performing the ABUS exam, we experienced difficulties (limitations) during acquisition in 115/444 (25.9%) of Between August 2017 and July 2018, we enrolled a total of the cases. The most common limitations were acoustic 444 asymptomatic women that were referred for screening shadowing artifacts, firm breasts (leading to difficulties on mammogram report (classified as BI-RADS as C or D regard- the probe positioning), and large breasts (►Table 2). We had ing breast density), after they accepted and signed an in- to exclude 4/115 (2.8%) exams (as previous mentioned) due formed consent to participate in the study. Four patients to important acoustic shadowing artifacts related to lack of were excluded from the study due to important limitations adequate breast compression. during ABUS exams. The clinical and epidemiological char- Recall for additional HHBUS due to doubts (n ¼ 4) or acteristics of the patients included in the study (n ¼ 440) are suspicious lesion (n ¼ 6) during ABUS exam was only needed shown in ►Table 1. Most patients had heterogeneously in 10/440 (2.27%) exams. In all recalls due to doubts, they dense breasts (95%). occurred in the first months of the study; the other recalls Regarding HHBUS, 99/440 (22.5%) exams were performed were from BI-RADS 4 findings. by breast radiologists (n ¼ 13), who took an overall 7 minutes In ►Table 1, we also show the overall distribution of BI- and 45 seconds (range, 2–27 minute) to perform the exam. RADS classification obtained by HHBUS and ABUS for each exam. Both methods found out more BI-RADS 1 or 2 exams. Regarding the comparison between lesions classified by BI- Table 1 Clinical and imaging data RADS, in ►Table 3 we summarized the main findings. Hand- held breast ultrasound detected 15 BI-RADS 2 masses and Characteristic HHBUS ABUS N(%) N(%) ABUS 12 BI-RADS 2 masses. We observed 175 lesions BI- RADS 3 with HHBUS; from those, 4 were clustered micro- Age (yr) cysts, 2 ductal ectasias, and the other lesions (n ¼ 169) were Median 48 solid masses. With ABUS, 75 lesions were BI-RADS 3; from Range 20–79 those, 75 were solid masses. Both methods detected 6 lesions Breast parenchyma at mammography each BI-RADS 4. Heterogeneously dense (C) 418 (95) Considering lesion detection rates, HHBUS showed 126 lesions not seen by ABUS. Automated breast ultrasound Extremely dense (D) 22 (5) Pain (during ABUS) Table 2 Limitations during automated breast ultrasound Absence – 292 (66.4) exam, related by technicians Minimal – 83 (18.9) Mild – 42 (9.5) Limitations Patients Severe – 23 (5.2) Artifacts 26 Final exams BI-RADS Firm Breast 24 1 (negative) 153 (34.8) 189 (42.9) Large breast 20 2 (benign) 188 (42.7) 201 (45.7) Small breast 16 3 (probably benign) 96 (21.8) 46 (10.5) Protruding sternum 15 4 (suspicious) 3 (0.7) 4 (0.9) Flabby breast 14 Total 115 (25.9%) Abbreviations: ABUS, automated breast ultrasound; BI-RADS, Breast Imaging Reporting and Data System; HHBUS, hand-held breast 4 patients were excluded due to major artifacts (lack of adequate ultrasound. breast compression).

Table 3 Breast Imaging Reporting and Data System lesions detected 23 lesions not seen by HHBUS, and 70 lesions were obtained by hand-held breast ultrasound and automated breast seen by both methods. No significant difference was ob- ultrasound exams served in the average size of the lesions detected by both methods—HHBUS 1.17 cm versus ABUS 1.14 cm (p ¼ 0.662). Lesions and BI-RADS HHBUS ABUS The overall concordance between the two methods was N(%) N(%) 80.9%. The lesions missed by ABUS were not suspicious; BI-RADS 2 masses 15 (7.7) 12 (12.9) 85% (107/126) of them were cysts, fat lesions or normal BI-RADS 3 lesions 175 (89.3) 75 (80.0) ducts. From the others misdiagnosed lesions by ABUS, one Solid masses 169 (86.3) 75 (80) lesion was near the axilla (measuring 1.0 cm) and 18 lesions had an average of 0.6 cm (range, 0.4–1.0 cm) in both breasts Clustered microcysts 4 (2) 0 (data not shown). Ductal ectasias 2 (1) 0 Lesions classified as BI-RADS 4 were detected by each BI-RADS 4 masses 6 (3) 6 (6.4) method in six cases (►Table 3). Three were invasive ductal carcinomas (IDCs) in the same patient, correctly described by Abbreviations: ABUS, automated breast ultrasound; BI-RADS, Breast ►Fig. 3 Imaging Reporting and Data System; HHBUS, hand-held breast both methods ( ). Hand-held breast ultrasound also ultrasound. described 3 other BI-RADS 4 lesions that were BI-RADS 3 or 2 by ABUS; 2 of them were fibroadenomas, and 1 was an

Fig. 3 Female, asymptomatic, 65-year-old patient. Automated breast ultrasound exam. Coronal (upper) and longitudinal (bottom) images shows three hypoechogenic, irregular and spiculated masses in the right breast, also detected by Hand-held breast ultrasound. The lesion was classified as Breast Imaging Reporting and Data System 4. Histopathological findings confirmed malignancy - grade 2 infiltrating ductal carcinomas.

Fig. 4 Female, asymptomatic, 60-year-old patient. Automated breast ultrasound showed a hypoechogenic, irregular and indistinct mass in the right breast – classified as a Breast Imaging Reporting and Data System 4 lesion. Histopathologic result confirmed an infiltrating lobular carcinoma.

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. 196 Comparison of Automated Breast Ultrasound and Hand-Held Breast Ultrasound Philadelpho et al.

Table 4 Breast Imaging Reporting and Data System 4 lesions: for asymptomatic women with dense breast tissue. However, comparison between hand-held breast ultrasound, automated most of the time, the operator is a general radiologist, with breast ultrasound, and histopathology results low experience in breast imaging, which might lead to misdiagnosis or overdiagnosis of lesions.3,10,11 In our prac- HHBUS ABUS tice, and as reflected in the present study, 77.5% of the 3spiculatedmasses 3spiculatedmasses HHBUS were performed by non-specialiazed radiologists in (invasive ductal carcinomas) (invasive ductal carcinomas) breast imaging, thus reducing cancer detection and increas- 1complexmass Described as solid mass, ing false positives. In addition to a lack of experience in breast (fibroadenoma) BI-RADS 3 imaging, the poor quality of HHBUS exams performed by Not diagnosed by HHBUS 1 solid spiculated 1.3 cm radiologists non-speciliazed in breast imaging may be ac- mass (radial scar) centuated by the shorter time taken to perform the exam, 1 solid palpable 3.6 cm Described as solid mass, which was statistically inferior when compared to the mass (fibroadenoma) BI-RADS 3 amount of time taken for specialized radiologists to perform Not diagnosed by HHBUS 1 solid intraductal 0.7 cm the exam, in our study. mass (papilloma) Automated breast ultrasound comes as a new imaging 1complex1.3cmmass Inflammatory cyst, technology for automatic breast scanning with US to overlap described as BI-RADS 2 the main limitations of HHBUS. Moreover, in countries like Not diagnosed by HHBUS 1 solid irregular 0.9 cm mass Brazil, where only physicians are allowed to perform clinical (invasive lobular carcinoma) ultrasounds, ABUS allows acquisition by non-physician personnel. As previously mentioned, it also has the advantage of Abbreviations: ABUS, automated breast ultrasound; BI-RADS, Breast decoupling acquisition and interpretation, with the possibil- Imaging Reporting and Data System; HHBUS, hand-held breast ultrasound. ity of double-reading and objective comparison with previous exams.21 Another benefit is the ability to document the entire breast volume and to provide 3D images, thus reduc- inflammatory cyst. So, HHBUS resulted in 50% false positives. ing potential misdiagnosis of lesions, and, as the radiologist Meanwhile, ABUS also described 3 additional BI-RADS 4 will be focused only on the interpretation of the findings, it lesions not seen by HHBUS, one malignant (►Fig. 4)and may improve diagnostic rates.22 two high-risk lesions (►Table 4). In our study, the cancer Regarding the amount of time required for ABUS reading, – detecion rate was 4.5 per 1,000 women for ABUS (all per- several studies have reported it.21,23 25 Skaane et al.25 formed by breast radiologists) against 2.3 per 1,000 women showed that the mean interpretation time was 9 minutes for HHBUS (performed by breast radiologists and non-spe- for a bilateral examination. In our study, the reading time of cialist radiologists). ABUS was shorter, compared with that reported in Skaane’s study, at 4 minutes and 25 seconds for both breasts. Discussion In relation to scan time, as in other studies, HHBUS took less time to be performed compared with ABUS, considering The main concern for the research of new technologies in the time from start to finish. It is important to highlight that, breast cancer screening is based on the increasing number of unfortunately, we had some outlier results considering cases worldwide and the limitations of mammography, HHBUS scan time. Some operators took an extremely short especially when it comes to dense breasts. Several reports amount of time to perform it, which, in turn, influenced our show that US may be a useful complementary screening results to lower the average time when compared with the method for women with dense breast tissue to detect occult literature; this could also influence the proper evaluation of breast lesions.4,10,11,13,20 Unfortunately, even though US is an the exam. Lin et al.26 reported an average ABUS scanning extremely valuable tool and is recommended as a supple- time of 11.9 minutes compared with an average HHBUS mental imaging method, it is an operator-dependent method scanning time of 6.8 minutes. In our study, ABUS scanning associated with low sensitivity and false positives when time took an average of 14 minutes. However, the main performed by inexperient personnel, thus leading to une- advantage of ABUS, in our point of view, is the possibility cessary biopsies in the case of misdiagnosis.19 Therefore, of being performed by a technician rather than the physician, ABUS comes as an important alternative tool to overlap these who can then use his/her entire time to read the exam. technical issues regarding experience and operator-depen- The use of both HHBUS and ABUS has been described to dent methods, as it can be mainly interpreted by breast improve detection of small invasive cancers in women with radiologists.20 dense breasts, compared with screening with mammogra- Hand-held breast ultrasound is the routine supplemental phy.27 An increase in cancer detection rate (CDR) has also screening technique. It has the major advantage of not using been described when HHBUS is performed during the radiation, and it allows for a detailed evaluation of an screening.16,20,27,28 Automated breast ultrasound is also abnormality. You can also add more details about a potential described as a supplemental screening method that can – lesion using color Doppler and elastography to establish the improve CDR.19,29 Although some studies15,26,30 32 compare accurate diagnosis.10,20 In Brazil, the use HHBUS is a common ABUS and HHBUS regarding CDR, these reports are based on screening method, as an adjunct method to mammography relatively small populations and focus primarily on the

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. Comparison of Automated Breast Ultrasound and Hand-Held Breast Ultrasound Philadelpho et al. 197 diagnostic setting. They show similar performance of ABUS benign or probably benign lesions, as described in previous and HHBUS for detection and diagnosis of breast lesions. studies. Most studies using the new-generation ABUS scanners Regarding the clinical applications of ABUS, this technique reported a high sensitivity and specificity, comparable to, was first indicated as a screening method in an effort to improve – or sometimes better than, HHBUS.15,26,30 32 Specifically, Lin breast cancer diagnosis, especially in mammographically dense et al.26 reported optimal agreement between ABUS and breasts. Due to promising results observed in the screening HHBUS as well as between ABUS and the results of pathologic scenario, it was studied as a diagnostic method besides the diagnosis. A recent meta-analysis by Meng et al.33 revealed a screening and for evaluation of tumor response to neoadjuvant 92% (range: 89.9–93.8%) pooled sensitivity and an 84.9% chemotherapy, as well as being an additional US method after (range 82.4–87%) specificity of ABUS, with no significant magnetic resonance imaging doubts. difference between ABUS and HHBUS in terms of diagnostic The major limitations of the present study were a single- accuracy. Our study compared ABUS and HHBUS with focus site study with a small number of patients for a screening on the screening setting, and the cancer detecion rate was study, thus reducing the statistical power. Moreover, each 4.5/1,000 women for ABUS against 2.3/1,000 women for patient’s image was read by one radiologist without a second HHBUS, similarly to previous studies; however, we have to look from another radiologist; therefore, interobserver vari- take into account that all ABUS exams in our study were ability was not determined. Besides that, ABUS and HHBUS interpretated by breast radiologists, which may interfere were not performed and analyzed by the same radiologist, with the higher detection rates. and the majority of HHBUS were performed by non-special- As with other new technologies, the learning curve is ists, differently from ABUS, in which all exams were per- always an issue and must be taken into account when formed by breast radiologists. Other limitations were that we evaluated as well as when implemented for screening pur- did not follow up the lesions BI-RADS 3 in the exams and that poses. It is well known that when you have an operator- we had some scan time outliers (with extremely short time dependent device, accurate training is a key factor for the to perform the scan in the HHBUS) in some exams. results, especially regarding the sensitivity and specificity of Future improvements in ABUS, such as optimal parameter the method.25 This is well illustrated by Arleo et al.,34 who adjustment, whole-breast Doppler, and elastography, are under observed that after implementation of ABUS, they experi- invetigation and may provide further advantages in the screen- enced a drop out in recalls over time from the first month of ing and diagnosis.27,28 Also,theintegrationofABUSwith use (24.7%) to the third (12.6%). Despite the possibility that tomosynthesis may allow formation of hybrid images, which all ABUS exams may be read mainly by breast radiologists, can provide multimodal data for potential classification of specific training is still required, as any other new technolo- breast lesions.29 Lately, other features for ABUS technology gy, especially to avoid pitfalls.17,21 We had a low recall rate are being developed, and different computer-aided detection (2.27%), and it was observed on the first scanned patients, for (CAD) systems have been added to the device.21,35 the doubt lesions or due to suspicious lesions, probably due to our learning curve. With technicians’ learning curve, Conclusion exams presented less artifacts and, with radiologists’ learning curve, it was easier to differentiate an artifact from a real Compared with HHBUS, ABUS allowed for effective ultraso- lesion. Hence, radiologists and technologists need to be nographic performance in supplemental screening for breast familiar with these image artifacts and how to reduce them. cancer. With ABUS, the breast radiologists optimized their Hand-held breast ultrasound presented more than twice time, being able to read more exams in less time, and there as many BI-RADS 3 lesions compared with ABUS, resulting in was a reduction in the detection of probably benign lesions increased US follow-up scans. The increase in reported and the need for unecessary follow-up and biopsies. Auto- probably benign lesions, instead of benign lesions or negative mated breast ultrasound is a reliable and reproducible tool as exams, is most likely explained by the variability in the a complementary breast screening method. However, radi- HHBUS operator’s experience, which is a known disadvan- ologists must become familiar with ABUS images to accu- tage of the method. rately characterize and classify lesions. A learning curve and The mean diameter of the lesion is an important factor in specific limitations exist; hence, a specific training is re- lesion detectability for ABUS, as it may misdiagnose small quired, regardless of the examiner’s experience with HHBUS. – lesions.30 32 This represents a limitation of the technology Besides that, the financial aspect must be taken into account itself, but it is also observed with HHBUS. However, Wang due to the higher costs of the method; however, ABUS is et al.32 reported a higher diagnostic accuracy of ABUS expected to improve the detection of lesions, which, in a final compared with HHBUS for lesions smaller than 1 cm. Other analysis, may also end up saving money due to possible early investigators suggested lower detection rates for benign detection and, therefore, early treatment implementation. lesions compared with malignant lesions, with ABUS having lower diagnostic accuracy compared with HHBUS for lesions Contributors with a benign appearance and also regarding BI-RADS cate- All authors participated in the concept and design of the gory.30 In the present study, the misdiagnosed lesions by present study; analysis and interpretation of data; draft or ABUS measured 0.6 cm in average, and all of them were revision of the manuscript, and they have approved the

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. 198 Comparison of Automated Breast Ultrasound and Hand-Held Breast Ultrasound Philadelpho et al.

manuscript as submitted. All authors are responsible for 11 Calas MJG, Almeida RMVR, Gutfilen B, Pereira WCA. Interobserver the reported research. concordance in the BI-RADS classification of breast ultrasound exams. Clinics (São Paulo). 2012;67(02):185–189. Doi: 10.6061/ clinics/2012(02)16 Funding 12 Bae MS, Moon WK, Chang JM, Koo HR, Kim WH, Cho N, et al. Diagnósticos das Américas This research was supported by Breast cancer detected with screening US: reasons for nondetec- (DASA). We thank our directors, specially Romeu Dom- tion at mammography. Radiology. 2014;270(02):369–377. Doi: ingues and Roberto Domingues, and our colleagues from 10.1148/radiol.13130724 DASA who provided the structure, insight, and expertise 13 Berg WA. Current status of supplemental screening in dense – that greatly assisted the research. We also thank General breasts. J Clin Oncol. 2016;34(16):1840 1843. Doi: 10.1200/ JCO.2015.65.8674 Electric (GE) for lending us the device, providing all 14 Mendelson EB, Böhm-Vélez M, Berg WA, et al. ACR BI-RADS support for the project, and for the opportunity to evalu- Ultrasound. In: D’Orsi CJ, Sickles EA, Mendelson EB, Morris EA, ate the ABUS. We thank all the technicians (Roselane de editors. ACR BI-RADS® Atlas, breast imaging reporting and data Oliveira Sacramento, Marcia Cristina Dias Mendes, Kelly system. 5th ed. Reston: American College of Radiology; 2013: Rose Fontes Aragão, Gabriela da Silva Moraes, Rosália 1–173 15 Golatta M, Baggs C, Schweitzer-Martin M, Domschke C, Schott S, Aparecida Dutra Ribeiro and Thatyana Costa Fernandes) Harcos A, et al. Evaluation of an automated breast 3D-ultrasound for assistance with the performance of the ABUS. system by comparing it with hand-held ultrasound (HHUS) and mammography. Arch Gynecol Obstet. 2015;291(04):889–895. Conflict of Interests Doi: 10.1007/s00404-014-3509-9 The authors have no conflict of interests to declare. 16 Berg WA, Bandos AI, Mendelson EB, Lehrer D, Jong RA, Pisano ED. Ultrasound as the primary screening test for breast cancer: analysis from ACRIN 6666. J Natl Cancer Inst. 2015;108(04): References djv367. Doi: 10.1093/jnci/djv367 1 Santos MO. Estimativa 2018: incidência de câncer no Brasil. Rev 17 Kim SH. Image quality and artifacts in automated breast ultraso- Bras Cancerol. 2018;64(01):119–120. Doi: 10.32635/2176-9745. nography. Ultrasonography. 2019;38(01):83–91. Doi: 10.14366/ RBC.2018v64n1.115 usg.18016 2 Brem RF, Lenihan MJ, Lieberman J, Torrente J. Screening breast 18 Kaplan SS. Automated whole breast ultrasound. Radiol Clin North ultrasound: past, present, and future. AJR Am J Roentgenol. 2015; Am. 2014;52(03):539–546. Doi: 10.1016/j.rcl.2014.01.002 204(02):234–240. Doi: 10.2214/AJR.13.12072 19 Brem RF, Tabár L, Duffy SW, Inciardi MF, Guingrich JA, Hashimoto 3 Urban LABD, Schaefer MB, Duarte DL, et al. Recommendations of BE, et al. Assessing improvement in detection of breast cancer Colégio Brasileiro de Radiologia e Diagnóstico por Imagem, with three-dimensional automated breast US in women with Sociedade Brasileira de Mastologia, and Federação Brasileira dense breast tissue: the SomoInsight Study. Radiology. 2015;274 das Associações de Ginecologia e Obstetrícia for imaging screen- (03):663–673. Doi: 10.1148/radiol.14132832 ing for breast cancer. Radiol Bras. 2012;45(06):334–339. Doi: 20 Weigert JM. The Connecticut Experiment; The third installment: 10.1590/S0100-39842012000600009 4 years of screening women with dense breasts with bilateral – 4 Aripoli A, Fountain K, Winblad O, Gatewood J, Hill J, Wick JA, ultrasound. Breast J. 2017;23(01):34 39. Doi: 10.1111/tbj.12678 Inciardi M. Supplemental screening with automated breast ultra- 21 Rella R, Belli P, Giuliani M, Bufi E, Carlino G, Rinaldi P, Manfredi R. sound in women with dense breasts: comparing notification Automated Breast Ultrasonography (ABUS) in the screening and methods and screening behaviors. AJR Am J Roentgenol. 2018; diagnostic setting: indications and practical use. Acad Radiol. 210(01):W22–W28. Doi: 10.2214/AJR.17.18158 2018;25(11):1457–1470. Doi: 10.1016/j.acra.2018.02.014 5 American College of Radiology [Internet]. New ACR and SBI breast 22 Barr RG, DeVita R, Destounis S, Manzoni F, De Silvestri A, Tinelli C. cancer screening guidelines call for significant changes to screen- Agreement between an automated volume breast scanner and ing process. 2018 [cited 2020 May 11]. Available from: https:// handheld ultrasound for diagnostic breast examinations. J Ultra- www.acr.org/Media-Center/ACR-News-Releases/2018/New- sound Med. 2017;36(10):2087–2092. Doi: 10.1002/jum.14248 ACR-and-SBI-Breast-Cancer-Screening-Guidelines-Call-for-Sig- 23 Zanotel M, Bednarova I, Londero V, Linda A, Lorenzon M, Giro- nificant-Changes-to-Screening-Process metti R, Zuiani C. Automated breast ultrasound: basic principles 6 European Breast Cancer [Internet]. European Breast Cancer and emerging clinical applications. Radiol Med (Torino). 2018; guideline. 2020 [cited 2020 May 11]. Available from: https:// 123(01):1–12. Doi: 10.1007/s11547-017-0805-z healthcare-quality.jrc.ec.europa.eu/european-breast-cancer- 24 Chae EY, Cha JH, Kim HH, Shin HJ. Comparison of lesion detection guidelines in the transverse and coronal views on automated breast sonog- – 7 Wang AT, Vachon CM, Brandt KR, Ghosh K. Breast density and raphy. J Ultrasound Med. 2015;34(01):125 135. Doi: 10.7863/ breast cancer risk: a practical review. Mayo Clin Proc. 2014;89 ultra.34.1.125 (04):548–557. Doi: 10.1016/j.mayocp.2013.12.014 25 Skaane P, Gullien R, Eben EB, Sandhaug M, Schulz-Wendtland R, 8 Checka CM, Chun JE, Schnabel FR, Lee J, Toth H. The relationship of Stoeblen F. Interpretation of automated breast ultrasound (ABUS) mammographic density and age: implications for breast cancer with and without knowledge of mammography: a reader screening. AJR Am J Roentgenol. 2012;198(03):W292-5. Doi: performance study. Acta Radiol. 2015;56(04):404–412. Doi: 10.2214/AJR.10.6049 10.1177/0284185114528835 9 Sprague BL, Gangnon RE, Burt V, Trentham-Dietz A, Hampton JM, 26 Lin X, Wang J, Han F, Fu J, Li A. Analysis of eighty-one cases with Wellman RD, et al. Prevalence of mammographically dense breast lesions using automated breast volume scanner and com- breasts in the United States. J Natl Cancer Inst. 2014;106(10): parison with handheld ultrasound. Eur J Radiol. 2012;81(05): dju255. Doi: 10.1093/jnci/dju255 873–878. Doi: 10.1016/j.ejrad.2011.02.038 10 Calas MJG, Almeida RMVR, Gutfilen B, Pereira WCA. Intraobserver 27 Shen S, Zhou Y, Xu Y, Zhang B, Duan X, Huang R, et al. A multi- interpretation of breast ultrasonography following the BI-RADS centre randomised trial comparing ultrasound vs mammography classification. Eur J Radiol. 2010;74(03):525–528. Doi: 10.1016/j. for screening breast cancer in high-risk Chinese women. Br J ejrad.2009.04.015 Cancer. 2015;112(06):998–1004. Doi: 10.1038/bjc.2015.33

28 Ohuchi N, Suzuki A, Sobue T, Kawai M, Yamamoto S, Zheng YF, 32 Wang HY, Jiang YX, Zhu QL, Zhang J, Dai Q, Liu H, et al. Differenti- et al;J-START investigator groups. Sensitivity and specificity of ation of benign and malignant breast lesions: a comparison mammography and adjunctive ultrasonography to screen for between automatically generated breast volume scans and hand- breast cancer in the Japan Strategic Anti-cancer Randomized Trial held ultrasound examinations. Eur J Radiol. 2012;81(11):3190- (J-START): a randomised controlled trial. Lancet. 2016;387 –3200. Doi: 10.1016/j.ejrad.2012.01.034 (10016):341–348. Doi: 10.1016/S0140-6736(15)00774-6 33 Meng Z, Chen C, Zhu Y, Zhang S, Wei C, Hu B, et al. Diagnostic 29 Wilczek B, Wilczek HE, Rasouliyan L, Leifland K. Adding 3D performance of the automated breast volume scanner: a system- automated breast ultrasound to mammography screening in atic review of inter-rater reliability/agreement and meta-analysis women with heterogeneously and extremely dense breasts: of diagnostic accuracy for differentiating benign and malignant Report from a hospital-based, high-volume, single-center breast breast lesions. Eur Radiol. 2015;25(12):3638–3647. Doi: 10.1007/ cancer screening program. Eur J Radiol. 2016;85(09):1554–1563. s00330-015-3759-3 Doi: 10.1016/j.ejrad.2016.06.004 34 Arleo EK, Saleh M, Ionescu D, Drotman M, Min RJ, Hentel K. Recall 30 Jeh SK, Kim SH, Choi JJ, Jung SS, Choe BJ, Park S, Park MS. rate of screening ultrasound with automated breast volumetric Comparison of automated breast ultrasonography to handheld scanning (ABVS) in women with dense breasts: a first quarter ultrasonography in detecting and diagnosing breast lesions. Acta experience. Clin Imaging. 2014;38(04):439–444. Doi: 10.1016/j. Radiol. 2016;57(02):162–169. Doi: 10.1177/0284185115574872 clinimag.2014.03.012 31 Golatta M, Franz D, Harcos A, Junkermann H, Rauch G, Scharf A, 35 Kim JH, Cha JH, Kim N, Chang Y, Ko MS, Choi YW, Kim HH. et al. Interobserver reliability of automated breast volume scan- Computer-aided detection system for masses in automated whole ner (ABVS) interpretation and agreement of ABVS findings with breast ultrasonography: development and evaluation of the hand held breast ultrasound (HHUS), mammography and pathol- effectiveness. Ultrasonography. 2014;33(02):105–115. Doi: ogy results. Eur J Radiol. 2013;82(08):e332–e336. Doi: 10.1016/j. 10.14366/usg.13023 ejrad.2013.03.005

Comparison of Laboratory and Radiological Findings of Pregnant and Non-Pregnant Women with Covid-19

Kadir Burak Ozer1 Onder Sakin2 Kazibe Koyuncu2 Berk Cimenoglu1 Recep Demirhan

1 Department of Thoracic Surgery, Kartal Training and Research Address for correspondence Kazibe Koyuncu, Kartal City Hospital, Hospital, University of Health Sciences, Istanbul, Turkey Kartal, Istanbul, Turkey (e-mail: [email protected]). 2 Department of Obstetrics and Gynecology, Kartal Training and Research Hospital, University of Health Sciences, Istanbul, Turkey

Rev Bras Ginecol Obstet 2021;43(3):200–206.

Abstract Objective Covid-19 became a pandemic, and researchers have not been able to establish a treatment algorithm. The pregnant population is also another concern for health care professionals. There are physiological changes related to pregnancy that result in different laboratory levels, radiological findings and disease progression. The goal of the present article is to determine whether the laboratory results and radiological findings were different in non-pregnant women (NPWs) of reproductive age and pregnant women (PWs) diagnosed with the Covid-19 infection. Methods Out of 34 patients, 15 (44.11%) PWs and 19 (55.8%) NPWs were included in the study. Age, comorbidities, complaints, vitals, respiratory rates, computed tomography (CT) findings and stages, as well as laboratory parameters, were recorded from the hospital database. Results The mean age of the PWs was of 27.6 0.99 years, and that of the NPWs was of 37.63 2.00; when age was compared between the groups, a statistically significant difference (p ¼ 0.001) was found. The mean systolic blood pressure of the PWs was of 116.53 11.35, and that of the NPWs was of 125.53 13.00, and their difference was statistically significant (p ¼ 0.05). The difference in the minimum respiratory rates of the patients was also statistically significant (p ¼ 0.05). The platelet levels observed among the PWs with Covid-19 were lower than those of the NPWs (185.40 39.09 109/mcL and 232.00 71.04 109/mcL respectively; p ¼ 0.05). The mean D-dimer value of the PWs was lower in comparison to that of the NPWs Keywords (p < 0.05). ► covid-19 Conclusion The laboratory findings and imaging studies may differ between pregnant ► pregnancy and non-pregnant populations. It is important to properly interpret these studies. ► laboratory Future studies with a higher number of patients are required to confirm these ► imaging studies preliminary data.

received DOI https://doi.org/ © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights June 26, 2020 10.1055/s-0041-1726054. reserved. accepted ISSN 0100-7203. This is an open access article published by Thieme under the terms of the December 16, 2020 Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda., Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil Comparison of Laboratory and Radiological Findings of Pregnant Ozer et al. 201

Introduction logical findings could lead to misdiagnosis and alter the management of the pregnancy. The objective of the present The Covid-19 pandemic was declared by the World Health study is to compare laboratory parameters and radiological Organization (WHO) on March 11, 2020. As of today, approx- findings between PWs and NPWs of reproductive age hospi- imately 4.115 million Covid-19 cases have been reported talized for Covid-19 infection. worldwide, and 280 thousand of them were fatal.1 The virus causing symptoms ranging from flu-like symptoms to signs Methods of severe respiratory failure similar to severe acute respiratory syndrome (SARS) and Middle-East respiratory syn- The present retrospective cross-sectional study was con- drome (MERS) has been announced to be a novel ducted between March 18 and May 1st, 2020, in a Turkish coronavirus (2019-nCoV) that had never been previously tertiary healthcare center which is one of the country’s first detected in humans. Studies2 have demonstrated that this pandemic hospitals. A total of 34 patients treated in the type of coronavirus has 96.3% of homology with bat SARS- pandemic wards were included in the study, 15 of whom like coronavirus (BatCoV RaTG13), and bats can be natural were pregnant. Age, comorbid diseases, complaints, systolic hosts for 2019-nCoV. and diastolic arterial blood pressures and the minimum and The symptoms reported to be associated with Covid-19 maximum values of oxygen saturation, respiratory rates, infection are cough (50%), fever (43%), myalgia (36%), headache computed tomography (CT) findings and stages, and labora- (34%), dyspnea (29%), sore throat (20%), diarrhea (19%), nau- tory parameters, such as CRP, D-dimer, neutrophil, lympho- sea/vomiting (12%), loss of smell/taste (10%), abdominal pain cyte, leukocyte and platelet counts, were collected from (10%), and rhinorrhea (10%).3 Moreover, particular laboratory hospital records. The present study included PWs and results were found to be related to poor prognosis, and they are NPWs of reproductive age with positive Covid-19 test results listed as lymphopenia, thrombocytopenia, elevated liver who were submitted to inpatient treatment. enzymes, elevated lactate dehydrogenase (LDH), elevated At the first visit to the emergency room or Covid-19 inflammatory markers (such as C-reactive protein [CRP] and outpatient clinics, PWs and NPWs with fever, low oxygen ferritin), elevated D-dimer (> 1 mcg/mL), elevated prothrom- saturation (< 93% mmHg in the air in the room), presence of bin time (PT), elevated troponin, elevated creatine phosphoki- comorbidities, and asymptomatic PWs in the last trimester – nase (CPK), and acute kidney injury.4 6 These changes were not were hospitalized in pandemic wards. Female patients under subclassified into specific populations. the age of 18, those not of childbearing age, all male patients, The laboratory results of pregnant women (PWs) differ and patients without CT findings specifictoCovid-19disease from those of non-pregnant women (NPWs); they even differ or who were not positive after a polymerase chain reaction regarding pregnant women in different trimesters. For ex- (PCR) test were excluded from the study. All retrospective ample, the leukocyte count and the levels of alkaline phos- data were examined, and informed consent was obtained phatase continuously rise during a normal pregnancy. from the patients and their relatives. The present study was Similarly, D-dimer values approximately double during approved by the institutional Ethics Committee and the mid-pregnancy. Several hormones and coagulation factors Ministry of Health, General Directorate of Health Services are also known to increase substantially. Furthermore, in- (2020/514/176/17). flammation markers such as ferritin and CRP levels were The PWs underwent CT scans after delivery, and the shown to rise. Unless these normal, pregnancy-related alter- NPWS, at the time of hospitalization. The lesions detected ations are taken into account when evaluating the laboratory on the CT scans were divided into three stages: early stage, results of PWs, many of the physiological adaptations of progressive stage, and severe stage, according to their loca- pregnancy can be misinterpreted as pathological, or they tions, density, presence of air bronchograms ,and multiple- may mask the diagnosis of a disease process. lobe involvement.9 The early stage is characterized by the Pregnancy causes specific physiological changes, and ground-glass opacity (GGO), which is common in Covid-19 laboratory results differ during pregnancy. Therefore, it is disease, located in the peripheral and subpleural area.9,10 important to know these changes to properly interpret these The GGO is described as an irregular-shaped shadow image studies. Dyspnea and discomfort in breathing are common that reduces the density of the lung tissue.10 In the progres- during pregnancy, and are also common in cases of Covid-19 sive stage, areas of inflammation that are more intense and infection. Moreover, the diaphragm is elevated since the first apparent than the GGO, as well as centrally-located consol- trimester, and it rises up to 4 cm, and the diameter of the idations that contain air bronchograms, are observed. The CT chest can increase by 2 cm or more.7 These changes could finding in which bilateral and diffuse intensely-consolidated make it hard to clarify the radiological findings in PWs areas in both lungs acquire a marble-like appearance is infected with Covid-19. Respiratory rates were shown to considered as the severe stage.9 In the present study, we be unchanged.8 Systolic blood pressure tends to decrease classified the CT findings of all patients according to their between the 12th and 19th weeks of gestation, then tend to stages, and evaluated them through a statistical analysis progressively rise until the 40th week. Similarly, diastolic (►Fig. 1). blood pressure decreases and increases throughout preg- All retrospectively-collected data were analyzed with the nancy. Notwithstanding the knowledge of these normal, Statistical Package for the Social Sciences (SPSS, IBM Corp., pregnancy-related alterations, laboratory results and radio- Armonk, NY, US) software, version 22.0. the relationships

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. 202 Comparison of Laboratory and Radiological Findings of Pregnant Ozer et al.

Fig. 1 Stages of Covid-19 infection according to computed tomography ﬁndings (1A:earlystage;1B:progressivestage;1C: severe stage – diffuse consolidation).

among the values found for the PWs and NPWs were Results evaluated using the Chi-Squared test, and the analysis of the continuous variables was performed through the Student A total of 34 patients, 15 (44.11%) PWs and 19 (55.8%) NPWs, t-test. One-way analysis of variance (ANOVA) was performed were included in the present study. The mean age of the for the evaluation of the relationships among more than two patients was of 33.7 1.49). The mean age of PWs was of groups. The correlations of two continuous variables were 27.6 0.999, while the mean age of the NPWs was of determined by the Pearson correlation test. Values of p lower 37.63 2.009. The difference between the average ages of than 0.05 were considered statistically signiﬁcant. these two groups was statistically signiﬁcant (p ¼ 0.001). The

Table 1 Statistical analysis of the vital parameters of the two study groups

Pregnant Non-pregnant p-value Mean standard (Minimum– Mean standard (Minimum– deviation maximjum) deviation maximum) Systolic blood pressure 116.53 11.351 mm/Hg 148–85 mm/Hg 125.53 13.006 mm/Hg 150–90 mm/Hg < 0.05 Diastolic blood pressure 76.00 11.212 mm/Hg 110–60 mm/Hg 79.47 10.260 mm/Hg 100–50 mm/Hg > 0.05 Oxygen saturation (maximum) 98.53 0.915% 99–94% 98.21 0.631% 99–93% > 0.05 Oxygen saturation (minimum) 96.20 6.213% 96–89% 96.58 1.677% 94–88% > 0.05 Fever (maximum) 37.247 0.7039° 38.–36.2° 37.405 0.8508° 39.–36.5° > 0.05 Fever (minimum) 36.487 0.6490° 37.5– 35.5° 36.558 0.4682° 37.3– 35.7° > 0.05 Respiratory rate (maximum) 21.531. 959 per minute 27–20 20.05 2.592 per minute 27–17 > 0.05 Respiratory rate (minimum) 19.73 1.981 per minute 26–18 19.73 1.981 per minute 20–16 < 0.05

Table 2 Statistical analysis of laboratory parameters and radiological ﬁndings

Pregnant Non-pregnant p-value Leukocytes (x103/mcL) 6,486.67 2,861.285 14,473.68 32,941.292 > 0.05 Lymphocytes (mm3) 896.00 235.184 1488.42 2596.513 > 0.05 Neutrophils (mm3) 4293.33 1338.158 12989.47 30327.397 > 0.05 Platelets (x109/mcL) 185.40 39.089 232.00 71.040 < 0.05 C-reactive protein (mg/dL) 46.107 53.3711 44.842 71.2431 > 0.05 D-dimer (ng/mL) 962.00 523.644 3732.11 6605.985 < 0.05 Computed tomography findings – early stage: n (%) 2 (13.3%) 10 (52.63%) > 0.05 Computed tomography findings – progressive stage: n (%) 4 (26.6%) 5 (26.3%) > 0.05 Computed tomography findings – severe stage: n (%) 2 (13.3%) 1 (5.2%) > 0.05

Table 3 Number of pregnant patients and D-dimer values according to the stages of Covid-19 infection assessed through computed tomography

Normal Early stage Progressive stage Severe stage Patients – n (%) 7 (46.6%) 2 (13.3%) 4(26.6%) 2 (13.3%) D-dimer values (ng/ml) 637.14 141.03 925.00 176.77 1,505.00 754.29 1,050.00 212.13 (mean standard deviation)

Table 4 Number of non-pregnant patients and D-dimer values according to the stages of Covid-19 infection assessed through computed tomography

Normal Early stage Progressive stage Severe stage Patients – n (%) 2 (10.5%) 10 (52.6%) 5(26.3%) 1 (5.2%) D-dimer values (ng/ml) 613.33 270.24 1,633.00 1,178.74 9,574.00 11,483.00 4,900.00 (mean standard deviation)

mean gestational week among the PWs was 31 7.92 (11 to chronic renal failure that did not require dialysis. The most 40 weeks). One of the PWs had allergic asthma and another common abnormal vital sign in the whole sample was fever. had hypothyroidism. Among the NPWs, 4 had hypertension, The analysis of the vital signs of the patients is outlined 3 had diabetes mellitus, 2 had allergic asthma, and 1 had in table 1. The maximum and minimum values of all vital

Fig. 2 Distribution of stages according to computed tomography ﬁndings.

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. 204 Comparison of Laboratory and Radiological Findings of Pregnant Ozer et al.

parameters were recorded, and a statistical comparison was outbreaks, the sheer number of deaths recorded due to the performed between the PWs and NPWs. According to this great number of patients. In the general population, 81% of analysis, a significant difference was found between the the cases reported so far are mild, 14% are moderate, and 5% maximum values of arterial blood pressure (p ¼ 0.039) and are severe in terms of clinical condition.11 Huang et al.2 the minimum respiratory rates per minute (p ¼ 0.013). There emphasized that the severity of the disease has a positive was no significant difference regarding the other vital correlation with age. In the Covid-19 disease, the mortality parameters of two groups (►Table 1). rates have been found to be higher, particularly in patients The mean leukocyte count of the PWs was of older than 50 years of age.12 In a review of the studies in 6,486.6 2,86128 103/mcl; the mean lymphocyte count which PWs with Covid-19 were followed up, low morbidity was of 896 235.184 mm3; the neutrophil count was of and mortality rates were detected in PWs in comparison – 4,293.3 1,338.158 mm3; and the mean platelet count was with the general population.13 15 The fact that pregnant of 185.4 39.089 x109/mcL. When the average laboratory Covid-19 patients were usually younger than 40 years, as results of the NPWs were evaluated, the leukocyte count was is the case in the present study, can be the explanation of 1,4473.6 32,941.292 103/mcl, the lymphocyte count behind the low morbidity and mortality rates. was of 1,488.4 2,596.513) mm3, the neutrophil count was We observed that the maximum systolic blood pressure of 12,989.4 30,327.397 mm3, and the platelet count was of was higher among NPWs. This is related to the presence of 232 71,040 x109/mcL. Although the platelet counts were history of chronic hypertension in 4/19 of the population of within normal limits in both groups, the fact that the PWs NPWs. In a study conducted by Li et al.,16 the Covid-19 had lower platelet counts was found to be statistically disease was shown to be significantly more aggressive in significant (p ¼ 0.026) (►Table 2). individuals with preexisting comorbidities. According to The mean CRP values of the PWs at the time of admission their data, the fact that fewer comorbid diseases were found was of 46.1053.371 mg/dl (minimum: 3 mg/dl; maximum: among the PWs with Covid-19 is the probable explanation 148 mg/dl), and, regarding the NPWs, it was of for the milder course of Covid-19 during pregnancy. Through 44.8 71.243) mg/dl (minimum: 235 mg/dl; maximum: 2,1 the comparative analysis of the laboratory parameters of mg/dl). The difference between these two groups was not PWs and NPWS with Covid-19, the platelet counts were statistically significant (p > 0.05). The mean value of the D- found to be significantly higher among NPWs, even though dimer of the PWs with Covid-19 was of 962 523.644 ng/ml they were within the normal range for both groups. (minimum: 540 ng/ml; maximum: 2,560 ng/ml), and, re- Ranucci et al.17 determined that the formation of micro- garding the NPWs, it was of 3,732.1 6,605.985 ng/ml (min- thrombi in the pulmonary vascular bed was an important imum: 200 ng/ml; maximum: 30,000 ng/ml). This difference factor in the development of acute respiratory distress was found to be statistically significant (p < 0.05). It was syndrome (ARDS) among Covid-19 patients. In addition, determined that the CRP and D-dimer values of all patients they did not observe any major thromboembolic events after were positively correlated with each other. According to the initiating the anticoagulant treatment in a case series with postnatal CT findings of PWs with Covid-19, 2 (13.3%) 16 patients.17 It could be said that low molecular weight patients were in the early stage, 4 (26.6%) were in the heparin (LMWH) should be used in the prophylaxis, espe- progressive stage, and 2 (13.3%) were in the severe stage cially when the increased risk of thrombosis risk in cases of (►Fig. 1). No abnormal CT findings were detected in 7 (46.6%) Covid-19 is added to the increased risk of hypercoagulopathy patients. We observed that 10 (52.63%) NPWs with Covid-19 during pregnancy. It is known that D-dimer values rise had early-stage CT findings, 5 (26.3%) had progressive-stage during pregnancy. The normal D-Dimer values reported findings, and 1 (5.2%) had severe-stage findings. In the according to the trimester were of 200 ng/mL to 900 ng/mL comparative analysis between the two groups, no significant in the first trimester, 200 ng/mL to 1600 ng/mL in the second difference was found in terms of tomography findings trimester, and 400 ng/mL to 500 ng/ mL in the third trimester. (p > 0.05). The CT stages and laboratory and vital parameters The mean D-dimer level found in the present study was a were compared, and the relationship between CT stages and little higher than expected. Our recommendation is to use D-dimer values among PWs with Covid-19 was statistically LMWH at the prophylaxis dose in infected PWs, and to use significant (p ¼ 0.045) (►Tables 3 and 4)(►Fig. 2). the treatment dose in the PWs with high D-dimer levels. A statistically significant difference was found between Tang et al.18 stated that patients with significantly high D- the CRP values of PWs with CT findings of all 3 stages dimer levels would benefit from the anticoagulant treatment (p ¼ 0.002). There was no statistically significant difference given at the treatment dose. As a result of the autopsies between the oxygen saturation values of patients in different performed in 5 patients who died from Covid-19, Magro stages according ot the CT findings (p > 0.05). et al.19 declared that microtrombi tend to join in different vascular zones. In our study, we found that D-dimer values Discussion were significantly higher among the NPWs. The lower D- dimer values among PWs may explain their lower mortality The highly-transmissible Covid-19 disease affected the and morbidity rates. However, studies with larger samples whole world within a few weeks. The morbidity and mortal- are required for more precise results. ity rates quickly became fairly high. Although the overall There was no statistically significant difference in CRP mortality rate was lower than that of other coronavirus values between PWs and NPWs. The CRP values of the

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. Comparison of Laboratory and Radiological Findings of Pregnant Ozer et al. 205 patients who required additional antibiotherapy for condi- Conflicts to Interest tions such as fever are significantly higher than those of the The authors have no conflict of interests to declare. patients who did not require antibiotherapy. Therefore, a high CRP value is an important factor to take into consider- References ation before initiating antibiotherapy. On the other hand, it 1 World Health Organization. Novel coronavirus - China [Internet]. should be kept in mind that antibiotherapy should be added 2020 [cited 2020 Mar 18]. Available from: http://www.who.- to the current treatment protocol, as an increase in CRP int/csr/don/12-january-2020-novel-coronavirus-china/en/ values is detected during the follow-up. In the present study, 2 Huang X, Wei F, Hu L, Wen L, Chen K. · Epidemiology and clinical a positive correlation was found between elevated CRP and characteristics of COVID-19. Arch Iran Med. 2020;23(04): – D-dimer values. Sun et al.20 also determined a positive 268 271. Doi: 10.34172/aim.2020.09 3 Stokes EK, Zambrano LD, Anderson KN, Marder EP, Raz KM, Felix correlation between the increase in CRP and D-dimer values. SEB, et al. Coronavirus Disease 2019 Case Surveillance - United According to the radiological studies on Covid-19 disease, States, January 22-May 30, 2020. MMWR Morb Mortal Wkly Rep. many disease-specific findings were detected in CT of the 2020;69(24):759–765. Doi: 10.15585/mmwr.mm6924e2 thorax, such as the GGO and consolidation. In a study con- 4 Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk factors ducted by Wang et al.,9 the patients were staged radiologically associated with acute respiratory distress syndrome and death in according to the CT findings. In the present study, all patients patients with Coronavirus Disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(07):934–943. Doi: 10.1001/ were divided into three different stages according to the CT jamainternmed.2020.0994 fi fi ndings. There was no statistically signi cant difference re- 5 Shi S, Qin M, Shen B, et al. Association of cardiac injury with garding the tomographic stages of the PWs and NPWs with mortality in hospitalized patients with COVID-19 in Wuhan, Covid-19. However, the differences in CRP and D-dimer values China. JAMA Cardiol. 2020;5(07):802–810. Doi: 10.1001/jama- among CT stages were statistically significant (p < 0.05). The cardio.2020.0950 6 Liao D, Zhou F, Luo L, Cai Y, Liu T, Yang F, et al. Haematological highest mean CRP values (130 25.4) were observed in characteristics and risk factors in the classification and prognosis patients in the severe stage , and the highest mean of D-dimer evaluation of COVID-19: a retrospective cohort study. Lancet values (1505 754) were observed in patients in the progres- Haematol. 2020;7(09):e671–e678. Doi: 10.1016/S2352-3026 sive stage. Adding antibiotherapy and anticoagulant treatment (20)30217-9 according to the CT stage should be considered while planning 7 Gilroy RJ, Mangura BT, Lavietes MH. Rib cage and abdominal the treatment protocols for pregnant patients. This will also be volume displacements during breathing in pregnancy. Am Rev Respir Dis. 1988;137(03):668–672. Doi: 10.1164/ajrccm/ clarified with more data. 137.3.668 The limitations of the present study include the small 8 Elkus R, Popovich J Jr. Respiratory physiology in pregnancy. Clin number of the patients, which was due to the low number of Chest Med. 1992;13(04):555–565 PWs diagnosed with Covid-19. This may be related to the 9 Wang K, Kang S, Tian R, Zhang X, Zhang X, Wang Y. Imaging better adaptation of PWs to social isolation and sanitary manifestations and diagnostic value of chest CT of coronavirus habits. We also wish we had preliminary data to better disease 2019 (COVID-19) in the Xiaogan area. Clin Radiol. 2020;75 (05):341–347. Doi: 10.1016/j.crad.2020.03.004 understand the laboratory results in order to take immediate 10 Guan CS, Lv ZB, Yan S, Du YN, Chen H, Wei LG, et al. Imaging action for the pandemic process. features of Coronavirus disease 2019 (COVID-19): evaluation on thin-section CT. Acad Radiol. 2020;27(05):609–613. Doi: Conclusion 10.1016/j.acra.2020.03.002 11 Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: There is very little data on the Covid-19 disease, and infor- summary of a report of 72 314 cases from the Chinese Center for mation on pregnancy and its consequences is particularly Disease Control and Prevention. JAMA. 2020;323(13):1239- limited. We observed that pregnancy did not have any effect –1242. Doi: 10.1001/jama.2020.2648 on laboratory values or radiological findings in Covid-19 12 Dotters-Katz SK, Hughes BL. Considerations for obstetric care infection period. Especially in pregnant patients, we recog- during the COVID-19 pandemic. Am J Perinatol. 2020;37(08): – nized that different laboratory results appeared according to 773 779. Doi: 10.1055/s-0040-1710051 13 Zaigham M, Andersson O. Maternal and perinatal outcomes with tomographic stages. As a result, taking tomographic staging COVID-19: A systematic review of 108 pregnancies. Acta Obstet into consideration while creating treatment algorithms for Gynecol Scand. 2020;99(07):823–829. Doi: 10.1111/aogs.13867 pregnant patients was found to be necessary. On its own, 14 Yang H, Sun G, Tang F, Peng M, Gao Y, Peng J, et al. Clinical features pregnancy was not found to be a poor prognostic factor for and outcomes of pregnant women suspected of coronavirus Covid-19 disease if the radiological and laboratory findings disease 2019. J Infect. 2020;81(01):e40–e44. Doi: 10.1016/j. were evaluated. However, with extensive studies in the jinf.2020.04.003 15 Breslin N, Baptiste C, Gyamfi-Bannerman C, Miller R, Martinez R, future, clearer comments will be made on this subject. Bernstein K, et al. Coronavirus disease 2019 infection among asymptomatic and symptomatic pregnant women: two weeks of Contributors confirmed presentations to an affiliated pair of New York City All authors were involved in the design and interpretation hospitals. Am J Obstet Gynecol MFM. 2020;2(02):100118. Doi: 10.1016/j.ajogmf.2020.100118 of the analyses, contributed to the writing of the manu- 16 Li K, Wu J, Wu F, Guo D, Chen L, Fang Z, Li C. The clinical and chest fi script, and read and approved the nal manuscript. CT features associated with severe and critical COVID-19

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. 206 Comparison of Laboratory and Radiological Findings of Pregnant Ozer et al.

pneumonia. Invest Radiol. 2020;55(06):327–331. Doi: 10.1097/ 19 Magro C, Mulvey JJ, Berlin D, Nuovo G, Salvatore S, Harp J, et al. RLI.0000000000000672 Complement associated microvascular injury and thrombosis in 17 Ranucci M, Ballotta A, Di Dedda U, Bayshnikova E, Dei Poli M, Resta the pathogenesis of severe COVID-19 infection: A report of ﬁve M, et al. The procoagulant pattern of patients with COVID-19 cases. Transl Res. 2020;220:1–13. Doi: 10.1016/j.trsl.2020.04.007 acute respiratory distress syndrome. J Thromb Haemost. 2020;18 20 Sun C, Zhang XB, Dai Y, Xu XZ, Zhao J. [Clinical analysis of 150 cases (07):1747–1751. Doi: 10.1111/jth.14854 of 2019 novel coronavirus infection in Nanyang City, Henan Prov- 18 Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment ince]. Zhonghua Jie He He Hu Xi Za Zhi. 2020;43(06):503–508. Doi: is associated with decreased mortality in severe coronavirus 10.3760/cma.j.cn112147-20200224-00168 Chinese. disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(05):1094–1099. Doi: 10.1111/jth.14817

Vertical Transmission of SARS-CoV-2: A Systematic Review Transmissão vertical do SARS-CoV-2: Revisão sistemática

Ionara Diniz Evangelista Santos Barcelos1 Ivan Andrade de Araújo Penna2 Adriana de Góes Soligo3 Zelma Bernardes Costa4 Wellington Paula Martins5

1 Department of Obstetrics and Gynecology, Universidade Estadual do Address for correspondence Ionara Diniz Evangelista Santos Oeste do Paraná, Cascavel, Paraná, PR, Brazil Barcelos, MD, PhD, Departmento de Ginecologia e Obstetrícia, 2 Department of Maternal-Infant Care, Universidade Federal Universidade Estadual do Oeste do Paraná, Cascavel, Paraná, PR, Brazil Fluminense, Niterói, Rio de Janeiro, RJ, Brazil (e-mail: [email protected]). 3 Private Clinic of Human Reproduction Dra. Adriana de Góes, São Paulo, SP, Brazil 4 Department of Obstetrics and Gynecology, Universidade Federal de Goiás, Goiânia, GO, Brazil 5 SEMEARFertilidade,RibeirãoPreto,SãoPaulo,SP,Brazil

Rev Bras Ginecol Obstet 2021;43(3):207–215.

Abstract Objective The evaluation of the available evidence on vertical transmission by severe acute respiratory syndrome coronavirus 2 (SARS-CoV)-2. Data Sources An electronic search was performed on June 13, 2020 on the Embase, PubMed and Scopus databases using the following search terms: (Coronavirus OR COVID-19 OR COVID19 OR SARS-CoV-2 OR SARS-CoV2 OR SARSCoV2)AND(vertical OR pregnancy OR fetal). Selection of Studies The electronic search resulted in a total of 2,073 records. Titles and abstracts were reviewed by two authors (WPM, IDESB), who checked for duplicates using the pre-established criteria for screening (studies published in English without limitation regarding the date or the status of the publication). Data Collection Data extraction was performed in a standardized way, and the final eligibility was assessed by reading the full text of the articles. We retrieved data regardingthe deliveryof the potential cases of verticaltransmission, as wellas the main findings and conclusions of systematic reviews. Data Synthesis The 2,073 records were reviewed; 1,000 duplicates and 896 clearly not eligible records were excluded. We evaluated the full text of 177 records, and identified only 9 suspected cases of possible vertical transmission. The only case with Keywords sufficient evidence of vertical transmission was reported in France. ► vertical transmission Conclusion The risk of vertical transmission by SARS-CoV-2 is probably very low. Despite ► SARS-CoV-2 several thousands of affected pregnant women, we have identified only one case that has ► COVID-19 fulfilled sufficient criteria to be confirmed as a case of vertical transmission. Well-designed ► perinatal outcomes observational studies evaluating large samples are still necessary to determine the risk of ► maternal morbidity vertical transmission depending on the gestational age at infection.

received DOI https://doi.org/ © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights October 12, 2020 10.1055/s-0040-1722256. reserved. accepted ISSN 0100-7203. This is an open access article published by Thieme under the terms of the November 6, 2020 Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda., Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil 208 Vertical Transmission of SARS-CoV-2 Barcelos et al.

Resumo Objetivo Avaliar a evidência disponível acerca da transmissão vertical do coronavírus da síndrome respiratória aguda grave 2 (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, em inglês). Fontes de Dados Foi realizada uma busca eletrônica em 13 de junho de 2020 nas plataformas Embase, PubMed e “Scopus utilizando os seguintes termos de busca: (Coronavirus OU COVID-19 OU COVID19 OU SARS-CoV-2 OU SARS-CoV2 OU SARSCoV2)E (vertical OU pregnancy OU fetal). Seleção dos Estudos A busca eletrônica resultou em um total de 2.073 registros. Títulos e resumos foram revisados por dois autores (WPM, IDESB), que verificaram a ocorrência de duplicidade e utilizaram critérios preestabelecidos para o rastreamento (estudos publicados em inglês sem limitações quanto à data ou à situação da publicação). Aquisição dos Dados A extração de dados foi realizada de forma padrão, e a eligibilidade final foi definida poir meio da leitura do artigo completo. Foram coletados dados dos partos de casos com potencial transmissão vertical, bem como os principais achados e conclusões de revisões sistemáticas. Síntese dos Dados Foram revisados os 2.073 registros; 1.000 duplicatas e 896 registrosclaramentenãoelegíveisforamexcluídos.Avaliamososartigoscompletos de 177 registros, e identificamos apenas 9 casos de potencial transmissão vertical. O único caso com evidência suficiente de transmissão vertical foi relatado na França. Conclusão O risco de transmissão vertical pelo vírus SARS-CoV-2 é provavelmente muito Palavras-chave baixo. Apesar de milhares de gestantes afetadas, identificamosapenasumcasoque ► transmissão vertical preencheu critérios suficientes para que fosse confirmadocomoumcasodetransmissão ► SARS-CoV-2 vertical. Estudos observacionais bem desenhados que avaliem grandes amostras ainda são ► COVID-19 necessários para se determinar o risco de transmissão vertical, a depender da idade ► resultados perinatais gestacional na infecção. ► morbidade materna

Introduction women and newborns. However, the impact of COVID-19 during pregnancy and the neonatal period is not yet fully At the end of 2019, a new virus was discovered: SARS-CoV-2. supported by scientific research.1 It first emerged in China, in the city of Wuhan, and quickly A better understanding of the viral pathogenesis in the spread throughout the world, causing the coronavirus-19 pregnancy cycle is necessary to enable the monitoring of this disease (COVID-19).1 This virus transmits extraordinarily group who is considered susceptible to this infection. The rapidly. Therefore, pregnant women have become a concern, present review aims to identify the available evidence re- given their susceptibility to respiratory infections, due to the garding the risk of vertical transmission by SARS-CoV-2 to physiological changes during pregnancy and the restriction guide family, gestational, and perinatal planning. of lung expansion.2,3 The current coronavirus (SARS-CoV-2), shares many Methods structural similarities with other coronaviruses, like SARS- CoV and Middle East respiratory syndrome coronavirus Eligibility Criteria (MERS-CoV). However, SARS-CoV-2 is less virulent, and its Observational studies with suspected vertical transmission performance, as well as that of SARS-CoV, is mediated by the and systematic reviews assessing the risk of vertical trans- angiotensin-converting enzyme 2 (ACE2) receptor, a compo- mission were considered eligible. nent of the renin-angiotensin system present in the lungs, heart, kidneys, and placenta.4,5 Search and Selection of the Studies Affinity with the receptor determines the route of the We searched the PubMed, Scopus, and Embase databases viral infection, and its identification in the placenta alerts to using the following search terms: (Coronavirus OR COVID-19 the possibility of vertical transmission.6 Although present, OR COVID19 OR SARS-CoV-2 OR SARS-CoV2 OR SARSCoV2) the link between SARS-CoV-2 and the ACE2 receptor in the AND (vertical OR pregnancy OR fetal). Titles and abstracts placenta is poorly expressed, which can be a protective factor were reviewed by two authors (WPM, IDESB), who checked for vertical transmission. Several studies have been pub- for duplicates using the pre-established criteria for screen- lished in recent months describing viral behavior in pregnant ing. We limited the search to studies published in English, but

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. Vertical Transmission of SARS-CoV-2 Barcelos et al. 209 there was no limitation regarding the date or the status of the – One report of a potential vertical transmission at Renmin publication. After screening, the full texts of the records Hospital, Wuhan, China.10 considered potentially eligible were retrieved for the final – One report of a potential vertical transmission at Imam evaluation of eligibility. Khomeini Hospital, Sari, Iran.11 – One report of two suspect cases at hospital maternity Data Collection/Extraction units of the COVID-network in Lombardy and units of Data extraction was performed in a standardized way, and Padua and Modena, northern Italy.12 final eligibility was assessed by reading the full text of the – One report of a potential vertical transmission at the articles. The studies were characterized according to their British American Hospital, Lima, Peru.13 design. We retrieved data regarding the delivery of the – One report of a potential vertical transmission at Paris potential cases of vertical transmission, as well as the Saclay University Hospitals, France.14 main findings and conclusions of systematic reviews and – One report of a potential vertical transmission at Saint the conclusions from other reviews. The extracted data are Barnabas Medical Center, United States.15 presented in tables. – One report of potential vertical transmission at Henan Provincial People’s Hospital, China.16 Results Seventeen Systematic Reviews (►Box 1) The last electronic search was performed on June 13, 2020, We found a total of 17 systematic reviews: resulting in a total of 2,073 records from the 3 databasis – One systematic review including 79 pregnancies based on consulted: Embase (n ¼ 698), PubMed (n ¼ 738), and Scopus 19 studies from China, Saudi Arabia, South Korea, the (n ¼ 637). We excluded 1,000 duplicates, and 1,073 records United Arab Emirates, Jordan, Canada, Hong Kong, and the were screened based on titles and abstracts, resulting in the US.17 exclusion of 896 records, as they were not related to the – One systematic review including 51 pregnancies based on vertical transmission of COVID-19. We evaluated the full text 6 studies from China.18 of 177 records (►Fig. 1); out of those, we considered the – One systematic review including 108 pregnancies based following studies eligible: on 18 studies from China, Sweden, South Korea, and Nine cases of potential vertical transmission were de- Honduras.19 scribed in ten reports (►Table 1). – One systematic review not reporting the number of cases, – Three reports of the same case of a potential vertical based on 29 studies from China, Iran, France, and the US.20 – transmission at Tongji Hospital, Wuhan, China.7 9 – One systematic review including 123 cases based on 16 studies from China.21 – One systematic review including 222 cases based on 17 studies from China, Australia, Iran, and Spain.22 – One systematic review including 385 pregnancies and 256 newborns based on 33 studies from China, Australia, Honduras, Iran, South Korea, Sweden, Turkey, Italy, The Netherlands, and the US.23 – One systematic review including 46 cases based on 8 studies from China, Belgium, Spain, Iran, and Peru.24 – One systematic review including 538 pregnancies based on 13 studies from China, Italy, and the US.25 – One systematic review including 324 pregnancies based on 24 studies from China, Iran, the US, Italy, Spain, Peru, Sweden, Turkey, South Korea, Australia, Canada, and France.26 – One systematic review including 87 pregnancies based on 9 studies from China and Iran.27 – One systematic review including 89 pregnancies based on 9 studies from China.28 – One systematic review including 89 pregnancies based on 9 studies from China.29 – One systematic review including 92 pregnancies based on 9 studies from China.30 – One systematic review including 665 pregnancies based on 49 studies from China.31 – One systematic review including 83 neonates based on 22 32 Fig. 1 Flowchart of the selection of studies. studies from China, Peru, South Korea, and Spain.

Table 1 Reports of potential vertical transmission

Case Country; city; Age Gestational Birth Apgar Delivery Main findings Interval between Reasons why vertical hospital (years) age weight score onset of maternal transmission is not disease and diagnosis justified (or justified) in the neonate #1 China; Wuhan; 34 39 weeks 6 3,250 g 8/9 Cesarean Positive RT-PCR in 8 hours of maternal Not justified: RT-PCR Wang Tongji Hospital days th oropharynx symptoms þ 36 hours the in oropharynx swab et al.,7 Hu swab – newborn postpartum collected after more et al.,8 Yu 36 hours after than 12 hours of et al.9 delivery. delivery. #2 China; Wuhan; 29 37weeks 6 3,120 g 9/10 Cesarean Positive IgM and 25 days Not justified: discor- Dong Renmin Hospitalof days IgG 2 hours after dance among exams et al.10 Wuhan University delivery; and negative RT-PCR in negative RT-PCR in the oropharynx swab. the oropharynx swab; IgM and IgG levels were reduced after 2 weeks; discharged. #3 Iran; Sari; Imam 22 32 weeks 2,350 g 8/9 Cesarean Positive RT-PCR in 7days Notjustified: positive Zamaniyan Khomeini Hospital the amniotic fluid RT-PCR in the amniotic et al.11 collected during fluid, but with the pos- cesarean section sibility of contamina- (contamination?); tion with no other negative RT-PCR in confirmation of the the oropharynx virus. swab of the newborn; maternal death postpartum. #4 China; Wuhan; NR NR NR NR Vaginal Positive RT-PCR in Not informed Not justified: the swab Li et al.5 Hubei Provincial two newborns. In test was not performed and Fer- Maternal and Child these two cases, shortly after birth. razzi Health Center;5 because viral test- et al.12 and Italy; Lom- ing was not per- bardy and Units of formed immedi- Padua and ately after birth, Modena12 postpartum transmission cannot be excluded. #6 Peru; Lima; British 41 33 weeks 2,970 g 6/8 Cesarean Positive RT-PCR in 5days Notjustified: RT-PCR in Alzamora American Hospital the nasopharyn- the nasopharyngeal et al.13 geal swab – new- swab collected born 16 hours after 12 hours after delivery. delivery. Repeated in 48 hours: also positive. #7 France; Paris Saclay 23 35 weeks 5 2,540 g 4/1 Cesarean Amniotic fluid col- 5days Justified: positive RT- Vivanti University days lected during ce- PCR in the amniotic et al.14 Hospitals sarean section fluid and in the neonate positive on RT-PCR blood sample collected (Genes E and S). before 12 hours of Nasopharyngeal delivery. and rectal swabs collected within 1hour,3daysand 18 days of life were positive on RT-PCR (Genes E and S). Blood and non- bronchoscopic bronchoalveolar lavage fluid collected before extubation (6 hours after delivery) positive on RT-PCR (Genes E and S). #8 United States; 39 27 weeks Baby A: Baby A: Cesarean Twin A tested posi- 14 days Not justified: the type Mehta Liningston; Saint 925 g; 1/3; tive and twin B of test performed is not et al.15 Barnabas Medical Baby B: Baby B: tested negative for described properly, Center 1,050 g 5/6 SARS-CoV-2 at and it was performed 72 hours, and it is 12 hours after delivery. not clear what type

Table 1 (Continued)

Case Country; city; Age Gestational Birth Apgar Delivery Main findings Interval between Reasons why vertical hospital (years) age weight score onset of maternal transmission is not disease and diagnosis justified (or justified) in the neonate of test was performed. The authors believe that twin A tested positive due to vertical transmission. #9 China; Henan; 28 37 weeks Not in- 9/9 Cesarean Obstetricians, 9 days of maternal Not justiﬁed: RT-PCR in Sun et al.16 Henan Provincial formed anesthesiologists, symptoms þ 6postna- the oropharynx swab People’sHospital neonatologists, tal days collected 12 hours af- and nurses wore ter delivery. full personal protective equipment, including an N95 mask, eye goggles, face shield, and a top-to-bottom tight-ﬁtting gown, entering the operating theaters 5 minutes before the patients. Neo- nate tested positive for SARS-CoV-2 at day 6 postpartum.

Abbreviations: IgG, immunoglobulin G; IgM, immuniglobulin M; NR, not reported; RT-PCR, real-time polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

– One systematic review including 114 pregnancies based reported in Peru showed positivity for the virus by PCR in the on 18 studies from China.33 sample collected after 16 hours, and in the controls 48 hours 13 Discussion later. In this case report, the patient presented a positive PCR with a short interval between diagnosis and delivery, but Most studies published so far have registered the absence of the authors did not evaluate different tissues, nor performed vertical transmission, few cases of possible vertical trans- serological tests. More recently, there was another report15 mission, and exceptionally, one case described as confirmed of a case of a twin pregnancy in a medical center in the United transplacental transmission of SARS-CoV-2 infection.14 The States. Twin A tested positive 72 hours after birth; however, identified cases were reported as case reports; therefore, she did not exhibit any symptoms of infection. Twin B tested there is a very high risk of selection bias. After defining the negative 72 hours after birth. The authors argue that ,because eighteen eligible articles, we identified only seven suspected the patient was intubated at the time of delivery, that would cases of possible vertical transmission: two cases in China, make droplet transmission unlikely. Moreover, they claim one in Iran, two in Italy, one in Peru, and one in France that, because the babies were delivered via cesarean section, (►Table 1). that would eliminate the possibility of fetal contact with – The first are three different reports7 9 on the same case maternal feces, which has been reported as a mode of report from China that present a methodology bias, since the transmission. Maternal contact with the neonates was collection of the newborn’s oropharynx swab for the poly- avoided, they were not breastfed, and appropriate aerosol merase chain reaction (PCR) test was not performed at the and contact precautions were taken during their handling in time of delivery, which does not unequivocally guarantee the the neonatal intensive care unit (NICU). Due to the afore- occurrence of vertical transmission. In the second Chinese mentioned reasonse, they believe that Twin A tested positive case,10 the diagnosis of possible vertical transmission was due to vertical transmission. There are crucial limitations to made by positive immunoglobulin M (IgM) testing two hours this theory. First, the placenta and umbilical cord blood were after delivery, but was followed by PCR swab tests that did not tested for COVID-19, and, second, vertical transmission not identify the virus in the neonate’spharynx.Inthe would have affected both twins, but Twin B, in that case, reported case from Iran,11 the virus in the amniotic fluid tested negative. Another article recently published with was identified by PCR during the cesarean section, but there regards to possible evidence of mother-to-newborn was no positivity in the nasopharynx samples, which sug- COVID-19 infection reported a case of a neonate that tested gests the possibility of perioperative contamination.11 With- positive for SARS-CoV-2 at ay 6 post-partum. In this specific in the two reported cases in Italy, in which the swab was not case, obstetricians, anesthesiologists, neonatologists, and performed shortly after birth, the authors themselves sug- nurses wore full personal protective equipment (PPE), in- gest the possibility of postpartum transmission.12 The case13 cluding an N95 mask, eye goggles, face shield, and a top-to-

Box 1 Conclusions from systematic reviews, narrative reviews and large observational studies identiﬁed in the present review

Systematic reviews Di Mascio et al. (2020):17 “In mothers infected with coronavirus infections, including COVID-19, > 90% of whom also had pneumonia, PTB is the most common adverse pregnancy outcome. Miscarriage, preeclampsia, cesarean, and perinatal death (7- 11%) were also more common than in the general population. There have been no published cases of clinical evidence of vertical transmission.” Della Gatta et al. (2020):18 “The available data on COVID-19 illness in pregnant patients do not provide a clear conclusion into the clinical implications for mother and fetus. The outcomethus far described is favorable, but fetal and maternal risks should be underestimated. Although preterm delivery was mostly the consequence of elective interventions, a trend towards spontaneous prematurity is present. It is essential that future studies provide more detailed information on maternal and fetal conditions, as well as the rationale for obstetric interventions. Experience, thus far, is limited to patients that developed the disease in late gestation and were delivered shortly after the diagnosis. The fetal consequences of long-standing infections occurring in early gestation are unknown.” Zaigham and Andersson (2020):19 “Current evidence suggests the possibility of severe maternal morbidity requiring ICU admission and perinatal death with COVID-19 infection in pregnancy. Maternal-fetal transmission of the SARSCoV-2 virus was not detected in the majority of the reported cases, although one neonate had a positive qRT-PCR 36 hours after birth despite being isolated from the mother. Careful monitoring of pregnancies with COVID-19 and measures to prevent neonatal infection are warranted.” Abdollahpour and Khadivzadeh (2020):20 “No trustworthy evidence is available yet to support the possibility of vertical transmission of COVID-19 infection from the mother–baby. Mother-to-child transmission of respiratory viruses mostly happens via the birth canal and during breastfeeding or close contact among health care providers, family members. To our knowledge, no article has reconnoitered that reporting a newly vertically transmitted case.” Banaei et al. (2020):21 “There was some evidence about neonates COVID-19 in the included studies, but it is not clear whether the source of the infection in these neonates is from the mother or from the environment. In the majority of studies, there was no evidence of vertical transmission. In most studies, the neonates were separated from the mother after birth to reduce the chance of transmission, but there is also currently insufficient evidence regarding the mother/baby separation. If the mother is severely or critically ill, separation should be considered. The result of a review showed that in SARS vertical transmissions were not seen. Duran et al. (2020):22 “There is still no evidence supporting vertical transmission of COVID-19. Some newborns were positive for COVID-19 in spite of the reported use of preventive measures during and after delivery, but even in these cases there was no evidence supporting vertical transmission.” Elshafeey et al. (2020):23 “We extracted data regarding potential vertical transmission. In four neonates who had RT-PCR confirmed infection, samples from cord blood and amniotic fluid were negative. Based on the available data, we are uncertain of the mode of transmission, since there is no evidence that these four cases were the result of a vertical transmission.” Gordon et al. (2020):24 “Neonatal infection is uncommon, with only two previously reported cases likely to be of vertical transmission. The case we report is still RT-PCR-positive on day 28, and is asymptomatic.” Huntley et al. (2020):25 “Data from early in the pandemic is reassuring that there are low rates of maternal and neonatal mortality and vertical transmission with SARS-CoV-2.” Juan et al. (2020):26 “Despite the increasing number of published studies on COVID-19 in pregnancy, there are insufficient good- quality data to draw unbiased conclusions with regard to the severity of the disease or specific complications of COVID-19 in pregnant women, as well as vertical transmission, perinatal and neonatal complications.” Kasraeian et al. (2020):27 “Currently, no evidence of vertical transmission has been suggested at least in late pregnancy. No hazards have been detected for fetuses or neonates. Although pregnant women are at an immunosuppressive state due to the physiological changes during pregnancy, most patients suffered from mild or moderate COVID-19 pneumonia with no pregnancy loss, proposing a similar pattern of the clinical characteristics of COVID-19 pneumonia to that of other adult populations.” Ludvigsson (2020):28 “Newborn infants have developed symptomatic COVID-19, but evidence of vertical intrauterine transmission was scarce.” Muhidin et al. (2020):29 “No fetal infection through intrauterine vertical transmission was reported.” Smith et al. (2020)30: “It is unclear if this is evidence of vertical transmission or if it was contracted post-delivery due to delayed RT-PCR testing 36 hours from birth. The evidence for vertical transmission appears equivocal.” Walker et al. (2020):31 “To date, there have been 28 cases published where the possibility for vertical transmission to have occurred have been reported. To confirm definite vertical transmission, it has been proposed that detection of the virus by PCR in either umbilical cord blood, neonatal blood collected within the first 12 hours of birth, or amniotic fluid collected prior to rupture of membranes is needed. In no cases reported to date have these criteria been met although some report negative testing. A few cases deserve special mention: one case reports a positive nasopharyngeal swab in the neonate on the day of birth. The authors do not describe any procedure or care taken to clean the infant’s oropharynx / mouth/nares / face prior to procuring the swab and we speculate that the presence of the virus may be due to contamination by maternal stool. Of note, the virus was not detected on repeat swab and the infant remained well. The presence of IgG would be maternal, so again not diagnostic. The UKOSS study reports 12/24 cases of possible vertical transmission. Limited information is given for the 12 neonates but 6/12 infants tested positive for COVID-19 within 12 hours of birth. It is unclear what method of testing was used and if this was a nasopharyngeal swab without precautions to clean the infant prior to testing, may again be a result of

Box 1 (Continued)

Systematic reviews contamination. In another case, a positive nasopharyngeal swab in the neonate on the day of birth occurred after careful separation of the baby and cleansing of the baby prior to taking the swab.” Yang and Liu (2020)32: “There is currently no direct evidence to support intrauterine vertical transmission of SARS-CoV-2. Additional RT-PCR tests on amniotic ﬂuid, placenta, and cord blood are needed to ascertain the possibility of intrauterine vertical transmission. For pregnant women infected during their ﬁrst and second trimesters, further studies focusing on long-term outcomes are needed.” Yang et al. (2020):33 “Currently, there is no direct evidence suggesting that COVID-19 in pregnancy could lead to fetal infection via intrauterine vertical transmission. Long-term outcomes and potential intrauterine vertical transmission need further analysis.”

Abbreviations: ICU, intensive care unit; IgG, immunoglobulin G; PTB, preterm birth; qRT-PCR, real-time quantitative polymerase chain reaction; RT- PCR,real-timepolymerasechainreaction;SARS,severeacuterespiratorysyndrome ; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; UKOSS, United Kingdom Obstetric Surveillance System.

bottom tight-fitting gown, entering the operating theaters however, a recently-published study demonstrated that the 5 minutes before the patients. However, the newborn was ACE2 and the transmembrane protease serine 2 (TMPRSS2) discharged home 11h after birth, and tested positive for are expressed in human trophectoderm and placentas SARS-CoV-2 on postnatal day (PND) 1. Three days later, his throughout the 3 trimesters of pregnancy.36 Therefore, the caregiver (his grandmother) also tested positive for SARS- cells of the trophectoderm and the placenta should also be CoV-2. In this case, it is not possible to establish vertical considered target sites for this coronavirus infection. This transmission as the route of contamination, once the new- might suggest that pregnancies complicated with COVID-19 born had contact with other potentially-infected people.16 are potentially at risk of intrauterine fetal or placental SARS- According to a recently published classification system34 for CoV-2 infection.36 This information was obtained through a the definition of SARS-CoV-2 infection in pregnant women, bioinformatic analysis, and the immunohistochemical fetuses, and neonates, a neonatal congenital infection is experiments were based on a limited number of samples. considered confirmed if the PCR detects the virus in the Considering the impact of individual heterogeneity, further amniotic fluid collected before the rupture of the membrane analyses are required to investigate whether the expression or in the umbilical cord blood or neonatal blood collected patterns of ACE2 and TMPRSS2 can be extended to the within the first 12 hours of birth. general population. The only case14 with sufficient evidence of vertical trans- On the other hand, a recent study37 evaluating the protein mission was reported in France: a pregnant woman, 23 years expression of ACE2, both in placentas and fetal organs from old, 35 weeks of gestational age, was admitted with fever and non-infected pregnancies throughout gestation, has ob- severe cough, and diagnosed with SARS-CoV-2 through real- served the absence of ACE2 expression in the fetal brain time quantitative PCR (qRT-PCR) analysis (genes E and S) of and heart. This is reassuring regarding the risk of congenital blood and swab (vaginal and nasopharinx). She delivered malformation, but the clinical follow-up of infected pregnant through cesarean section due to acute fetal distress, and women and their children is required to validate these presented a positive result in the amniotic fluid on the qRT- observations.37 With regards to vertical transmission, what PCR (genes E and S). In the diagnosis of the newborn, we have observed so far is that the risk is very low. The nasopharyngeal and rectal swabs were collected within mechanisms that might be involved in the maternal-fetus 1 hour, 3 days, and 18 days of life, and were found positive transmission are not clear. on the qRT-PCR (genes E and S). Blood and non-broncho- Among the systematic reviews that were eligible for the scopic bronchoalveolar lavage fluid collected before extuba- present study, a total of 238 pregnancies and 174 deliveries tion (6 hours after delivery) were also positive the on qRT- were evaluated, and only 1 case of suspected vertical trans- PCR (genes E and S). According to the study,14 the samples mission, which was also mentioned in the present review were properly collected. Within the first few days of life, the (case #7–►Table 1), was identified. newborn presented neurological symptoms and impairment on a magnetic resonance scan of the central nervous system Conclusion similar to those described for adults in a previous study.35 The histological examination of the placenta showed a severe The risk of vertical transmission by SARS-CoV-2 is probably inflammatory process, and the qRT-PCR was extremely very low. Despite millions of confirmed cases of COVID-19 positive for both SARS-CoV-2 genes, suggesting placental worldwide, which probably include several thousands of transmission. pregnant women, we have identified only 1 case that has Considering the interval between maternal infection and fulfilled sufficient criteria to be nominated as a confirmed the alleged vertical transmission, the information varies vertical transmission. Well-designed observational studies considerably. So far, conventional knowledge dictates that evaluating large samples are still necessary to determine the the placenta delays transmission for maternal viral infection; risk of vertical transmission depending on the gestational

age at infection. Additionally, we also need large observa- 15 Mehta H, Ivanovic S, Cronin A, VanBrunt L, Mistry N, Miller R, tional studies to evaluate whether the infection by SARS- Yodice P, et al. Novel coronavirus-related acute respiratory dis- CoV-2 during pregnancy is related to an increased risk of tress syndrome in a patient with twin pregnancy: A case report. Case Rep Womens Health. 2020;27:e00220. Doi: 10.1016/j. adverse obstetrical outcomes or birth defects. crwh.2020.e00220 16 Sun M, Xu G, Yang Y, Tao Y, Pian-Smith M, Madhavan V, et al. fl Con icts to Interest Evidence of mother-to-newborn infection with COVID-19. Br J The authors have no conflict of interests to declare. Anaesth. 2020;125(02):e245–e247. Doi: 10.1016/j.bja.2020.04.066 17 Di Mascio D, Khalil A, Saccone G, Rizzo G, Buca D, Liberati M, et al. Outcome of coronavirus spectrum infections (SARS, MERS, References COVID-19) during pregnancy: a systematic review and meta- 1 Karimi-Zarchi M, Neamatzadeh H, Dastgheib SA, Abbasi H, Mir- analysis. Am J Obstet Gynecol MFM. 2020;2(02):100107. Doi: jalili SR, Behforouz A, Ferdosian F, et al. Vertical transmission of 10.1016/j.ajogmf.2020.100107 Coronavirus Disease 19 (COVID-19) from infected pregnant 18 Della Gatta AN, Rizzo R, Pilu G, Simonazzi G. Coronavirus disease mothers to neonates: a review. Fetal Pediatr Pathol. 2020;39 2019 during pregnancy: a systematic review of reported cases. (03):246–250. Doi: 10.1080/15513815.2020.1747120 Am J Obstet Gynecol. 2020;223(01):36–41. Doi: 10.1016/j. 2 Liu H, Wang LL, Zhao SJ, Kwak-Kim J, Mor G, Liao AH. Why are ajog.2020.04.013 pregnant women susceptible to COVID-19? An immunological 19 Zaigham M, Andersson O. Maternal and perinatal outcomes viewpoint. J Reprod Immunol. 2020;139:103122. Doi: 10.1016/j. with COVID-19: A systematic review of 108 pregnancies. Acta jri.2020.103122 Obstet Gynecol Scand. 2020;99(07):823–829. Doi: 10.1111/ 3 Liu Y, Chen H, Tang K, Guo Y. Clinical manifestations and outcome aogs.13867 of SARS-CoV-2 infection during pregnancy. J Infect. 2020;•••: 20 Abdollahpour S, Khadivzadeh T. Improving the quality of care in S0163-4453(20)30109-2. Doi: 10.1016/j.jinf.2020.02.028 [ahead pregnancy and childbirth with coronavirus (COVID-19): a sys- of print] tematic review. J Matern Fetal Neonatal Med. 2020;•••:1–9. Doi: 4 Li M, Chen L, Zhang J, Xiong C, Li X. The SARS-CoV-2 receptor ACE2 10.1080/14767058.2020.1759540 [ahead of print] expression of maternal-fetal interface and fetal organs by single- 21 Banaei M, Ghasemi V, Saei Ghare Naz M, Kiani Z, Rashidi-Fakari F, cell transcriptome study. PLoS One. 2020;15(04):e0230295. Doi: Banaei S, et al. Obstetrics and neonatal outcomes in pregnant 10.1371/journal.pone.0230295 women with COVID-19: a systematic review. Iran J Public Health. 5 Li N, Han L, Peng M, Lv Y, Ouyang Y, Liu K, et al. Maternal and 2020;49(Suppl 1):38–47 Neonatal Outcomes of Pregnant Women With Coronavirus Dis- 22 Duran P, Berman S, Niermeyer S, Jaenisch T, Forster T, Ponce de ease 2019 (COVID-19) Pneumonia: A Case-Control Study. Clin León RG, et al. COVID-19 and newborn health: systematic review. Infect Dis. 2020;71(16):2035–2041 Rev Panam Salud Publica. 2020;44:e54. Doi: 10.26633/ 6 Zheng QL, Duan T, Jin LP. Single-cell RNA expression profiling of RPSP.2020.54 ACE2 and AXL in the human maternal–fetal interface. Reprod Dev 23 Elshafeey F, Magdi R, Hindi N, Elshebiny M, Farrag N, Mahdy S, Med.. 2020;4(01):7–10. Doi: 10.4103/2096-2924.278679 et al. A systematic scoping review of COVID-19 during pregnancy 7 Wang S, Guo L, Chen L, Liu W, Cao Y, Zhang J, Feng L. A case report and childbirth. Int J Gynaecol Obstet. 2020;150(01):47–52. Doi: of neonatal 2019 Coronavirus Disease in China. Clin Infect Dis. 10.1002/ijgo.13182 2020;71(15):853–857. Doi: 10.1093/cid/ciaa225 24 Gordon M, Kagalwala T, Rezk K, Rawlingson C, Ahmed MI, Guleri 8 Hu X, Gao J, Luo X, Feng L, Liu W, Chen J, et al. Severe Acute A. Rapid systematic review of neonatal COVID-19 including a case Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vertical of presumed vertical transmission. BMJ Paediatr Open. 2020;4 transmission in neonates born to mothers with Coronavirus (01):e000718. Doi: 10.1136/bmjpo-2020-000718 Disease 2019 (COVID-19) pneumonia. Obstet Gynecol. 2020; 25 Huntley BJF, Huntley ES, Di Mascio D, Chen T, Berghella V, 136(01):65–67. Doi: 10.1097/AOG.0000000000003926 Chauhan SP. Rates of maternal and perinatal mortality and 9 Yu N, Li W, Kang Q, Xiong Z, Wang S, Lin X, et al. Clinical features vertical transmission in pregnancies complicated by Severe Acute and obstetric and neonatal outcomes of pregnant patients with Respiratory Syndrome Coronavirus 2 (SARS-Co-V-2) infection: a COVID-19 in Wuhan, China: a retrospective, single-centre, de- systematic review. Obstet Gynecol. 2020;136(02):303–312. Doi: scriptive study. Lancet Infect Dis. 2020;20(05):559–564. Doi: 10.1097/AOG.0000000000004010 10.1016/S1473-3099(20)30176-6 26 Juan J, Gil MM, Rong Z, Zhang Y, Yang H, Poon LC. Effect of 10 Dong L, Tian J, He S, Zhu C, Wang J, Liu C, Yang J. Possible vertical coronavirus disease 2019 (COVID-19) on maternal, perinatal transmission of SARS-CoV-2 from an infected mother to her and neonatal outcome: systematic review. Ultrasound Obstet newborn. JAMA. 2020;323(18):1846–1848. Doi: 10.1001/ Gynecol. 2020;56(01):15–27. Doi: 10.1002/uog.22088 jama.2020.4621 27 Kasraeian M, Zare M, Vafaei H, Asadi N, Faraji A, Bazrafshan K, 11 Zamaniyan M, Ebadi A, Aghajanpoor Mir S, Rahmani Z, Haghshe- Roozmeh S. COVID-19 pneumonia and pregnancy; a systematic nas M, Azizi S. Preterm delivery, maternal death, and vertical review and meta-analysis. J Matern Fetal Neonatal Med. 2020; transmission in a pregnant woman with COVID-19 infection. •••:1–8. Doi: 10.1080/14767058.2020.1763952 [ahead of print] Prenat Diagn. 2020 [ahead of print] 28 Ludvigsson JF. Systematic review of COVID-19 in children shows 12 Ferrazzi E, Frigerio L, Savasi V, Vergani P, Prefumo F, Barresi S, et al. milder cases and a better prognosis than adults. Acta Paediatr. Vaginal delivery in SARS-CoV-2-infected pregnant women in 2020;109(06):1088–1095. Doi: 10.1111/apa.15270 Northern Italy: a retrospective analysis. BJOG. 2020;127(09): 29 Muhidin S, Behboodi Moghadam Z, Vizheh M. Analysis of mater- 1116–1121. Doi: 10.1111/1471-0528.16278 nal Coronavirus Infections and neonates born to mothers with 13 Alzamora MC, Paredes T, Caceres D, Webb CM, Valdez LM, La Rosa 2019-nCoV; a systematic review. Arch Acad Emerg Med. 2020;8 M. Severe COVID-19 during pregnancy and possible vertical (01):e49 transmission. Am J Perinatol. 2020;37(08):861–865. Doi: 30 Smith V, Seo D, Warty R, Payne O, Salih M, Chin KL, et al. Maternal 10.1055/s-0040-1710050 and neonatal outcomes associated with COVID-19 infection: A 14 Vivanti AJ, Vauloup-Fellous C, Prevot S, Zupan V, Suffee C, Do Cao J, systematic review. PLoS One. 2020;15(06):e0234187. Doi: Benachi A, et al. Transplacental transmission of SARS-CoV-2 10.1371/journal.pone.0234187 infection. Nat Commun. 2020;11(01):3572. Doi: 10.1038/ 31 Walker KF, O’Donoghue K, Grace N, Dorling J, Comeau JL, Li W, s41467-020-17436-6 Thornton JG. Maternal transmission of SARS-COV-2 to the

neonate, and possible routes for such transmission: a systematic 35 Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. Neurologic review and critical analysis. BJOG. 2020;127(11):1324–1336. Doi: manifestations of hospitalized patients with Coronavirus Disease 10.1111/1471-0528.16362 2019 in Wuhan, China. JAMA Neurol. 2020;77(06):683–690. Doi: 32 Yang Z, Liu Y. Vertical Transmission of Severe Acute Respiratory 10.1001/jamaneurol.2020.1127 Syndrome Coronavirus 2: A Systematic Review. Am J Perinatol. 36 Cui D, Liu Y, Jiang X, Ding C, Poon LC, Wang H, Yang H. Single-cell 2020;37(10):1055–1060. Doi: 10.1055/s-0040-1712161 RNA expression profiling of ACE2 and TMPRSS2 in the human 33 Yang Z, Wang M, Zhu Z, Liu Y. Coronavirus disease 2019 (COVID- trophectoderm and placenta. Ultrasound Obstet Gynecol. 2020; 19) and pregnancy: a systematic review. J Matern Fetal Neonatal •••;. Doi: 10.1002/uog.22186 [ahead of print] Med. 2020;•••:1–4. Doi: 10.1080/14767058.2020.1759541 [ahead 37 Faure-Bardon V, Isnard P, Roux N, Leruez-Ville M, Molina T, of print] Bessieres B, Ville Y. Anatomical and timely assessment of protein 34 Shah PS, Diambomba Y, Acharya G, Morris SK, Bitnun A. Classifi- expression of angiotensin-converting enzyme 2, SARS-CoV-2 cation system and case definition for SARS-CoV-2 infection in specific receptor, in fetal and placental tissues: new insight for pregnant women, fetuses, and neonates. Acta Obstet Gynecol perinatal counseling. Ultrasound Obstet Gynecol. 2020;•••;. Doi: Scand. 2020;99(05):565–568. Doi: 10.1111/aogs.13870 10.1002/uog.22178 [ahead of print]

Evaluation of the Seroprevalence of Infectious Diseases in 2,445 in vitro Fertilization Cycles Avaliação da soroprevalência de doenças infecciosas em 2.445 ciclos de fertilização in vitro

João Guilherme Grassi dos Anjos1 Newton Sergio de Carvalho1 Karam Abou Saab1 Edward Araujo Júnior2,3 Jaime Kulak Junior1

1 Universidade Federal do Paraná, Curitiba, PR, Brazil Address for correspondence Edward Araujo Júnior, PhD, Rua 2 Escola Paulista de Medicina, Universidade Federal de São Paulo, São Botucatu, 740, 04023-062, Vila Clementino, São Paulo, SP, Brazil Paulo, SP, Brazil (e-mail: [email protected]). 3 Universidade Municipal de São Caetano do Sul, São Paulo, SP, Brazil

Rev Bras Ginecol Obstet 2021;43(3):216–219.

Abstract Objective To evaluate the seroprevalence of positive markers for syphilis, human immunodeﬁciency virus (HIV) I and II, human T cell lymphotropic virus (HTLV) I and II, and hepatitis B and C among women undergoing in vitro fertilization (IVF). Methods We conducted a retrospective analysis among patients who underwent IVF, between January 2013 and February 2016, and who had complete screening records. Results We analyzed 1,008 patients who underwent IVF, amounting to 2,445 cycles. Two patients (0.2%) tested positive for HIV I and II and none for HTLV I and II. Three patients (0.3%) had positive screening for syphilis, and two (0.2%) had positive hepatitis Keywords C antibody test (anti-HCV). A positive hepatitis B virus surface antigen (HbsAg) test was ► fertilization in vitro observed in 4 patients (0.4%), while 47 (4.7%) patients were positive for IgG antibody to ► human hepatitis B core antigen (anti-HbC IgG), and only 1 (0.1%) was positive for IgM antibody immunodeﬁciency to hepatitis B core antigen (anti-HbC IgM). The anti-HbS test was negative in 659 virus patients (65.3%). Only 34.7% of the patients had immunity against the Hepatitis B virus. ► syphilis Patients with an anti-HbS negative result were older than those with a hepatitis B test p < ► hepatitis B (anti-HbS) positive result (36.3 versus 34.9; 0.001). ► hepatitis C Conclusion The present study showed lower infection rates than the Brazilian ones ► human T- for the diseases studied in patients undergoing IVF. Only a few patients were lymphotropic virus 1 immunized against hepatitis B.

Resumo Objetivo Avaliar a soroprevalência de marcadores positivos para síﬁlis, vírus da imunodeﬁciência humana (HIV) I e II, vírus linfotrópicos de células T humanas (HTLV) I e II e hepatite B e C em mulheres submetidas a fertilização in vitro (FIV). Métodos Realizamos uma análise retrospectiva entre as pacientes submetidas a FIV, entre janeiro de 2013 e fevereiro de 2016, e que possuíam prontuários completos.

received DOI https://doi.org/ © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights July 5, 2020 10.1055/s-0041-1725055. reserved. accepted ISSN 0100-7203. This is an open access article published by Thieme under the terms of the January 6, 2021 Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda., Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil Evaluation of the Seroprevalence of Infectious Diseases in 2,445 in vitro Fertilization Cycles dos Anjos et al. 217

Resultados Foram analisadas 1.008 pacientes submetidas a FIV, totalizando 2,445 ciclos. Duas pacientes (0,2%) apresentaram resultado positivo para HIV I e II, e nenhuma para HTLV I e II. Três pacientes (0,3%) apresentaram triagem positiva para sífilis, e duas (0,2%) apresentaram teste de pesquisa de anticorpos anti-HCV (anti-HCV) positivo. Um teste de antígeno de superfície do vírus da hepatite B (HbsAg) positivo foi Palavras-chave observado em 4 pacientes (0,4%), enquanto 47 (4,7%) pacientes foram positivas para ► fertilização in vitro anticorpos IgG contra o antígeno de superfície da hepatite B (IgG anti-HbC), e apenas 1 ► vírus da (0,1%) foi positiva para anticorpos IgM contra o antígeno central da hepatite B (IgM imunodeficiência anti-HbC). O teste de anticorpos contra hepatite B (anti-HbS) foi negativo em 659 humana pacientes (65,3%). Apenas 34,7% das pacientes tinham imunidade contra o vírus da ► sífilis hepatite B. Pacientes com resultado negativo anti-HbS eram mais velhas do que aquelas ► hepatite B com resultado positivo anti-HbS (36,3 versus 34,9; p < 0,001). ► hepatite C Conclusão Este estudo mostrou taxas de infecção inferiores às taxas brasileiras para ► vírus linfotrópico T as doenças estudadas em pacientes submetidas à FIV. Apenas alguns pacientes foram humano 1 imunizados contra a hepatite B.

Introduction Methods

The need for assisted reproductive techniques has increased In the present study, we performed a retrospective analysis of recently, primarily due to an aging population, as well as to women undergoing IVF treatment in a specialized center for the prioritization of studies, and to financial and marital assisted reproduction in Curitiba, PR, Brazil, between January stability.1 With the advancing of age of women, there is also a 2013 and February 2016. The study was approved by the Ethics greater cumulative exposure to diseases that cause tubeper- Committee on Research of Hospital das Clínicas da Universi- itoneal involvement, such as endometriosis, thereby increas- dade Federal do Paraná (UFPR). Due to the retrospective study ing the importance of assisted reproductive techniques for design, the need for informed consent was waived. treatment.2 In addition to the increasing need for assisted All patients who completed IVF cycles between January reproductive techniques, we have been witnessing a high 2013 and February 2016 with complete routine screening prevalence of certain infectious diseases, most importantly records were included. All patients underwent routine labo- syphilis, in the general population.3 ratory testing at thetime of IVF indication. If the patients hadto In assisted reproduction laboratories, there are concerns repeat the routine screening during the treatment, the first about the transmission of viral and bacterial diseases routine results were taken for data acquisition. among infertile partners and between couples in the facili- Data on age, number of IVF cycles performed, syphilis ty. This concern is justified, because the burden and risk serologic testing, anti-HIV I and II testing, anti-HTLV testing, involved in the majority of these diseases are very high, HbsAg, anti-Hbs, anti-Hbs IgM and IgG, and anti-HCV testing some leading to impairments in quality of life and, ulti- were extracted from the records of the patients. All proce- mately, mortality. It has become common practice among dures related to laboratory testing were performed in stan- fertility clinics worldwide to carry out viral and bacterial dardized and certified laboratories. screening of sexually transmitted diseases (STDs).4 In Brazil, Prevalence confidence intervals were calculated using human immunodeficiency virus (HIV) I and II, syphilis, the exact method proposed by Clopper-Pearson. The student’s human T cell lymphotropic virus (HTLV) I and II, and t-test for independent samples was used to evaluate the associ- hepatitis B (hepatitis B test [anti-Hbs]; hepatitis B virus ation between age and number of positive serology results for surface antigen [HbsAg]; IgM and IgG antibody to hepatitis anti-HbSAg. The calculated statistical power was 99%. Normali- B core antigen [anti-Hbc IgM and IgG] and hepatitis C (anti- ty was evaluated using the Kolmogorov-Smirnov test. Values of HCV) are routinely tested for. p < 0.05 indicated statistical significance. Statistical analyses Although widespread testing has been performed in this were performed using IBM SPSS Statistics for Windows, version population, little is known about the prevalence of these 20.0 (IBM Corp. Armonk, NY, USA) software. diseases among women undergoing in vitro fertilization (IVF) treatment. There are no studies from Brazil that have Results investigated all these tests together in this population. The present study was conducted in a specialized center in A total of 1,008 patients who underwent IVF between January southern Brazil and, therefore, aimed to determine the 2013 and February 2016 were included in the present study, prevalence of positivity of tests performed for STDs among and all patients underwent routine laboratory testing. The women undergoing IVF procedures. mean age ( standard deviation [SD]) was 35.8 4.9 years old.

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. 218 Evaluation of the Seroprevalence of Infectious Diseases in 2,445 in vitro Fertilization Cycles dos Anjos et al.

Table 1 Age distribution of all women Table 3 Conﬁdence interval of the seroprevalences

Age (years old) n (%) Serologic testing Positive 95%CI n (%) 25 17 (1.7) Syphilis 3 (0.30) 0.06–0.87% 26 to 30 144 (14.3) HIV I and II 2 (0.20) 0.02–0.71% 31 to 35 375 (37.2) Anti-HCV 2 (0.20) 0.02–0.72% 36 to 40 290 (28.8) HbsAg 4 (0.40) 0.10–1.01% 40 182 (18.1) Anti-HbC IgM 1 (0.10) 0.002–0.55% Total 1008 (100) Anti-HbC IgG 47 (4.7) 3.5–6.2% Table 2 Serologic prevalence among 1,008 in vitro fertilization Abbreviations: anti-HbC IgM, IgM antibody to hepatitis B core antigen; women from a fertility clinic between 2013 and 2016 anti-HbC IgG, IgG antibody to hepatitis B core antigen; anti-HCV, hepatitis C antibody test; HbsAg, hepatitis B virus surface antigen; HIV, Serologic testing Positive human immunodeﬁciency virus. n (%) Exact method (Clopper-Pearson) Syphilis 3 (0.3) HIV I and II 2 (0.2) Table 4 Conﬁdence interval of the hepatitis B antibody HTLV I and II 0 (0) seroprevalence

Anti-HCV 2 (0.2) Serologic testing Positive 95%CI HbsAg 4 (0.4) Anti-HbS 344 (34.3%) 31.4–37.3% Anti-HbC IgM 1 (0.1) Anti-HbS restricted 302 (31.7%) 28.7–34.7% Anti-HbC IgG 47 (4.7) to negative Anti-HbS 344 (34.3) anti-HbC IgG Anti-HbS restricted 39 (84.8%) 71.1–93.7% Abbreviations: anti-HbC IgM, IgM antibody to hepatitis B core antigen; to positive anti-HbC IgG, IgG antibody to hepatitis B core antigen; anti-HbS, anti-HbC IgG hepatitisBtest;HbsAg,hepatitisBvirussurfaceantigen;HIV,human immunodeficiency virus; HTLV, human T cell lymphotropic virus. Abbreviations: anti-HbC IgG, IgG antibody to hepatitis B core antigen; anti-HbS, hepatitis B test. ►Table 1 The age distribution of the women is presented in . Exact method (Clopper-Pearson) The total number of IVF cycles was 2,445. Three patients (0.3%) had positive syphilis screening test Table 5 Hepatitis B antibody positivity versus age results. Two patients (0.2%) had positive HIV screening results. None tested positive for HTLV. Positive anti-HCV Age (years old) serology results were found in 2 patients (0.2%). A positive n Mean Minimum Maximum SD p-value HbsAg test result was observed in 4 patients (0.4%). The anti- HbC IgM test was positive in 1 patient (0.1%), whereas the Negative 659 36.3 19.8 56.7 4.8 anti-HbC IgG test was positive in 47 patients (4.7%). The Positive 344 34.9 21.3 52.6 5.0 < 0.001 positive results obtained for the serology tests are shown Abbreviation: SD, standard deviation. ►Table 2 in . t-Student’sTest,p < 0.05; Power: 99% To estimate the possible seroprevalence of these markers in a larger population (all women undergoing IVF in Brazil), the confidence interval (CI) for the seroprevalence of the with an anti-HbS negative result were older than those with markers was calculated. The values are shown in ►Table 3. an anti-HbS positive result (36.3 versus 34.9; p < 0.001). The Among the anti-Hbs-positive patients, 302 (31.7%) had results of descriptive statistics of age according to anti-HbS anti-HbS positive and anti-HbC IgG negative; these patients are shown in ►Table 5. are likely to have acquired immunity to hepatitis B through effective vaccination. The remaining 39 were probably immu- Discussion nized due to contact with the virus (positive anti-HbC IgG). The confidence interval for the anti-HbS seroprevalence So far, no study has evaluated the seroprevalence of HIV I and was calculated for the whole sample and for patients who II, HTLV I and II, syphilis, and hepatitis B and C in patients showed a positive result for anti-HbS and a negative result undergoing IVF. However, one study evaluated the preva- (probable vaccination) or a positive result (probable prior lence of syphilis only in couples who underwent assisted disease) for anti-HbC IgG, respectively. The values are shown reproduction treatment.5 The importance of the present in ►Table 4. study is reinforced by its important external validity, reiter- We tested the following hypothesis: the mean age of ated by the number of patients analyzed (n ¼ 1,008), which is patients who showed an immune response result against a massive sample for a procedure performed in such a hepatitis B differed depending on the type of result. Patients restricted population.

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. Evaluation of the Seroprevalence of Infectious Diseases in 2,445 in vitro Fertilization Cycles dos Anjos et al. 219

Age stratification followed a normality distribution, but tion policy of Brazil starting from 1989 and becoming part of with a deviation to the right of the normality curve; this was the vaccine calendar in some states only in 1992. demonstrated by a mean age of 35.8 ( 4.9) years old and a The prevalence of HTLVamong IVF patients in Sweden was median of 35.6 years old, varying between 19 years and described by Malm et al.11 The recorded seroprevalence was 10 months old and 56 years and 9 months old. This variation 2.3 per 10,000 patients undergoing IVF in that country. Due is due to the characteristics of the female population studied, to the smaller sample size in our study, it was impossible to along with the increase in the involvement of factors causing compare the results with those of the Swedish study. infertility over time.6 The results for the seroprevalences observed in our study Conclusion were lower than those found in two similar studies, one conducted in Ghana, Africa, and the other in London, England. All the seroprevalences were shown to be inferior to those In the African study, the seroprevalence of HIV, hepatitis B, reported in the compared studies. We found that a significant and hepatitis C was evaluated, with a prevalence of 1.7%, 7.9%, part ofour IVF population was not immunized against hepatitis and 0.4%, respectively. The prevalence described in the IVF B. More attention should be paid to the guidance onvaccination population was similar to that reported for the general preva- for these patients. Despite the significant number of patients lence in Ghana. This study presents the particularity of having evaluated in the present study, more epidemiological studies been performed in an African country, with seropositivity rates are needed to better guide public practices and regulations to for diseases such as HIV and hepatitis B well above the world optimize results and available resources, because Brazil is a averages.7 IntheLondonstudy,theseroprevalenceofHIV, country that still experiences a shortage of financial resources. hepatitis B, and hepatitis C were 0.13%, 1.7%, and 0.5%, respectively. The data were also comparable to that reported for the Conflict of Interests general population of that country.8 The authors have no conflict of interests to declare. The seroprevalence of syphilis in patients undergoing assisted reproductive techniques was previously studied by References Cavalcante et al.5 in Goiânia, GO, Brazil, covering patients of 1 Jain T, Grainger DA, Ball GD, et al. 30 years of data: impact of the high and low complexity in a public hospital and in a private United States in vitro fertilization data registry on advancing center. In this study, among the 253 female patients who fertility care. Fertil Steril. 2019;111(03):477–488. Doi: 10.1016/j. underwent venereal disease research laboratory (VDRL) fertnstert.2018.11.015 examination in the public hospital, there was not a single 2 Haas D, Chvatal R, Reichert B, et al. Endometriosis: a premeno- case of syphilis diagnosis. Of the 896 patients surveyed at the pausal disease? Age pattern in 42,079 patients with endometriosis. Arch Gynecol Obstet. 2012;286(03):667–670. Doi: 10.1007/ private center, only 1 (0.11%) was diagnosed with syphilis, s00404-012-2361-z fl with positive VDRL followed by positive uorescent trepo- 3 World Health Organization. Report on global sexually transmitted nemal antibody absorption test (FTA-ABS). Our data showed infection surveillance. Geneva: WHO; 2018 asignificantly higher prevalence of positive results for 4 Gold E, Mizrachi Y, Shalev A, et al. Screening for blood born viruses in syphilis in our population (0.3%; 95%CI: 0.06–0.87%), but assisted reproduction: is annual testing necessary? Arch Gynecol – we did not register any cases of active disease because the 3 Obstet. 2019;299(06):1709 1713. Doi: 10.1007/s00404-019-05112-0 5 Cavalcante GMCC, Amaral WN. Soroprevalência de sífilis em patients described were already diagnosed and treated. pacientes submetidos à fertilização assistida. Reprod Clim.. 9 Monich et al. studied the seroprevalence of HIV, syphilis, 2014;29(01):3–7. Doi: 10.1016/j.recli.2014.05.004 HTLV, and hepatitis B and C among blood donors in Curitiba, 6 Practice Committee of American Society for Reproductive Medi- PR, Brazil, between 2003 and 2012. Among 399,280 blood cine. Diagnostic evaluation of the infertile female: a committee – donations, the seroprevalence was 0.9%, 0.5%, 0.2%, 0.3%, and opinion. Fertil Steril. 2012;98(02):302 307. Doi: 10.1016/j.fertnstert.2012.05.032 0.8%, respectively. 7 Yakass MB, Woodward BJ, Otoo MA, Hiadzi EK. Prevalence of blood When we evaluated the presence of hepatitis B immuni- borne viruses in IVF: an audit of a fertility Centre. JBRA Assist zation markers, we found a significant proportion of the Reprod. 2016;20(03):132–136. Doi: 10.5935/1518-0557.20160030 patients (65.3%) not immune to the virus. Considering only 8 Hart R, Khalaf Y, Lawson R, Bickerstaff H, Taylor A, Braude P. vaccinated patients (with anti-HBs positive and anti-Hbc IgG Screening for HIV, hepatitis B and C infection in a population negative results), the proportion of patients who were seeking assisted reproduction in an inner London hospital. BJOG. 2001;108(06):654–656. Doi: 10.1111/j.1471-0528.2001.00146.x immunized was 31.5% (95%CI: 28.7–34.7%). Even though 9 Monich AG, Dantas TW, Fávero KB, et al. Blood discard rate in a blood between 5 and 10% of adults who receive the 3-dose vacci- center in Curitiba - Brazil. Ten years of study. Transfus Apheresis Sci. nation schedule do not present seroconversion, the rate of 2017;56(02):130–134. Doi: 10.1016/j.transci.2016.10.007 nonimmune patients is high, considering that the vaccine is 10 David MC, Ha SH, Paynter S, Lau C. A systematic review and meta- part of the national adult immunization schedule, for an age analysis of management options for adults who respond poorly to – range of 19 to 49 years old.10 hepatitis B vaccination. Vaccine. 2015;33(48):6564 6569. Doi: 10.1016/j.vaccine.2015.09.051 The correlation between absence of immunization and 11 Malm K, Ekermo B, Hillgren K, Britton S, Fredlund H, Andersson S. ►Table 5 advancement of the age of the patients, as shown in , Prevalence of human T-lymphotropic virus type 1 and 2 infection also reflects the lack of a vaccine for hepatitis B before its in Sweden. Scand J Infect Dis. 2012;44(11):852–859. Doi: invention (in 1982), in addition to the hepatitis B immuniza- 10.3109/00365548.2012.689847

Familial Chylomicronemia Syndrome-Induced Acute Necrotizing Pancreatitis during Pregnancy

Julia Cristina Coronado Arroyo1 Marcio José Concepción Zavaleta2 Eilhart Jorge García Villasante3 Mikaela Kcomt Lam4 Luis Alberto Concepción Urteaga5 Francisca Elena Zavaleta Gutiérrez6

1 Department of Obstetrics and Gynecology, Hospital Nacional Address for correspondence Mikaela Kcomt Lam, MD, Department of Edgardo Rebagliati Martins, Lima, Peru Medicine, Universidad Privada Antenor Orrego, América Sur 2 Department of Endocrinology, Hospital Nacional Guillermo Avenue 3145, Trujillo, Peru (e-mail: [email protected]). Almenara Irigoyen, Lima, Peru 3 Department of Endocrinology, Hospital Nacional Daniel Alcides Carrion, Lima, Peru 4 Department of Medicine, Universidad Privada Antenor Orrego, Trujillo, Peru 5 Department of Pulmonology, Hospital Regional Docente de Trujillo, Universidad Nacional de Trujillo, Trujillo, Peru 6 Department of Neonatology, Hospital Belen de Trujillo, Universidad Privada Antenor Orrego, Trujillo, Peru

Rev Bras Ginecol Obstet 2021;43(3):220–224.

Abstract Acute pancreatitis is a rare condition in pregnancy, associated with a high mortality rate. Hypertriglyceridemia represents its second most common cause. We present the case of a 38-year-old woman in the 24th week of gestation with a history of hypertriglyceridemia and recurrent episodes of pancreatitis. She was admitted to our hospital with acute pancreatitis due to severe hypertriglyceridemia. She was stabilized and treated with ﬁbrates. Despite her favorable clinical course, she developed a second episode of acute pancreatitis complicated by multi-organ dysfunction and pancreatic necrosis, requiring a necrosectomy. The pregnancy was ended by cesarean section, Keywords after which three plasmapheresis sessions were performed. She is currently asymp- ► familial tomatic with stable triglyceride levels. Acute pancreatitis due to hypertriglyceridemia chylomicronemia represents a diagnostic and therapeutic challenge in pregnant women, associated with ► necrotizing serious maternal and fetal complications. When primary hypertriglyceridemia is pancreatitis suspected, such as familial chylomicronemia syndrome, the most important objective ► pregnancy is preventing the onset of pancreatitis.

Introduction hypothyroidism, alcohol, sepsis, renal failure, and drugs, while genetic causes represent < 5% of cases, among which Acute pancreatitis is an uncommon complication of preg- is familial chylomicronemia syndrome.3 nancy, with an incidence of 1 case per between 1,000 and Multiple treatment modalities have been established that 10,000 pregnancies.1,2 The most common causes of acute range from conservative management based on diet, exer- pancreatitis are gallstones and hypertriglyceridemia. The cise, and ﬁbrates to other therapeutic options such as latter may be due to diabetes, obesity, pregnancy, diet, plasmapheresis, insulin, and heparin.4

received DOI https://doi.org/ © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights June 11, 2020 10.1055/s-0040-1722173. reserved. accepted ISSN 0100-7203. This is an open access article published by Thieme under the terms of the October 23, 2020 Creative Commons Attribution License, permitting unrestricted use, published online distribution, and reproduction so long as the original work is properly cited. February 18, 2021 (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda., Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil Familial Chylomicronemia Syndrome-Induced Acute Coronado et al. 221

Acute pancreatitis during pregnancy can lead to maternal terol, 34 mg/dL; LDL cholesterol, 28 mg/dL; triglycerides, complications such as pancreatic necrosis, pancreatic ab- 1,130 mg/dL; and apolipoprotein B (apoB) 48.7 mg/dL (refer- scess, and multi-organ failure as well as fetal complications ence value, 55–125 mg/dL). An abdominal ultrasound revealed such as prematurity, fetal distress, and death.5 Therefore, decreased pancreatic echogenicity and a heterogeneous lesion timely diagnosis and treatment are important to reduce 9 Â 7 cm in size in the tail of the pancreas, which was com- maternal-fetal morbidity and mortality. plemented by magnetic resonance imaging (MRI), in which We present the case of a pregnant woman who developed signs of acute pancreatitis were observed (►Fig. 1A). acute necrotizing pancreatitis secondary to familial chylo- The initial treatment included fluid replacement, vaso- micronemia syndrome. pressors, antibiotic therapy, and analgesia. Afterward, the patient was transferred to the intensive care unit (ICU) with Case Description the diagnosis of septic shock due to acute pancreatitis (APACHE II score, 8 points) secondary to severe hyper- A 38-year-old female patient, secundigravida, in the 24th triglyceridemia. Upon hemodynamic stabilization and im- week of gestation, presented to the emergency room with provement in mental status, 160 mg fenofibrate QID and somnolence and oppressive epigastric pain radiating to parenteral nutrition were initiated. The patient exhibited the back, which was associated with bilious emesis. She clinical improvement until day 39 of hospitalization, at was diagnosed with hypertriglyceridemia at the age of which point she developed intense abdominal pain, hemo- 20 years old and was treated sporadically with 600 mg dynamic instability, fetal bradycardia, and elevation of gemfibrozil TID. She also had a history of four episodes of pancreatic enzymes. An emergency cesarean section was pancreatitis, the first of which occurred at the age of 28 years performed, which resulted in the delivery of a severely old, and the last during the 16th week of her current preg- depressed male with a birth weight of 914 g. He was then nancy; three of these episodes were due to hypertriglycer- transferred to the neonatal ICU, where he died on day 7 of idemia, as her triglyceride levels were as high as 7,500 mg/dL, life due to necrotizing enterocolitis. The neonate’striglyc- while the 4th episode was due to biliary etiology, for which eride levels were 1,000 mg/dL. During surgery, 900 mm3 of she underwent laparoscopic cholecystectomy. No record of pus was found, which led to identification of the pancreas alcoholism or contributory family history was found. as the origin. During the postpartum period, the patient’s Upon admission, general examination revealed weight: 60 clinical condition deteriorated, and she developed lung Kg, height: 158 cm, temperature of 37.2°C, blood pressure of injury that required invasive mechanical ventilation, liver 70/40 mm Hg, heart rate of 136 beats/minute and respiratory and kidney dysfunction, and bacteremia due to Pseudomo- rate of 28 breaths/minute. Relevant findings in the physical nas aeruginosa. Hepatosplenomegaly and pancreatic necro- examination were marked pallor, decreased passage of vesicu- sis were identified by abdominal computed tomography lar murmur at the base of thelungs, and pain in the epigastrium (CT) scan with contrast (►Fig. 1B); as a result, the patient without peritoneal signs. Laboratory tests revealed lipemic underwent two necrosectomy procedures, after which a serum with the following results: leukocyte count, 7,200 histological analysis confirmed the lipid etiology (►Fig. 2). cells/mm3 (neutrophils, 70%; band cells, 15%); hemoglobin, In terms of managing refractory hypertriglyceridemia, three 13.3 g/dL; platelet count, 161,000 cells/mm3; serum glucose, plasmapheresis sessions were required, which resulted in 160 mg/dL; serum creatinine, 1 mg/dL; ALT, 126 U/L; AST, favorable clinical and laboratory outcomes (►Fig. 3), which 100 U/L; amylase, 365 U/L; lipase, 305 U/L; C-reactive protein, allowed to continue treatment outside the ICU during the 20.5 mg/L; albumin, 3.2 g/dL; sodium, 152 mEq/L; potassium, remainder of her hospitalization, with subsequent medical 4.6 mEq/L; corrected serum calcium, 6.2 mg/dL; HDL choles- discharge.

Fig. 1 (A) Abdominal T2-weighted magnetic resonance, performed during pregnancy, shows an edematous and heterogeneous pancreas, with surrounding edema. (B) Abdominal computed tomography scan with contrast, performed in the postpartum, shows area of hypoperfusion where the pancreatic body and head meet, suggestive of an area of necrosis.

Fig. 2 Histological changes of acute necrotizing pancreatitis with hematoxylin-eosin staining. (A) Lipid vacuoles immersed in pancreatic tissue with necrotic zones in the periphery. (B) Necrotic pancreatic tissue, where hemorrhagic focus is evident.

Fig. 3 Serum amylase, lipase and triglyceride levels. Notice the elevation of pancreatic enzymes, compatible with the second episode of acute pancreatitis, which required necrosectomies. Likewise, a fall in triglyceride levels after plasmapheresis sessions is evidenced.

Currently, the patient is asymptomatic, is being treated ing the second trimester, and the etiology of all episodes, the with 160 mg fenoﬁbrate BID and 25,000 IU pancreatic last of which was severe, was hypertriglyceridemia. enzymes QID, has adopted a fat-restricted diet and consumes The higher incidence of hypertriglyceridemia during preg- foods high in omega-3 fatty acids. Her fasting triglyceride nancy is due to an increase in estrogens, progestogens, and levels range from 170 to 250 mg/dL and remains euglycemic. human placental lactogen, which reduce the activity of lipopro- tein lipase (LPL) by 85%.10 Likewise, estrogens increase the 11 Discussion hepatic synthesis of triglycerides and VLDL. In contrast, insulin resistance increases, which lowers LPL activity in adipocytes.12 In Acute pancreatitis during pregnancy is a rare condition general, the concentration of triglycerides typically increases 2 to – with high maternal-fetal mortality.5 7 The most frequent 3times,5,8 especially in the third trimester. However, the triglyc- cause is biliary, while the second most frequent cause is eride concentration rarely exceeds 300 mg/dL,11 except in hypertriglyceridemia, which is associated with between 4 patients with defects in lipid metabolism who develop severe and 14.4% of all cases.8,9 The etiology also varies according to hypertriglyceridemia,11 such as our patient. Two theories explain the trimester of gestation5; the cause in the ﬁrst trimester is why hypertriglyceridemia causes acute pancreatitis. One theory usually biliary, whereas, in the second and third trimesters, proposes that high levels of chylomicrons increase the viscosity the cause is hypertriglyceridemia. A relationship has been of plasma, inducing ischemia in the pancreatic capillaries, which reported between severity and etiology, considering that the in turn generates acidosis and activates trypsinogen.7,13,14 cause is biliary in 39% of mild cases and that 58% of moderate According to the other theory, the increase in triglyceride and 100% of severe cases are due to hypertriglyceridemia.5 metabolism leads to increased production of free fatty acids, Our patient experienced three episodes of pancreatitis dur- which causes cytotoxic damage to pancreatic acinar cells.8

Hypertriglyceridemia can cause acute pancreatitis when the decreased.8 The pregnancy should be terminated in 24 to triglyceride levels are > 1,000 mg/dL or if they are between 500 48 hours if clinical deterioration occurs,6,7 as was the case and 999 mg/dL and associated with lipemic serum.6 It can be with our patient. primary or secondary to diabetes, obesity, pregnancy, and Maternal mortality ranges from 20 to 37%, while fetal – alcoholism, among other conditions.14 16 Familial chylomicro- mortality ranges from 50 to 60%, which are related to the nemia syndrome is an autosomal recessive disorder caused by a severity of the pancreatitis.4,5,11,15 The primary factors that mutation in the LPL gene and is characterized by severe hyper- influence the prognosis are early diagnosis and disease triglyceridemia and a poor response to traditional lipid-lower- management.7 For this reason, when primary hypertrigly- ing agents, which causes recurrent episodes of acute ceridemia is suspected, preventing the onset of pancreatitis pancreatitis.14,17 In our case, the earlyage at onset of symptoms, is crucial,13 since severe complications, such as pancreatic triglyceride levels > 10 mmol/L (885 mg/dL) in 3 consecutive necrosis and shock, can develop in addition to maternal and blood samples, atriglyceride/total cholesterol ratio > 5, reduced perinatal pathologies, such as preeclampsia, diabetes, mac- levels of apoB, and decreased levels of HDL and LDL cholesterol rosomia, prematurity, and stillbirth.10,11 In the reported suggest familial chylomicronemia syndrome as the etiolo- case, the complications developed in the mother were pan- gy.17,18 A genetic analysis to identify specificmutationswas creatic necrosis and lung, liver, and kidney dysfunction, not performed given that this exam is not available in Peru. while the newborn was born prematurely and died. The diagnosis of acute pancreatitis during pregnancy Once acute pancreatitis has resolved, it is recommended requires two of thefollowing three criteria: clinical, laboratory, that the lipid profile and physical activity be strictly monitored and imaging findings. The symptoms do not differ from other and that nutritional therapy based on a low-fat diet with a high presentations of acute pancreatitis, but peritoneal signs may content of omega-3 fatty acids be consumed.11 Fibrates can be be absent because stretching of the anterior abdominal wall effective in patients with residual LPL activity.18 The goal of leads to distancing from the area of inflammation; moreover, therapy should be reducing triglyceride levels below the the size of the uterus limits the movement of the omentum threshold for significant chylomicronemia (750 to 880 mg/ toward the inflamed area.8 Our patient presented upper dL) to reduce the risk of pancreatitis and improve the quality abdominal pain and vomiting, but no evidence of peritonism. of life.19 Regarding the etiology, identifying the signs of hypertriglyceridemia, such as lipemic serum, xanthomas, lipemia retinalis, Conclusion and hepatosplenomegaly is important.10,11 Our patient presented lipemic serum and hepatosplenomegaly. In terms of Acute pancreatitis due to hypertriglyceridemia represents a laboratory findings, the levels of amylase and lipase typically diagnostic and therapeutic challenge in pregnancy, as it is increase more than three times their normal values. However, associated with serious maternal and fetal complications. in 50% of cases, amylase levels may be normal or low due to the Therefore, considering primary causes in cases of severe presence of a serum amylase inhibitor.8 Our patient had hypertriglyceridemia is important. Finally, additional studies fluctuations in amylase and lipase levels during hospitaliza- are needed to gather clinical data to establish guidelines for tion, which were correlated with the clinical evolution. In the management of acute pancreatitis secondary to hyper- terms of imaging, ultrasound is the preferred modality since it triglyceridemia in pregnancy. is safe and confirms biliary etiology.8 Magnetic resonance imaging is indicated if ultrasound is unsuccessful.8 In our Conflict of Interests case, both abdominal ultrasound and abdominal MRI without The authors have no conflict of interests to declare. contrast revealed signs of acute pancreatitis. Initial treatment includes fasting, hydration and analgesia. Acknowledgments Then, measures such as a low-fat diet should be implemented Segundo Enrique Cabrera Hipólito. Department of Radi- to decrease triglyceride intake.8 When enteral nutrition is ology, Clínica Internacional; María Medrano Huallanca. impossible, intravenous lipids should be considered only Department of Pathology, Hospital Nacional Edgardo when the triglyceride level is < 250 mg/dL.8 Fibrates increase Rebagliati Martins. clearance, which decreases the triglyceride concentration by 50%.13,16 The use of plasmapheresis is reserved for refractory References cases, lactic acidosis, organic dysfunction and in cases inwhich 1 Zhang DL, Huang Y, Yan L, Phu A, Ran X, Li SS. Thirty-eight cases of the triglyceride levels exceed 1,000 mg/dL.6,11 These are low- 8,16 acute pancreatitis in pregnancy: a 6-year single center retrospec- ered by 70% after each session. Furthermore, heparin and tive analysis. J Huazhong Univ Sci Technolog Med Sci. 2013;33 8,16 insulin increase the action of LPL, and because insulin (03):361–367. Doi: 10.1007/s11596-013-1125-8 accelerates the breakdown of chylomicrons, it serves as an 2 Igbinosa O, Poddar S, Pitchumoni C. Pregnancy associated pan- alternative when plasmapheresis is contraindicated and when creatitis revisited. Clin Res Hepatol Gastroenterol. 2013;37(02): – the serum glucose is > 500 mg/dL.11 In our case, the hyper- 177 181. Doi: 10.1016/j.clinre.2012.07.011 3 Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ, Sacks F, Murad triglyceridemia was refractory to fenofibrate therapy and MH, Stalenhoef AFHEndocrine society. Evaluation and treatment dietary restrictions, and required three sessions of plasma- of hypertriglyceridemia: an Endocrine Society clinical practice pheresis and cesarean section. In relation to labor, it produces a guideline. J Clin Endocrinol Metab. 2012;97(09):2969–2989. Doi: rapid fall in estrogen levels; thus, triglyceride levels are also 10.1210/jc.2011-3213

4 Cruciat G, Nemeti G, Goidescu I, Anitan S, Florian A. Hyper- 12 Patni N, Ahmad Z, Wilson DP. Genetics and dyslipidemia. In: triglyceridemia triggered acute pancreatitis in pregnancy - diag- Feingold K, Anawalt B, Boyce A, editors. Endotext [Internet]. South nostic approach, management and follow-up care. Lipids Health Dartmouth: MDText.com, Inc; 2000 [cited 2020 Feb 11]. Available Dis. 2020;19(01):2. Doi: 10.1186/s12944-019-1180-7 from: https://www.ncbi.nlm.nih.gov/books/NBK395584/ 5 Tang M, Xu JM, Song SS, Mei Q, Zhang LJ. What may cause fetus loss 13 Kashyap P, Prasad S, Singh CB. A rare case of severe hypertriglycer- from acute pancreatitis in pregnancy: Analysis of 54 cases. idemia induced pancreatitis in pregnancy. Int J Reprod Contracept Medicine (Baltimore). 2018;97(07):e9755. Doi: 10.1097/MD.00 Obstet Gynecol. 2017;6(12):5625–5627. Doi: 10.18203/2320-1770. 00000000009755 ijrcog20175294 6 Luo L, Zen H, Xu H, Zhu Y, Liu P, Xia L, et al. Clinical characteristics of 14 de Pretis N, Amodio A, Frulloni L. Hypertriglyceridemic pancrea- acute pancreatitis in pregnancy: experience based on 121 cases. titis: Epidemiology, pathophysiology and clinical management. Arch Gynecol Obstet. 2018;297(02):333–339. Doi: 10.1007/s00 United European Gastroenterol J. 2018;6(05):649–655. Doi: 404-017-4558-7 10.1177/2050640618755002 7 Jeon HR, Kim SY, Cho YJ, Chon SJ. Hypertriglyceridemia-induced 15 Göksever Çelik H, Çelik E, Dikmen S, Aydin AA. Hypertriglycer- acute pancreatitis in pregnancy causing maternal death. Obstet idemia-induced acute pancreatitis during pregnancy. J Clin Obstet Gynecol Sci. 2016;59(02):148–151. Doi: 10.5468/ogs.2016.59.2.148 Gynecol.. 2018;28(01):26–29. Doi: 10.5336/gynobstet.2015- 8 Serpytis M, Karosas V, Tamosauskas R, Dementaviciene J, Strupas 48356 K, Sileikis A, Sipylaite J. Hypertriglyceridemia-induced acute 16 Dzenkeviciute V, Skujaite A, Rinkuniene E, et al. Pregnancy- pancreatitis in pregnancy. JOP. 2012;13(06):677–680. Doi: related severe hypertriglyceridemia. Clin Lipidol. 2015;10(04): 10.6092/1590-8577/1148 299–304. Doi: 10.2217/clp.15.25 9 Zhu Y, Pan X, Zeng H, He W, Xia L, Liu P, et al. A study on the 17 Stroes E, Moulin P, Parhofer KG, Rebours V, Löhr JM, Averna M. etiology, severity, and mortality of 3260 patients with acute Diagnostic algorithm for familial chylomicronemia syndrome. pancreatitis according to the revised Atlanta classiﬁcation in Atheroscler Suppl. 2017;23:1–7. Doi: 10.1016/j.atherosclero- Jiangxi, China over an 8-year period. Pancreas. 2017;46(04): sissup.2016.10.002 504–509. Doi: 10.1097/MPA.0000000000000776 18 Chaudhry R, Viljoen A, Wierzbicki AS. Pharmacological treatment 10 Cortés-Vásquez J, Noreña I, Mockus I. Hypertriglyceridemia and options for severe hypertriglyceridemia and familial chylomicro- adverse outcomes during pregnancy. Rev Fac Med (Caracas). nemia syndrome. Expert Rev Clin Pharmacol. 2018;11(06): 2018;66(02):247–253. Doi: 10.15446/revfacmed.v66n2.60791 589–598. Doi: 10.1080/17512433.2018.1480368 11 Gupta N, Ahmed S, Shaffer L, Cavens P, Blankstein J. Severe hyper- 19 Falko JM. Familial chylomicronemia syndrome: a clinical guide for triglyceridemia induced pancreatitis in pregnancy. Case Rep Obstet endocrinologists. Endocr Pract. 2018;24(08):756–763. Doi: 10.4158/ Gynecol. 2014;2014:485493. Doi: 10.1155/2014/485493 EP-2018-0157

Ex vivo Retrieval of Mature Oocytes for Fertility Preservation in a Patient with Bilateral Borderline Ovarian Tumor Recuperação ex vivo de oócitos maduros para preservação da fertilidade em paciente com tumor ovariano borderline bilateral

Bruno Ramalho de Carvalho1 Geórgia Fontes Cintra1 Taise Moura Franceschi2 Íris de Oliveira Cabral2 Leandro Santos de Araújo Resende1 Brenda Pires Gumz1 Thiago David Alves Pinto3

1 Hospital Sírio-Libanês, Brasília, DF, Brazil Address for correspondence Bruno Ramalho de Carvalho, SGAS 614, 2 Genesis, Centro de Assistência em Reprodução Humana, Brasília, DF,Brazil Conjunto C, Sala 177, Edifício VITRIUM - Centro Médico Inteligente, 3 Diagnose, Laboratório de Anatomia Patológica e Citologia, Brasília, Asa Sul, Brasília, Distrito Federal, 70200-740, Brazil DF, Brazil (e-mail: [email protected]).

Rev Bras Ginecol Obstet 2021;43(3):225–231.

Abstract We report a case of ultrasound-guided ex vivo oocyte retrieval for fertility preservation in a woman with bilateral borderline ovarian tumor, for whom conventional trans- Keywords vaginal oocyte retrieval was deemed unsafe because of the increased risk of malignant ► cryopreservation cell spillage. Ovarian stimulation with gonadotropins was performed. Surgery was ► ex vivo oocyte scheduled according to the ovarian response to exogenous gonadotropic stimulation; retrieval oophorectomized specimens were obtained by laparoscopy, and oocyte retrieval was ► fertility preservation performed 37 hours after the ovulatory trigger. The sum of 20 ovarian follicles were ► ovarian cancer aspirated, and 16 oocytes were obtained. We performed vitriﬁcation of 12 metaphase II ► borderline ovarian oocytes and 3 oocytes matured in vitro. Our result emphasizes the viability of ex vivo tumor mature oocyte retrieval after controlled ovarian stimulation for those with high risk of ► vitriﬁcation malignant dissemination by conventional approach.

Resumo Relatamos um caso de obtenção ex vivo de óvulos, guiada por ultrassonografia, para Palavras-chave preservação da fertilidade em uma mulher com tumor ovariano borderline bilateral, para ► criopreservação quem a recuperação transvaginal convencional foi considerada insegura, devido ao ► recuperação aumento do risco de disseminação de células malignas. Foi realizada estimulação ovariana extracorpórea de com gonadotrofinas. A cirurgia foi agendada de acordo com a resposta ovariana à oócitos estimulação gonadotrófica exógena; após ooforectomia por laparoscopia, 37 horas ► preservação de após a maturação folicular, procedeu-se à recuperação extracorpórea de oócitos. Um total fertilidade de 20 folículos ovarianos foi aspirado e 16 complexos cumulus foram obtidos, resultando na ► câncer do ovário vitrificação de 12 oócitos maduros e de 3 oócitos imaturos amadurecidos in vitro. Nosso ► tumor borderline de resultado enfatiza a viabilidade da recuperação ex vivo de oócitos maduros após ovário estimulação ovariana controlada para mulheres com alto risco de disseminação maligna ► vitrificação pela captação oocitária realizada convencionalmente pela via transvaginal.

received DOI https://doi.org/ © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights June 10, 2020 10.1055/s-0040-1718436. reserved. accepted ISSN 0100-7203. This is an open access article published by Thieme under the terms of the August 3, 2020 Creative Commons Attribution License, permitting unrestricted use, published online distribution, and reproduction so long as the original work is properly cited. January 19, 2021 (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda., Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil 226 Ex vivo Retrieval of Mature Oocytes for Fertility Preservation Carvalho et al.

Introduction according to case reports and series, especially involving the aspiration of immature eggs, then submitted to in vitro – According to the literature, the incidence of borderline maturation (IVM) before vitrification.5 10 As a matter of fact, ovarian tumors (BOTs) in women < 45 years old varies be- in spite of being a patient-friendly intervention, reducing – tween 27 and 59%.1 3 Indeed, the expected good prognosis of costs and avoiding the risk of ovarian hyperstimulation BOT and the current trends of having a first baby after syndrome, the outcomes of IVM are not sufficiently good 30 years old lead to the fact that more women presenting for its use as a technique of choice in assisted reproduction with the tumor should not have started their offspring yet at centers all over the world. Moreover, information on risks is the time of diagnosis. Moreover, childbearing has been still lacking, especially those related to genetic and epigenet- reported to be an important issue for BOT survivors.3 Then, ic alterations.11 the issue of both conservative approach of ovarian tumors In a scenario where the reproductive outcomes from and alternative options to preserve childbearing potential oocytes matured in vitro seem to be worse than those becomes definitely important. obtained from in vivo mature oocytes,11 ovarian stimulation In the context, fertility preservation strategies arise with for the ex vivo retrieval of mature eggs has been eventually – the aim of improving and maintaining the quality of life after performed and documented as a possible strategy.12 15 In cancer. Fertility-sparing surgery is a viable alternative for the present paper, we report a case of ultrasound-guided young women presenting BOT, since they have better prog- retrieval of mature oocytes from stimulated ovaries after nosis when compared with other malignancies of the female laparoscopic bilateral salpingo-oophorectomy, in a woman gonad.4 However, oocytes are usually obtained by endova- with bilateral borderline serous ovarian tumor. ginal puncture of the ovaries and the procedure is considered to be unsafe in the presence of adnexal tumors, given the risk Case Report of tumor capsule rupture and malignant cells spillage. The feasibility of ex vivo egg collection has been demon- A 28-year-old married nulligravida, weighting 62.5 kg (body strated and it has been a seemingly successful strategy, mass index 21.37 kg/m2), was referred by her gynecologic

Fig. 1 Oocyte retrieval set. Up in the right, follicular aspiration with a standard aspiration single lumen needle, in a closed system connected directly to the tubes, under ultrasound guidance, using a 6–13 MHz linear probe applied directly to the specimen. Down in the right, sonographic view of the needle during guided follicular aspiration.

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. Ex vivo Retrieval of Mature Oocytes for Fertility Preservation Carvalho et al. 227 oncologist on July 2019 for an emergency consultation follitropin (Puregon, Schering-Plough, Kenilworth, NJ, USA). A regarding fertility preservation options, due to the finding SC dose of 0.2 mg of the gonadotropin-releasing hormone of a bilateral adnexal mass, with the suspicion of being a agonist triporelin acetate (Gonapeptyl Daily, Ferring, Saint- borderline tumor. Indeed, there was an elevated chance of Prex, Switzerland) was administered for final follicular matura- malignancy according to the criteria stablished by the tion on treatment day 11, when at least 11 follicles were International Ovarian Tumor Analysis group,16 based on expected to present with a mean diameter 16 mm. the finding of an irregular solid tumor with capsular Surgery was scheduled according to the ovarian response projections in the right ovary, and elevated tumor marker to gonadotropic stimulation, and the patient was conducted CA-125. Bilateral salpingo-oophorectomy was the proposed to the operating room 36 hours after the ovulatory trigger. treatment. Bilateral salpingo-oophorectomy was proceeded by laparos- Five days after the initial consultation (day 14 of the men- copy and both gonads were placed in plastic endobags for strual cycle), the patient received corifollitropin alfa (Elonva, cavity protection, following the oncological procedure to Schering-Plough, Kenilworth, NJ, USA) in a subcutaneous (SC) avoid the dissemination of the disease. Extraction, then, single dose of 150 µg, for controlled ovarian stimulation (COS). was performed through a 5 cm vertical midline incision in Endovaginal ultrasound allowed the identification of 15 and 12 the abdominal wall. The endobags containing the removed antral follicles < 10 mm in the right and left ovaries, respective- nonruptured ovaries were taken to the oocyte ex vivo ly, and no dominant follicles were observed. To prevent prema- retrieval set by the main surgeon, in the operating room, ture Luteinizing Hormone (LH) surge, SC dailysingle dosesofthe with a maximum ischemia time of 6 minutes. GnRH antagonist ganirelix acetate (Orgalutran, Schering- In the oocyte retrieval set, the ovaries were placed over a Plough, Kenilworth, NJ, USA) were administered from day 6 sterile surgical cloth at room temperature. Oocyte retrieval onwards. From treatment day 8 to day 10, ovarian stimulation was performed 37 hours after the ovulatory trigger, with a was continued by SC daily doses of 250 IU of recombinant standard aspiration single lumen needle (Wallace 17G Oocyte

Fig. 2 Photomicrograph, 200x, of the mature oocytes which were vitriﬁed.

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. 228 Ex vivo Retrieval of Mature Oocytes for Fertility Preservation Carvalho et al.

Fig. 3 Macroscopic external view of the tumor in both ovaries. Photomicrographs, in hematoxycilin-eosin, are disposed as: (A) 40x, branched ﬁbroconjunctive papillae covered by serous epithelium, sometimes forming micropapillae. (B) 40x, area of endophytic growth, with no evidence of stromal invasion. (C) 100x, area with micropapillae, measuring < 5.0 mm (which means that it is not a low-grade noninvasive serous carcinoma). (D) 800x, microinvasion focus in stroma, < 5.0 mm, consisting of terminally differentiated/senescent-looking epithelioid cells (no clinical repercussions). (E) 40x, focus of peritoneal endometriosis containing glands and stroma. (F) Immunohistochemistry, CD 10 positive in stromal cells of the endometriosis focus.

Recovery Set 330 mm; Smiths Medical International, UK), in a and 7.09 U/mL in the last mensuration, which was made closed system connected directly to the tubes, which were 4 days before we finished this report. placed in a preheated tube warmer (model TW37, Origio, Målov, Denmark). All enlarged follicles were punctured and Discussion aspirated under ultrasound guidance, using a 6–13 MHz linear probe applied directly to the specimens (►Fig. 1). We report a case of ultrasound-guided ex vivo retrieval of A total of 20 ovarian follicles were aspirated, filling ten mature oocytes for fertility preservation in a woman with 14 mL tubes with follicular fluids, which were transported in bilateral borderline ovarian tumor, for whom conventional the tube warmer, placed in a thermal box, with the intention transvaginal follicular aspiration was deemed unsafe be- of simulating optimal temperature to the embryology labo- cause of the increased risk of malignant cell spillage. To ratory. The journey from the hospital to the laboratory was of our knowledge, this is the first report of an ex vivo retrieval 9 km, completed in 16 minutes. of mature oocytes in Brazil, and the second using standard Sixteen cumulus complexes were obtained. Cumulus cells ultrasound guidance in the international literature. were removed with hyaluronidase 40 IU/mL, yielding 12 Conservative surgery with the intention of preserving the metaphase II (mature) and 3 metaphase I (immature) ability to conceive has been increasingly practiced in surgical oocytes, and 1 germinal vesicle. The 3 immature oocytes gynecological oncology and is no longer limited to ovarian were matured in vitro, and the final 15 mature oocytes transposition before radiotherapy. Preservation of the pelvic obtained (►Fig. 2) were vitrified, 2,5 hours after being anatomy is currently desirable for young women without yielded, using a modified oocyte vitrification method as constituted offspring, especially concerning the uterus, and, previously described by Kuwayama.17 in many cases, at least the contralateral ovary.18,19 In the Of note, the entire procedure was performed using meantime, there is consensus on the recommendation of absolute sterile steps. The surgical staging procedure was caution regarding conservative surgery for hormone-sensi- completed by oncological surgeons, and after safety evalu- tive ovarian tumors, as well as for high-risk serous borderline ation, the uterus was preserved. Final histopathology con- tumors20 and those in advanced stages.3 firmed the diagnosis of bilateral serous borderline tumor on To date, the safety of fertility sparing approaches to the surface of both ovaries with microinvasion of 0.2 mm different ovarian tumors in childbearing age patients really (►Fig. 3), without tubal commitment. As an accidental seems to be realistic. The recent meta-analysis of eight finding, endometriosis implants were identified in the observational studies, comparing 2,223 women undergoing rectosigmoid and in the right uterosacral ligament, also conservative surgery with 5,809 undergoing radical surgery confirmed by histopathology. Finally, the postoperative did not find differences in overall survival and disease-free follow-up of CA-125 levels showed a decrease from 273 survival with either surgical techniques for stage 1 epithelial U/mL in day 10 after surgery to 9.62 U/mL after 3 months, ovarian cancer.21 In the same way, observational studies that

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. Ex vivo Retrieval of Mature Oocytes for Fertility Preservation Carvalho et al. 229 evaluated the prognosis of malignant ovarian germ cell the disease. Ex vivo recovery of oocytes eliminates that risk of tumors22 suggested that fertility sparing surgery is a safe peritoneal dissemination and the literature on the subject has treatment option, regardless of tumor stage and histological been built from reports and case series. Conversely, oftentimes type, and a recent encouraging French casuistic demonstrat- the puncture of oophorectomized specimens is proceeded ed the experience of live births in two thirds of the women without any stimulation, obtaining immature oocytes to be submitted to conservative surgery for borderline ovarian subsequently matured in vitro.5,7,8,10 As an example, in the tumors, some occurring after recurrence.23 series of 34 cases published by Segers et al,9 ex vivo recovery of As interventions to be added to the oncological approach immature oocytes resulted in obtaining mature oocytes invitro with the aim to preserve female reproductive capacity, tech- or embryos available for cryopreservation in 79% of women, niques of cryopreservation of oocytes, embryos, or even the with an overall maturation rate of 36% after IVM. – ovarian cortex have been increasingly used worldwide.24 27 In In spite of being a widely studied technique, IVM has not oncological cases, cryopreservation of mature oocytes seems reached the status of a routine or widely used technique, to be the most interesting option, mainly for single women, since outcomes are far below expectations.11 For this reason, those who do not wish to use donor sperm, or have religious or developing protocols and techniques that allow the capture ethical objections to embryo freezing.26,28 Fortunately, preg- of in vivo matured oocytes means a great advance for fertility nancy rates from in vitro fertilization of frozen eggs are very preservation in women with ovarian malignancies. close to those seen with fresh eggs nowadays.29 To date, there are four case reports of ex vivo retrieval of It is noteworthy, however, that oocyte recovery is conven- mature oocytes after ovarian stimulation by exogenous gona- – tionally performed by follicular puncture through the vaginal dotropins in the literature.12 15 Fatemi et al12 and Bocca et al13 fornix and, therefore, carrying the risk of rupture of the tumor were pioneers in the idea, both reporting the intervention capsule and tumor cellsspillage, then changing the prognosis of occurring in women < 30 years old, and obtaining satisfactory

Table 1 Summary of fertility preservation case reports using ex vivo retrieval of mature oocytes in ovarian tumors

Reference Age Marital status; COS Surgery type Pathology US guidance Total mature Total parity; brief (yes/no) oocytes in vitro medical history yielded matured oocytes † Fatemi et al 27 Not mentioned; rFSH 200 IU/day; ganirelix Laparotomy Papillary serous No 13 0 (2011)12 nulliparous; previous acetate, 0,25 mg/day, adenocarcinoma infertility reported; from day 6; maturation (recurrence) previous laparoscopic trigger with urinary hCG left salpingo- 10,000 IU oophorectomy, papillary serous adenocarcinoma; ovarian reserve not mentioned Bocca et al 25 Single; nulliparous; rFSH 200 IU/day; ganirelix Laparoscopy, Serous No 14 0 (2011)13 previous acetate, 0,25 mg/day, 34–35 hours borderline tumor laparoscopic left from day 7 to day 10; after maturation ‡ salpingo- maturation trigger with trigger oophorectomy, rhCG 250 µg on day 10 serous borderline ovarian tumor; AFC 10 Pereira et al 37 Single; nulliparous; rFSH Laparotomy, Not mentioned No 7 0 (2017)14 AFC 14 300 IU/day þ hpHMG 34 hours after 150 IU/day þ letrozol maturation 5 mg/day; rFSH reduced to trigger 150 IU/day from day 8 to day 11; ganirelix acetate, 0,25 mg/day; maturation trigger with rhCG 250 µg on day 12 de la Blanca 31 Single; nulliparous; Chorifollitropin α 150 µg, Laparoscopy, Struma ovarii Yes 5 0 et al (2018)15 previous rFSH 35 hours after laparoscopic left 200 IU/day from day 8 to maturation salpingo- day 9; ganirelix acetate, trigger oophorectomy, 0,25 mg/day, from day 6 mature teratoma; to day 10; maturation AFC unfeasible, trigger with rhCG 250 µg AMH 1.1 ng/mL on day 10

Abbreviations: AFC, Antral Follicle Count; AMH, Anti-Müllerian Hormone; COS, Controlled Ovarian hyperStimulation; hCG, Human Chorionic Gonadotropin; hpHMG, highly puriﬁed Menotropin; rhCG, recombinant Human Chorionic Gonadotropin; rFSH, recombinant Follicle Stimulating Hormone. † Intracytoplasmic sperm injection was proceeded, and 7 top quality zygotes were vitriﬁed. ‡ Informationobtainedwiththemainauthor, Silvina Bocca, by e-mail, on May 6, 2020.

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. 230 Ex vivo Retrieval of Mature Oocytes for Fertility Preservation Carvalho et al.

amounts of mature oocytes, even aspirating the follicles iden- 3 Plett H, Harter P, Ataseven B, Heitz F, Prader S, Schneider S. tified by the external view. However, Pereira et al14 recognized Fertility-sparing surgery and reproductive-outcomes in patients a technical limitation of the extracorporeal uptake of mature with borderline ovarian tumors. Gynecol Oncol. 2020;157(02): 411–417. Doi: 10.1016/j.ygyno.2020.02.007 oocytes without ultrasound guidance, and the lack of this 4 Candotti G, Peiretti M, Mangili G, Bergamini A, Candiani M, Cioffi approach may be the reason for the small amount of gametes R, et al. What women want: Fertility sparing surgery in Borderline recovered, even though this was similar or superior to the ovarian tumours patients and pregnancy outcome. Eur J Surg number of oocytes obtained after ex vivo recovery of immature Oncol. 2020;46(05):888–892. Doi: 10.1016/j.ejso.2019.11.001 oocytes in published studies that included young women.8,10 5 Revel A, Safran A, Benshushan A, Shushan A, Laufer N, Simon A. In De la Blanca et al15 were the first to use ultrasound vitro maturation and fertilization of oocytes from an intact ovary of a surgically treated patient with endometrial carcinoma: case guidance directly applied to the specimens; an endovaginal report. Hum Reprod. 2004;19(07):1608–1611. Doi: 10.1093/ probe was used to facilitate access to the follicles. Unfor- humrep/deh241 tunately, the number of mature eggs retrieved was not 6 Huang JY, Buckett WM, Gilbert L, Tan SL, Chian RC. Retrieval of exactly satisfactory, especially considering that the patient immature oocytes followed by in vitro maturation and vitrifica- was 31 years old and the ovarian reserve seemed to be tion: a case report on a new strategy of fertility preservation in women with borderline ovarian malignancy. Gynecol Oncol. normal. The reports describing the preservation of mature 2007;105(02):542–544. Doi: 10.1016/j.ygyno.2007.01.036 oocytes obtained by ex vivo capture are summarized 7 Fadini R, Dal Canto M, Mignini Renzini M, Milani R, Fruscio R, in ►Table 1. Cantù MG, et al. Embryo transfer following in vitro maturation We believe that the use of a 6–13 MHz linear probe for and cryopreservation of oocytes recovered from antral follicles ultrasound guidance to ovarian follicles aspiration helped us during conservative surgery for ovarian cancer. J Assist Reprod – to achieve what we considered an excellent number of Genet. 2012;29(08):779 781. Doi: 10.1007/s10815-012-9768-0 8 Prasath EB, Chan ML, Wong WH, Lim CJW, Tharmalingam MD, vitrified mature eggs. Also, it seems that we are the first to Hendricks M, et al. First pregnancy and live birth resulting from use IVM as an additional intervention, resulting in the cryopreserved embryos obtained from in vitro matured oocytes highest number of mature vitrified oocytes for women after oophorectomy in an ovarian cancer patient. Hum Reprod. with BOT ever published. 2014;29(02):276–278. Doi: 10.1093/humrep/det420 Of note, ovarian stimulation has not been associated with 9 Segers I, Mateizel I, Van Moer E, Smitz J, Tournaye H, Verheyen G, recurrence of ovarian malignancies to date,30 even in wom- De Vos M. In vitro maturation (IVM) of oocytes recovered from ovariectomy specimens in the laboratory: a promising “ex vivo” en with a high-risk Breast Cancer Gene (BRCA) mutation.31 method of oocyte cryopreservation resulting in the first report of Moreover, reports of live births following in vitro fertiliza- an ongoing pregnancy in Europe. J Assist Reprod Genet. 2015;32 tion (IVF) after fertility-sparing surgery in patients with (08):1221–1231. Doi: 10.1007/s10815-015-0528-9 ovarian tumors suggest that pregnancy outcomes may be 10 Park CW, Lee SH, Yang KM, Lee IH, Lim KT, Lee KH, Kim TJ. even better for them than those observed for infertile Cryopreservation of in vitro matured oocytes after ex vivo oocyte women, and that assisted reproductive techniques have retrieval from gynecologic cancer patients undergoing radical – 32 surgery. Clin Exp Reprod Med. 2016;43(02):119 125. Doi: no negative impact on the prognosis of cancer. 10.5653/cerm.2016.43.2.119 11 Lu C, Zhang Y, Zheng X, Song X, Yang R, Yan J, et al. Current Conclusion perspectives on in vitro maturation and its effects on oocyte genetic and epigenetic profiles. Sci China Life Sci. 2018;61(06): – In conclusion, our report emphasizes the viability of ex vivo 633 643. Doi: 10.1007/s11427-017-9280-4 12 Fatemi HM, Kyrou D, Al-Azemi M, Stoop D, de Sutter P, Bourgain C, mature oocyte retrieval after controlled ovarian stimulation Devroey P. Ex-vivo oocyte retrieval for fertility preservation. Fertil for those with high risk of malignant dissemination by the Steril. 2011;95(05):1787.e15–1787.e17. Doi: 10.1016/j.fertn- conventional vaginal approach. Also, it reinforces the benefit stert.2010.11.023 of using ultrasound guidance for the access to ovarian 13 Bocca S, Dedmond D, Jones E, Stadtmauer L, Oehninger S. Suc- follicles, which can be an important additive to achieve the cessful extracorporeal mature oocyte harvesting after laparosco- best possible result. pic oophorectomy following controlled ovarian hyperstimulation for the purpose of fertility preservation in a patient with borderline ovarian tumor. J Assist Reprod Genet. 2011;28(09):771–772. fl Con ict of Interests Doi: 10.1007/s10815-011-9596-7 The authors have no conflict of interests to declare. 14 Pereira N, Hubschmann AG, Lekovich JP, Schattman GL, Rose- nwaks Z. Ex vivo retrieval and cryopreservation of oocytes from oophorectomized specimens for fertility preservation in a BRCA1 mutation carrier with ovarian cancer. Fertil Steril. 2017;108(02): References 357–360. Doi: 10.1016/j.fertnstert.2017.05.025 1 Yoshida A, Tavares BVG, Sarian LO, Andrade LALA, Derchain SF. 15 de la Blanca EP, Fernandez-Perez MF, Martin-Diaz EDM, Lozano M, Clinical features and management of women with borderline Garcia-Sanchez M, Monedero C. Ultrasound-guided ex-vivo retrieval ovarian tumors in a single center in Brazil. Rev Bras Ginecol of mature oocytes for fertility preservation during laparoscopic – Obstet. 2019;41(03):176 182. Doi: 10.1055/s-0039-1683415 oophorectomy: a case report. J Reprod Infertil. 2018;19(03):174–181 2 Schuurman MS, Timmermans M, van Gorp T, Van de Vijver KK, 16 Timmerman D, Valentin L, Bourne TH, Collins WP, Verrelst H, Kruitwagen RFPM, Lemmens VEPP, van der Aa MA. Trends in Vergote IInternational Ovarian Tumor Analysis (IOTA) Group. incidence, treatment and survival of borderline ovarian tumors in Terms, definitions and measurements to describe the sonograph- the Netherlands: a nationwide analysis. Acta Oncol. 2019;58(07): ic features of adnexal tumors: a consensus opinion from the – 983 989. Doi: 10.1080/0284186X.2019.1619935 International Ovarian Tumor Analysis (IOTA) Group. Ultrasound

Obstet Gynecol. 2000;16(05):500–505. Doi: 10.1046/j.1469- 24 Wright JD, Shah M, Mathew L, Burke WM, Culhane J, Goldman N, 0705.2000.00287.x et al. Fertility preservation in young women with epithelial ovarian 17 Kuwayama M. Highly efficient vitrification for cryopreservation of cancer. Cancer. 2009;115(18):4118–4126. Doi: 10.1002/cncr.24461 human oocytes and embryos: the Cryotop method. Theriogenology. 25 Rashedi AS, de Roo SF, Ataman LM, Edmonds ME, Silva AA, Scarella 2007;67(01):73–80. Doi: 10.1016/j.theriogenology.2006.09.014 A, et al. Survey of fertility preservation options available to 18 Mandelbaum RS, Blake EA, Machida H, Grubbs BH, Roman LD, patients with cancer around the globe. J Glob Oncol. 2018; Matsuo K. Utero-ovarian preservation and overall survival of 4:1–16. Doi: 10.1200/JGO.2016.008144 young women with early-stage borderline ovarian tumors. Arch 26 Oktay K, Harvey BE, Loren AW. Fertility preservation in patients Gynecol Obstet. 2019;299(06):1651–1658. Doi: 10.1007/s00404- with cancer: ASCO Clinical Practice Guideline update summary. 019-05121-z J Oncol Pract. 2018;14(06):381–385. Doi: 10.1200/JOP.18.00160 19 Bourdel N, Huchon C, Cendos AW, Azaïs H, Bendifallah S, Bolze PA, 27 Practice Committee of the American Society for Reproductive et al. Tumeurs frontières de l’ovaire. Recommandations pour la Medicine. Electronic address: [email protected]. Fertility preserva- pratique clinique du CNGOF – Texte court. Gynécol Obstét Fertil tion in patients undergoing gonadotoxic therapy or gonadecto- Sénol. 2020;48(03):223–235. Doi: 10.1016/j.gofs.2020.01.022 my: a committee opinion. Fertil Steril. 2019;112(06):1022–1033. 20 Rousset-Jablonski C, Selle F, Adda-Herzog E, Planchamp F, Selleret Doi: 10.1016/j.fertnstert.2019.09.013 L, Pomel C, et al. Fertility preservation, contraception and meno- 28 Carvalho BR, Kliemchen J, Woodruff TK. Ethical, moral and other pause hormone therapy in women treated for rare ovarian aspects related to fertility preservation in cancer patients. JBRA Assist tumours: guidelines from the French national network dedicated Reprod. 2017;21(01):45–48. Doi: 10.5935/1518-0557.20170011 to rare gynaecological cancers. Eur J Cancer. 2019;116:35–44. 29 Cobo A, Garcia-Velasco JA, Domingo J, Remohí J, Pellicer A. Is Doi: 10.1016/j.ejca.2019.04.018 vitrification of oocytes useful for fertility preservation for age- 21 Liu D, Cai J, Gao A, Wang Z, Cai L. Fertility sparing surgery vs related fertility decline and in cancer patients? Fertil Steril. 2013; radical surgery for epithelial ovarian cancer: a meta-analysis of 99(06):1485–1495. Doi: 10.1016/j.fertnstert.2013.02.050 overall survival and disease-free survival. BMC Cancer. 2020;20 30 Feichtinger M, Rodriguez-Wallberg KA. Fertility preservation in (01):320. Doi: 10.1186/s12885-020-06828-y women with cervical, endometrial or ovarian cancers. Gynecol 22 Mikuš M, Benco N, Matak L, Planicić P, Ćoric M, Lovrić H, et al. Oncol Res Pract. 2016;3:8. Doi: 10.1186/s40661-016-0029-2 Fertility-sparing surgery for patients with malignant ovarian 31 Perri T, Lifshitz D, Sadetzki S, Oberman B, Meirow D, Ben-Baruch germ cell tumors: 10 years of clinical experience from a tertiary G, et al. Fertility treatments and invasive epithelial ovarian referral center. Arch Gynecol Obstet. 2020;301(05):1227–1233. cancer risk in Jewish Israeli BRCA1 or BRCA2 mutation carriers. Doi: 10.1007/s00404-020-05522-5 Fertil Steril. 2015;103(05):1305–1312. Doi: 10.1016/j.fertn- 23 Chevrot A, Pouget N, Bats AS, Huchon C, Guyon F, Chopin N, et al. stert.2015.02.011 Fertility and prognosis of borderline ovarian tumor after conser- 32 Li S, Lin H, Xie Y, Jiao X, Qiu Q, Zhang Q. Live births after in vitro vative management: Results of the multicentric OPTIBOTstudy by fertilization with fertility-sparing surgery for borderline ovarian the GINECO & TMRG group. Gynecol Oncol. 2020;157(01):29–35. tumors: a case series and literature review. Gynecol Obstet Invest. Doi: 10.1016/j.ygyno.2019.12.046 2019;84(05):445–454. Doi: 10.1159/000497203

Are Endocan Plasma Levels Altered in Preeclampsia?

Ana Cristina dos Santos Lopes1 Suellen Rodrigues Martins1 Luci Maria SantAna Dusse1 Melina de Barros Pinheiro2 Patrícia Nessralla Alpoim1

1 Department of Clinical and Toxicological Analysis, Faculdade de Address for correspondence Patrícia Nessralla Alpoim, Room 4104– Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, B3, 6627, Antônio Carlos Ave, Belo Horizonte, MG, 31270-901, Brazil Brazil (e-mail: [email protected]). 2 Universidade Federal de São Joao del-Rei, Divinópolis, MG, Brazil

Rev Bras Ginecol Obstet 2021;43(3):232–234.

Dear Editor, normality was tested by the Shapiro-Wilk test. The differ- Our research group has been studying preeclampsia (PE) ences in endocan levels between the PE and normotensive for over a decade aiming to detect possible blood biomarkers groups were assessed by the Mann-Whitney test. P-values – of hemostasis,1 5 inflammation,6,7 and endothelial dysfunc- < 0.05 were considered statistically significant. – tion8 10 that could be useful for the diagnosis of PE. Until Surprisingly, no significant difference was observed com- today, only the onset of hypertension ( 140 mmHg systolic paring endocan plasma levels between PE (0.388 ng/mL or 90 mmHg diastolic) on or after 20 weeks of gestation in [0.346–0.516]) and normotensive pregnant women (0.393 association or not with proteinuria and/or evidences of ng/mL [0.321–0.623]) (p ¼ 0.870). We classified PE by the multisystem impairment (such as renal, liver and neurologi- onset time of clinical symptoms, such as early (< 34 weeks) cal dysfunctions) is an acceptable criterion to establish the or late PE ( 34 weeks),3 and compared endocan levels in diagnosis of this gestational disease.11 It is important to these groups. Again, no significant difference was observed emphasize that PE affects between 2 and 8% of all pregnan- for early (0.385 ng/mL [0.311–0.459]) and late PE (0.407 ng/ cies worldwide, an early diagnosis of the disease, before the mL [0.313–0.500]) and normotensive pregnant women occurrence of systematic impairment, is still not available, (0.393 ng/mL [0.244–0.542]) (p ¼ 0.851). which motivates our arduous search for laboratory markers A review of the literature showed eight studies that – of PE.12,13 investigated endocan in women with PE.16 23 According to Endocan is a biochemical marker of endothelial dysfunc- our data, two studies showed no significant difference tion that is potentially associated with immunoinflamma- between endocan levels in preeclamptic versus normoten- tory response.14,15 Previous data of our group showed that sive pregnancy.16,18 However, five studies revealed in- endothelial dysfunction and inflammation are important creased levels in women with PE versus normotensive – features in PE.6,8,9 Aiming to determine if endocan plasma pregnancy17,19,21 23 and two studies showed that endocan levels could be useful for determining PE predisposition and/ protein in the placenta tissue is upregulated in PE18,20 or development, we investigate its levels in preeclamptic and suggesting its involvement in the pathogenesis of PE. Of normotensive pregnant women from the southeastern state note, among the studies that found a positive association of Minas Gerais, Brazil. between endocan levels and PE development, one was also Our case-control study included 80 Brazilian pregnant conducted in Brazil.22 It is well-established that high levels women, 40 with severe PE ( 160 mmHg systolic or > 110 of tumor necrosis factor-α (TNF-α) and vascular endothelial mmHg diastolic pressure) and 40 normotensive pregnant growth factor (VEGF) are able to stimulate the expression women (controls). Endocan levels were investigated by of endocan.24,25 It should be highlighted that the women enzyme-linked immunosorbent assay (ELISA). The statistical with PE of the present study showed no previous increase analysis was performed using IBM SPSS Statistics for Win- of TNF-α plasma levels3 and lower VEGF levels26 comparing dows, version 19.0 (IBM Corp., Armonk, NY, USA). Data with normotensive pregnant. These data could justify why

received DOI https://doi.org/ © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights August 21, 2020 10.1055/s-0041-1728661. reserved. accepted ISSN 0100-7203. This is an open access article published by Thieme under the terms of the February 4, 2021 Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda., Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil Letter to the Editor 233 endocan levels were not elevated in the women with PE clinical manifestations of preeclampsia. PLoS One. 2014;9(05): studied. e97632. Doi: 10.1371/journal.pone.0097632 Interestingly, Chang et al.18 related that, although plasma 8 Alpoim PN, Godoi LC, Freitas LG, Gomes KB, Dusse LM. Assessment of L-arginine asymmetric 1 dimethyl (ADMA) in early-onset and levels of endocan do not correlate with the occurrence of PE, late-onset (severe) preeclampsia. Nitric Oxide. 2013;33:81–82. an increased expression of mRNA and endocan were found in Doi: 10.1016/j.niox.2013.07.006 the placenta of women with PE, it could suggest that endocan 9 Alpoim PN, Gomes KB, Pinheiro MdeB, Godoi LC, Jardim LL, Muniz is related to PE pathophysiology, but only in the microenvi- LG, et al. Polymorphisms in endothelial nitric oxide synthase gene ronment of the placenta, not reflecting the placental changes in early and late severe preeclampsia. Nitric Oxide. 2014; – in plasma. Therefore, our research group aims to evaluate the 42:19 23. Doi: 10.1016/j.niox.2014.07.006 10 Alpoim PN, Perucci LO, Godoi LC, Goulart COL, Dusse LMS. expression of endocan in the placenta, in addition to repeat- Oxidative stress markers and thrombomodulin plasma levels in fi ing the plasma analyzes in a larger sample, to con rm that women with early and late severe preeclampsia. Clin Chim Acta. the results are in fact not significant in the population 2018;483:234–238. Doi: 10.1016/j.cca.2018.04.039 studied. 11 American College of Obstetricians and Gynecologists Task Force on In conclusion, our findings showed no association be- Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force tween endocan levels and PE occurrence in Brazilian preg- on Hypertension in Pregnancy. Obstet Gynecol. 2013;122(05): nant women. The role of endocan as endothelial function 1122–1131. Doi: 10.1097/01.AOG.0000437382.03963.88 biomarker is unquestionable. Since endothelial dysfunction 12 Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look PF. WHO and systematic inflammatory response are among the key analysis of causes of maternal death: a systematic review. Lancet. pathophysiological mechanisms for PE, future studies are 2006;367(9516):1066–1074. Doi: 10.1016/S0140-6736(06) required to investigate how endocan is involved in the 68397-9 13 Duley L. The global impact of pre-eclampsia and eclampsia. occurrence of PE. Semin Perinatol. 2009;33(03):130–137. Doi: 10.1053/j.sem- peri.2009.02.010 Funding 14 Kali A, Shetty KS. Endocan: a novel circulating proteoglycan. Indian J Pharmacol. 2014;46(06):579–583. Doi: 10.4103/0253- The authors thank the staff of the hospitals and the 7613.144891 women who participated in the present study. Dusse L. 15 Balta S, Mikhailidis DP, Demirkol S, Ozturk C, Celik T, Iyisoy A. M. S. is grateful for the CNPq fellowship. The present study Endocan: A novel inflammatory indicator in cardiovascular dis- was supported by FAPEMIG under grant number 00764- ease? Atherosclerosis. 2015;243(01):339–343. Doi: 10.1016/j. 16; and CNPq/Brazil under grant number 404353/2016-9. atherosclerosis.2015.09.030 16 Yuksel MA, Tuten A, Oncul M, Acikgoz AS, Yuksel IT, Toprak MS, et al. Serum endocan concentration in women with pre-eclamp- Conflict to Interests sia. Arch Gynecol Obstet. 2015;292(01):69–73. Doi: 10.1007/ fl The authors have no con ict of interests to declare. s00404-014-3605-x 17 Cakmak M, Yilmaz H, Bağlar E, Darcin T, Inan O, Aktas A, et al. Serum levels of endocan correlate with the presence and severity References of pre-eclampsia. Clin Exp Hypertens. 2016;38(02):137–142. Doi: 1 Dusse L, Godoi L, Kazmi RS, Alpoim P, Petterson J, Lwaleed BA, 10.3109/10641963.2015.1060993 et al. Sources of thrombomodulin in pre-eclampsia: renal dys- 18 Chang X, Bian Y, Wu Y, Huang Y, Wang K, Duan T. Endocan of the function or endothelial damage? Semin Thromb Hemost. 2011;37 maternal placenta tissue is increased in pre-eclampsia. Int J Clin (02):153–157. Doi: 10.1055/s-0030-1270343 Exp Pathol. 2015;8(11):14733–14740 2 Dusse LM, Alpoim PN, Lwaleed BA, de Sousa LP,Carvalho Md, Gomes 19 Hentschke MR, Lucas LS, Mistry HD, Pinheiro da Costa BE, Poli-de- KB. Is there a link between endothelial dysfunction, coagulation Figueiredo CE. Endocan-1 concentrations in maternal and fetal activation and nitric oxide synthesis in preeclampsia? Clin Chim plasma and placentae in pre-eclampsia in the third trimester of – Acta. 2013;415:226 229. Doi: 10.1016/j.cca.2012.10.006 pregnancy. Cytokine. 2015;74(01):152–156. Doi: 10.1016/j. 3 Pinheiro MB, Carvalho MG, Martins-Filho OA, Freitas LG, Godoi LC, cyto.2015.04.013 Alpoim PN, et al. Severe preeclampsia: are hemostatic and 20 Chew BS, Ghazali R, Othman H, Ismail NAM, Othman AS, Laim fl in ammatory parameters associated? Clin Chim Acta. 2014; NMST, et al. Endocan expression in placenta of women with – 427:65 70. Doi: 10.1016/j.cca.2013.09.050 hypertension. J Obstet Gynaecol Res. 2019;45(02):345–351. 4 Alpoim PN, Godoi LC, Freitas LG, Pinheiro MdeB, Gomes KB, Dusse Doi: 10.1111/jog.13836 LM. Is intraplatelet cGMP jeopardized to inhibit platelet activation 21 Adekola H, Romero R, Chaemsaithong P, Korzeniweski SJ, Dong Z, in severe preeclampsia? Blood Coagul Fibrinolysis. 2015;26(06): Yeo L, et al. Endocan, a putative endothelial cell marker, is 711–713. Doi: 10.1097/MBC.0000000000000226 elevated in preeclampsia, decreased in acute pyelonephritis, 5 Lucena FC, Lage EM, Teixeira PG, Barbosa AS, Diniz R, Lwaleed B, and unchanged in other obstetrical syndromes. J Matern Fetal et al. Longitudinal assessment of D-dimer and plasminogen Neonatal Med. 2015;28(14):1621–1632. Doi: 10.3109/ activator inhibitor type-1 plasma levels in pregnant women 14767058.2014.964676 with risk factors for preeclampsia. Hypertens Pregnancy. 2019; 22 Hentschke MR, da Cunha Filho EV, Vieira MC, Paula LG, Mistry HD, – 38(01):58 63. Doi: 10.1080/10641955.2019.1577435 Costa BEP, et al. Negative correlation between placental growth 6 Pinheiro MB, Martins-Filho OA, Mota AP, Alpoim PN, Godoi LC, factorand endocan-1 inwomenwith preeclampsia. Rev Bras Ginecol Silveira ACO, et al. Severe preeclampsia goes along with a cytokine Obstet. 2018;40(10):593–598. Doi: 10.1055/s-0038-1670713 fl network disturbance towards a systemic in ammatory state. 23 Schuitemaker JHN, Cremers TIFH, Van Pampus MG, Scherjon SA, – Cytokine. 2013;62(01):165 173. Doi: 10.1016/j.cyto.2013.02.027 Faas MM. Changes in endothelial cell specific molecule 1 plasma 7 Perucci LO, Gomes KB, Freitas LG, Godoi LC, Alpoim PN, Pinheiro levels during preeclamptic pregnancies compared to healthy MB, et al. Soluble endoglin, transforming growth factor-Beta 1 pregnancies. Pregnancy Hypertens. 2018;12:58–64. Doi: and soluble tumor necrosis factor alpha receptors in different 10.1016/j.preghy.2018.02.012

24 Delehedde M, Devenyns L, Maurage CA, Vivès RR. Endocan in lymphangiogenesis. Blood. 2008;112(06):2318–2326. Doi: cancers: a lesson from a circulating dermatan sulfate proteogly- 10.1182/blood-2008-05-156331 can. Int J Cell Biol. 2013;2013:705027. Doi: 10.1155/2013/705027 26 Rios DRA, Alpoim PN, Godoi LC, Perucci LO, Sousa LR, Gomes KB, 25 Shin JW, Huggenberger R, Detmar M. Transcriptional proﬁling of et al. Increased levels of sENG and sVCAM-1 and decreased levels VEGF-A and VEGF-C target genes in lymphatic endothelium of VEGF in severe preeclampsia. Am J Hypertens. 2016;29(11): reveals endothelial-speciﬁc molecule-1 as a novel mediator of 1307–1310. Doi: 10.1093/ajh/hpv170

Advanced Cervical Cancer: Leveraging the Historical Threshold of Overall Survival

Eduardo Paulino1,2 Andreia Cristina de Melo1,2

1 Insituto Nacional do Câncer, Rio de Janeiro, RJ, Brazil Address for correspondence Eduardo Paulino, National Cancer 2 Grupo Oncoclínicas, Rio de Janeiro, RJ, Brazil Institute, Avenida Via Binário do Porto, 831, 20081-250, Rio de Janeiro, RJ, Brazil (e-mail: [email protected]). Rev Bras Ginecol Obstet 2021;43(3):235–237.

Dear Editor, Important advances have been shown in the last decade Cervical cancer is a public health problem in low- and with immunotherapy leveraging the 30% 12-month survival middle-income countries, where many patients are diagnosed limit seen in historical studies by the GOG. Examples include at an advanced stage. After the Gynecology Oncology Group vaccines (bioengineered modified listeria monocytogenes, (GOG) 240 study, the first-line standard of care for patients in Axalimogene filolisbac), anti-PD1 monotherapy (nivolumab, recurrent and/or metastatic settings includes the incorporation pembrolizumab, balsilimab) or combined with anti-cytotox- of bevacizumab with chemotherapy. Regarding the second line, ic T lymphocyte-associated protein 4 (anti-CTLA4), such as no drug demonstrates a survival benefitand,therefore,no nivolumab plus ipilimumab and balstimab plus zalifreli- – therapy can be considered the gold standard. The association mab.1,4 7 Although the Axalimogene filolisbac vaccine of human papillomavirus (HPV) infection and immunosuppres- showed a discouraging response rate of 2%, the 12-month sion with an increased risk of cervical cancer led to the hypoth- survival reached 38%.4 Monotherapy with nivolumab esisthattheimmunesystemmayhaveanimportantroleinthis showed responses of 26%, and the 12-month survival reach- disease. More recently, pembrolizumab received Food and Drug ing 77%; balsilimab demonstrated a RR of13% and a duration Administration (FDA) approval as second-line therapy based on of response of 15 months.5,7 Better results have been shown durable responses for patients with cervical cancer who combining anti-PD1 with anti-CTLA-4. The combination of expressed a combined positive score of > 1%, although the nivolumab (1 mg/Kg) plus ipilimumab (3 mg/Kg) showed a response rate (RR) in this scenario was still poor (14%).1 12-month survival of 84% and a RR of 36% in previously Over the past 3 decades, the GOG has studied many treated patients; balstimab added to zalifrelimab showed a chemotherapeutic agents and has shown that the 12-month RR of 20%, with a median duration of response not achieved survival, RRs, and duration of response are low with chemo- in previously treated patients.6,7 This combination received therapy alone.2 Based on these findings, the 12-month fast track designation from the FDA. survival has never increased beyond 30%, with RRs < 15%. A promising approach has also been demonstrated with Lan et al.3 recently published in the Journal of Clinical the adoptive transfer of T lymphocytes. Stevanović et al.8 Oncology the impressive results of camrelizumab, an anti- showed that the infusion of tumor-infiltrating T cells programmed cell death-1 antibody (anti-PD1), plus apatinib, resulted in two complete responses lasting 67 and 53 months a tyrosine kinase inhibitor against vascular endothelial at the time of publication. It is interesting to note that, growth factor receptor-2 (anti-VEGFR-2) in 45 patients although the tumor-infiltrating T cells were selected based with advanced cervical cancer who progressed after at least on the reactivity of HPV 16 E6 and E7 oncoproteins, immu- 1 line of systemic therapy. This heavily pretreated population nodominant T cell reactivities were directed against mutated (57.8% received 2 lines of chemotherapy) showed RRs of neoantigens or a cancer germline antigen, rather than ca- 55.6%, and 12-month survival 60%. Of note, the median nonical viral antigens.8 duration of the response and the median overall survival Impressive results have also been demonstrated in addi- were not reached yet.3 This combination compares favorably tion to immunotherapy. Examples include antidrug factor to each drug alone and highlights the exciting moment in against tissue factor and antihuman epidermal growth factor cervical cancer research. receptor 2 (anti-HER2).9,10 The tissue factor is overexpressed

received DOI https://doi.org/ © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights November 15, 2020 10.1055/s-0041-1728662. reserved. accepted ISSN 0100-7203. This is an open access article published by Thieme under the terms of the November 16, 2020 Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda., Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil 236 Letter to Editor

Fig. 1 Summary of some recent compelling studies showing the evolution of 12-month survival and response rates. Nivolumab 1mg/Kgþ ipilimumab 3 mg/Kg in previously-treated patients.

Conflict of Interests in cervical cancer. Tisotumab vedotin (antibody-drug conju- The authors have no conflict of interests to declare. gate against tissue factor) showed a RR of 24% and a 12- month survival 50%.10 This drug has also been tested in combination with immunotherapy (NCT03786081). Human References epidermal growth factor receptor 2 mutations are present in 1 Chung HC, Ros W, Delord JP, Perets R, Italiano A, Shapira-Frommer between 3 and 6% of cervical cancers according to sequenc- R, et al. Efficacy and safety of pembrolizumab in previously ing studies. Neratinib, a pan-HER tyrosine kinase inhibitor, treated advanced cervical cancer: results from the Phase II KEYNOTE-158 Study. J Clin Oncol. 2019;37(17):1470–1478. showed a RR of 25% and 12-month overall survival (12m-OS) Doi: 10.1200/JCO.18.01265 9 ►Fig. 1 of 60%. summarizes the 12m-OS evolution in the last 2 Tewari KS, Monk BJ. Gynecologic oncology group trials of chemo- 2 decades. therapy for metastatic and recurrent cervical cancer. Curr Oncol In the study by Lan et al.,3 only 22.2% of the population Rep. 2005;7(06):419–434. Doi: 10.1007/s11912-005-0007-z received bevacizumab previously. In the era of fast-growing 3 Lan C, Shen J, Wang Y, Li J, Liu Z, He Mian, et al. Camrelizumab plus evidence, immunotherapy combined (NCT03556839) or not apatinib in patients with advanced cervical cancer (CLAP): a multicenter, open-label, single-arm, Phase II trial. J Clin Oncol. (NCT03635567) with antiangiogenic agents is already being 2020;38(34):4095–4106. Doi: 10.1200/JCO.20.01920 studied in a frontline, and even in combined curative chemo- 4 Huh WK, Brady WE, Fracasso PM, Dizon DS, Powell MA, Monk BJ, radiation for locally advanced tumors (NCT03830866, et al. Phase II study of axalimogene filolisbac (ADXS-HPV) for NCT04221945, NCT03833479). So, how would the platinum-refractory cervical carcinoma: An NRG camrelizumab/apatinib combination respond in this scenario? oncology/gynecologic oncology group study. Gynecol Oncol. – In a post-hoc analysis, no difference in RR was observed 2020;158(03):562 569. Doi: 10.1016/j.ygyno.2020.06.493 5 Naumann RW, Hollebecque A, Meyer T, Devlim M-J, Oaknin A, between patients with PD-L1-positive and PD-L1-negative Kerger J, et al. Safety and efficacy of nivolumab monotherapy in fi tumors. This nding goes in the opposite direction to that of recurrent or metastatic cervical, vaginal, or vulvar carcinoma: Keynote 158, and is in line with the previously discussed results from the Phase I/II CheckMate 358 trial. J Clin Oncol. 2019; studies that show RRs regardless of the expression of PD-L1, 37(31):2825–2834. Doi: 10.1200/JCO.19.00739 highlighting the importance of the search for a predictive 6 Naumann RW, Oaknin A, Meyer T, Lopez-Picazo JM, Lao C, Bang Y- J, et al. Efficacy and safety of nivolumab (Nivo) ipilimumab (Ipi) in biomarker for immunotherapy. patients (pts) with recurrent/metastatic (R/M) cervical cancer: Treatment for advanced cervical cancer is an unmet need. results from CheckMate 358. Ann Oncol. 2019;30(Suppl 5):v898- Although we can clearly observe progress, < 20% of cancer –v899. Doi: 10.1093/annonc/mdz394.059 discoveries touted as highly promising translates into clinical 7 O’Malley DM, Oaknin A, Monk BJ, Ancukiewicz M, Shapiro I, Ray- practice,11 and the ongoing confirmatory phase III studies Coquard IL, et al. LBA34 Single-agent anti-PD-1 balstilimab or in (NCT03257267) are essential to include immunotherapy as combination with anti-CTLA-4 zalifrelimab for recurrent/metastatic (R/M) cervical cancer (CC): preliminary standard of care.

results of two independent phase II trials. Ann Oncol. 2020;31 10 Coleman RL, Lorusso D, Gennigens C, Smith M, Monk BJ, (Suppl 4):S1164–S1165. Doi: 10.1016/j.annonc.2020.08.2264 Vergote IB, et al. LBA32 Tisotumab vedotin in previously 8 Stevanović S, Pasetto A, Helman SR, Gatner JJ, Prickett TD, Howie treated recurrent or metastatic cervical cancer: results from B, et al. Landscape of immunogenic tumor antigens in successful the phase II innovaTV 204/GOG-3023/ENGOT-cx6 study. Ann immunotherapy of virally induced epithelial cancer. Science. Oncol. 2020;31(Suppl 4):S1162–S1163. Doi: 10.1016/j. 2017;356(6334):200–205. Doi: 10.1126/science.aak9510 annonc.2020.08.2262 9 Oaknin A, Friedman CF, Roman LD, D’Souza A, Brana I, Bidard F-C, 11 Waters RS, Prasad V. How often do highly promising et al. Neratinib in patients with HER2-mutant, metastatic cervical cancer biology discoveries translate into effective treatments? cancer: Findings from the phase 2 SUMMIT basket trial. Gynecol Ann Oncol. 2021;32(02):136–138. Doi: 10.1016/j. Oncol. 2020;159(01):150–156. Doi: 10.1016/j.ygyno.2020.07.025 annonc.2020.10.484

COVID-19 in Brazil: A Message to the World

Bruno Ramalho de Carvalho1

1 Hospital Sírio-Libanês, Brasília, DF, Brazil Address for correspondence BrunoRamalhodeCarvalho,SGAS614,conjuntoc,sala177,Edifício Rev Bras Ginecol Obstet 2021;43(3):238–239. Vitrium – Centro Médico Inteligente, Asa Sul, 70200-740, Brasília, DF, Brazil (e-mail: [email protected]).

Dear Editor, treatment with hydroxychloroquine or ivermectin,13 even Although the spread and severity of the Spanish Flu after several satisfactorily well-designed studies have point- pandemic in 1918 have been much more significant than ed out the ineffectiveness of those drugs, whether for the numbers of COVID-19 so far,1 no one is able to affirm that prevention, early treatment or decreased mortality of people – the current crisis is nearing its end, and it is plausible to affected by SARS-CoV-2.14 21 expect that it will overcome the “mother of all pandemics” Not without reason, the whole world is watching closely the and become the greatest pandemic event in human history. curves of COVID-19 in Brazil. Currently, the growth of the Such a fear is valid for the whole planet, but even more for Brazilian epidemic is too worrying. If we are still below the Brazil. An observer attentive to the Brazilian scenario today, United States in absolute numbers (we just passed India),22 the March 15, 2021, can assume exactly the reverse of the reality relative numbers demonstrate that our epidemiological catas- we would like to see: the country is considered a new global trophe has requirements to take the lead soon. It is worth saying epicenter of the disease, having recorded rising curves of here that many Brazilian citizens have been inspired by the cases and deaths, and recently reached more than 2 thousand intransigence coming from federal managers and have ignored daily deaths.2 even the basic measures to combat the transmission of the virus, The emergency of COVID-19 in Brazil is noticed all over such as wearing a mask and social distance. There is no way to the world and makes the country’s mistakes in facing the ignore this popular behavior as a potential catalyst for this threaten more than evident. However, the announcement of movement toward the complete lack of control of the disease. scientific inconsistency in the discourse and actions of the At the moment we are dealing with the threat of new – Brazilian government in the face of the pandemic does not variants,23 26 which appear to be easier to transmit and, come from today: native and foreign researchers have been therefore, can lead to the worsening of the situation, regard- – trying, over the last year, to warn about it.3 9 Furthermore, less of leading to more severe clinical conditions. Also, with the apparent ineptitude of those who hold power is com- the imminent collapse of the health system, which, according pounded by the neglect of a significant portion of the to the COVID-19 Observatory of the Oswaldo Cruz Founda- population, which, according to the mainstream media, tion, had an occupancy of intensive care beds greater than preferred to form agglomerations from the Christmas festiv- 80% in 19 of the 27 federative units, in the last week.27 ities to the carnival, in spite of following the contrary Finally, we are facing a vaccination program well below recommendations from the World Health Organization.10 the desirable for a country of continental dimensions like Yes, what we see here is the clear effect of the so-called Brazil. Between conflicts with the National Health Surveil- post-truth11 echoing in science, mixing reason and emotion lance Agency and resistance (at least in the beginning) to the in a contradictory broth, and taking people to the extreme of acquisition of vaccines, the federal government does not a faithful belief in any speech that relieves fears or promises a inspire confidence in predicting the availability of immun- miracle of healing. In September 2020, we ourselves warned izers quickly and in a number satisfactory to our people. about the alternation between the useful, the uncertain and We are in the eye of the storm, with just over 4% of the the futile in the COVID-19 epidemic in Brazil,12 where the population vaccinated,28 almost two months after the start of consumption of pseudoscientific or pre-scientificinforma- the immunization campaign. With optimism, we will achieve tion has led authorities and deniers to indisputable misun- the 50% in 2021. And we wait for the actions of the new derstandings. A clear example is the defense of early minister of health, the fourth to assume the Ministry since the

received DOI https://doi.org/ © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights March 17, 2021 10.1055/s-0041-1728660. reserved. accepted ISSN 0100-7203. This is an open access article published by Thieme under the terms of the March 17, 2021 Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda., Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil Letter to the Editor 239

beginning of the pandemic, which already comes up facing the 14 Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial enormous challenge of controlling the Brazilian ship adrift. of hydroxychloroquine as postexposure prophylaxis for Covid-19. – This message to the world is both a vent and an appeal for N Engl J Med. 2020;383(06):517 525. Doi: 10.1056/NEJ- Moa2016638 the rescue of science in the conduct of COVID-19 in Brazil. 15 Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with fi Here, we have good researchers and solid scienti cinstitu- mainly mild to moderate coronavirus disease 2019: open label, tions, capable of providing proper support to such a move- randomised controlled trial. BMJ. 2020;369:m1849. Doi: ment. Science (and only it) will provide the answers we need 10.1136/bmj.m1849 and there is no doubt that denying it has been the most 16 Horby P, Mafham M, Linsell L, et al; RECOVERY Collaborative serious mistake of our government so far. It is time to change Group. Effect of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med. 2020;383(21):2030–2040. Doi: 10.1056/ course. Otherwise, we will be charged by the world for NEJMoa2022926 something that we will not be able to reimburse. 17 Kim MS, An MH, Kim WJ, Hwang TH. Comparative efficacy and safety of pharmacological interventions for the treatment of COVID-19: A systematic review and network meta-analysis. References PLoS Med. 2020;17(12):e1003501. Doi: 10.1371/journal. 1 Taubenberger JK, Morens DM. 1918 Influenza: the mother of all pmed.1003501 – pandemics. Emerg Infect Dis. 2006;12(01):15 22. Doi: 10.3201/ 18 Self WH, Semler MW, Leither LM, et al; National Heart, Lung, and eid1201.050979 Blood Institute PETAL Clinical Trials Network. Effect of hydroxy- 2 Ministério da Saúde. COVID-19 no Brasil: dados até 10/03/2021 chloroquine on clinical status at 14 days in hospitalized patients [Internet]. 2021 [cited 2021 Mar 11]. Available from: https:// with COVID-19: a randomized clinical trial. JAMA. 2020;324(21): susanalitico.saude.gov.br/extensions/covid-19_html/covid- 2165–2176. Doi: 10.1001/jama.2020.22240 19_html.html#/dashboard 19 Mitjà O, Corbacho-Monné M, Ubals M, et al; BCN-PEP-CoV2 3 The Lancet. COVID-19 in Brazil: “So what?” Lancet. 2020;395 Research Group. A cluster-randomized trial of hydroxychloro- (10235):1461. Doi: 10.1016/S0140-6736(20)31095-3 quine for prevention of Covid-19. N Engl J Med. 2021;384(05): 4 Dyer O. Covid-19: Bolsonaro under fire as Brazil hides figures. 417–427. Doi: 10.1056/NEJMoa2021801 BMJ. 2020;369:m2296. Doi: 10.1136/bmj.m2296 20 López-Medina E, López P, Hurtado IC, et al. Effect of ivermectin on 5 Ortega F, Orsini M. Governing COVID-19 without government in time to resolution of symptoms among adults with mild COVID- Brazil: Ignorance, neoliberal authoritarianism, and the collapse of 19: a randomized clinical trial. JAMA. 2021;•••;. Doi: 10.1001/ public health leadership. Glob Public Health. 2020;15(09): jama.2021.3071 [ahead of print] – 1257 1277. Doi: 10.1080/17441692.2020.1795223 21 Galan LEB, Santos NMD, Asato MS, et al. Phase 2 randomized study 6 Lasco G. Medical populism and the COVID-19 pandemic. Glob on chloroquine, hydroxychloroquine or ivermectin in hospital- – Public Health. 2020;15(10):1417 1429. Doi: 10.1080/ ized patients with severe manifestations of SARS-CoV-2 infection. 17441692.2020.1807581 Pathog Glob Health. 2021;•••:1–8. Doi: 10.1080/ 7 Ferigato S, Fernandez M, Amorim M, Ambrogi I, Fernandes LMM, 20477724.2021.1890887 [ahead of print] ’ Pacheco R. The Brazilian Government s mistakes in responding to 22 World Health Organization. WHO Coronavirus (COVID-19) Dash- the COVID-19 pandemic. Lancet. 2020;396(10263):1636. Doi: board [Internet]. 2021 [cited 2021 Mar 15]. Available from: 10.1016/S0140-6736(20)32164-4 https://covid19.who.int/table 8 Carnut L, Mendes Á, Guerra L. Coronavirus, capitalism in crisis and 23 Fujino T, Nomoto H, Kutsuna S, et al. Novel SARS-CoV-2 variant the perversity of public health in Bolsonaro’s Brazil. Int J Health identified in travelers from Brazil to Japan. Emerg Infect Dis. 2021; Serv. 2021;51(01):18–30. Doi: 10.1177/0020731420965137 27(04):. Doi: 10.3201/eid2704.210138 9 Idrovo AJ, Manrique-Hernández EF, Fernández Niño JA. 24 Maggi F, Novazzi F, Genoni A, et al. Imported SARS-COV-2 variant Report from Bolsonaro’s Brazil: the consequences of ignoring P.1 detected in traveler returning from Brazil to Italy. Emerg Infect science. Int J Health Serv. 2021;51(01):31–36. Doi: 10.1177/ Dis. 2021;27(04):1249–1251. Doi: 10.3201/eid2704.210183 0020731420968446 25 Claro IM, da Silva Sales FC, Ramundo MS, et al. Local Transmission 10 World Health Organization. Coronavirus disease (COVID-19) ad- of SARS-CoV-2 Lineage B.1.1.7, Brazil, December 2020. Emerg vice for the public [Internet]. 2021 [cited 2021 Mar 15]. Available Infect Dis. 2021;27(03):970–972. Doi: 10.3201/eid2703.210038 from: https://www.who.int/emergencies/diseases/novel-coro- 26 Faria NR, Mellan TA, Whittaker C, et al. Genomics and epidemiol- navirus-2019/advice-for-public ogy of a novel SARS-CoV-2 lineage in Manaus, Brazil. medRxiv 11 Oxford University Press Oxford Languages. Word of the Year 2016: [Preprint]. 2021 Mar 3:2021.02.26.21252554 Doi: 10.1101/ post-truth [Internet]. 2016 [cited 2020 Apr 8]. Available from: 2021.02.26.21252554 https://languages.oup.com/word-of-the-year/2016/ 27 Ministério da Saúde Fundação Oswaldo Cruz (FIOCRUZ) Série 12 Carvalho BR, Fonseca FF, Beltrão HBM. Thinking about COVID-19 histórica da situação de ocupação de leitos de UTI Covid-19 para scenario in Brazil: the alternation between the useful, the uncer- adultos no SUS [Internet]. 2021 [cited 2021 Mar 15]. Available tain and the futile. Rev Bras Ginecol Obstet. 2020;42(09): from: https://portal.fiocruz.br/sites/portal.fiocruz.br/files/docu- 519–521. Doi: 10.1055/s-0040-1717142 mentos/serie_historica_leitos_uti_covid-19_adultos.pdf 13 Ministério da Saúde Conselho Nacional de Saúde. CNS pede que 28 Ministério da Saúde. COVID-19 Vacinação, Doses Aplicadas [In- Ministério da Saúde retire publicações sobre tratamento precoce ternet]. 2021 [cited 2021 Mar 15]. Available from: https://viz. para Covid-19 [Internet]. 2021 [cited 2021 Mar 15]. Available saude.gov.br/extensions/DEMAS_C19Vacina/DEMAS_C19Vacina. from: http://conselho.saude.gov.br/ultimas-noticias-cns/1570- html cns-pede-que-ministerio-da-saude-retire-publicacoes-sobre- tratamento-precoce-para-covid-19

Rev Bras Ginecol Obstet Vol. 43 No. 3/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. FEBRASGO POSITION STATEMENT HPV infection - Screening, diagnosis and management of HPV-induced lesions Number 3 - March 2021 DOI: https://doi.org/10.1055/s-0041-1727285

The National Specialty Commission for Lower Genital Tract of the Brazilian Federation of Gynecology and Obstetrics Associations (FEBRASGO) endorses to this document. The content production is based on scientific studies on a thematic proposal and the findings presented contribute to clinical practice.

Key points: • Address the importance of organized screening for cervical cancer. • Indicate new technologies in screening. • Anogenital warts are caused by HPV, mainly 6 and 11. • The diagnosis of condyloma acuminata is clinical with several effective therapeutic options. • Low-grade squamous intraepithelial lesion (LSIL) and atypias of undetermined significance in squamous cells (ASC-US). • As the risk of histological high-grade squamous intraepithelial lesion (HSIL) in a patient with cytological LSIL is significant, the quality of the cytopathological examination is essential. • Cases of cytological HSIL should be systematically referred to colposcopy. • “See-and-treat” is a diagnostic and therapeutic procedure and must be performed according to rules established for non-pregnant women over 25 years of age. • “See-and-treat” should not be performed in adolescents given the future possibility of obstetric comorbidities.

Recommendations: • Screening should be organized based on population data records with wide coverage. • The HPV DNA test must be offered for screening. • The therapeutic method for warts should be changed if there is no significant improvement within four weeks of treatment. • Podophyllin, 5-fluorouracil and imiquimod should not be used during pregnancy. • Conservative therapy for HSIL is preferred in patients ≤ 25 years of age. • In patients ≥ 25 years of age, risk estimates such as immunosuppression, HPV DNA positive and previous altered cytology and/or biopsy results should be considered. • The cytopathology of HSIL should be referred to colposcopy, it is not acceptable to repeat the cytopathology exam. • The endocervical canal should be evaluated with cytological brushing or curettage when the squamocolumnar junction (SCJ) is not visible. • After treatment of HSIL, follow-up with cytology and colposcopy is recommended every six months for two years then, annual cytology until completing five years. If possible, perform HPV DNA test on high-risk patients after six months and annually for three years; if tests are negative, return to triennial screening for 25 years.

Background female lower genital tract cancer. It is estimated that Human papillomavirus (HPV) is the most common sex- 33,369 cases of HPV-associated cancers are diagnosed ually transmitted infection in the world. The risk of be- each year in the USA, with 21,290 (13.2/100,000) cases ing infected with the virus at least once in your life is in women.(1) More than 600,000 cancer cases worldwide of 50%.(1) The most common oncogenic types are HPV- are attributed to HPV annually, which is the most im- 16 and 18, and their persistence is the main cause of portant risk factor in the development of cervical, va-

FEBRASGO POSITION STATEMENT 240 Oliveira AK, Jacyntho CM, Tso FK, Boldrini NA, Speck NM, Peixoto RA, et al. gina, vulva, penis, anus and oropharynx neoplasms, in varies from three to five years, depending on the meth- addition to causing anogenital warts.(2) od - cytology, HPV DNA test or co-test.(8)

Cervical cancer screening What are the screening methods? Cervical cancer is a public health problem worldwide Pap smear and the fourth most common type of tumor among The Brazilian Guidelines recommend the periodic per- women, with 500,000 new cases and 250,000 deaths formance of conventional cytology, although this is per year.(3) In Brazil, it is the third most common cancer characterized by low reproducibility among observers. in women. According to the National Cancer Institute, Liquid-based cytology (LBC), created with the aim of estimates for 2020 are of 16,590 new cases; and 6,526 reducing unsatisfactory smears, is an alternative meth- deaths occurred in 2018.(4) The main cause of the de- od of screening. Cells are deposited in a fixative sus- velopment of cervical cancer is persistent infection pension, which allows their uniform distribution on the with oncogenic HPV types. Infections are more preva- slides after processing. Another advantage is the pos- lent in adolescents and young adults, with peak prev- sibility to carry out new tests on the material residue alence in the early years of sexual activity.(5) Effective in the liquid medium, such as HPV DNA test, although screening has shown a reduction in the incidence of LBC has not shown a gain in sensitivity, compared to this neoplasia and mortality due to it. Precursor lesions conventional smears. (9) of cancer, when diagnosed and treated, prevent progression to invasive lesion.(6) Brazil still has an opportu- HPV DNA tests nistic form of screening.(5) The strategy that has been Evidence of the causal relationship between infection shown to be most effective is the organized population by oncogenic HPV types and the onset of precursor le- based screening program adopted by most European sions and cervical cancer favored the creation of new countries. This program advocates a system of active HPV DNA detection technologies.(10) Current evidence approach (call/recall system), based on the personal supports the use of the test in primary screening in invitation of the target population.(6) The organized women aged ≥ 30 years. Screening with this test can be screening program has reached more women, showing performed every five years. Brazilian Guidelines recom- high coverage of the territory.(3,5) mend HPV DNA testing from the age of 30, extending it to 64 years of age. When positive for oncogenic types, What is the target population the reflex cytological examination must be performed. for screening and how often (10) Another advantage of HPV DNA testing is the pos- should it be done? sibility of self-sampling, which is done by the woman According to Brazilian Guidelines for the Screening of herself anywhere. Detection rates of HPV in this form Cervical Cancer (Ministry of Health - MH), (7) the screen- have been similar to clinician-collected rates.(5) The ing method used is oncotic cytology from 25 years of American Cancer Society recommends HPV DNA test- age for women who have already started sexual life. ing as a primary screening or in association with cytol- Tests must continue until the age of 64, and in women ogy, called a co-test, although this is already advocated with no previous history of pre-neoplastic disease, they as primary screening in future guidelines.(8) About 19 of should be stopped when they have had at least two 28 countries in Europe already track this way. (6) negative tests in the last five years.(7) For women over 64 years of age who have never undergone the exam, What is Febrasgo’s recommendation two exams should be carried out every one to three for cervical cancer screening years. If both tests are negative, these women may be in Brazilian women? excused from screening. The recommended periodic- In 2018, Febrasgo published the dossier proposing ity is every three years after two negative exams with strategies to add to the 2016 Brazilian Guidelines a one-year interval in between. Immunosuppressed (Ministry of Health - National Cancer Institute): (7,11,12) women must undergo the screening test after the • Population based screening; beginning of sexual activity with semiannual intervals • Insertion of the HPV DNA test as a primary test; in the first year, maintaining an annual follow-up af- • Refer women positive for HPV-16/18 directly to terwards. In HIV + women with a TCD4 + lymphocyte colposcopy; count below 200 cells/mm3, semiannual screening • HPV DNA self-sampling for women who reject the should be maintained.(7) The American Cancer Society professional exam or live in remote areas. (ACS – 2020),(8) like most European countries, recommends that screening should also start at 25 years of What diseases are caused by HPV? age and be suspended at 65 years of age; in Europe, the Condyloma acuminata age ranges between 59 and 65 years.(6) The frequency • What is condyloma acuminata?

FEBRASGO POSITION STATEMENT 241 HPV infection - Screening, diagnosis and management of HPV-induced lesions

They are exophytic lesions caused by HPV, main- CO2 laser: promotes tissue evaporation with little ly types 6 and 11. They can be painful and/or itchy. In deleterious effect. The advantage is the aesthetic and women, they are located in the vulva, perineum, peri- functional result. When epithelial planes are not re- anal region, vagina and cervix. Less often they develop spected, hypochromia, retraction and alopecia of the in extragenital areas, such as nasal and oral mucosa.(13) treated area may occur. Disadvantages include the cost • How is the diagnosis of condyloma? of equipment and the need for professional training.(16) Clinical diagnosis; biopsy is only indicated in the Exeresis: lesions can be removed with a scalpel, following cases: scissors or even with electrocautery. There is a risk of -- Doubt in the diagnosis or suspicion of scarring and retraction.(14) neoplasia; Podophyllin, 5-fluorouracil and imiquimod should -- Lack of response to conventional treatment; not be used during pregnancy; trichloroacetic acid, la- -- When located in the transformation zone of ser or cryotherapy are good options. In case of mas- the cervix or anal canal; sive lesions, electrocoagulation or tangential exeresis -- Immunocompromised patients. (shaving) are alternatives. There is no indication of • What are the therapeutic modalities? cesarean delivery due to the presence of lesions, ex- They can be self-administered, outpatient or asso- cept in obstruction of the birth canal or bleeding.(13) ciated.(14) Recommendations are the same for immunocompromised patients, although closer monitoring is required. Self-administered treatments Therapeutic options should be changed if there is no Imiquimod cream 5%: triggers local cellular immune significant improvement after three to four weeks of response. Apply to the vulva at night, three times a treatment or if lesions remain after six to eight ses- week on alternate days, washing the area after six to sions.(13) The treatment of anogenital warts does not ten hours. It can be used for up to 16 weeks, with an eliminate the virus, so lesions can reappear. Infected average response in eight weeks.(15) Local reactions persons and their partners should return to service if such as erythema, itching and burning can occur and new lesions are identified. are due to the immune response. Systemic adverse effects are rare. Low-grade squamous Podophyllotoxin cream 0.15%: has antimitotic ac- intraepithelial lesion (LSIL) tion. Self-application twice a day for three consecutive What is LSIL? days, followed by a four-day pause, repeated weekly for The natural history of cervical cancer involves cellu- four weeks.(13) Its commercialization was discontinued lar changes that can lead to invasive carcinoma.(17) in Brazil. Purchase by direct import is available. Cytological screening is based on this sequence of 5-fluorouracil 5%: for vulvar lesions, biweekly ap- changes.(18) LSILs can progress to HSIL and invasive can- plication on lesions and removal after 4 hours is recom- cer or they can regress to a normal state.(19) mended. There may be erythema, burning and itching. LSIL corresponds to the cytological manifestation Treatment in the vagina with application of 2.5g week- of HPV infection and has a high potential for regres- ly or biweekly should be restricted to selected cases sion.(7) Atypical squamous cells of undetermined sig- with strict monitoring. Indiscriminate use in the past nificance (ASC-US), possibly non-neoplastic ones are has caused ulcers and vaginal adenosis.(16) characterized by the presence of insufficient cellular alterations for the diagnosis of intraepithelial lesions, Outpatient treatments although they are more significant than those found in 80%-90% Trichloroacetic Acid (TCA), solution: pro- inflammatory processes.(19) These two cytological cate- motes chemical coagulation of the condyloma protein gories have very similar risks of progressing to HSIL and content. Apply a small amount to lesions at weekly in- can be managed in a similar way.(20,21) tervals for eight to ten weeks. A burning sensation oc- On the other hand, the reliability of oncotic cytol- curs at the time of application. ogy is important, since the diagnosed LSIL can be asso- Podophyllin 10%-25% solution: vegetable res- ciated with the presence of histological HSIL, demon- in with cytotoxic action that inhibits cell metaphase. strating that most of these lesions already existed Apply weekly on each wart, washing after four hours; previously and did not correspond to the evolution of it is a good option in keratinized lesions. Use must be less severe lesions.(20-22) careful because it is neurotoxic and nephrotoxic. The advent of HPV DNA testing allowed risk strat- Cryotherapy: promotes thermo-induced cytolysis ification in patients with LSIL/ASC-US.(17,18) Detection of with liquid nitrogen. It is useful in keratinized lesions. high-risk HPV DNA in LSIL is associated with a higher Side effects include pain, erythema and blisters on the risk of progression to HSIL.(21-23) Studies have already spot.

242 FEBRASGO POSITION STATEMENT Oliveira AK, Jacyntho CM, Tso FK, Boldrini NA, Speck NM, Peixoto RA, et al. demonstrated the significant benefits of using the HPV High-grade squamous DNA testing in dubious cytologies.(20,21,23-25) intraepithelial lesion (HSIL) What is HSIL? How should we conduct LSIL? The importance of HSIL diagnosis is based on the Recommendations for patients with a cytopathological fact that 70-75% of women with this result will have diagnosis of LSIL/ASC-US range from immediate refer- diagnostic histopathological confirmation of 1-2% of ral to colposcopy, repeat cytology or HPV DNA test- invasive carcinoma.(26) The prevalence of HSIL in cyto- ing with referral to colposcopy if the result is positive. pathology was 0.26% of tests performed and 9.1% of (7,19,20-25) all tests changed in 2013 in Brazil.(26,27) The term HSIL Several protocols recommend similar approach- encompasses cervical intraepithelial neoplasia grades es for the cytopathological diagnosis of LSIL and 2 and 3 (CIN 2 and CIN 3) and according to the Lower ASC-US:(7,20) Anogenital Squamous Terminology (LAST), it can be • <25 years of age: repeat cytology in three years; stratified using the p16 immunohistochemical study, • 25-29 years of age: repeat the cytology in 12 especially in cases of CIN 2 below 30 years of age.(20,28) months; • ≥30 years of age: repeat the cytology in six months; How should we conduct HSIL? • Treat infectious processes or atrophy; The diagnosis of HSIL is made through cytology; referral • If the repeat cytology is negative in two consecu- to colposcopy is mandatory and cytological examination tive exams, return to routine screening; should not be repeated. Biopsy is indicated in the pres- • If one of subsequent cytologies is positive, per- ence of major or discrepant colposcopic findings.(7) form colposcopy; When there is cytocolposcopic agreement (HSIL • Indicate colposcopy for immunocompromised cytology and major findings) in non-pregnant patients women with cytopathological examination show- over 25 years of age with visible transformation zone ing LSIL. (types 1 or 2), without suspicion of invasion or glandular In a recent protocol (2019), the(American Society disease, the “See-and-Treat” procedure is indicated. This for Colposcopy and Cervical Pathology (ASCCP) recom- method avoids unnecessary returns and reduces costs.(7) mended that patients under 25 years of age presenting When the lesion is not fully visible, try to expose LSIL cytology, HPV-positive ASC-US or ASC-US without the SCJ with a good examination of the vagina to ex- HPV DNA test should repeat isolated cytology one and clude the presence of lesions and indicate excision of two years after the initial abnormal result.(21) the type 3 transformation zone (EZT) with a length of In patients with ASC-US and negative HPV DNA test, 1.5-2.5 cm.(7) The high-risk HPV DNA testing can be repeat the cytology in three years. After two negative cy- used in the disagreement of methods, with a recog- tological tests, return to routine age-based screening.(20,21) nized high negative predictive value.(10) For patients ≥ 25 years of age, if the initial colpos- The main objective of excisional treatment is to copy is compatible with low grade (histological LSIL/ rule out stromal invasion and assess the state of the ASC-US/cytological LSIL), repeat cytology and colpos- surgical margins.(29,30) Therefore, excision should be copy in one year. In addition, risk estimates should be preferred over ablation. Treatment prevents progres- used: (20) sion to cancer. Destructive treatment is accepted in • HPV DNA standard; selected cases of young patients with a small lesion, • Patient’s age; ectocervix fully visualized and without suspected inva- • Immunosuppression; sive disease.(20) Pregnant women with HSIL should be • Changed results of previous cytology and/or biop- referred to colposcopy to rule out invasion and redo sy.(20) the exams three months after delivery. For patients aged 25 years or older with histolo- Post-treatment follow-up should be done with the gy of LSIL diagnosed in consecutive visits for up to two HPV-based test (HPV DNA or co-test) six months after years, observation is preferred, but treatment is ac- the procedure and then annually, until there are three ceptable. If treatment is chosen and SCJ and limits of consecutive negative tests. If one of the tests is posi- lesions are completely displayed in colposcopic exam- tive, colposcopy is indicated. If the margins are posi- ination, excision or ablation treatments are acceptable. tive with HSIL (CIN 2+), patient is older than 25 years Considering that the biological behavior of smears cor- and formed offspring, repeated excision or observation responding to ASC-US/HPV + and LSIL are similar, the are acceptable. If recurrent histological HSIL (CIN 2+) approach can be the same.(5) Since regression rates are is identified and another transformation zone excision high and the diagnosis of HSIL in these women is un- does not present technical conditions or is not desired, common, continued observation is recommended for hysterectomy is recommended.(20) Another option is a two-year period.(20) to follow up with semiannual cytology and colposcopy

FEBRASGO POSITION STATEMENT 243 HPV infection - Screening, diagnosis and management of HPV-induced lesions

7. Ministério da Saúde. Instituto Nacional de Câncer José Alencar for two years and annual cytology for five years in the Gomes da Silva. Diretrizes brasileiras para rastreamento do case of compromised margins, when HPV DNA testing câncer do colo do útero [Internet]. 2a ed. Rio de Janeiro: is unavailable. (7) Continuous three-year surveillance INCA; 2016 [cited 2019 Nov 18]. Available from: https://www. should be recommended for 25 years, even if patient inca.gov.br/sites/ufu.sti.inca.local/files//media/document// diretrizesparaorastreamentodocancerdocolodoutero_2016_ is over 65 years of age, as the risk of cancer remains corrigido.pdf twice as high and seems to increase after 50 years of 8. Fontham ETH, Wolf AMD, Church TR, Etzioni R, Flowers CR, Herzig (20) age. Immunosuppressed women are treated like im- A, et al. Cervical cancer screening for individuals at average risk: munocompetent women, with annual post-treatment 2020 guideline update from the American Cancer Society. CA follow-up throughout their lives, due to the higher risk Cancer J Clin. 2020;70(5):321-46. doi: 10.3322/caac.21628 of recurrences. 9. Chrysostomou AC, Stylianou DC, Constantinidou A, Kostrikis LG. Cervical cancer screening Programs in Europe: The Final considerations transition towards HPV vaccination and population-based HPV testing. Viruses. 2018;10(12):729. doi: 10.3390/v10120729 HPV infection is universal in the female genital tract, and can compromise both skin and mucous mem- 10. Zeferino LC, Bastos JB, Vale DBAP, Zanine RM, Furtado de Melo YLM, Pereira Primo WQS, et al. Guidelines for HPV-DNA testing branes, causing a series of important nosological for cervical cancer screening in Brazil. Rev Bras Ginecol Obstet. manifestations, including genital warts, intraepithelial 2018;40(6):360-8. doi: 10.1055/s-0038-1657754 neoplasms and cancers. Broad coverage of the popu- 11. Speck NMG, Carvalho JP. Dossiê de estratégias do lation through organized screening and vaccination rastreamento do câncer de colo uterino no Brasil. São Paulo: could substantially decrease HPV-induced diseases. FEBRASGO; 2018 [cited 2019 Dec 15]. Available from: https:// The World Health Organization issued a call in 2018 www.febrasgo.org.br/pt/noticias/item/download/167_ d8aac29103a80d079e7031cf127c72d6#:~:text=Baseado%20 for the elimination of cervical cancer as a serious public em%20revis%C3%A3o%20extensa%20de,o%20 health problem (Cervical Cancer Elimination Modeling rastreamento%20baseado%20em%20citologia Consortium - CCEMC): primary prevention strategies, 12. Federação Brasileira das Associações de Ginecologia e such as the HPV vaccine, and secondary prevention Obstetrícia (FEBRASGO). Rastreamento do câncer de colo strategies, such as screening, should be strength- útero no Brasil [Internet]. 2019 [cited 2020 Dec 15]. Available ened in the coming years. By 2030, the goals are: 90% from: https://www.febrasgo.org.br/pt/noticias/item/551- rastreamento-do-cancer-de-colo-uterino-no-brasil?highlight= of girls vaccinated by the age of 15, 70% of women WyJkb3NzaWUiXQ== screened with a high-effectiveness test at 35 and 45 13. Ministerio da Saude. Secretaria de Vigilância em Saúde. years of age; 90% of precursor lesions and invasive can- Departamento de Doenças de Condições Crônicas e Infecções cer treated. Febrasgo, through its National Specialized Sexualmente Transmissíveis. Protocolo clinico e diretrizes Commissions on the Lower Genital Tract, Oncology and terapeuticas para atenço integral às pessoas com Infecçes Vaccines endorses and supports the call. Sexualmente Transmissiveis (IST). Brasilia (DF): Ministerio da Saude; 2020. References 14. Centers for Disease Control and Prevention (CDC). Sexually 1. Hirth J. Disparities in HPV vaccination rates and HPV transmitted diseases treatment guidelines [Internet]. 2015 prevalence in the United States: a review of the literature. [cited 2019 Oct 10]. Available from: https://www.cdc.gov/std/ Hum Vaccin Immmunother. 2019;15(1):146-55. doi: tg2015/default.htm 10.1080/21645515.2018.1512453 15. Grillo-Ardila CF, Angel-Muller E, Salazar-Díaz LC, Gaitán HG, 2. Brianti P, De Flammineis E, Mercuri SR. Review of HPV-related Ruiz-Parra AI, Lethaby A. Imiquimod for anogenital warts in diseases and cancers. New Microbiol. 2017;40(2):80-5. non-immunocompromised adults. Cochrane Database Syst Rev. 2014;(11):CD010389. doi: 10.1002/14651858.CD010389. 3. Gultekin M, Karaca MZ, Kucukyildiz I, Dundar S, Keskinkilic pub2 B, Turkyilmaz M. Mega HPV laboratories for cervical cancer control: challenges and recommendations from a case study 16. Speck NMG, Ribalta JCL, Focchi J, Costa RRL, Kesselring F, Freitas VG. Low-dose 5-fluoruracil adjuvant in laser therapy of Turkey. Papillomavirus Res. 2019;7:118-22. doi: 10.1016/j. pvr.2019.03.002 for HPV lesions in immunosuppressed patients and cases of difficult control. Eur J Gynaecol Oncol. 2004;25(5):597-9. 4. Ministério da Saúde. Instituto Nacional de Câncer. Tipos de câncer: câncer do colo do útero [Internet]. 2020 [cited 2020 17. Meijer CJ, van den Brule AJ, Snijders PJ, Helmerhorst T, Kenemans Oct 15]. Available from: https://www.inca.gov.br/tipos-de- P, Walboomers JM. Detection of human papillomavirus in cancer/cancer-do-colo-do-utero cervical scrapes by the polymerase chain reaction in relation to cytology: possible implications for cervical cancer screening. 5. Possati-Resende JC, Vazquez FL, Pantano NP, Fregnani JHTG, IARC Sci Publ. 1992;(119):271-81. Mauad EC, Longatto-Filho A. Implementation of a cervical cancer screening strategy using HPV self-sampling for women 18. Mitchell MF, Hittelman WN, Hong WK, Lotan R, Schottenfeld living in rural areas. Acta Cytol. 2019;64(1-2):7-15. doi: D. The natural history of cervical intraepithelial neoplasia: 10.1159/000493333 an argument for intermediate endpoint biomarkers. Cancer Epidemiol Biomarkers Prev. 1994;3(7):619-26. 6. Jansen EEL, Zielonke N, Gini A, Anttila A, Segnan N, Vokó Z, et al. Effect of organised cervical cancer screening on cervical 19. Holowaty P, Miller AB, Rohan T, To T. Natural history of dysplasia cancer mortality in Europe: a systematic review. Eur J Cancer. of the uterine cervix. J Natl Cancer Inst. 1999;91(3):252-8. doi: 2020;127:207-23. doi: 10.1016/j.ejca.2019.12.013 10.1093/jnci/91.3.252

244 FEBRASGO POSITION STATEMENT Oliveira AK, Jacyntho CM, Tso FK, Boldrini NA, Speck NM, Peixoto RA, et al.

20. Perkins RB, Guido RS, Castle PE, Chelmow D, Einstein MH, Garcia F, et al. ASCCP risk-based management consensus Ana Katherine da Silveira Gonçalves de Oliveira1 guidelines for abnormal cervical cancer screening tests and 1- Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil. cancer precursors. J Low Genit Tract Dis. 2020;24(2):102-31. doi: 10.1097/LGT.0000000000000525 Claudia Marcia de Azevedo Jacyntho2 21. Rufail M, Lew M, Pang J, Jing X, Heider A, Cantley RL. Low-grade 2 - Hospital Federal dos Servidores do Estado do Rio de Janeiro, squamous intraepithelial lesion on Papanicolaou test: follow- Rio de Janeiro, RJ, Brazil. up rates and stratification of risk for high-grade squamous Fernanda Kesselring Tso3 intraepithelial lesion. J Am Soc Cytopathol. 2020;9(4):258-65. 3 - Escola Paulista de Medicina, Universidade Federal de São doi: 10.1016/j.jasc.2020.02.003 Paulo, São Paulo, SP, Brazil. 22. Queiroz Filho J, Freitas JOC, Pessoa DC, Eleutério Júnior 4 J, Giraldo PC, Gonçalves AK. Assessment of 100% rapid Neide Aparecida Tosato Boldrini review as an effective tool for internal quality control in 4 - Universidade Federal do Espírito Santo, Vitória, ES, Brazil.

cytopathological services. Acta Cytol. 2017;61(3):207-13. doi: 5 10.1159/000475833 Neila Maria de Góis Speck 5 - Escola Paulista de Medicina, Universidade Federal de São 23. Federação Brasileira das Associações de Ginecologia e Paulo, São Paulo, SP, Brazil. Obstetrícia. Rastreio, diagnóstico e tratamento do câncer de colo de útero. São Paulo: FEBRASGO; 2017. Raquel Autran Coelho Peixoto6 24. Wong OGW, Tsun OKL, Tsui EY, Chow JNK, Ip PPC, Cheung 6 - Universidade Federal do Ceará, Fortaleza, CE, Brazil. ANY. HPV genotyping and E6/E7 transcript assays for cervical Rita Maira Zanine7 lesion detection in an Asian screening population-Cobas and 7 - Universidade Federal do Paraná, Curitiba, PR, Brazil. Aptima HPV tests. J Clin Virol. 2018;109:13-8. doi: 10.1016/j. jcv.2018.10.004 Yara Lucia Mendes Furtado de Melo8,9 25. ASCUS-LSIL Traige Study (ALTS) Group. A randomized trial 8 - Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, on the management of low-grade squamous intraepithelial Brazil. lesion cytology interpretations. Am J Obstet Gynecol. 9 - Universidade Federal do Estado do Rio de Janeiro, Rio de 2003;188(6):1393-400. doi: 10.1067/mob.2003.462 Janeiro, RJ, Brazil. 26. Massad LS, Collins YC, Meyer PM. Biopsy correlates of abnormal Conflict of interest: none to declare. cervical cytology classified using the Bethesda System. Gynecol National Specialty Commission for Lower Genital Tract of the Oncol. 2001;82(3):516-22. doi: 10.1006/gyno.2001.6323 Brazilian Federation of Gynecology and Obstetrics Associations 27. Ministério da Saúde. Departamento de Informática do SUS (FEBRASGO) (Datasus). Sistema de Informação do Câncer do Colo do Útero (SISCOLO) [Internet]. 2013 [cited 2018 Aug 13]. Available President: Neila Maria de Gois Speck from: http://w3.datasus.gov.br/siscam/index.php 28. Castle PE, Adcock R, Cuzick J, Wentzensen N, Torrez- Vice-President: Martinez NE, Torres SM, et al. Relationships of p16 Márcia Fuzaro Terra Cardial immunohistochemistry and other biomarkers with diagnoses Secretary: of cervical abnormalities: implications for LAST terminology. Mila de Moura Behar Pontremoli Salcedo Arch Pathol Lab Med. 2020;144(6):725-34. doi: 10.5858/ arpa.2019-0241-OA Members: Adriana Bittencourt Campaner 29. Chen JY, Wang ZL, Wang ZY, Yang XS. The risk factors of Ana Katherine da Silveira Goncalves residual lesions and recurrence of the high-grade of cervical Cláudia Márcia de Azevedo Jacyntho intraepithelial lesions (HSIL) patients with positive-margin Fernanda Kesselring Tso after conization. Medicine (Baltimore). 2018;97(41):e12792. Gustavo Rubino de Azevedo Fochi doi: 10.1097/MD.0000000000012792 Isabel Cristina Chulvis do Val Guimarães 30. Brisson M, Kim JJ, Canfell K, Drolet M, Gingras G, Burger EA, José Humberto Belmino Chaves et al. Impact of HPV vaccination and cervical screening on Neide Aparecida Tosato Boldrini cervical cancer elimination: a comparative modelling analysis Raquel Autran Coelho Peixoto in 78 low-income and lower-middle-income countries. Rita Maira Zanine Lancet. 2020;395(10224):575-90. doi: 10.1016/S0140- Silvana Maria Quintana 6736(20)30068-4 Yara Lucia Mendes Furtado de Melo

FEBRASGO POSITION STATEMENT 245