RBGO Eissn 1806-9339 Gynecology & Obstetrics

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

Revista Brasileira de Ginecologia e Obstetrícia Number 2 • Volume 43 • Pages 81–154 • February 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 2/2021 RBGO Gynecology and Obstetrics Revista Brasileira de Ginecologia e Obstetrícia

Editorial

81 We have Vaccine for COVID-19! What to Recommend for Pregnant Women? Silvana Maria Quintana

Original Articles

Obstetrics

84 Gestational Risk as a Determining Factor for Cesarean Section according to the Robson Classiﬁ cation Groups Karina Biaggio Soares, Vanessa Cristina Grolli Klein, José Antônio Reis Ferreira de Lima, Lucas Gadenz, Larissa Emile Paulo, and Cristine Kolling Konopka

91 Factors Associated with Exclusive Breastfeeding in a Maternity Hospital Reference in Humanized Birth Gabriela Pinheiro Brandt, Alan Messala A. Britto, Camila Carla De Paula Leite, and Luciana Garangau Marin

High Risk Pregnancy

97 Temporal Trend of Near Miss and its Regional Variations in Brazil from 2010 to 2018 Maria Carolina Wensing Herdt, Flávio Ricardo Liberal Magajewski, Andressa Linzmeyer, Rafaela Rodolfo Tomazzoni, Nicole Pereira Domingues, and Milla Pereira Domingues

107 Gestational Diabetes Mellitus and Obesity are Related to Persistent Hyperglycemia in the Postpartum Period Patricia Moretti Rehder, Anderson Borovac-Pinheiro, Raquel Oliveira Mena Barreto de Araujo, Juliana Alves Pereira Matiuck Diniz, Nathalia Lonardoni Crozatti Ferreira, Ana Claudia Rolim Branco, Aline de Fatima Dias, and Belmiro Gonçalves Pereira

113 Risk Factors for Postpartum Hemorrhage and its Severe Forms with Blood Loss Evaluated Objectively – A Prospective Cohort Study Anderson Borovac-Pinheiro, Filipe Moraes Ribeiro, and Rodolfo Carvalho Pacagnella

Basic And Translational Science /Endometriosis

119 Follicular Fluid from Infertile Women with Mild Endometriosis Impairs In Vitro Bovine Embryo Development: Potential Role of Oxidative Stress Vanessa Silvestre Innocenti Giorgi, Rui Alberto Ferriani, and Paula Andrea Navarro

Menopause

126 The Eﬀ ectiveness of Melissa Oﬃ cinalis L. versus Citalopram on Quality of Life of Menopausal Women with Sleep Disorder: A Randomized Double-Blind Clinical Trial Mahboobeh Shirazi, Mohamad Naser Jalalian, Masoumeh Abed, and Marjan Ghaemi

Thieme Revinter Publicações Ltda online www.thieme-connect.com/products RBGO Gynecology and Obstetrics Volume 43, Number 2/2021

Urogynecology

131 Eﬀ ect of Preoperative Urodynamic Study on Urinary Outcomes after Transobturator Sling Pedro Rincon Cintra da Cruz, Aderivaldo Cabral Dias Filho, Gabriel Nardi Furtado, Rhaniellen Silva Ferreira, and Ceres Nunes Resende

Oncology

137 Malignant Uterine Neoplasms Attended at a Brazilian Regional Hospital: 16-years Proﬁ le and Time Elapsed for Diagnosis and Treatment Elaine Cristina Candido, Nelio Neves Veiga Junior, Monique Possari Minari, Maria Carolina Szymanski Toledo, Daniela Angerame Yela, and Julio Cesar Teixeira

Case Report

145 Transmediastinal Gunshot Wound in a Pregnant Patient with Stable Hemodynamics Ozhan Ozdemır and Cemal Resat Atalay

Letter to the Editor

148 Management of Ectopic Pregnancy and the COVID-19 Pandemic Rujittika Mungmunpuntipantip and Viroj Wiwanitkit

Febrasgo Statement

150 Vaccination in women with cancer Nilma Antas Neves, Júlio César Teixeira, André Luis Ferreira Santos, Fabíola Zoppas Fridman, and Cecília Maria Roteli-Martins

Complementary material is available online at www.rbgo.org.br.

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Editorial We have Vaccine for COVID-19! What to Recommend for Pregnant Women? Silvana Maria Quintana1

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

Rev Bras Ginecol Obstet 2021;43(2):81–83.

On January 17, 2021, two vaccines were approved by ANVISA quality that protect against 22 diseases, in addition to for emergency use to help combat COVID-19: Coronavac and other immunobiologicals. Covishield/Oxford. The first vaccine is composed of inacti- Vaccines are substances that aim to induce specificim- vated (killed) viruses, was produced by the Chinese company munity by preventing invasion or eliminating pathogens Sinovac and in Brazil, will be produced by the Butantã circulating in the host or neutralizing microbial toxins, but Institute (São Paulo). The second is an adenovirus non- without causing disease in the recipient. It is very important replicating viral vector vaccine and was produced by the to know the composition of vaccines, especially to indicate pharmaceutical company Serum Institute of India in part- their use in the pregnancy-puerperal cycle. Vaccines con- nership with AstraZeneca/Oxford University. In Brazil, it will taining live (attenuated or modified) or inactivated (killed) be produced by the Oswaldo Cruz Foundation (FIOCRUZ), Rio antigen are considered safe techniques and have been known de Janeiro. for more than 80 years. Recently, thanks to the evolution of In view of the worrying and prolonged scenario of the scientific research, subunit or recombinant vaccines, vac- COVID-19 pandemic, it is essential that Brazilian scientific cines using viral vectors, replicating or non-replicating, and societies share scientific knowledge free of political ideolo- nucleic acid vaccines such as messenger RNA (mRNA) have gies with their peers and position themselves based on the been developed. available evidence in relation to vaccines against COVID-19. Vaccines prepared with attenuated antigens contain the In this context, gynecologists and obstetricians have living but weakened form of the antigen, promoting a robust requested guidelines on the indication of these vaccines in immune response with a prolonged duration, sometimes for pregnant, puerperal and nursing women. I will highlight the rest of life. The main representatives of this group are some points I consider important to support my opinion with BCG, chickenpox, rubella, mumps, measles and yellow fever. which I will conclude this editorial. As a general rule, they are not recommended during preg- Vaccines occupy a prominent position among the pil- nancy. Inactivated vaccines consist of dead antigens after lars of public health and allow both the eradication of their exposure to chemical and physical agents and induce a diseases such as smallpox, and a significant reduction in less lasting immune response, requiring more doses to diseases such as polio, rubella, tetanus and whooping induce prolonged protection. Vaccines for influenza (flu), cough,whichusedtobecommoninthepast.1 Two hepatitis A and rabies stand out in this group. All vaccines in programs offered by the Brazilian Ministry of Health to this group can be used by pregnant women, but influenza the population through the National Health Service (Bra- vaccines are expressly recommended during pregnancy and zilian SUS) should be a reason for pride for all Brazilians: the postpartum period.2 Toxoid vaccines contain inactivated the STI/AIDS program and the National Immunization bacterial toxin and lead to weak immunization with need for Program, active since 1973. The National Immunization a booster dose after a few years, such as tetanus and Program of the Ministry of Health offers free of charge to diphtheria vaccines, both recommended during the preg- the Brazilian population a set of vaccines of excellent nancy-puerperal cycle. Recombinant vaccines are produced

Address for correspondence © 2021. Federação Brasileira de DOI https://doi.org/ Silvana Maria Quintana, Av. Ginecologia e Obstetrícia. All rights 10.1055/s-0041-1726090. Bandeirantes, 3900, 14049-900, reserved. ISSN 0100-7203. Ribeirão Preto, SP, Brazil This is an open access article published by (e-mail: [email protected]). Thieme under the terms of the 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 82 Editorial

by genetic engineering techniques in which other agents are from the obstetric point of view, higher rates of preterm birth – programmed to produce the desired antigenic fraction by and operative deliveries were observed.3 5 In Brazil, data stimulating a very effective immune response. Vaccines released by the Ministry of Health showed that SARS CoV-2 against hepatitis B and acellular pertussis are recombinant infection was the main cause of severe acute respiratory and recommended for application during pregnancy and the syndrome (SARS) in pregnant women in the third trimester puerperal period. Viral vector vaccines insert a modified and the mortality rate, especially in cases of concomitant virus protein into another genetically weakened virus that is comorbidities such as diabetes, hypertension and obesity, unable to replicate in the human body. When this vaccine is was alarmingly high. According to a study by FIOCRUZ and a injected into the body, the immune system promotes an group of Brazilian researchers, Brazil is the country with the immune response to this protein that was hidden within the highest number of deaths by COVID-19 in women in the vector, leading to the production of antibodies and other pregnancy-puerperal cycle in the world.6,7 Therefore, national defense cells capable of protecting the individual. Finally, and international data available so far allow to state that nucleic acid vaccines such as messenger RNA (mRNA) contain women during the pregnancy-puerperal cycle are part of a molecule with the SARS CoV-2 genetic code with instruc- the group at higher risk for complications from COVID-19, tions for cytoplasm ribosomes to initiate the synthesis of maternal death and unfavorable obstetric outcomes. In view of specific proteins of the surface of this virus. When these these results, in January 2021, the Ministryof Health released a proteins are exposed to the immune system, they will be technical standard8 recommending the withdrawal of preg- identified as an antigen, thereby triggering the immune nant and postpartum women from face-to-face work given the response with the production of antibodies. There are still important risks of COVID-19 to their health, reaffirming that no controlled studies on the use of these vaccines in pregnant they are a risk group for this infection. women. The National Immunization Program of the Ministry Throughout these 11 months of the pandemic, the world of Health recommends that pregnant women routinely population has been experiencing a major health crisis. We receive three vaccines to protect against five diseases: Hep- are facing a serious epidemiological situation with no pros- atitis B, DPT (diphtheria, pertussis, tetanus) and influenza. If pect of a short-term resolution. When women in the preg- needed, other vaccination schedules should be individual- nancy-puerperal cycle acquire SARS CoV-2 infection, they ized and discussed with the pregnant/puerperal woman. are at a higher risk for progressing to severe conditions and After the authorization for emergency use of vaccines for death, and this is even more relevant if they have comorbid- COVID-19 by ANVISA, at this time for priority groups such as ities. The medications used to treat severe cases of this health professionals, it is natural to question whether we infection have not been tested for efficacy and safety in should/can recommend these vaccines for women in the this group of women. In view of this scenario, the arrival pregnancy-puerperal cycle and/or breastfeeding their chil- of vaccines against COVID-19 brought hope of controlling the dren. Although the published clinical trials on vaccines against situation, but given the lack of information on efficacy and COVID-19 indicate safety and efficacy in the populations safety in pregnant and puerperal women, doubts arise evaluated, there is no data on the immunogenicity, efficacy regarding its recommendation. In this context, International or safety of these vaccines in women in the pregnancy- Societies such as the American College of Obstetrics and puerperal cycle, as no clinical trial for these vaccines included Gynecology (ACOG),9 the Society of Maternal-Fetal Medicine this population. However, I emphasize that the Coronavac (SMFM)10 and the Royal College11 mentioned the need to vaccine contains inactivated (killed) viruses, a technique include pregnant and lactating women in clinical trials, and with proven safety during the pregnancy-puerperal cycle for recommended that vaccines against COVID-19 should not be several years. In addition, the official package insert of this denied to this group of women, especially if they are health vaccine classifies the product as class B for use during preg- professionals or have comorbidities. Note that the mRNA nancy, that is, there are no studies in pregnant women, but vaccine was the type released in these countries. In Brazil, studies in animals have not shown fetal damage. The other the FEBRASGO Vaccine Commission12 released a note that vaccine approved in Brazil, Covishield is a recombinant vaccine pregnant and lactating women belonging to the risk group that uses chimpanzee adenovirus non-replicating viral vector may receive the vaccine after assessing the risks and benefits technology. Although it is a relatively recent technique, in in a decision shared between the woman and her doctor. theory, the vaccine is safe for use during pregnancy. Considering the increase in maternal morbidity and mor- Pregnant women experience important adaptations of tality associated with COVID-19 and previous experience their organism to provide adequate nutrition and oxygenation with inactivated (killed) virus vaccines demonstrating the to the fetus, thus their predisposition to viral infections during safety and efficacy of these immunobiologicals in pregnant this period. Studies comparing the behavior of COVID-19 in women, the concern to indicate this vaccine due to the lack of pregnant women with non-pregnant women showed that data on efficacy and safety is not a justification for denying pregnant women who acquired SARS CoV-2 and developed the vaccine to pregnant and puerperal women, especially symptoms of the infection were at a higher risk for: requiring those working as health professionals or who have comor- hospitalization; developing severe conditions with admission bidities. In fact, this group should be considered a priority to to intensive care units (ICU); progressing to respiratory failure receive vaccines against COVID-19. and requiring invasive ventilation (orotracheal intubation); Obviously, information about the lack of data on efficacy and and consequently, were at greater risk of death. In addition, safety, and about the performance of vaccines against COVID-19

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. Editorial 83 in populations already studied should be clearly exposed to study of the impact of influenza during pregnancy among women pregnant and puerperal women. The pregnant-puerperal wom- in middle-income countries. Reprod Health. 2018;15(01):159. an’s decision to be vaccinated must be taken after receiving this Doi: 10.1186/s12978-018-0600-x 3 Allotey J, Stallings E, Bonet M, Yap M, Chatterjee S, Kew T, et al; for information and considering the risks of SARS-CoV-2 infection PregCOV-19 Living Systematic Review Consortium. Clinical man- for pregnant women, their individual risk for COVID-19 infec- ifestations, risk factors, and maternal and perinatal outcomes of tion and progression to serious illness (comorbidities, active coronavirus disease 2019 in pregnancy: living systematic review health professional), and the vaccine safety. After these consid- and meta-analysis. BMJ. 2020;370:m3320. Doi: 10.1136/bmj. erations, if the pregnant woman decides not to be vaccinated, m3320 her decision must be respected. The health professional must 4 Zambrano LD, Ellington S, Strid P, Galang RR, Oduyebo T, Tong VT, et al; CDC COVID-19 Response Pregnancy and Infant Linked address the issue of vaccination in the prenatal consultation, Outcomes Team. Update: characteristics of symptomatic women including the vaccine against COVID-19 in addition to all of reproductive age with laboratory-confirmed SARS-CoV-2 in- vaccines recommended during pregnancy and the puerperal fection by pregnancy status - United States, January 22-October 3, period, expose evidence-based information, assess the pregnant 2020. MMWR Morb Mortal Wkly Rep. 2020;69(44):1641–1647. woman’s risk and respect the woman’s decision. Doi: 10.15585/mmwr.mm6944e3 5 Di Mascio D, Sen C, Saccone G, Galindo A, Grünebaum A, Yoshi- For puerperal and lactating women, who were also ex- matsu J, et al. Risk factors associated with adverse fetal outcomes cluded from clinical trials, there are no data on the excretion in pregnancies affected by Coronavirus disease 2019 (COVID-19): of this substance in breast milk, but obviously, if puerperal a secondary analysis of the WAPM study on COVID-19. J Perinat women infected with SARS CoV-2 are allowed to breastfeed, Med. 2020;49(01):111–115. Doi: 10.1515/jpm-2020-0539 that is, if the disease is compatible with breastfeeding, 6 Nakamura-Pereira M, Betina Andreucci C, de Oliveira Menezes M, vaccination should be directed at these women.13 Knobel R, Takemoto MLS. Worldwide maternal deaths due to COVID-19: A brief review. Int J Gynaecol Obstet. 2020;151(01): Finally, it is a fact that pregnant women are at a higher risk 148–150. Doi: 10.1002/ijgo.13328 of progressing to severe COVID-19 and that being a health 7 Takemoto MLS, Menezes MO, Andreucci CB, Nakamura&Pereira professional or having comorbidities such as diabetes, obe- M, Amorim MMR, Katz L, et al. The tragedy of COVID-19 in Brazil: sity, hypertension can add risk to the lives of these women. In 124 maternal deaths and counting. Int J Gynaecol Obstet. 2020; addition, a significant number of pregnant women will 151(01):154–156. Doi: 10.1002/ijgo.13300 potentially be eligible to receive the vaccine against 8 do Trabalho MPProcuradoria Geral do Trabalho Nota Técnica 01/2021 do GT Nacional COVID-19. Nota Técnica sobre a proteção COVID-19 before the development of clinical trials to define à saúde e igualdade de oportunidades no trabalho para trabalha- fi ef cacy and safety. We could lose many lives unless we adopt doras gestantes em face da segunda onda da pandemia do COVID a more pragmatic position. I argue that pregnant women 19 [Internet]. 2021 [cited 2021 Jan 12]. Available from: https:// who have comorbidities or continue working as health www.conjur.com.br/dl/nota-tecnica-gestante1.pdf professionals should be part of the priority group to receive 9 The American College of Obstetricians and Gynecologists. Vacci- the vaccine against COVID-19. The final decision whether or nating pregnant and lactating patients against covid-19 [Inter- net]. 2020 [cited 2020 Dec 27]. Available from: https://www. not to receive the vaccine will be made by the woman after acog.org/clinical/clinical-guidance/practice-advisory/articles/ receiving the appropriate information. This same principle 2020/12/vaccinating-pregnant-and-lactating-patients-against- applies with even greater emphasis to puerperal and lactat- covid-19 ing women. Regardless of the decision to vaccinate, antenatal 10 Society for Maternal-Fetal Medicine. Society for Maternal-Fetal care must be maintained and all pregnant women should Medicine (SMFM) Statement: SARS-CoV-2 vaccination in pregnancy [Internet]. 2020 [cited 2020 Dec 27]. Available from: receive guidance on infection prevention with emphasis on https://s3.amazonaws.com/cdn.smfm.org/media/2591/ hand hygiene, social distance and wearing a mask. SMFM_Vaccine_Statement_12-1-20_(final).pdf 11 Royal College of Obstetricians and Gynaecologists. Updated ad- Conflicts to Interest vice on COVID-19 vaccination in pregnancy and women who are None to declare. breastfeeding [Internet]. 2020 [cited 2021 Jan 12]. Available from: https://www.rcog.org.uk/en/news/updated-advice-on-covid-19- vaccination-in-pregnancy-and-women-who-are-breastfeeding/ References 12 Federação Brasileira das Associações de Ginecologia e Obstetrícia 1 Guimarães R. Anti-Covid vaccines: a look from the Collective (FEBRASGO) Importância da vacinação materna [Internet]. 2020 Health. Cien Saude Colet. 2020;25(09):3579–3585. Doi: [cited 2020 Dec 21]. Available from: https://www.febrasgo.org.- 10.1590/1413-81232020259.24542020 br/pt/campanhas/campanha-gestante-consciente/item/1130- 2 Dawood FS, Hunt D, Patel A, Kittikraisak W, Tinoco Y, Kurhe K, importancia-da-vacinacao-materna et al; Pregnancy and Influenza Multinational Epidemiologic 13 COVID-19 vaccine [Internet]. 2021 [cited 2021 Jan 12]. (PRIME) Study Working GroupÃ The Pregnancy and Influenza Available from: http://www.e-lactancia.org/breastfeeding/covid- Multinational Epidemiologic (PRIME) study: a prospective cohort 19-vaccine/product/

Gestational Risk as a Determining Factor for Cesarean Section according to the Robson Classiﬁcation Groups Risco gestacional como fator determinante para cesariana de acordo com os grupos da Classiﬁcação Robson Karina Biaggio Soares1 Vanessa Cristina Grolli Klein1 José Antônio Reis Ferreira de Lima1 Lucas Gadenz1 Larissa Emile Paulo1 Cristine Kolling Konopka1

1 Department of Gynecology and Obstetrics, Universidade Federal de Address for correspondence Cristine Kolling Konopka, MD, PhD, Av. Santa Maria, Santa Maria, RS, Brazil Roraima, 1000, Cidade Universitária, Camobi, Santa Maria, RS, 97105-900, Brazil (e-mail: [email protected]). Rev Bras Ginecol Obstet 2021;43(2):84–90.

Abstract Objective To analyze and compare the frequency of cesarean sections and vaginal deliveries through the Robson Classification in pregnant women attended at a tertiary hospital in two different periods. Methods Cross-sectional, retrospective study of birth records, comprising 4,010 women, conducted from January 2014 to December 2015 in the only public regional referral hospital for the care of high- risk pregnancies, located in Southern Brazil. Results The overall cesarean section rate reached 57.5% and the main indication was the existence of a previous uterine cesarean scar. Based on the Robson Classification, Keywords groups 5 (26.3%) and 10 (17.4%) were the most frequent ones. In 2015, there was a ► pregnancy significant increase in the frequency of groups 1 and 3 (p < 0.001), when compared ► high-risk pregnancy with the previous year, resulting in an increase in the number of vaginal deliveries ► parturition (p < 0.0001) and a reduction in cesarean section rates. ► cesarean section Conclusion The Robson Classification proved to be a useful tool to identify the profile ► robson classification of parturients and the groups with the highest risk of cesarean sections in different periods in the same service. Thus, it allows monitoring in a dynamic way the indications and delivery routes and developing actions to reduce cesarean rates according to the characteristics of the pregnant women attended.

Resumo Objetivo Analisar e comparar a frequência de partos cesáreos e vaginais através da classificação de Robson em gestantes atendidas em um hospital terciário em dois períodos distintos. Métodos Estudo transversal retrospectivo de registros de nascimento, compreen- dendo 4.010 mulheres, realizado de janeiro de 2014 a dezembro de 2015 no único hospital público de referência regional para atendimento de gestações de alto risco, localizado no sul do Brasil. A via de parto foi avaliada e as mulheres foram classificadas de acordo com a Classificação de Robson.

received DOI https://doi.org/ © 2021. Federação Brasileira das Associações de Ginecologia e January 8, 2020 10.1055/s-0040-1718446. Obstetrícia. All rights reserved. accepted ISSN 0100-7203. This is an open access article published by Thieme under the terms of the August 13, 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 Gestational Risk as a Determining Factor for Cesarean Section Soares et al. 85

Resultados A taxa geral de cesariana foi de 57,5% e a principal indicação foi a existência de cicatriz uterina por cesariana prévia. Quando aplicada a Classificação de Robson, os grupos mais frequentes foram o 5 (26,3%) e o 10 (17,4%). No ano de 2015, ocorreu um aumento significativo da frequência dos grupos 1 e 3 (p < 0,001), quando Palavras-chave comparado ao ano anterior, resultando em aumento do número de partos vaginais ► gestação (p < 0,0001) e redução das taxas de cesariana. ► gravidez de risco Conclusão AClassificaçãodeRobsonmostraserumaferramentaútilparaidentificar ► trabalho de parto operfil das parturientes e os grupos com maior risco de cesariana em diferentes ► cesárea períodos em um mesmo serviço. Desta forma, permite monitorar de forma dinâmica as ► classificação de indicações e vias de parto e desenvolver ações para redução das taxas de cesariana robson conforme as características das gestantes atendidas.

Introduction hand, if one takes into consideration only childbirths performed in the Brazilian Unified Health System (SUS, in the Surgical interventions are necessary when labor does not have Portuguese acronym), the number of vaginal deliveries is the expected physiological progression. However, nowadays, higher (59.8%) than that of cesarean sections (40.2%).8 there is a remarkable global increase in cesarean section rates, Santa Maria County, which has one of the reference as documented in different countries worldwide.1 These pro- regional obstetric services for high-risk pregnancies in the cedures help reducing maternal and neonatal morbidity and countryside of the state of Rio Grande do Sul, recorded only mortality when they are properly indicated. Although safe, 32.9% of vaginal deliveries in 2010.7 Despite this finding, cesarean sections comprise surgery-inherent risks such as there are no regional studies that can be compared with infection, bleedings, thromboembolic events, placental abnor- national and international data. malities (placenta previa, placental abruption, placenta accreta) The Robson Classification, which was developed by Robson in future pregnancies, chronic pain and internal adhesions.2 In in 2001,9 has been suggested by the WHO as the standard addition, there are newborn-associated risks such as prematu- instrument to evaluate and monitor cesarean section rates in rity, transient tachypnea or respiratory distress syndrome.2,3 different hospital services.4 This classification allows distrib- According to the World Health Organization (WHO), uting all pregnant women in groups based on individual childbirth care aims at assuring the safety of mothers and features such as number of childbirths, number of previous newborns by intervening as little as possible in this process cesarean sections, gestational age, fetal presentation and twin and by performing cesarean sections in case of real need. The pregnancy.9,10 Given the clarity, objectivity and easy applica- internationally accepted ideal cesarean section rate ranges tion of this classification method, it has been used to survey, from 10 to 15% of childbirths; this range is based on lack of monitor and compare cesarean section rates within and benefit on mortality rates when cesarean sections exceed between institutions; it also allows analyzing these data, as 10% of childbirths, as shown in previous studies.4 well as identifying safe alternatives to help reducing cesarean – However, Brazilian rates are much higher than the estab- section rates.11 14 lished limit. According to Nakamura-Pereira et al.,5 cesarean The present study has analyzed childbirths performed at sections account for 51.9% of childbirths in the country. In this the Hospital Universitário de Santa Maria (HUSM, in the study, high-risk pregnant women had significantly greater Portuguese acronym), as well as classified them based on the cesarean section rates compared with low-risk women in Robson Classification, to help better understanding the real the public sector. Older primiparous and more educated situation of cesarean section indications and the profile of pregnant women who have access to private services are childbirths performed in the investigated institution. The more susceptible to abdominal delivery indications based on results may collaborate with the creation of strategies to nonclinical factors.6 The increased number of cesarean deliv- reduce the high cesarean rates in Brazilian institutions. eries changes from region to region in the country, mainly between the public and private care sectors. Southern Brazil Methods has one of the highest cesarean section rates in the country; it accounted for 58,1% of all childbirths in 2010, whereas the The current research is a retrospective cross-sectional study Southeastern region accounted for 58.3% and the Midwestern comprising data about the hospitalization of pregnant wom- region for 57.4%. The Northern and Northeastern regions en who had vaginal or cesarean delivery at the Obstetric recorded the lowest cesarean delivery indices in 2010–44.4% Center of the HUSM (a regional reference hospital for high- and 41.8%, respectively.7 The number of cesarean sections, risk pregnancies) from January 2014 to December 2015. Data which presented an upward curve, decreased by 1.5% in 2015; were collected through the review of medical records. Par- 55.5% of 3 million deliveries performed in Brazil were cesarean turients whose data did not allow their classification into sections, whereas 44.5% were vaginal deliveries. On the other Robson groups were excluded from the study.

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. 86 Gestational Risk as a Determining Factor for Cesarean Section Soares et al.

During hospitalization for childbirth, labor care was man- aged according to the hospital service protocols. The evolution of births was monitored using a partogram and fetal vitality was accessed by intermittent auscultation of the fetal heart rate and cardiotocography if abnormal fetal heart rate or in high-risk pregnancies. A high-risk pregnancy was considered the one with increased risk for complications for the pregnant woman, the fetus or the newborn. Risk factors for a high-risk pregnancy were considered existing health conditions, such as high blood pressure, diabetes, thyropathies, hematopathies, infectious diseases, heart diseases, obesity, multiple births, among others. Parturients were distributed into 10 groups based on the Robson Classiﬁcation by following instructions provided in the base article.9 Data were subjected to descriptive and analytical analyses. The chi-squared test was used to calculate differences between Robson groups in 2014 and 2015; Fig. 1 Comparison between delivery routes per year. Chi-squared p < 0.05 was set as statistically signiﬁcant. test, p < 0.0001. The project was approved by the Research Ethics Committee of the investigated institution (CAAE 58212416.3.0000.5346). childbirths, whereas cesarean section before labor corre- Results sponded to 24.6% of cases (►Table 1). In the case of induced childbirths, 41.5% of nulliparous women and 57.4% of mul- A total of 4,061 births were recorded in the period and 51 were tiparous women evolved to vaginal delivery. Nulliparous excluded from the research due to incomplete data, remaining women who were subjected to induced delivery evolved to 4,010 for analysis. The mean maternal age was 26.2 (7.1) years cesarean section, whereas multiparous women evolved to old, the mean number of childbirths was 1.2, the mean gesta- vaginal delivery (p < 0.0001). tional age at birth was 37.8 weeks (►Table 1), and 49.4% of the Cesarean section was the most adopted delivery route pregnant women had at least one cesarean section prior to the (57.6% of cases); however, this rate changed depending on assessed pregnancy. Of the total number of childbirths, vaginal the number of childbirths (►Table 1) and on the investigated deliveries corresponded to 1,702 (42.4%) and cesarean sections period (►Fig. 1); 49.7% of the total number of nulliparous to 2,308 (57.6%) comprised cesarean sections. Sixty-one cases women and 62.6% of the total of multiparous women evolved of fetal death (1.5%) were recorded throughout the studied to cesarean section. The main indications for cesarean sec- period; 83.6% of them happened in preterm pregnancies. tion comprised previous cesarean section (39.7%), nonreas- Parturients were hospitalized for spontaneous delivery in suring fetal status (16.4%), cephalopelvic disproportion 49.7% of cases, induced deliveries accounted for 25.7% of (12.6%), induction failure (8.4%) and pelvic presentation of

Table 1 Demographic and obstetric features of Parturients

Total (n ¼ 4,010) Nulliparous (n ¼ 1,568) Multiparous (n ¼ 2,442) Maternal age 26.2 (7.1) 21.9 (5.78) 28.9 (6.48) Previous pregnancies 2.4 (1.60) 1.1 (0.40) 3.3 (1.52) Number of childbirths 1.2 (1.44) 0 (0) 2.0 (1.35) Number of previous cesarean sections 0.6 (0.98) 0 (0) 0.9 (1.12) Miscarriages 0.2 (0.51) 0.1 (0.39) 0.3 (0.57) Gestational age 37.8 (4.51) 37.7 (3.96) 37.8 (4.83) Hospitalization due to spontaneous labor 1,991 (49.7%) 760 (48.5%) 1,231 (50.5%) Induced labor 1,031 (25.7%) 627 (40.0%) 404 (16.5%) Cesarean section without labor 988 (24.6%) 181 (11.5%) 807 (33.0%) Delivery type Vaginal delivery 1,693 (42.2%) 782 (49.9%) 911 (37.31%) Instrumented delivery 9 (0.2%) 6 (0.4%) 3 (0.1%) Cesarean section 2,308 (57.6%) 780 (49.7%) 1,528 (62.6%)

Deliveries at Hospital Universitário de Santa Maria, from January 2014 to December 2015; Mean standard deviation; number and percentage of cases.

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. Gestational Risk as a Determining Factor for Cesarean Section Soares et al. 87

tion. The age group 20 years was associated with spontaneous and induced labor onset (p < 0.0001), whereas the age group between 26 and 40 years old was associated with cesarean section without labor (p < 0.0001), as shown in ►Fig. 2. The age group 20 years old was also associated with vaginal deliveries (p < 0.0001), whereas the others were associated with cesarean sections; such association was only significant in the age group between 26 and 40 years old (p < 0.0001). Based on the comparative analysis between 2014 and 2015, the number of childbirths increased from 1,769 in 2014 to 2,241 in 2015, mainly at the expense of the total number of vaginal deliveries (►Fig. 1). In 2014, vaginal deliveries accounted for 37.9% of childbirths, whereas cesarean sections accounted for 62.1% of cases. In 2015, vaginal deliveries accounted for 46.1% of childbirths, whereas cesarean sections accounted for 53.9% of cases. The number of cesarean deliveries was larger in 2014 than in 2015, whereas 2015 recorded higher rates of vaginal deliveries than 2014 Fig. 2 Labor onset time divided into groups, based on age group. (p < 0.0001). Another important aspect was the attendance of a greater number of healthy pregnant women in 2015. In the fetus (7.4%). In the studied periods (2014 and 2015), 2014, the number of high-risk pregnancies was 17.4% and in previous cesarean sections were the main indication for 2015, 14.1% (p ¼ 0.016). operative delivery and the number of previous cesareans, After data collection, parturients were distributed into 10 one or two or more did not vary (p ¼ 0.141). groups based on the Robson Classification (►Table 2). Most The stratification of pregnant women by age group women were allocated to group 5 (26.4%), which was fol- revealed differences in labor onset and in delivery evolu- lowed by groups 10 (17.5%) and 2 (16.0%).

Table 2 Cesarean section distribution based on Robson 10-group classiﬁcation

Births Features 2,308/ Rate per Cesarean section Contribution from Group 4,010 group rate per group each group 1 Nulliparous, single fetus, cephalic presenta- 125/517 12.9% 24.2% 3.1% tion, > 37 weeks, spontaneous labor 2 Nulliparous, single fetus, cephalic presenta- 422/642 16.0% 65.7% 10.5% tion, > 37 weeks, induced labor or cesarean section before labor 3 Multiparous, no previous cesarean section, single 59/491 12.2% 12.0% 1.5% fetus, cephalic presentation, > 37 weeks, spontaneous labor 4 Multiparous, no previous cesarean section, single 181/364 9.1% 49.7% 4.5% fetus, cephalic presentation, > 37 weeks, induced labor or cesarean section before labor 5 Multiparous with at least 1 previous cesarean 930/1,057 26.4% 80.0% 23.2% section, single fetus, cephalic presentation, > 37 weeks 6 Nulliparous, single fetus in pelvic presentation 80/81 2.0% 98.8% 2.0% 7 Multiparous, single fetus in pelvic presentation, 76/78 1.9% 97.4% 1.9% likelihood of previous cesarean section 8 Anywomanwithtwinpregnancy;likelihoodof 64/68 1.7% 94.1% 1.6% previous cesarean section 9 Any woman with oblique or transverse fetal pre- 12/12 0.3% 100.0% 0.3% sentation; likelihood of previous cesarean section 10 Any woman with a single fetus in cephalic presen- 359/700 17.5% 51.23% 8.9% tation, < 37 weeks, likelihood of previous cesarean section

Deliveries at the Hospital Universitário de Santa Maria, from January 2014 to December 2015.

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. 88 Gestational Risk as a Determining Factor for Cesarean Section Soares et al.

tioned study in comparison to 23.2% in the study conducted at our institution).15,16 Although Santa Maria County has two public maternity hospitals – one for high-risk pregnancies (HUSM) and another for habitual-risk pregnancies –,intheyear2015,the HUSM was the only reference for pregnant women treated by the SUS, both at local and regional levels, because the habitual-risk maternity hospital was temporarily closed. Thus, the HUSM conducted both high-risk and habitual- risk childbirths. This specific event has affected the total number of childbirths, as well as increased the vaginal delivery rate and the number of spontaneous childbirths in the institution in 2015, a fact that proportionally increased the number of pregnant women in groups 1 and 3. The HUSM presented results similar to the ones recorded by Tapia et al. (2016)17 in Latin America and by Yadav et al. (2016)18 in India when it started to perform all childbirths, not just the high-risk ones.17,18 Therefore, the comparison between Rob- son Classification results and data available in the literature Fig. 3 Robson groups analysis per year. Chi-squared test, p < 0.001. allowed observing that the frequency of pregnant women in each group was associated with population type, as it was also reported by Zahumensky et al. (2019),14 who compared Based on the analysis of 2014 and 2015 (in separate), three Slovak centers presenting different healthcare profiles: Robson groups 5 and 10 (►Fig. 3) were the most frequent one tertiary center with neonatal intensive care unit (NICU), ones. However, based on the association between the evaluat- intensive care unit (ICU) and two other centers that only ed years (2014 and 2015) and Robson classification groups, treated pregnant women with gestational age > 32 weeks. there was a significant increase in the number of pregnant The aforementioned study has found differences in the most women in groups 1 and 3 in 2015 (p < 0.001). The number of recurrent Robson groups in each service, as well as cesarean cases in Group 1 increased from 10.7% to 14.6% in 2014, and section rate variations from service to service. This outcome from 9.9% to 14.1% in Group 3. Thus, Group 1 became the third highlighted the influence of healthcare profile on the deliv- most frequent one in 2015; it took the position of Group 2 in ery and cesarean rates in each service.14 2014, although most women remained in groups 5 and 10. Based on results of the present study, most women Thus, the year of 2015 had higher number of parturients belonged to group 5 during data collection at the HUSM – without comorbidities (p ¼ 0.016), greater number of primip- this group accounted for 25% of childbirths. This finding arous and multiparous women with spontaneous onset of confirms the fact that the incidence of previous cesarean labor without previous cesarean sections (p < 0.001) and sections was the main indication for cesarean section in the higher rates of vaginal delivery (p < 0.0001). However, despite investigated service. Group 10 was the second most frequent the lower rate of cesarean section in 2015, there was no one, corresponding to births before the 37th gestational reduction in the need for newborns to be admitted to the week. This finding is justified by the fact that the investigated neonatal therapy unit (p ¼ 0.542) nor reduction in the number hospital is the only regional reference center for high-risk of fetal deaths (p ¼ 0.777). pregnancies, including prematurity cases. The distribution of parturients into Robson groups Discussion changes from service to service depending on the profile of pregnant women. In comparison to other studies that have The comparison between 2014 and 2015 has shown changes applied the Robson Classification in Brazil, a WHO survey in the profile of parturients; Robson groups 1 and 3 increased conducted in Latin America has shown that the most fre- and, consequently, the number of vaginal deliveries also quent groups were 1 and 3.15 According to a study conducted increased in 2015. This difference between the investigated in a tertiary hospital in Campinas County, the main groups years is justified by the fact that the profile of pregnant were 1 and 5.11 Groups 1, 3 and 10 were the most frequent in women changed between 2014 and 2015. In other words, the Peru, whereas an analysis of childbirths conducted in India introduction of habitual-risk pregnant women in the group based on the same classification method has also found that treated in the investigated service has generated a healthcare groups 1 and 3 were the most frequent.16,17 On the other profile with tendencies similar to the ones reported by hand, Zahumensky et al. (2019)14 compared three different Senanayake et al. (2019),15 who conducted a study with Slovak obstetric centers and found differences in the fre- 7,504 women in Sri Lanka. According to the aforementioned quency of cesarean sections, mainly in groups 1, 2 and 5. researchers, groups 1 and 3 were the most prevalent ones, Group 1, which was the largest group in the three services, whereas Group 5 was the one that mostly increased the accounted for the most significant difference between the cesarean section rates (29.6% of indications in the aforemen- absolute and relative numbers of cesarean sections.14

Since the HUSM is a reference center for high-risk preg- in countries investigated by Vogel et al. (2015),13 there is a nancies in the central region of the state of Rio Grande do Sul worldwide trend toward increased numbers of obstetric inter- and has a neonatal ICU, this hospital receives a large number ventions, as well as increased labor induction rates and larger of referrals for cesarean sections (indicated in the county of number of cesarean sections without labor. This outcome also origin of the pregnant women), for induced or preterm labor highlights the association between the increased number of management, as well as for other maternal and fetal com- women with previous cesarean section and the increased plications such as premature rupture of membranes, mater- number of cesarean delivery indications in countries present- nal hypertension and twin pregnancy, which may lead to ing moderate or low HDI.13 preterm births. These conditions make groups 2, 5 and 10 the According to the Department of Informatics of the SUS most frequent ones in the service. Women who have had one (DATASUS, in the Portuguese acronym), the state of Rio cesarean section, as the ones in Group 5, are important Grande do Sul recorded 37% of vaginal deliveries in 2014. determinants of the overall high cesarean section rates. Based on the current results, the HUSM recorded a vaginal Strategies focused on reducing the frequency of cesarean delivery rate equal to 37.7% in 2014; this value was in sections should encourage women to avoid clinically unnec- compliance with the ones recorded for the state.7 However, essary primary cesarean sections, correctly manage labor in since the HUSM also performed habitual-risk deliveries in women with history of cesarean delivery, perform the exter- 2015, the vaginal delivery rate increased to 46% and reached nal cephalic version for pelvic presentations, as well as values higher than the mean recorded for the state. vaginal delivery of twins with the first fetus in cephalic The secondary and retrospective data source used in presentation, and reduce iatrogenic preterm delivery.13,14 the present study may have led to selection and measure- Another important effort focused on reducing cesarean ment bias. The case loss rate was low; it accounted for delivery rates lies on labor induction when childbirth is 1.5% of cases, which were excluded from the analysis. It indicated. According to a Portuguese study, the cesarean happened because the variables required to classify preg- section rate resulting from labor induction reached 20.9%; nant women based on the Robson Classification were not this number corresponded to 23% of the total number of available in the hospital records. Despite these limitations, cesarean sections. According to the aforementioned study, themainstrengthofthepresentstudyliesonthefactthat the Foley catheter for cervical preparation was the most it was the first research focused on analyzing childbirth adopted method in labor induction cases comprising preg- profiles at the HUSM, which is a reference regional tertia- nant women with previous cesarean section. These cases ry hospital with high-risk pregnancy representativeness were associated with high rates of labor induction failure in the SUS. and, consequently, with high rates of cesarean sections due Although the Robson classification is a great tool to help to their direct association with Robson group 5.18 identifying and monitoring the main groups at risk of being According to studies available in the literature, induction subjected to cesarean section, many countries and institu- failure rates range from 23.4 to 33.8%.19,20 The present study tions have been questioning the risk of bias when the method recorded the following induction failure rates: 42.5% for is used to compare different maternity hospitals due to multiparous women and 58.5% for primiparous women, different care levels and maternal features. A recently pub- which corresponded to the 4th largest cesarean section lished Italian study has shown that higher complexity hos- age.21,22 Since the HUSM is a regional reference for high- pitals are associated with higher cesarean section rates and risk deliveries – including prematurity and maternal pathol- with maternal features such as maternal age and gestational ogy cases –, the large number of induced delivery failures in diabetes, which are seen as independent risk factors for this hospital has an impact on cesarean section rates. Such cesarean section.23,24 number also represents the risk of having another cesarean Based on the current results, the cesarean section rate in section in the future, a fact that hinders intervention meas- the HUSM is higher than that found in other national and ures focused on reducing cesarean section rates in the international studies, but it is similar to the rate recorded investigated service, in the short term. In addition, different for the state, as reported by Brunherotti et al. (2019),25 who induction methods and induction failure concepts may found a cesarean section rate of 60.7% in Southern Brazil. hinder the analysis of and the comparison between studies. Since Group 5 presents a larger number of cesarean sections Despite the recommendation of the WHO to maintain than the other groups, and since the incidence of previous cesarean section rates in, at most, 15%, the national cesarean cesarean section is the main indication for cesarean sec- delivery rate reached 52% in 2009; the present study recorded tions, it is necessary to take actions focused on changing the the following rates for the HUSM: 62.1% in 2014 and 53.9% in current scenario, mainly on raising the awareness about 2015.7 Cesarean deliveries in Campinas County accounted for first cesarean section avoidance when it is not really 46.6% of the total number of childbirths from 2009 to 2013.11 necessary. Based on another WHO survey, which was conducted in The Robson 10-group Classification System was a useful several countries, cesarean sections performed in Brazil tool in the initial analysis of childbirth profiles in the service from 2010 to 2011 accounted for 47% of childbirths.12 The investigated herein. This classification allows monitoring the cesarean section rate between 2008 and 2010 reached 30.1% in evolution of cesarean section rates in the hospital, based on Peru, whereas in India it reached 25.1% between 2004 and actions aimed at reducing cesarean section rates, labor26 and 2013.16,17 Regardless of the Human Development Index (HDI) achieving rates closer to the ones recommended by the WHO.

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. 90 Gestational Risk as a Determining Factor for Cesarean Section Soares et al.

Conclusion referral hospital in Brazil. Int J Gynaecol Obstet. 2015;129(03): 236–239. Doi: 10.1016/j.ijgo.2014.11.026 The Robson Classification proved to be a useful tool to identify the 12 Torloni MR, Betrán AP, Souza JP, Widmer M, Allen T, Gulmezoglu M, Merialdi M. Classifications for cesarean section: a systematic profile of parturients and the groups with the highest risk of review. PLoS One. 2011;6(01):e14566. Doi: 10.1371/journal. cesarean sections in different periods in the same service. Thus, it pone.0014566 allows monitoring in a dynamic way the indications and delivery 13 Vogel JP, Betrán AP, Vindevoghel N, Souza JP, Torloni MR, Zhang J, routes and developing actions to reduce cesarean rates according et al; WHO Multi-Country Survey on Maternal and Newborn to the characteristics of the pregnant women attended. Health Research Network. Use of the Robson classification to assess caesarean section trends in 21 countries: a secondary analysis of two WHO multicountry surveys. Lancet Glob Health. Contributors 2015;3(05):e260–e270. Doi: 10.1016/S2214-109X(15)70094-X All authors participated in the concept and design of the 14 Zahumensky J, Psenkova P, Nemethova B, Halasova D, Kascak P, present study; analysis and interpretation of data; draft- Korbel M. Evaluation of cesarean delivery rates at three university ing or revising of the manuscript, and they have approved hospital labor units using the Robson classification system. Int J the manuscript as submitted. All authors are responsible Gynaecol Obstet. 2019;146(01):118–125. Doi: 10.1002/ijgo.12842 15 Senanayake H, Piccoli M, Valente EP, Businelli V, Mohamed R, for the reported research. Fernando R, et al. Implementation of the WHO manual for Robson classification: an example from Sri Lanka using a local database Conflict of Interests for developing quality improvement recommendations. BMJ The authors have no conflict of interests to declare. Open. 2019;9(02):e027317. Doi: 10.1136/bmjopen-2018-027317 16 Betrán AP, Gulmezoglu AM, Robson M, Merialdi M, Souza JP, Wojdyla D, et al. WHO global survey on maternal and perinatal References health in Latin America: classifying caesarean sections. Reprod 1 Patah LEM, Malik AM. Modelos de assistência ao parto e taxa de Health. 2009;6:18. Doi: 10.1186/1742-4755-6-18 cesárea em diferentes países. Rev Saude Publica. 2011;45(01): 17 Tapia V, Betrán AP, Gonzales GF. Caesarean section in Peru: 85–94. Doi: 10.1590/S0034-89102011000100021 analysis of trends using the Robson classification system. PLoS 2 Silver RM. Implications of the first cesarean: perinatal and future One. 2016;11(02):e0148138. Doi: 10.1371/journal.pone.0148138 reproductive health and subsequent cesareans, placentation issues, 18 Yadav RG, Maitra N. Examining cesarean delivery rates using the uterine rupture risk, morbidity, and mortality. Semin Perinatol. Robson’s ten-group classification. J Obstet Gynaecol India. 2016; 2012;36(05):315–323. Doi: 10.1053/j.semperi.2012.04.013 66(Suppl 1):1–6. Doi: 10.1007/s13224-015-0738-1 3 Kozhimannil KB, Arcaya MC, Subramanian SV. Maternal clinical 19 Vargas S, Rego S, Clode N. Robson classification system applied to diagnoses and hospital variation in the risk of cesarean delivery: induction of labor. Rev Bras Ginecol Obstet. 2018;40(09): analyses of a National US Hospital Discharge Database. PLoS Med. 513–517. Doi: 10.1055/s-0038-1667340 2014;11(10):e1001745. Doi: 10.1371/journal.pmed.1001745 20 Vrouenraets FP, Roumen FJ, Dehing CJ, van den Akker ES, Aarts MJ, 4 Organização Mundial da Saúde. Declaração da OMS sobre taxas de Scheve EJ. Bishop score and risk of cesarean delivery after induc- cesáreas [Internet]. GenebraOrganização Mundial da Saúde2015 tion of labor in nulliparous women. Obstet Gynecol. 2005;105 [cited 2019 Mar 01]. Available from: https://apps.who.int/iris/ (04):690–697. Doi: 10.1097/01.AOG.0000152338.76759.38 bitstream/handle/10665/161442/WHO_RHR_15.02_por.pdf 21 Thangarajah F, Scheufen P, Kirn V, Mallmann P. Induction of labour 5 Nakamura-Pereira M, do Carmo Leal M, Esteves-Pereira AP, et al. in late and postterm pregnancies and its impact on maternal and Use of Robson classification to assess cesarean section rate in neonatal outcome. Geburtshilfe Frauenheilkd. 2016;76(07): Brazil: the role of source of payment for childbirth. Reprod Health. 793–798. Doi: 10.1055/s-0042-107672 2016;13(Suppl 3):128. Doi: 10.1186/s12978-016-0228-7 22 Bettiol H, Barbieri MA, da Silva AA. [Epidemiology of preterm 6 Dias MAB, Domingues RMSM, Pereira APE, FonsecaSC, daGamaSGN, birth: current trends]. Rev Bras Ginecol Obstet. 2010;32(02): Theme Filha MM, et al. Trajetória das mulheres na definição pelo 57–60. Doi: 10.1590/S0100-72032010000200001 parto cesáreo: estudo de caso em duas unidades do sistema de saúde 23 Gabbay-Benziv R, Hadar E, Ashwal E, Chen R, Wiznitzer A, suplementar do estado do Rio de Janeiro. Cien Saude Colet. 2008;13 Hiersch L. Induction of labor: does indication matter? Arch (05):1521–1534. Doi: 10.1590/S1413-81232008000500017 Gynecol Obstet. 2016;294(06):1195–1201. Doi: 10.1007/ 7 Ministério da Saúde DATASUS. Indicadores e dados básicos [In- s00404-016-4171-1 ternet]. 2016 [cited 2019 Mar 01]. Available from: http://tabnet. 24 Gerli S, Favilli A, Franchini D, De Giorgi M, Casucci P, Parazzini F. Is datasus.gov.br/cgi/tabcgi.exe?idb2012/f08.def the Robson’s classification system burdened by obstetric pathol- 8 Valadares C. Pela primeira vez número de cesarianas não cresce no ogies, maternal characteristics and assistential levels in compar- país. Agência Saúde [Internet] 2017 Mar 10 [cited 2019 Mar 01]. ing hospitals cesarean rates? A regional analysis of class 1 and 3. Available from: http://portalms.saude.gov.br/noticias/%20agen- J Matern Fetal Neonatal Med. 2018;31(02):173–177. Doi: cia-saude/27782 10.1080/14767058.2017.1279142 9 Robson MS. Classification of cesarean sections. Fetal Matern Med 25 Brunherotti MAA, Prado MF, Martinez EZ. Spatial distribution of Rev. 2001;12(01):23–39. Doi: 10.1017/S0965539501000122 Robson 10-group classification system and poverty in southern 10 Robson M, Murphy M, Byrne F. Quality assurance: The 10-Group and southeastern Brazil. Int J Gynaecol Obstet. 2019;146(01): Classification System (Robson classification), induction of labor, 88–94. Doi: 10.1002/ijgo.12831 and cesarean delivery. Int J Gynaecol Obstet. 2015;131(Suppl 1): 26 Bolognani CV, Reis LBSM, Dias A, Calderon IMP. Robson 10-groups S23–S27. Doi: 10.1016/j.ijgo.2015.04.026 classification system to access C-section in two public hospitals of 11 Ferreira EC, Pacagnella RC, Costa ML, Cecatti JG. The Robson ten- the Federal District/Brazil. PLoS One. 2018;13(02):e0192997. Doi: group classification system for appraising deliveries at a tertiary 10.1371/journal.pone.0192997

Factors Associated with Exclusive Breastfeeding in a Maternity Hospital Reference in Humanized Birth Fatoresassociadosaoaleitamentomaternoexclusivo em uma maternidade referência em parto humanizado Gabriela Pinheiro Brandt1 Alan Messala A. Britto2,3 Camila Carla De Paula Leite1 Luciana Garangau Marin1

1 Maternidade Bairro Novo, Curitiba, PR, Brazil Address for correspondence Gabriela Pinheiro Brandt, Rua Barão de 2 Programa de Oncovirologia, Instituto Nacional de Câncer, Rio de Antonina, 522, Curitiba - PR, 80530-050, Brazil Janeiro, RJ, Brazil (e-mail: [email protected]). 3 Department of Genetics, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

Rev Bras Ginecol Obstet 2021;43(2):91–96.

Abstract Objective To analyze the factors associated with the prevalence of exclusive breastfeeding (EBF) for up to six months in mother/infant binomials cared for at a usual-risk maternity hospital. Methods The present is a descriptive, longitudinal, prospective, quantitative study. Socioeconomic, obstetric and perinatal variables from 101 mother/infant binomials in a Public Maternity Hospital in the city of Curitiba, state of Paraná, Brazil, were investigated during hospitalization after delivery and 6 months after birth. For the statistical analysis, the Chi-squared test was used. The variables that showed values of p < 0.25 for the Chi-squared test were also submitted to an odds ratio (OR) analysis. Keywords Results The prevalence (42.6%) of EBF was observed. Most women (93.1%) had had ► breastfeeding more than 6 prenatal consultations, and the variables maternity leave and support to ► weaning breastfeeding were associated with EBF. Support to breastfeeding by professionals and ► humanization family members increased 4-fold the chance of maintenance of EBF (OR ¼ 0.232; 95% ► natural childbirth conﬁdence intercal [95%CI]: 0.079 to 0.679; p ¼ 0.008). Cracked nipples were the ► cesarean section biggest obstacle to breastfeeding, and low milk production was the main responsible factor for weaning. Conclusion The encouragement of breastfeeding and the mother’sstayforalonger period with the child contributed to the maintenance of EBF until the sixth month of life of the infant.

Resumo Objetivo Analisar os fatores associados à prevalência do aleitamento materno exclusivo (AME) até seis meses em binômios mãe/recém-nascido atendidos em uma maternidadederiscohabitual.

received DOI https://doi.org/ © 2021. Federação Brasileira das Associações de Ginecologia e May 7, 2020 10.1055/s-0040-1718450. Obstetrícia. All rights reserved. accepted ISSN 0100-7203. This is an open access article published by Thieme under the terms of the August 14, 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 92 Exclusive Breastfeeding in a Maternity Hospital Reference in Humanized Birth Brandt et al.

Métodos Trata-se de um estudo descritivo, longitudinal, prospectivo e quantitativo. Foram investigadas variáveis socioeconômicas, obstétricas e perinatais de 101 binô- mios mãe/recém-nascido de uma maternidade pública em Curitiba-PR no interna- mento após o parto e 6 meses após o nascimento. Para a análise estatística, utilizou-se o teste do qui-quadrado. As variáveis cujo teste do qui-quadrado tiveram valores de p < 0,25 foram testadas para análises de razão de probabilidades (RP). Resultados Observou-se a prevalência (42,6%) do AME. A maioria das mulheres (93,1%) havia realizado mais de 6 consultas de pré-natal, e as variáveis licença maternidade e apoio para amamentar estiveram associadas ao AME. O apoio para Palavras-chave amamentar por parte do profissional e do familiar aumentou em 4 vezes a chance da ¼ fi ► aleitamento materno permanência em AME (RP 0,232; intervalo de con ança de 95% [IC95%]: 0,079 a p ¼ fi ► desmame 0.679; 0,008). A ssura foi o maior obstáculo para a amamentação, e a baixa ► humanização produção de leite, o principal responsável pelo desmame. ► parto normal Conclusão O incentivo ao aleitamento e a permanência da mãe por mais tempo com ► cesárea a criança contribuíram para a manutenção do AME até o sexto mês de vida do bebê.

Introduction Methods

The World Health Organization (WHO) recommends exclu- The present is a descriptive, longitudinal, prospective study sive breastfeeding (EBF) on demand, in the first six months of with a quantitative approach. It was performed in a habitual- life, and, later, breastfeeding must be supplemented with risk public maternity hospital in the city of Curitiba, state of other foods up to 2 years of age or older.1 It is said that an Paraná (PR), Brazil, a reference in humanization, with the infant is in EBF when he/she feeds only on breast milk, BFHI reputation. The inclusion criteria were: women aged without consuming other foods or liquids.2 This is the 18 years who gave birth to live newborns at term ( 37 most complete food, and it meets the nutritional needs in weeks), by normal delivery or cesarean section, at the the first six months of life.3 The benefits of breastfeeding go maternity hospital. Women who had premature births, beyond nutritional gains, as breast milk has immunological stillbirths, whose newborn or themselves were transferred properties, favors cognitive development, and protects to high-complexity care, and who did not answer the second infants from diseases such as dehydration, diarrhea and questionnaire were excluded. pneumonia, which are important causes of infant mortality.4 Data were collected in two moments: 1) by interview in For the puerperal woman, it promotes the affective bond the maternity hospital, within the first 48 hours of life, in the with her baby, prevents bleeding, and reduces the risk of months of January and February 2019; and 2) through a developing cancer.3 phone call with the mother, at 6 months of life of the infant, Increasing EBF rates are a goal to be achieved worldwide, in August 2019. The collection was prospective and used 2 and the WHO and the United Nations Children’s Fund (UNI- structured questionnaires, composed of 12 and 10 questions – CEF) promote and encourage the continuity of EBF.2 6 In respectively, prepared by the researchers and previously 2011, the global EBF rate in infants from 0 to 6 months was of tested. In the first questionnaire, socioeconomic, obstetric 35%, and it increased to 40% in 2019.2,7 In Brazil, although the and perinatal variables were collected, while in the second, EBF index is gradually increasing, its maintenance is ob- we collected information about the duration of the EBF and served for shorter periods than the recommended six the type of breastfeeding the infant was on at six months.8 months. ►Fig. 1 shows the flowchart of the data collection Research3,4,6 shows that the duration and continuity of and the selection of mother/infant binomials based on the EBF are linked to socioeconomic variables such as age and inclusion and exclusion criteria. maternal schooling, family income and occupation, and to In the first contact, the women who agreed to participate obstetric and perinatal variables, such as assiduous par- signed the free and informed consent form (FICF), with a total ticipation in prenatal care, delivery and type of assistance of 141 participants. Telephone contact was obtained with only received during childbirth, as well as the support provided 101 participants in the second collection, even after 3 attempts by the professionals and family members to breastfeeding. to call at different dates and times. We analyzed the outcome Given the aforementioned information, the present study and the type of breastfeeding according to the classification by intended to analyze the factors associated with the prev- the WHO: EBF, when the infant is fed only breast milk, without alence of EBF for up to six months in mother/infant the addition of other foods or liquids; breastfeeding (BF), binomials cared for at a maternity of usual risk that is when, in addition to breast milk, the infant is fed other liquid reference in good practices in care for childbirth, with and/or solid foods; and mixed breastfeeding (MBF), when the Baby–Friendly Hospital Initiative (BFHI) reputation. infant is fed breast milk and baby formula.9

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. Exclusive Breastfeeding in a Maternity Hospital Reference in Humanized Birth Brandt et al. 93

Table 1 Breastfeeding outcome (n ¼ 101)

Variable n % Breastfeeding Yes 75 74.3 No 26 25.7 Breastfeeding type Exclusive breasfeeding 43 42.6 Breastfeeding 19 18.8 Mixed breastfeeding 13 12.9 Weaning 26 25.7

nicipality of Curitiba (under opinion No. 3,060,900 on December 6, 2018).

Results

Overall, 101 mother/newborn binomials were interviewed, most of which were still breastfeeding (74.3%) (►Table 1). As for the type of breastfeeding at six months of life, 42.6% remained on EBF, and almost a third of the sample continued to breastfeed, but not exclusively (BF ¼ 18.8%; MBF ¼ 12.9%), and only 25.7% of the infants weaned early (►Table 1). Regarding the characteristics of the population, the most prevalent maternal age group was 20 to 34 years (80.2%), and just over 80% of the mothers had more than 8 years of Fig. 1 Flowchart of the data collection and selection of mother/infant schooling (►Table 2). It is noteworthy that there were no binomials. illiterate women, and that 71.3% of them had at least We collected socioeconomic variables (age and maternal graduated from High School. The most frequent family schooling, family income, occupation and maternity leave), income was more than 2 minimum wages (74.3%), and half obstetric variables (type of delivery, parity, and number of of the women reported contributing to the houehold income, prenatal consultations), and variables related to good peri- since they worked (49.5%; ►Table 2). As for the employment natal practices (skin-to-skin contact [when the infant stays relationship, 36.6% were employed with a formal contract, with the mother immediately after the birth for at least and 12.9% declared themselves self-employed. Regarding 1 hour], breastfeeding in the first hour of life, and support to maternity leave, 38.6% enjoyed a period of 4 to 6 months breastfeeding from a professional or family member) to look of maternity leave. Most women were primiparous (47.5%), for an association with EBF. Regarding the variable maternal had a normal birth (73.3%), and had regular prenatal care schooling, illiterate women and those with incomplete ele- with more than 6 consultations (93.1%). Regarding good mentary education were included in the ‘less than 8 years of practices, skin-to-skin contact stood out as the experience schooling’ group, while those with complete elementary most lived by women (78.2%), which results in a good rate of education up to complete higher education were included breastfeeding in the first hour of life (65.3%). Also notewor- in the ‘more than 8 years of schooling’ group. The factors that thy is the high prevalence of ‘support to breastfeeding’ made breastfeeding difficult and the factors that motivated (74.3%), showing the engagement of the team and family weaning were also analyzed. members in breastfeeding. This support was defined as a set The information was tabulated in Excel 2016 (Microsoft of practices and information that the puerperal woman Corp., Redmond, WA, US) spreadsheets, and the statistical received from the multiprofessional team during hospitali- analysis was performed using the Statistical Package for the zation, and, later, the support she received at home from the Social Sciences (SPSS, IBM Corp., Armonk, NY, US), version family to continue breastfeeding. 21.0. The absolute and relative frequencies were calculated, The comparison between the mother/infant binomials in addition to the search for an association of the variables who maintained EBF with those that did not, and the with EBF through the chi-squared test of independence, in association with the socioeconomic, obstetric and perinatal which values of p < 0.05 were considered significant. The variables were performed using the Chi-squared test variables that had values of p < 0.25 in the Chi-squared test (►Table 2). Regarding the socioeconomic variables, only were tested for an analysis of the odds ratio (OR) using the maternity leave was statistically different among the groups. MedCalc web site (https://www.medcalc.org/calc/odds_ra- Contrary to expectations, the women who did not take tio.php). The present research was submitted to analysis and maternity leave maintained EBF for longer periods when approved by the Ethics in Research Committee of the mu- compared with those who took leave (p ¼ 0.02). The obstetric

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. 94 Exclusive Breastfeeding in a Maternity Hospital Reference in Humanized Birth Brandt et al.

Table 2 Association of exclusive breastfeeding and socioeconomic, obstetric and perinatal variables (n ¼ 101)

Variable Exclusive breastfeeding p-value Total Yes No n(%) n(%) n(%) 43 58 101 Age 18–19 years 4 (9.3) 5 (8.6) 0.96 9 (8.9) 20–34 years 34 (79.1) 47 (81.0) 81 (80.2) > 35 years 5(11.6) 6 (10.4) 11 (10.9) Schooling < 8 years 11(25.6) 8 (13.8) 0.71 19 (18.8) > 8 years 32 (74.4) 50 (86.2) 82 (81.2) Family income 2 minimum wages 9 (20.9) 17 (29.3) 0.56 26 (25.7) > 2 minimum wages 34 (79.1) 41 (70.7) 75 (74.3) Currently employed Yes 19 (44.2) 31 (53.4) 0.26 50 (49.5) No 24 (55.8) 27 (46.6) 51 (50.5) Maternityleave Yes 13(30.2) 26(44.8) 0.02 39 (38.6) No 30 (69.8) 32 (55.2) 62 (61.4) Birth type Normal 30 (69.8) 44 (75.9) 0.31 74 (73.3) Cesarean section 13 (30.2) 14 (24.1) 27 (26.7) Parity First pregnancy 19 (44.2) 29 (50.0) 48 (47.5) 2–3 pregnancies 21 (48.8) 24 (41.4) 0.75 45 (44.6) 4 pregnancies 3 (7.0) 5 (8.6) 8 (7.9) Prenatal consultation < 6 3(7.0) 4 (6.9) 0.98 7 (6.9) 6 40 (93.0) 54 (93.1) 94 (93.1) Skin-to-skin contact Yes 30 (69.8) 49 (84.5) 0.07 79 (78.2) No 13 (30.2) 9 (15.5) 22 (21.8) Breastfeeding in the ﬁrst hour Yes 26 (60.5) 40 (69.0) 0.37 66 (65.3) No 17 (39.5) 18 (31.0) 35 (34.7) Support to breastfeeding Yes 38 (88.4) 37 (63.8) 0.005 75 (74.3) No 5 (11.6) 21 (36.2) 26 (25.7)

Source: Data of the survey, 2019. Note: p < 0.05. Table 3 Main difficulties with breastfeeding and reasons for variables type of delivery, prenatal consultations,andparity weaning (n ¼ 101) did not present a statistically significant difference among the women who maintained EBF or not at six months Variable n % (►Table 2). As for the variables related to good perinatal Difficulty breastfeeding No 54 53.5 practices, EBF was more prevalent among the women who ¼ received support to breastfeed than among the women who N 101 Fissure 23 22.8 did not maintain EBF (p ¼ 0.005), and the variable skin-to- Mastitis 5 5.0 skin contact, despite not having presented a statistically Engorgement 1 1.0 fi signi cant difference, tended to be lower among the Lowmilkproduction 18 17.8 mother/infant binomials who maintained EBF. Reason for weaning Return to work 7 26.9 Then, we evaluated whether the variables maternity leave, N ¼ 26 support to breastfeeding (which were associated with breast- Lowmilkproduction 11 42.3 feeding) and skin-to-skin contact (which tended to be associ- By option 8 30.8 ated with breastfeeding) were risk or protective factors for EBF through the calculation of the OR. This analysis showed Source: Research data, 2019. that taking maternity leave tended to increase the probability of maintenance of the EBF (OR ¼ 0.533; 95% confidence interval [95%CI]: 0.232 to 1.225; p ¼ 0.138), and skin-to-skin breastfeeding 4-fold (OR ¼ 0.232; 95%CI: 0.079 to 0.679; contact tended to decrease this probability (OR ¼ 2.359; 95% p ¼ 0.008). CI: 0.90 to 6.1845; p ¼ 0.081). In contrast, professional and Finally, the factors that made breastfeeding difficult and family support to breastfeeding increased the chance of that influence weaning were investigated (►Table 3).

Approximately half of the interviewees (46.5%) reported The studied population had a high rate of normal delivery some difficulty in breastfeeding, the most predominant (73.3%), the most recommended route for birth by the WHO. being ‘nipple fissure’ (22.8%), followed by the complaint of Cesarean section, in turn, is considered a hindrance to low ‘milk production’ (17.8%). Weaning affected 25.7% of the breastfeeding in the first hour of life, a variable that has population, and low milk production appears as the main already been related to the longer duration of breastfeed- driver (42.3%), followed by weaning by maternal option ing.3,8 Although two thirds of the mothers studied had (30.8%) and return to work (26.9%). breastfed in the first hour of life, there was no association between this variable and EBF. 13 Discussion A Cochrane review sought randomized trials on skin-to- skin contact and breastfeeding, and concluded that mothers In view of the benefits for the mother/infant binomial and the who had skin-to-skin contact breastfed exclusively for longer – WHO recommendations regarding the maintenance of EBF in periods.5 13 Although skin-to-skin contact was more fre- the first six months of life of the infant, the aim of the present quent among women who weaned in this particular sample, study was to describe the socioeconomic, obstetric and the practice is encouraged by the WHO, and it corresponds to perinatal aspects related to childbirth care that influenced step four of the Ten Steps to Successful Breastfeeding in the EBF in an usual-risk maternity, a reference in good practices BFHI.12 in childbirth and birth care. There was a high rate of Women who received ‘support to breastfeeding’’ were 4 breastfeeding (73.4%) among the population studied, in times more likely to maintain EBF (p ¼ 0.008). The support addition to EBF rates (42.6%) above the data estimated for network for the puerperal woman must start in the prenatal Brazil (38.6%) and the world (40%), according to data from the period, and remain during the care received at the hospital and UNICEF.7 In Brazil, EBF rates have been gradually increasing, after discharge, since, due to the difficulties that arise during and although they are almost twice as high as those in the breastfeeding period, the puerperal woman can seek middle- and upper-income countries (23.9%), they are still support and continue to breastfeed.6 The support of the far behind the rates of countries like Rwanda (86.9%), Bur- partner in this network reinforces the importance of family undi (82.3%) and Sri Lanka (82%), which have the highest EBF members involvement in the whole process of gestating, rates in the world.7 In the state of Pernambuco, Brazil, a study giving birth and maternal. The importance of the team in revealed that the median period of EBF was of only 60.84 maintaining EBF during hospitalization at the maternity hos- days, which indicates that the good practices of the institu- pital is highlighted, as the mother/infant binomials discharged – tion studied here and the BFHI seem to have positively on EBF are 2.5 times more likely to maintain the EBF.3 14 The influenced the maintenance of EBF.8 hospital where the present study took place offers support AgeisoneofthefactorsthatcanaffectEBF.Someauthors through the promotion, protection and encouragement of believe that women over the age of 30 breastfeed longer than breastfeeding during the entire hospitalization. This is done younger women, and that adolescence can be a weaning through guidance and assistance in breastfeeding, added to the factor.3,4 In the present study, most women were aged between good practices of care during childbirth. The maternity in 20 and 34 years, but age was not associated with EBF. Likewise, question has an Interdisciplinary Committee on Breastfeeding, theEBFwasnotrelatedtoschooling.Therearereportsthat which is composed of an engaged multidisciplinary team mothers with more than eight years of schooling breastfeed (doctors, nurses, nutritionist, social worker and speech thera- more,astheyhavemoreaccesstoinformation.3 In addition, the pist) and promotes courses, workshops, lectures, research and low level of schooling can also delay the beginning of prenatal discussions in this field, with the objective of supporting care, which directly results in successful breastfeeding.3 In breastfeeding and increasing breastfeeding rates. The assis- contrast, the higher level of schooling of the women can tance team works with individualized care and daily physical increase the rate of formal employment and result in an early examination of the breasts to identify nipple fissures, engorge- return to work, which influenced the early weaning of 7 of the ment and solve the doubts of the women during the entire 26 patients who stopped breastfeeding before 6 months.8 hospitalization. The maternity hospital also has an exclusive In the present study, women who did not take maternity breastfeeding support room, a pleasant and reserved place, leave breastfed more. There are studies that state that the which is ideal for individualized and differentiated care. All mother's presence at home is positive for the continuity of women should be instructed on the importance of breastfeed- EBF, while others claim the opposite.3,10 In the present study, ing, on the correct position to breastfeed, on milking the all unemployed women belonged to the group who did not breasts when necessary, and on the prevention of fissures receive maternity leave, so we believe that staying at home and other complications, and as to when to seek help and for this population is a factor that protects breastfeeding. professional support. Regular prenatal care with more than six consultations Difficulties in breastfeeding usually occur in cascade. The and mainly with quality of care and guidance is a greatly for position of the mother/infant binomial affects the grip and the success of breastfeeding.2,8 A high adherence to prenatal suction, which can result in nipple fissure that generates care was observed in the studied group (93% had had 6 pain.5 Due to pain, the puerperal woman tends to offer the consultations). A longitudinal study2 with 531 infants in breast less often to the infant, which increases the likelihood 2012 found that the absence of prenatal care increased the of low milk production or results in breast engorgement.15 chance of reducing breastfeeding time by 173%. Nipple fissure, the most frequent complaint in this

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. 96 Exclusive Breastfeeding in a Maternity Hospital Reference in Humanized Birth Brandt et al.

population, is seen in the literature as an important factor for 3 Margotti E, Margotti W. [Factors related to exclusive breastfeed- weaning.15 Although many women have reported insuffi- ing in babies born in a child-friendly hospital in a northern – cient milk production, it is known that, biologically, the Brazilian capital]. Saúde Debate. 2017;41(114):860 871. Doi: 10.1590/0103-1104201711415 production is sufficient for their children. This statement 4 Cavalcanti SH, Caminha MdeF, Figueiroa JN, Serva VMSBD, Cruz denotes the insecurity that usually disappears over time, if RSBLC, de Lira PIC, Batista Filho M. Factors associated with 6 the mother receives adequate guidance and support. breastfeeding practice for at least six months in the state of The bias of postpartum memory failure and the fact that Pernambuco, Brazil. Rev Bras Epidemiol. 2015;18(01):208–219. the second part of the data collection was performed by Doi: 10.1590/1980-5497201500010016 telephone, which may allow for some misunderstanding in 5 Carreiro JA, Francisco AA, Abrão ACFV, Marcacine KO, Abuchaim ESV, Coca KP. Breastfeeding difficulties: analysis of a service the questions used, are the main limitations of the present specialized in breastfeeding. Acta Paul Enferm. 2018;31(04): study. Thus, it is necessary to conduct new studies with the local 430–438. Doi: 10.1590/1982-0194201800060 population, and to compare different institutions to promote 6 Amaral LJX, Sales SdosS, Carvalho DPSRP, Cruz GKP, Azevedo IC, current results that strengthen breastfeeding assistance. Ferreira Júnior MA. [Factors that influence the interruption of exclusive breastfeeding in nursing mothers]. Rev Gaúcha Enferm. 2015;36(Spec No):127–134. Doi: 10.1590/1983-1447.2015. Conclusion esp.56676 7 United Nations Organization. [UNICEF: only 40% of children in the The factors that were associated with the duration of EBF in world receive exclusive breastfeeding early in life] [Internet]. New the present study were staying at home with the child longer, York: United Nations; 2019 [cited 2019 Oct 15]. Available from: and the support of the professional or family members to https://nacoesunidas.org/unicef-apenas-40-das-criancas-no- breastfeeding, which reduced the chance of interrupting EBF mundo-recebem-amamentacao-exclusiva-no-inicio-da-vida/ 8 Santos EMD, Silva LSD, Rodrigues BFS, de Amorim TMAX, da Silva four-fold. Although the other variables discussed here are not CS, Borba JMC, Tavares FCLP. [Breastfeeding assessment in chil- fi fl signi cant, it is known that good practices re ect on all of dren up to 2 years of age assisted in primary health care of Recife assistance provided and throughout the life of the in the state of Pernambuco, Brazil]. Cien Saude Colet. 2019;24 mother/infant binomial. Finally, data on the factors associat- (03):1211–1222. Doi: 10.1590/1413-81232018243.126120171 ed with early weaning provide a basis to support interven- 9 Ministério da Saúde Secretaria de Atenção à Saúde Departamento tions and discussions capable of improving the quality of de Atenção Básica. [Child health: breastfeeding and complementary feeding]. Brasília (DF): Ministério da Saúde; 2015 care for the maternal and infant population. 10 Campos AMS, Chaoul CdeO, Carmona EV, Higa R, do Vale IN. Exclusive breastfeeding practices reported by mothers and the Contributors introduction of additional liquids. Rev Lat Am Enfermagem. 2015; All authors participated in the concept and design of the 23(02):283–290. Doi: 10.1590/0104-1169.0141.2553 present study, in the analysis and interpretation of data, in 11 Silva CM, Pereira SCL, Passos IR, Santos LC. [Factors associated the draft or revision of the manuscript, and they have with skin-to-skin contact between mother / child and breastfeeding in the delivery room]. Rev Nutr. 2016;29(04):457–471. Doi: approved the manuscript as submitted. All authors are 10.1590/1678-98652016000400002 responsible for the reported research. 12 D’Artibale EF, Bercini LO. The practice of the fourth step of the baby-friendly hospital initiative. Esc Anna Nery. 2014;18(02): Conflict of Interests 356–364. Doi: 10.5935/1414-8145.20140052 The authors have no conflict of interests to declare. 13 Moore ER, Bergman N, Anderson GC, Medley N. Early skin-to-skin contact for mothers and their healthy newborn infants. Cochrane Database Syst Rev. 2016;11(11):CD003519. Doi: 10.1002/ References 14651858.CD003519.pub4 1 World Health Organization. Guideline: protecting, promoting and 14 Cruz NACV, Reducino LM, Probst LF, Guerra LM, Ambrosano GMB, supporting breastfeeding in facilities providing maternity and Cortellazzi KL, et al. [Association between the type of breastfeed- newborn services [Internet]. Geneva: WHO; 2017 [cited 2019 Oct ing at discharge of the newborn and at six months of life]. 20]. Available from: http://www.who.int/nutrition/publications/ Cad Saude Colet. 2018;26(02):117–124. Doi: 10.1590/1414- guidelines/breastfeeding-facilities-maternity-newborn/en/ 462x201800020349 2 Ferreira HLOC, Oliveira MF, Bernardo EBR, Almeida PC, Aquino PS, 15 Moraes BA, Gonçalves AC, Strada JKR, Gouveia HG. Factors associ- Pinheiro AKB. Factors associated with adherence to exclusive ated with the interruption of exclusive breastfeeding in infants up breastfeeding. Cien Saude Colet. 2018;23(03):683–690. Doi: to 30 days old. Rev Gaúcha Enferm. 2017;37(spe):e2016-0044. 10.1590/1413-81232018233.06262016 Doi: 10.1590/1983-1447.2016.esp.2016-0044

Temporal Trend of Near Miss and its Regional Variations in Brazil from 2010 to 2018 Tendência temporal do near miss e suas variações regionais no Brasil de 2010 a 2018 Maria Carolina Wensing Herdt1 Flávio Ricardo Liberal Magajewski1 Andressa Linzmeyer1 Rafaela Rodolfo Tomazzoni1 Nicole Pereira Domingues1 Milla Pereira Domingues1

1 Universidade do Sul de Santa Catarina, Tubarão, SC, Brazil Address for correspondence MariaCarolinaWensingHerdt,Avenida José Acácio Moreira, 787, Bairro Dehon, Tubarão, SC, Brazil Rev Bras Ginecol Obstet 2021;43(2):97–106. (e-mail: [email protected]).

Abstract Cases of maternal near miss are those in which women survive severe maternal complications during pregnancy or the puerperium. This ecological study aimed to identify the temporal trend of near-miss cases in different regions of Brazil between 2010 and 2018, using data from the Hospital Information System (HIS) of the Unified Brazilian Health System (SUS, in the Portuguese acronym). Hospital admission records of women between 10 and 49 years old with diagnosis included in the 10th Revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) and codes indicating near- Keywords miss events were selected. From 20,891,040 admissions due to obstetric causes, 766,249 ► near miss (3.66%) near-miss cases were identified, and 31,475 women needed admission to the ► maternal mortality intensive care unit (ICU). The cases were found to be more predominant in black women ► hospital records over 35 years old from the North and Northeast regions. There was a trend of increase in ► complications of near-miss rates of 13.5% a year during the period of the study. The trend presented a pregnancy different behavior depending on the level of development of the region studied. The main ► morbidity causes of near miss were preeclampsia (47%), hemorrhage (24%), and sepsis (18%).

Resumo Casos de near miss materna são aqueles em que as mulheres sobrevivem a graves complicações maternas durante a gravidez ouopuerpério.Esteestudoecológicoteve como objetivo identificar a tendência temporal de casos de near miss em diferentes regiões do Brasil entre 2010 e 2018, utilizando dados do Sistema de Informações Hospitalares (SIH) do Sistema Único de Saúde (SUS). Foram selecionados registros de internação de mulheres entre 10 e 49 anos com diagnóstico incluído na 10ª revisão da Classificação Internacional de Doenças e Problemas Relacionados à Saúde (CID-10) e códigos indicando eventos de near miss.Das Palavras-chave 20.891.040 internações por causas obstétricas, 766.249 (3,66%) casos de near miss foram ► near miss identificados, e 31.475 mulheres necessitaram de internação na unidade de terapia intensive ► mortalidade materna (UTI). Constatou-se que os casos são mais predominantes em mulheres negras com mais de 35 ► registros hospitalares anos da região Norte e Nordeste. Houve uma tendência de aumento nas taxas de near miss de ► complicações da aproximadamente 13,5% ao ano durante o período do estudo. A tendência apresentou um gravidez comportamento diferente, dependendo do nível de desenvolvimento da região estudada. As ► morbidade principais causas de near miss foram pré-eclâmpsia (47%), hemorragia (24%), e sepse (18%).

received DOI https://doi.org/ © 2021. Federação Brasileira das Associações de Ginecologia e April 20, 2020 10.1055/s-0040-1719144. Obstetrícia. All rights reserved. accepted ISSN 0100-7203. This is an open access article published by Thieme under the terms of the September 14, 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 98 Temporal Trend of Near Miss and its Regional Variations in Brazil from 2010 to 2018 Herdt et al.

Introduction causes of maternal mortality.9 The identification of these cases is increasingly recognized as a useful strategy for assessing the The health of woman and child is a priority in the modern quality ofobstetric care. In other words, maternal near miss is a world, and losses during the pregnancy-puerperium cycle and sensitive and relevant indicator related to women’s health childhood are considered unacceptable to families and socie- care, and it seems to be associated with the level of human and ty.1 Rosendo and Roncalli2 demonstrated that the reduction of social development in different societies.10 the rates of maternal and perinatal morbidity and mortality The clarification of the temporal trend of maternal near depends on investments and the restructuring of the assis- miss, which is the main age range affected and its risk factors, tance provided to pregnant women and newborns to improve contributes to the expansion of knowledge on a subject that is its quality, which includes training and qualification of doctors not as much discussed, and can serve as a tool for monitoring and health professionals for promotion of safer maternity. To the network and add to the endorsement of public policies that achieve this, they must be able to manage pregnancy, child- protect women from maternal complications and, conse- birth, and risky situations or complications in women and/or quently, reduce the mortality and morbidity rates of this newborns.3 group. It is estimated that 273,000 maternal deaths occurred in The question that guided this research was: which were the world in 2011. However, reduction of the maternal mortali- the temporal trends of maternal near miss and its regional ty rate (MMR) has been slow, 2.3% a year, since 1990. In Brazil, variations in Brazil from 2010 to 2018. between 2000 and 2014, the average maternal mortality rate was 55.7 deaths/100,000 live births. Despite the good perfor- Methods mance as a nation, it is important to take a closer look at mortality rates in the macro-regions of the country, which This was an observational ecological study that analyzed tem- presented considerable disparity. From every 100,000 live poral series of data from the Hospital Information System of the births, 78.6 mothers died in the North region in 2014. The Unified Brazilian Health System (HIS/SUS, in the Portuguese Northeast presented the second-highest maternal mortality acronym). Records of women between 10 and 49 years old from rate (71.3 deaths/100,000 live births), followed by the South- different regions of Brazil, admitted between 2010 and 2018, west (54.6 deaths/100,000 live births), Central-West (54.3 were considered. The selectionwas done according to thefields: deaths/100,000 live births), and South (37.6 deaths/100,000 main diagnosis, secondary diagnosis, macro-region, race, and live births).4 admission to the ICU. Most pregnancies evolve in a physiological and healthy The database was composed following the algorithm pre- way, and end in uneventful labor, but among the spectrum of sented in ►Table 1, using the tabulation software, Tabwin. healthy pregnancy and maternal death, we can identify First, all hospital records of women living in Brazil, admitted several harmful conditions for women.5 The Maternal Mor- between 2010 and 2018, were selected, totaling 59,911,177 bidity Working Group of the World Health Organization admissions. Then, filters of age (10 to 49 years old) and main (WHO), when analyzing the epidemiology of the pregnan- diagnosis included in Chapter XV - Pregnancy, childbirth, and cy-obstetric-puerperal cycle, established and validated the the puerperium -ofthe10th Revision of the International concept of maternal near miss (near maternal death) or Severe Acute Maternal Morbidity (SAMM), which are situa- Table 1 Risk rates (x100 deliveries) of admissions due to a near- tions in which certain women almost died from complica- miss event by macroregion and year of occurrence tions that occurred during pregnancy, childbirth or the puerperium, but somehow survived.6 In practical terms, a Year\ North Northeast Southeast South Central- Total pregnant woman is considered a case of near miss when she Region West faces serious life-threatening conditions similar to those that 2010 6.40 5.65 5.31 4.78 5.57 5.52 lead to death, but survives. 2011 6.83 5.73 5.28 4.69 4.98 5.52 To standardize these criteria, the WHO developed a clas- 2012 6.87 5.90 5.38 4.67 4.34 5.55 sification based on three axes of severe maternal morbidity: 2013 6.95 5.91 5.33 4.83 4.66 5.58 clinical, laboratory and management markers. In addition to 2014 6.94 6.12 5.16 4.61 4.13 5.52 this classification, there are two more widely used classi- 2015 6.17 5.99 5.10 4.66 4.57 5.39 fi 7 cations, one elaborated by Mantel et al. and Waterstone 2016 6.67 6.91 5.54 5.79 5.12 6.11 8 et al., both being based on different approaches, with 2017 7.70 7.92 6.18 6.42 5.57 6.88 different specificities and sensitivities. The classification 2018 8.17 7.89 6.42 6.61 6.08 7.11 adopted by the WHO makes it possible to identify the Mean 6.95 6.41 5.52 5.18 4.99 5.89 most serious cases, with a higher risk of death; however, Spearman 0.5 0.97 0.55 0.53 0.34 0.64 the Waterstone criteria and the Mantel criteria, by using Beta 0.63 0.89 0.71 0.82 0.37 0.80 clinical disorders or identifiable organ dysfunctions, expand p-value 0.07 0.00 0.03 0.01 0.32 0.06 the possibility of detecting the cases.7,8 Taking into account that near miss cases occur more Spearman ¼ Spearman coefficient of correlation; Beta ¼ mean annual frequently than maternal deaths, their study allows a broader variation (near-miss cases/100 deliveries/year); p-value (ANOVA). ¼ p < identification of the risk factors most associated with the 0.05.

Statistical Classiﬁcation of Diseases and Related Health Prob- systems as long they are related to pregnancy, childbirth, and lems (ICD-10)11 were applied, resulting in 20,891,040 women the puerperium, whereas Waterstone’s criteria include clin- admitted as the population of the study. ical diagnoses of the most frequent pathological conditions To select the records of admissions due to SAMM - near of pregnancy, childbirth, and puerperium, such as severe miss - the ICD-10 codes corresponding to the near-miss preeclampsia, hemorrhage, sepsis, and uterine rupture.7,8 diagnosis were used according to the criteria and deﬁnitions Admission records that contained procedures regarding established by Mantel et al.7 and Waterstone et al.,8 as seen clinical complications of pregnancy were removed because in Chart 1.7,8 Mantel’s criteria include conditions that are the codes related to the complications do not discriminate typical of organic dysfunctions in organs and human body their severity and could encompass any complication, even

Chart 1 Near miss classiﬁcation

Mantel’s criteria A.1 Organ dysfunction Criteria/definitions Generic categorization of diagnoses [ICD-10 Codes] Pulmonary edema [J81] 1. Cardiac dysfunction Cardiomyopathy; congestive heart failure 1.1 Pulmonary edema [I11.0; I42.0; I42.1; I42.8; I42.9; I43.8; I46; I46.0; 1.2 Cardiac Arrest I46.9; I50.0; I50.1; I50.9; O75.4; O90.3; R57.0] 3. Immunological dysfunction Infection; sepsis; genital tract and pelvic infection complicating abortion 3.1 Admission to the ICU for sepsis Peritonitis; salpingitis [A02.1; A22.7; A26.7; A32.7; 3.2 Emergency hysterectomy for sepsis A40; A40.0; A40.1; A40.2; A40.3; A40.8; A40.9; A41; A41.0; A41.1; A41.2; A41.3; A41.4; A41.5; A41.8; A41.9; A42.7; A54.8; B37.7; K35.0; K35.9; K65.0; K65.8; K65.9; M86.9; N70.0; N70.9; N71.0; N73.3; N73.5; O03.0; O03.5; O04.0; O04.5; O05.0; O05.5; O06.0; O06.5; O07.0; O07.5; O08.0; O08.2; O08.3; O41.1; O75.3; O85; O86; O86.0; O86.8; O88.3; T80.2] 4. Respiratory dysfunction 4.1 Intubation and ventilation for more than 60 minutes except for Respiratory failure; respiratory arrest; embolism general anesthesia 4.2PeripheralO2saturation< 90% for more than 60 minutes Embolism complicating abortion [I26.9; J80; J96; J96.0; 4.3 Ratio Pa O2/ FiO2 3 J96.9; O03.7; O04.7; O05.2; O06.2; O06.7; O88.1; Ratio Pa O2/ FiO2 300 mm Hg R09.2] 5. Renal dysfunction Renal failure following abortion [O08.4; R34] 5.1 Oliguria, defined as diurese < 400 ml/24 hour 5.2 Acute urea deterioration to 15 mmol/l or Acute kidney failure [E72.2; I12.0; I13.1; I13.2; creatinine > 400 mmol/l N17; N17.0; N17.1; N17.2; N17.8; N17.9; N18.0; O08.4; O90.4] Mantel’s criteria A.1 Organ dysfunction Criteria/definitions Generic categorization of diagnoses [ICD-10 Codes] 6. Liver dysfunction Liver dysfunctions; viral hepatitis complicating pregnancy, childbirth 6.1Jaundiceduringpreeclampsia and the puerperium [K72; K72.0; K72.9; O26.6; O98.4] 7.Metabolicdysfunction Diabetesmellituswithcomaorketoacidosis[E10.0; (Continued)

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. 100 Temporal Trend of Near Miss and its Regional Variations in Brazil from 2010 to 2018 Herdt et al.

Chart 1 (Continued)

7.1DiabeticKetoacidosis E10.1;E11.0;E11.1;E12.0;E12.1;E13.0;E13.1; E14.0; E14.1] 7.2 Thyrotoxic crisis Thyrotoxicosis; metabolic disorder following abortion [E05; E05.0; E05.1; E05.2; E05.3; E05.4; E05.5; E05.8; E05.9; E06.0; E07; E07.8; E07.9; O08.5] 8. Coagulation dysfunction Disseminated intravascular coagulation; coagulation deficiencies 8.1 Acute thrombocytopenia requiring transfusion of platelets [D65; D68; D68.9; D69.4; D69.5; D69.6; D82.0; O45.0; O72.3] 9.Sub-arachnoid or intracerebral hemorrhage Intracerebral hemorrhage; stroke; vertebral venous thrombosis during pregnancy [G93.6; I60; I60.0; I60.1; I60.2; I60.3; I60.4; I60.5; I60.6; I60.7; I60.9; I61; I61.0; I61.1; I61.2; I61.3; I61.4; I61.5; I61.6; I61.8; I61.9; I64; I69.1; O22.5] Waterstone’s criteria Criteria/codes Generic categorization of diagnoses [ICD-10 Codes] 1.Severepreeclampsia Moderate,severeorunspecified pre-eclampsia; pre-existing hypertension with superimposed proteinuria [O11; O14.0; O14.1; O14.9] 2. Eclampsia Eclampsia complicating pregnancy, childbirth or the puerperium [O15; O15.0; O15.1; O15.2; O15.9] 3. HELLPc syndrome 4.Severehemorrhage Delayedorexcessivehemorrhagecomplicatingabortion.Placenta previa with hemorrhage. Premature separation of placenta [D62; O03.1; O03.6; O04.1; O04.6; O05.1; O05.6; O06.1; O06.6; O07.1; O07.6;O08.1; O44.1; O45.0; O45.8; O45.9; O46; O46.0; O46.8; O46.9; O67.0; O67.8; O67.9; O69.4; O72; O72.0; O72.1; O72.2] 5. Sepsis Infection; septicemia; genital tract infection complicating abortion. Peritonitis. Salpingitis [A02.1; A22.7; A26.7; A32.7; A40; A40.0; A40.1; A40.2; A40.3; A40.8; A40.9; A41; A41.0; A41.1; A41.2; A41.3; A41.4; A41.5; A41.8; A41.9; A42.7; A54.8; B37.7; K35.0; K35.9; K65.0; K65.8; K65.9; M86.9; N70.0; N70.9; N71.0; N73.3; N73.5; O03.0; O03.5; O04.0; O04.5; O05.0; O05.5; O06.0; O06.5; O07.0; O07.5; O08.0; O08.2; O08.3; O41.1; O75.3; O85; O86; O86.0; O86.8; O88.3; T80.2] 6. Uterine rupture Rupture of uterus before or during labor. Disruption of cesarean delivery wound [O71.0; O71.1; O90.0] Waterstone’s criteria Criteria/definitions Generic categorization of diagnoses [ICD-10 Codes] 1. Acute abdomen Acute abdomen [R10.0] 2.Diseasecausedbyhumanimmunodeficiency virus d Infection caused by the human immunodeficiency virus [B20; B20.0; B20.1; B20.4; B20.8; B20.9]

Abbreviations: ICD-10, 10th Revision of the International Statistical Classiﬁcation of Diseases and Related Health Problems; ICU, Intensive care unit; HELLP syndrome, hemolysis (H), high levels of liver enzymes (EL) and low platelet count (LP).

those not related to severe maternal morbidity, what would ICD-10 were removed – a total of 425 cases, which is less than allow the same patient to be included twice (by the main 0.05% of the cases considered. diagnosis and by the procedure they were submitted to). For each year of the temporal trend, the rate of SAMM was Importantly, the admissions due to near-miss events consid- calculated by dividing the number ofhospital admissions due to ered were chosen based on the application of the criteria for severe maternal morbidity by the total number of deliveries sequential selection, eliminating the risk of duplicates. during the same period, multiplied by 100. That is, the rate of To perform the temporal analysis of near-miss cases in SAMM ¼ (near-miss cases/total of deliveries) 100. The denom- Brazil, all admission records with codes included in Chapter inator considered the number of deliveries included in the XV of ICD-1011 were selected, totalizing 765,824 cases. Near- database according to the main diagnosis included in each miss cases with secondary diagnosis in other chapters of the inpatient hospital authorization (IHA) found at the HIS/SUS and

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. Temporal Trend of Near Miss and its Regional Variations in Brazil from 2010 to 2018 Herdt et al. 101 not the number of live births, since it is not possible to The collection sequence performed to meet the goals of distinguish between the births that are financially supported this research can be understood more clearly in the flowchart by the SUS and those that are not in the Brazilian Live Birth below (►Fig. 1): Information System (SINASC, in the Portuguese acronym). Only admissions supported by the SUS between 2010 and 2018 were Results included in this study. The absolute and relative frequencies of admissions for The retrospective research of women admitted to any hos- near-miss events were described according to the most pital, anywhere in the country, due to complications related recent criteria. The age was stratified in 5-year intervals to pregnancy, childbirth and the puerperium, financially with the intent to estimate the frequency and near-miss supported by the SUS, during a 9-year period (2010–2018), rates according to different age groups in the reproductive resulted in a total of 20,891,040 admissions. From this total, cycle. 766,249 admissions (3.66%) due to SAMM - near miss, were The average annual variation of each series, obtained by selected. From these cases, it was verified that 31,475 simple linear regression (Beta coefficient - β), was used to women (4.1%) needed to be admitted to the intensive care analyze the trends of severe acute maternal morbidity. The unit (ICU) (►Table 1). strength of the time-event correlation was obtained by ►Table 1 shows that near-miss rates presented a trend of calculating the Spearman’s correlation coefficient. The sta- increase in every region of Brazil. The Northeast region had tistical significance was calculated by the analysis of vari- the most expressive increase. The time-event correlations in ance (ANOVA), and 95% was adopted as the significance level all regions, except North and Central-West, represented by (p < 00.5). the Spearman correlation test, were strong and significant For being an ecological study with population aggregation (p < 0.05). Brazil, as a whole, presented a positive average analysis without research subjects and of public access, it was variation of 0.80 near-miss cases per every 100 deliveries a not necessary to subject it to registration and analysis of the year, which represents an increase of 13.5% a year. Women Ethics Committee of Research involving Human Beings, accord- from the North region presented a risk of a near-miss event ing to Resolution no. 510/2016 of the National Health Council 25% higher than those from the Central-West region, which (CNS) (Article 1, Paragraph one of one, clauses III and V). had the lowest average risk rate.

Fig. 1 Schematic ﬂowchart of the data collection process and selection of near-miss cases.

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. 102 Temporal Trend of Near Miss and its Regional Variations in Brazil from 2010 to 2018 Herdt et al.

Table 2 Risk rates (x100 deliveries) of admissions due to a near- rhage two times higher (RR 2.06; CI 95% 1.93 - 2.21; miss event by age group of the patient and year of occurrence p < 0.001) and a 33% higher risk of sepsis when compared with the Central-West region (RR 1.33; CI 95% 1.23–1.44; Year/Age 10–14 15–19 20–29 30–39 40–44 45–49 Total p < 0.001). In the Southeast region, the risk of uterine group rupture was 133% higher than in the Central-West region 2010 6.07 4.44 4.99 7.71 11.64 18.28 5.52 (RR 2.33; CI 95% 1.60-3.40; p < 0.001). The Central-West 2011 6.16 4.49 4.95 7.59 12.52 18.09 5.52 region presented the lowest risk rates for causes related to 2012 6.04 4.47 5.02 7.53 12.22 19.28 5.55 near-miss events, which is the reason why it was used as a 2013 6.38 4.47 5.02 7.59 12.87 19.51 5.58 base of comparison for the regions with higher specific risk. 2014 5.97 4.39 4.91 7.65 12.64 19.29 5.52 Women admitted due to a maternal near miss were 31 2015 5.43 4.21 4.81 7.43 12.98 18.37 5.39 times more likely to be admitted to the ICU (RR 31.32; CI 95%: 28.82 - 34.03, p < 00.001). 2016 5.70 4.56 5.42 8.65 14.24 19.52 6.11 2017 6.90 5.03 6.09 9.63 15.82 22.90 6.88 2018 6.70 5.14 6.26 9.87 16.14 22.39 7.11 Discussion Mean 6.12 4.56 5.26 8.21 13.51 19.61 5.89 The present study verified a trend of increase of 13.5% a year Spearman’s 0.18 0.53 0.56 0.51 0.97 0.85 0.64 in hospital admissions due to near-miss events in Brazil during Beta 0.31 0.65 0.77 0.79 0.92 0.79 0.80 the period of the study. This trend is corroborated by a Brazilian p-value 0.42 0.06 0.02 0.01 0.00 0.01 0.06 study that analyzed the period between 2000 and 2012 and also verified an increase in the risk rates of near miss.12 Spearman ¼ Spearman coefficient of correlation; Beta ¼ mean annual When taking into account the average rates of SAMM in variation (near-miss cases/100 deliveries/year); p-value (ANOVA). Brazil during the period between 2010 and 2018, there is a risk rate of 5.89 near-miss cases per every 100 deliveries, which is ►Table 2 indicates a trend of increase in all the series of higher than those of other studies that also used the HIS/SUS – rates analyzed, with statistical significance (p < 0.02) from database.2 13 In the population-based study of Sousa et al. in 20 years old on. The increase in risk occurred along with the 2008,14 they analyzed different Brazilian capitals and macro- increase in the maternal age, from 15 years old on, and was regions and found a rate of 44.3/1,000 live births. more prominent in the age groups 40 to 44 and 45 to 49 years Nevertheless, maternal mortality in Brazil remained sta- old (β ¼ 0.917 and 0.792, respectively). Moreover, patients ble during the last few years, contrary to the positive trend in aged 40 to 49 years old presented a chance of having a near- severe maternal morbidity.14 This apparent contradiction miss event almost 3 times higher than the age group with the highlights the importance of discussing near miss, as it is lowest risk—age group 15 to 19 years old (relative risk [RR] possible that the identification of a higher number of cases 2.61; confidence interval [CI] 95%: 2.39–2.89; p < 0.001). might have guaranteed more comprehensive assistance to a With regards to the skin color of the hospitalized women, greater number of women in a risky obstetric situation, black women presented a risk of a near-miss event 19% reducing the more severe outcomes. higher than white women (RR 1.19; CI 95%: 1.06–1.33; The average risk rate of near miss in the Northeast region p < 0.001) (►Table 2). found in the present study (6.41/100 deliveries), despite In ►Table 3, considering the Waterstone’s criteria, the using a different methodology, was higher than the estimates main causes of hospitalization due to a near-miss event were of SAMM presented in the study of Rosendo and Roncalli,2 preeclampsia, with a rate of 2.78 admissions per every 100 which analyzed 167 cities of the State of the Rio Grande do deliveries (47%), followed by severe hemorrhage (24%), sep- Norte between 2008 and 2012 and verified a near-miss rate sis (18%), eclampsia (8%), and uterine rupture (3%).8 Except of 36.76/1,000 obstetric admissions. for the age group 10 to 14 years old, there was a progressive There were severe inequalities between the Brazilian macro- increase in complications due to a near-miss event following regions, especially in relation to human development.15 Astudy the increase in maternal age. Preeclampsia was the most on the evolution of the Human Development Index (HDI) in the prevalent cause of admission due to a near-miss event in Brazilian macro-regions verified that the North and Northeast every age group, followed by severe hemorrhage, predomi- regions presented the highest positive variations in every nant in the intermediate age groups and sepsis, predominant component of the HDI between 2000 and 2010, despite remain- in the extreme age groups. ing with the lowest indexes among all Brazilian regions.16 In a The prevalence of admissions due to a near-miss event broad sense, even with the improvement of the indicators of (Waterstone’s criteria) according to the macro-region of maternal and child health care verified in several studies, occurrence highlighted important differences between socioeconomic and health-care differences are still prevalent them. In the Northeast region, admission for preeclampsia in the North and the Northeast, which might explain the had an incidence 42% higher than in the Central-West region possible negative association between the highest risk rates (RR 1.42; CI 95% 1.34–1.50; p < 0.001), whereas in the South and the lowest indexes of obstetric care verified in these – region, eclampsia had an incidence 39% higher than in the regions.9 20 Moreover, the North region presented a relative Central-West region (RR 1.39; CI 95% 1.23–1.57; p < 0.001). risk of hemorrhage two times higher and a 33% higher risk of of The North region presented a relative risk of severe hemor- infection than the region with the lowest rates. This context

Table 3 Rates of admissions due to a near-miss event in Brazil, between 2010 and 2018, by criteria and age group, per every 100 deliveries

Waterstone’s criteria Age groups Criteria 10 to 14 15 to 19 20 to 29 30 to 39 40 to 44 45 to 49 TOTAL Preeclampsia 2.31 1.91 2.48 4.20 6.45 6.40 2.78 Eclampsia 0.79 0.45 0.41 0.64 0.06 0.00 0.48 Severe hemorrhage 1.40 1.04 1.30 1.96 3.66 5.89 1.43 Sepsis 1.56 1.07 097 1.29 2.25 6.09 1.10 Uterine rupture 0.06 0.04 0.05 0.08 0.13 0.36 0.05 TOTAL 6.13 4.54 5.22 8.18 13.54 19.84 5.86 Mantel’scriteria Age groups Criteria 10 to 14 15 to 19 20 to 29 30 to 39 40 to 44 45 to 49 TOTAL Cardiac dysfunction 0.00 0.00 0.00 0.001 0.002 0.00 0.00 Vascular dysfunction 0.00 0.00 0.00 0.00 0.00 0.00 0.00 Sepsis 1.56 1.07 0.97 1.29 2.25 6.10 1.10 Respiratory dysfunction 0.015 0.01 0.01 0.01 0.04 0.06 0.01 Abortion 0.002 0.00 0.00 0.00 0.00 0.006 0.00 Acute kidney failure 0.002 0.001 0.002 0.003 0.003 0.01 0.002 Kidney dysfunction 0.003 0.004 0.007 0.01 0.01 0.00 0.007 Diabetic Ketoacidosis 0.00 0.00 0.001 0.003 0.005 0.00 0.001 Thyrotoxicosis 0.005 0.003 0.003 0.003 0.005 0.00 0.003 Coagulation dysfunction 0.04 0.04 0.05 0.07 0.10 0.12 0.05 Cerebral dysfunction 0.002 0.001 0.002 0.003 0.003 0.01 0.002 Pulmonary dysfunction 0.01 0.01 0.01 0.015 0.02 0.04 0.01 TOTAL 1.64 1.14 1.06 1.42 2.45 6.36 1.19 suggests challenges in the access of pregnant women to health With regards to the South region, the RR of eclampsia was care units and specialized treatment, and fits the Three Delays 39% higher than the region with the lowest risk, the Central- Model of Thaddeus and Maine,21 in which patients delay the West. This puts into question the effectiveness and quality of search for assistance due to sociocultural reasons, are not able to prenatal care in the most developed regions of Brazil. Con- access obstetric care, and when they manage to do it, they have cerning prenatal care, Viellas et al.,23 studying the period to wait for a long time to receive treatment. In these regions, between 2011 and 2012, reported a 98.7% coverage of prenatal investments aimed at organizing an efficient and articulate care throughout Brazil, and nearly 100% coverage in the South maternal care network that offers support and qualified human region. However, several obstacles might contribute to low- resources, to provide quality care to pregnant women, are quality prenatal care, such as the existence of structural essential. barriers, unavailability of medicaments and essential exams, The comparative analysis of the main near-miss complica- and problems in the provision of health-care actions involving tions in different Brazilian macro-regions demonstrated that individual attention and clinical care.23 In relation to eclamp- the Southeast region presented a 133% higher risk of uterine sia, which is preceded by well-known medical signs that are rupture. The fact that uterine rupture occurs more commonly easily identifiable in the prenatal examination, the question in women with a c-section scar makes this complication one of that arises is: what is reducing the effectiveness of the prenatal the most concerning. In this sense, the increased risk can be care offered to virtually the whole Brazilian population explained by the higher prevalence of cesarean delivery in the through the Family Health Strategy (FHS)? Concerning the Southeast region of the country. In a study of 2013, Eufrásio22 age groups, the highest near-miss rates are concentrated in the verified a prevalence of 53.03% of cesarean delivery through- population above 40 years old. This was also verified in a study out Brazil, whereas in the Southeast region the prevalence was by Morse that analyzed near-miss prevalence at a reference 59.32%. The high incidence of this type of delivery is concern- hospital in Rio de Janeiro in 2009.24 Several data found the ing, as it is known that it increases the risk of neonatal and literature point to age as a risk factor for the occurrence of maternal morbidity and mortality and has been becoming a obstetric complications, a fact associated with the increase in severe public health care problem in Brazil.22 the number of women pregnant after 40 years old. The

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. 104 Temporal Trend of Near Miss and its Regional Variations in Brazil from 2010 to 2018 Herdt et al.

increase in maternal age is related to the higher incidence of constitute the “main diagnosis” field in the HIS-SUS, easier.7,8 comorbidities, such as hypertensive disorders of pregnancy, Nevertheless, the classification adopted by the WHO is more gestational diabetes, obesity, placenta previa, and need for selective for severity as it identifies cases with a higher risk of cesarean section, which are connected to the increase in the death, whereas Waterstone’s criteria tend to encompass a risk of a near-miss event.25 A Finnish study that analyzed the higher number of cases, even the ones that are less severe.8 period between 1997 and 2008 indicated that women in Despite being difficult to systematize the identification of advanced age had a risk of preeclampsia 1.5 times higher near-miss cases, it is essential to understand them to plan for than women under 40 years old.25 the assistance provided during pregnancy, childbirth, and Preeclampsia remained as the complication with the high- the puerperium. Their identification reveals relevant infor- est risk rates in Brazil during the period studied. Adisasmita mation that health-care professionals can use to avoid et al.26 also verified that 57.3% of women in Indonesia pre- maternal morbidity and mortality. Filippi et al.,29 in a study sented hypertensive syndrome as a primary determining involving three countries,—Benin, Ivory Coast, and Morocco factor. Contrarily, studies performed by Rosendo and Roncalli,2 —proposed that near-miss cases should be estimated in two and Cecatti et al.3 presented hemorrhage as the main cause of moments: cases identified at the arrival at hospital, as a good near miss. The explanation for this differencemight befound in indicator of the obstetric care during emergencies; and cases the methodology used by the studies analyzed, which were that happened after admission, as a tool for monitoring the based on self-reported morbidity. Despite severe hemorrhage quality of the obstetric services.29 having a near-miss rate lower than that of preeclampsia, it It is important to emphasize that Brazil is one of the few suffered a trend of increase following the increase of the countries that counts with a well-structured hospital informa- maternal age during the period of the study. This is a relevant tion system, the HIS/SUS, which makes data of reasonable fact considering that, once again, the non-recognition or delay quality available for the analysis of hospital morbidity and in the identification of cases and institution of effective development of preventive measures.30 Its underutilization as therapy are the only possible explanations for this reality. diagnosis and monitoring of the improvement of the quality of With resources, accurate diagnosis and assistance at the right obstetric care in Brazil is a reflection of the stage of Brazil’s moment, hemorrhage can be the most preventable of scientific and technological development. The method used in the maternal mortality causes. Nonetheless, barriers, such as the present research proved to besuitablefor the identification the lack of systematization of assistance in emergencies, of near-miss cases upon analysis of the information from the inadequate medical approach that underestimates blood HIS/UHS. These findings are corroborated by the study of Silva loss, insufficient fluid resuscitation and delay in the surgical et al.,31 performed in the State of Paraná in 2010. approach after errors in the clinical treatment, are quite Regarding the limitations imposed on this paper resulting common in obstetric centers.27 The “Birth in Brazil” survey, from the use of secondary data, we can observe that the performed between February 2011 and October 2012, reliability of the information collected at the SIH/SUS not assessed data about near miss according to the criteria of only depends on the quality of the data filled in hospital the WHO. The near-miss rate found was of 10.2/1,000 live records but also on the competence of professionals who births and 30.8 near-miss cases per every maternal death. Such register the admission diagnoses in hospitals. One should findings are conservative, as cases of abortion and complica- also take into account the fact that the SIH/SUS has as its tions that occurred during the puerperium after the hospital main duty the directing of monetary resources to hospitals, discharge were not included.28 The present study found near- and it is sometimes necessary to change the codes of proce- miss rates almost five times higher than the aforementioned dures to better adjust the financial transfer.31 Still in relation survey. The utilization of Waterstone’sandMantel’sdefini- to the difficulties attributed to this work, it is important to tions widened the criteria used for the diagnosis of maternal highlight some of these characteristics of the ecological near-miss cases, which can be considered a plausible explana- study methodology. One of the restrictive aspects concerns tion for the higher incidence found.7,8 Regarding the result of the databases of the morbidities researched, which may hospitalizations for near miss, we affirm that there was a suffer the influence of the different levels of development proportional tendency of increase between the risk rates of of each region of the country and may impact the near miss and admission to the ICU in Brazil, during thestudied reliability of the information with qualitative errors and period. In other studies, ICU admissions also showed a direct underreporting. relationship with the number of maternal near miss cases, as 2–24 well as an association with a worse prognosis. Conclusion It is important to highlight that the WHO’s criteria for near miss were not used in this research due to the difficulty in The results of the present study demonstrate a trend of correlating them with the ICD-10 diagnoses used by HIS-SUS. increase in the average risk rates of severe acute maternal For the characterization of near-miss cases, the WHO pro- morbidity in Brazil, between 2010 and 2018. The highest poses the use of the diagnosis of organ dysfunction, which near-miss rates were concentrated in the North and North- can be revealed following clinical, laboratory and treatment east region, and cases were more predominant among black criteria.6 The choice for Waterstone’s and Mantel’s criteria to women over 40 years old. The main near-miss causes that identify maternal near-miss cases made the correlation affected Brazilian women were preeclampsia, severe hemor- between the medical conditions and the ICD-10 codes, which rhage, sepsis, and uterine rupture, in this order. Maternal

near miss stands out as a complement to the investigation of 9 De Souza MA, De Souza TH, Gonçalves AKS. [Determinants of maternal mortality. Its understanding helps the elaboration maternal near miss in an obstetric intensive care unit]. Rev Bras – of strategies for reducing maternal mortality as it allows for a Ginecol Obstet. 2015;37(11):498 504. Doi: 10.1590/SO100- 720320150005286 quicker obtainment of information about obstetric care since 10 Silva KS. Mortalidade materna: avaliação da situação no Rio de women that die go through the stage of organ dysfunction Janeiro, no período de 1977 a 1987. Cad Saude Publica. 1992;8 earlier. Thus, near-miss cases appear as a mean that allows (04):442–453. Doi: 10.1590/S0102-311 1992000400009 strategies for early diagnosis and prevention to be possible 11 World Health Organization. ICD-10: International Statistical Clas- and more effective. Primary prevention policies as well as sification of Diseases and Related Health Problems: 10th Revision. th well-structured programs that guarantee equity in the access 5 ed. Geneva: WHO; 2016 12 Magalhães MC, Raymundo CE, Bustamante-Teixeira MT. Morbid- to healthcare units, diagnosis, and follow-up are essential to ade materna extremamente grave a partir de registros de inter- reverse the current scenario and reduce the burden of this namento hospitalar no Sistema Único de Saúde: algoritmo para morbidity in Brazilian women. identificação dos casos. Rev Bras Saúde Mater Infant. 2013;13 (01):17–22. Doi: 10.1590/S1519-38292013000100002 Contributors 13 Carvalho BAS, Andrade AGBF, Dantas AS, Figueiredo IM, Silva JA, Rosendo TS, Rocalli A. Temporal trends of maternal near miss in All authors participated in the concept and design of the Brazil between 2000 and 2012. Rev Bras Saúde Mater Infant. study, as well as in the analysis and interpretation of data; 2019;19(01):115–124. Doi: 10.1590/1806-93042019000100007 draft or revision of the manuscript; and they have ap- 14 Sousa MH, Cecatti JG, Hardy EE, Serruya SJ. Severe maternal proved the manuscript as submitted. All authors are morbidity (near miss) as a sentinel event of maternal death. An responsible for reposted research. attempt to use routine data for surveillance. Reprod Health. 2008; 5:6. Doi: 10.1186/1742-4755-5-6 15 Szwarcwald CL, Escalante JJC, Rabello Neto DdeL, Souza Junior PR, Conflicts of Interests Victora CG. Estimation of maternal mortality rates in Brazil, 2008- fl The authors have no con ict of interests to declare. 2011. Cad Saude Publica. 2014;30(Suppl 1):S1–S12. Doi: 10.1590/0102-311X00125313 16 Atlas do Desenvolvimento Humano no Brasil [Internet]. 2013 References [cited 2019 Aug 2]. Available from: http://atlasbrasil.org.br/2013/ 1 Silva JMP, Fonseca SC, Dias MAB, Izzo AS, Teixeira GP, Belfort PP. 17 Vidor RC, Sakae TM, Magajewski FRL. 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Gestational Diabetes Mellitus and Obesity are Related to Persistent Hyperglycemia in the Postpartum Period Diabetes mellitus gestacional e obesidade estão relacionados à hiperglicemia persistente no período pós-parto Patricia Moretti Rehder1 Anderson Borovac-Pinheiro1 Raquel Oliveira Mena Barreto de Araujo1 Juliana Alves Pereira Matiuck Diniz1 Nathalia Lonardoni Crozatti Ferreira1 Ana Claudia Rolim Branco1 Aline de Fatima Dias1 Belmiro Gonçalves Pereira1

1 Obstetrics Departament, Universidade Estadual de Campinas, Address for correspondence Anderson Borovac-Pinheiro, MD, PhD, Campinas, SP, Brazil Cidade Universitária Zeferino Vaz, Barão Geraldo, 13083-970, Campinas, SP, Brazil (e-mail: [email protected]). Rev Bras Ginecol Obstet 2021;43(2):107–112.

Abstract Objective To evaluate the obstetric and sociodemographic characteristics of gestational diabetic women who maintained hyperglycemia in the postpartum period (6–12 weeks postpartum). Methods This is a longitudinal cohort study with women who have had gestational diabetes and/or macrosomic children between March 1st, 2016 and March 1st, 2017. Between 6 and 12 weeks after birth, women who had gestational diabetes collected fasting glycemia, glucose tolerance test, and glycated hemoglobin results. The data were collected from medical records and during an interview in the first postpartum consultation. A statistical analysis was performed using frequency, percentage, Chi- Squared test, Fisher exact test, Mann-Whitney test, and multivariate Poisson regression. The significance level adopted for the statistical tests was 5%. Results One hundred and twenty-two women were included. Most of the women were younger than 35 years old (70.5%), white, multiparous, and with no history of gestational diabetes. Thirteen percent of the participants developed persistent Keywords hyperglycemia. A univariate analysis showed that maternal age above 35 years, being ► gestational diabetes overweight, having grade 1 obesity and weight gain under 5 kg was related to the ► obesity persistence of hyperglycemia in the postpartum period. ► hyperglycemia Conclusion Maternal age above 35 years, obesity and overweight, and the diagnosis ► postpartum period of gestational diabetes in the first trimester of pregnancy are associated with ► overweight hyperglycemia during the postpartum period.

received DOI https://doi.org/ © 2021. Federação Brasileira das Associações de Ginecologia e January 9, 2020 10.1055/s-0040-1721356. Obstetrícia. All rights reserved. accepted ISSN 0100-7203. This is an open access article published by Thieme under the terms of the October 5, 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 108 Gestational Diabetes Mellitus and Obesity Rehder et al.

Resumo Objetivo Avaliar características sociodemográﬁcas e obstétricas de mulheres com diabetes gestacional que mantêm hiperglicemia no período pós-parto (6–12 semanas pós-parto). Métodos Este é um estudo longitudinal de coorte com mulheres com diagnóstico de diabetes gestacional e/ou macrossomia fetal entre 1° de março de 2016 a 1° de março de 2017. As mulheres coletaram glicemia de jejum, teste de tolerância a glicose e hemoglobina glicada entre 6 a 12 semanas pós-parto. Os dados foram coletados de prontuários médicos e durante entrevista na primeira consulta de revisão pós-parto. Uma análise estatística foi realizada através do cálculo de frequências, porcentagens, teste do qui-quadrado, teste exato de Fisher, teste de Mann-Whitney e regressão multivariada de Poisson. A signiﬁcância estatística adotada foi de 5%. Resultados Cento e vinte e duas mulheres foram incluídas. A maioria delas tinha menos de 35 anos de idade (70,5%), eram brancas, multíparas, e não tinham história de diabetes gestacional. Treze por cento das participantes desenvolveu hiperglicemia persistente. A análise univariada mostrou que os fatores relacionados com a persis- tência de hiperglicemia no período pós-natal foram: idade materna acima de 35 anos, Palavras-chave sobrepeso, obesidade grau 1 e ganho de peso abaixo de 5 quilos. A análise multivariada ► diabetes gestacional incluiu o diagnóstico no primeiro trimestre como fator de risco para hiperglicemia ► obesidade persistente. ► hiperglicemia Conclusão Mulheres acima de 35 anos, obesidade, sobrepeso e diagnóstico de ► período pós-parto diabetes gestacional no primeiro trimestre estão relacionados com hiperglicemia ► sobrepeso persistente no período pós-parto.

Introduction tum period (6–12 weeks) and evaluate the impact of obesity, overweight, and weight gain. Gestational diabetes (GD) is a condition in which a woman has increased blood glucose levels detected for the first time Methods during pregnancy and does not meet the diagnostic criteria for diabetes mellitus.1 It affects from 2.4 to 7.2% of pregnan- We performed a prospective cohort study at the Women’s cies in Brazil, and increased rates have been observed due to Hospital of Universidade Estadual de Campinas, Brazil, from the epidemic of obesity and overweight.2 March 2016 to March 2017. Women with GD and/or LGA It is estimated that approximately 58% of the cases of fetuses were invited to participate after delivery, and, if diabetes mellitus in Brazil are due to obesity.3 In pregnant accepted, they signed an informed consent form. The women women with GD, higher body mass index (BMI) was associ- included in the study took part in an interview and had their ated with type 2 diabetes in the postpartum period.4 prenatal card data assessed. Subsequently, women collected Gestational diabetes is related to maternal and fetal fasting glucose, OGTT with 75g of dextrose, and glycated complications, such as neonatal hypoglycemia, macrosomia, hemoglobin results from 6 to 12 weeks postpartum. fetuses being large for gestational age (LGA), and increased The diagnostic criteria for GD, PH, and diabetes mellitus perinatal mortality.5 The worse the maternal glycemic con- were established according to the International Diabetes and trol, the worse the perinatal results will be.6 Gestation Study (IADPSG) and adopted by the American – Between 30 and 84% of all women with GD have a Diabetes Association7 9: GD is considered when women recurrence of the disease in future pregnancies, and one show fasting glycemia values 92 mg/dL and/or 75g OGTT third of the patients will maintain postpartum hyperglyce- with 1h glycemia 180 mg/dL, and/or 2h glycemia 153 mg/ – mia.7 9 In 2014, Weinert et al.10 found that 24.1% of dL; PH is considered when women show fasting glycemia women with GD had a diagnosis of diabetes mellitus or between 100 and 125 mg/dL and/or OGTTvalues between 140 impaired glucose tolerance within 6 to 12 weeks postpar- and 199 mg/dL; diabetes mellitus is diagnosed when fasting tum. Persistent hyperglycemia (PH) was associated with glycaemia is > 126 mg/dL or OGTT values are > 200 mg/dL.8 family history, a diagnostic 2-h 75g oral glucose tolerance Newborns were classified as LGA based on the intergrowth test (OGTT) in pregnancy, insulin use during pregnancy, curve. and C-section.10 A statistical analysis was performed with mean and The present study aimed to evaluate the profile of GD percentages. Chi-Squared or Fisher exact tests were used women who maintained hyperglycemia during the postpar- to compare categorical variables, and the Mann-Whitney test

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. Gestational Diabetes Mellitus and Obesity Rehder et al. 109 was used to compare numerical variables. Multivariate Pois- Table 2 Gestational age at diagnosis, BMI, weight gain during son regression was performed to evaluate the prevalence pregnancy and treatment at current pregnancy ratio to develop PH. The significance level adopted for the statistical tests was 5%, that is, p < 0.05. Diagnosis N (%) The Institutional Ethics Review Board approved the study Gestational age at diagnosis (CAEE: 69791616.8.0000.5404). All research was performed < 12 w 46 (47) following relevant guidelines/regulations. Informed consent 12–24 w 24 (19.7) was obtained from all participants. 24 w 30(33.3) Results Body mass index Normal weight 27 (24.32) We included 177 women, of whom only 122 (69%) underwent Overweight 48 (43.24) laboratory tests, even after phone contact and attempts to Obese I 24 (21.62) reschedule collection. From the 122 women included, 96 had GD diagnosis during antenatal care through altered fasting Obese II 12 (10.82) glycemia values or altered OGTT. Twenty-six women had the Weight gain during pregnancy diagnosis after birthing babies classified as LGA. None of the 26 5 kg 42 (34.71) women had OGTT during antenatal care as a screening. 6–12 kg 45 (37.19) Sociodemographic and obstetric characteristics are de- 13–20 kg 31 (25.62) scribed in ►Table 1. Most women were younger than 35 years > 20 kg 4 (2.48) (70.5%), white, multiparous, and with no history of GD. ►Table 2 shows diagnostic and treatment details from Treatment the studied population. Almost 50% of the patients had the Diet No 37 (30.58) Table 1 Baseline characteristics Irregular 46 (38.02) Yes (1,800-2,700 Kcal) 38 (31.40) Variables N (%) Exercises Age Yes 25 (20.66) 20 y 13 (10.66) No 82 (79.34) 21–34 y 73 (59.84) Insulin 35–39 y 30 (24.59) Yes 17 (17.00) 40 y 6 (4.92) No 83 (83.00) Race White 80 (66.12) Missing 22 11 1 15. Non-white 42 (33.88) Parity diagnosis before 12 weeks of pregnancy, and 32.44% were Primiparous 34 (27.87) obese. Seventeen (17%) women used insulin during pregnancy. Multiparous 88 (72.13) During antenatal care, the majority of the participants (68.60%) did not diet for diabetes properly to treat GD: Previous GD 30.58% did not follow any diet, and 38.02% did not adhere Yes 13 (10.66) to dietary recommendations. Regarding physical activity, 25 No 72 (59.02) (20.66%) women reported having performed physical activi- Previous macrosomia ty during pregnancy. Yes 16 (13.11) We found 16 women (13.1%) with PH during the postpar- No 65 (53.28) tum period; 10 had glycated hemoglobin above 6.1, and 11 had altered OGTT (5 women had glycated hemoglobin AND Previous comorbidities altered OGTT). The factors related to the persistence were: Yes 32 (26.23) age >35 years, being overweight, obesity grade 1, and weight No 90 (73.77) gain < 5kg(►Table 3). Familial background DM ►Table 4 shows the influence of initial BMI, gestational DM 2 76 (63.33) age at diagnosis, diet, and exercises on gestational weight gain. The factors that were related to the lowest weight gain DM 1 3 (2.50) were GD diagnosis in the first trimester, correct diet follow- None 41 (34.17) up, and obesity or being overweight at the beginning of the Abbreviations: DM, diabetes mellitus; GD, gestational diabetes. pregnancy. The performance of physical activity did not Missing 2. show statistically significant weight gain.

Table 3 Factors related to postpartum hyperglycemia Table 5 Prevalence ratio of developing persistent hyperglycemia

Yes (%) No (%) p-value PR. (CI 95%) p-value Age 0.003 Age (years) 20 y 0 13 (12.26) < 35 1.00 (-) 21–34 5 (31.25) 68 (64.15) 35 5.26 (1.83–15.13) 0.002 35–39 9 (56.25) 21 (19.81) Parity 40 y 2 (12.50) 4 (3.77) Primiparous 1.00 (-) BMI 0.049 Multiparous 2.55 (0.55–11.80) 0.231 Normal weight 0 27 (27.27) BMI (kg/m2) Overweight 7 (46.67) 33 (33.33) Normal 1.00 (-) Obese I 6 (40.00) 18 (18.18) Overweight 10.24 (1.01–172.22) 0.023 Obese II 1 (6.67) 11 (11.11) Obese I 14.56 (1.01–245.60) 0.006 Obese III 1 (6.67) 10 (10.10) Obese II 6.46 (0.28–148.14) 0.134 Weight gain during 0.026 Weight gain during pregnancy pregnancy 13 kg 1.00 (–) – 5 kg 11 (68.75) 31 (29.52) 6–12 kg 3.02 (0.34–27.04) 0.323 6–12 kg 4 (25.00) 41 (39.05) < 5kg 8.91(1.15–68.98) 0.036 13–20 kg 1 (6.25) 30 (28.57) Previous GD > 20 kg 0 3 (2.86) No 1.00 (–) Fisher exact test missing 8 missing 1. Yes 6.52 (2.43–17.51) < 0.001 Previous macrosomia Table 4 Inﬂuence of initial BMI, Gestational age at diagnosis, No 1.00 (–) — Diet, and Exercises on gestational weight gain Yes 2.21 (0.71–6.85) 0.17

Gestational Weight Gain N(%) Gestational age at diagnosis < – < 5kg 6–12 kg > 12 kg p-value 12 weeks 3.20 (0.69 14.80) 0.086 BMIa 0.030 12 þ 1–23 þ 64.21(0.82–21.69) 0.137 Normal weight 3 (7.69) 12 (28.57) 12 (37.50) 24 weeks 1.00 (-) – Overweight 14 (35.9) 16 (38.1) 10 (31.25) Diet Obese I 11 (28.11) 5 (11.90) 7(21.88) No 1.00 (–) – Obese II 5 (18.82) 4 (9.52) 3 (9.38) Yes 24.36 (1.49–397.05) < 0.001 Obese III 6 (15.38) 5 (11.90) 0 Irregular 7.28 (0.40–130.97) 0.068 b Gestational age at diagnosis 0.002 Insulin < 12 w 22 (59.46) 17 (50.00) 6 (25.00) No 1.00 (–) – 12–24 w 5 (13.51) 11 (32.35) 3 (12.5) Yes 2.81 (0.98–8.08) 0.056 24 w 10 (27.03) 6 (17.65) 15 (52.50) Dietc 0.023 Abbreviation: PR, prevalence ratio. No 10 (23.81) 11 (24.44) 16 (48.48) Irregular 13 (30.95) 19 (42.22) 13 (39.39) Discussion < 1,800 Kcal 2 (4.76) 1 (2.22) 0 1,800–2,200 Kcal 10 (23.81) 6 (13.33) 0 Our study aimed to investigate PH during the postpartum period among women who developed GD. We found that > 2,200 Kcal 2 (4.76) 4 (8.89) 0 13.1% of women with GD maintained hyperglycemia be- Exercisesd 0.752 tween 6 and 12 weeks after delivery. The main factors Yes 10 (24.39) 8 (17.78) 7 (20.59) associated with PH were age > 35 years, overweight, obesity No 31 (75.61) 37 (82.22) 27 (79.41) grade 1, and weight gain < 5 kg during pregnancy. Chi-squared test Fisher Exact Test; Missing a9 b27 c15 d2. Among the gestational metabolic changes, increased insulin resistance is observed during pregnancy due to an The prevalence ratios of developing PH in the postpartum increase of gestational hormones, such as placental lactogen, period are shown in ►Table 5.Age35 years, overweight or cortisol, and progesterone.5 These physiological changes are obesity grade 1, weight gain < 5 kg, previous GD, and intended to guarantee glycemic support to the fetus.5 Wom- performance of adequate diet are related to PH. en develop hyperglycemia when increased insulin resistance

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. Gestational Diabetes Mellitus and Obesity Rehder et al. 111 is not adequately compensated for by increased pancreatic Conflict of Interests beta-cell insulin production.11 The authors have no conflict of interests to declare. Data from the literature show discrepancies. Gante et al.12 found an overall rate of 10.9% of PH after a 6-week follow-up, Acknowledgments while Durnwald et al.13 found a higher rate (31.7%) of PH. On We would like to thank all the women who participated in the other hand, Sudasinghe et al.14 found 21.3% of PH after this study and the medical and nursing staff from the 6 weeks follow-up and an overall rate of 10% of diabetes Women’s Hospital of Universidade Estadual de Campinas mellitus. who cared for the participants. In our study, we found that women who were overweight or obese at the start of pregnancy had more chance of developing PH during the postpartum period, while greater References weight gain during prenatal care had no influence. On the 1 Brasileira de Diabetes S. (SBD) [Internet]. São Paulo: SBD; 2020 other hand, we observed that patients who presented a lower [cited 2020 Jan 5]. Available from: https://www.diabetes.org.br/ fi weight gain (< 5 kg) were those who maintained hypergly- pro ssionais/ 2 Negrato CA, Jovanovic L, Rafacho A, Tambascia MA, Geloneze B, cemia during the postpartum period. Women who were Dias A, Rudge MVC. Association between different levels of overweight/obese and who had GD diagnosed within the dysglycemia and metabolic syndrome in pregnancy. Diabetol first trimester of pregnancy composed this group. This may Metab Syndr. 2009;1(01):3. Doi: 10.1186/1758-5996-1-3 justify why we found lower weight gain as a risk factor for PH 3 Oliveira AF, Valente JG, Leite IdaC. [Fraction of the global burden of in our study. diabetes mellitus attributable to overweight and obesity in – Greater weight gain during pregnancy was also not relat- Brazil]. Rev Panam Salud Publica. 2010;27(05):338 344. Doi: 10.1590/s1020-49892010000500003 ed to PH in a systematic review involving 95,750 women.15 4 Pastore I, Chiefari E, Vero R, Brunetti A. Postpartum glucose 16 Nevertheless, Xiang et al. observed that a greater weight intolerance: an updated overview. Endocrine. 2018;59(03): gain during pregnancy was associated with a decrease in the 481–494. Doi: 10.1007/s12020-017-1388-0 functioning of pancreatic beta cells, which led to increased 5 Denney JM, Quinn KH. Gestational diabetes: underpinning prin- hyperglycemia.16 ciples, surveillance, and management. Obstet Gynecol Clin North – We found that age and obesity/being overweight were the Am. 2018;45(02):299 314. Doi: 10.1016/j.ogc.2018.01.003 6 Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan main factors related to PH during the postpartum period. DR, et al; HAPO Study Cooperative Research Group. Hyperglyce- > Pastore at al. found that women with GD and a BMI 25 had a mia and adverse pregnancy outcomes. N Engl J Med. 2008;358 4 higher risk of developing type 2 diabetes. A systematic (19):1991–2002. Doi: 10.1056/NEJMoa0707943 review with meta-analysis showed that a BMI > 25, a family 7 Diagnostic criteria and classification of hyperglycaemia first history of type 2 diabetes, and advanced maternal age are detected in pregnancy: a World Health Organization Guideline. Diabetes Res Clin Pract. 2014;103(03):341–363. Doi: 10.1016/j. risk factors for developing type 2 diabetes.15 diabres.2013.10.012 One of the limitations of the present study was the time 8 American Diabetes Association. 2. Classification and diagnosis of that the women were followed up postpartum. We followed diabetes. Diabetes Care. 2017;40(Suppl 1):S11–S24. Doi: 10.2337/ up the women for 6 to 12 weeks, but it is believed that over dc17-S005 the years, and with other pregnancies, hyperglycemia or 9 Dalfrà MG, Nicolucci A, Bisson T, Bonsembiante B, Lapolla AQLISG even cases of type 2 diabetes may appear.14,17 It is important (Quality of Life Italian Study Group). Quality of life in pregnancy and post-partum: a study in diabetic patients. Qual Life Res. 2012; to encourage women to perform diagnostic screening over 21(02):291–298. Doi: 10.1007/s11136-011-9940-5 17 the years. In a meta-analysis, Bellamy et al. showed a 10 Weinert LS, Mastella LS, Oppermann MLR, Silveiro SP, Guimarães cumulative 60% incidence of type 2 diabetes within 10 years LSP, Reichelt AJ. Postpartum glucose tolerance status 6 to 12 weeks following GD and a 7-fold increased risk of developing type 2- after gestational diabetes mellitus: a Brazilian cohort. Arq Bras diabetes compared with women without GD.4,17 Endocrinol Metabol. 2014;58(02):197–204. Doi: 10.1590/0004- 2730000003069 11 Di Cianni G, Miccoli R, Volpe L, Lencioni C, Del Prato S. Intermedi- Conclusion ate metabolism in normal pregnancy and in gestational diabetes. Diabetes Metab Res Rev. 2003;19(04):259–270. Doi: 10.1002/ Persistent hyperglycemia between 6 and 12 weeks postpartum dmrr.390 is associated with a maternal age above 35 years, a BMI in the 12 Gante I, Ferreira AC, Pestana G, Pires D, Amaral N, Dores J, et al. overweight and obesity grade 1 ranges before gestation, and Maternal educational level and the risk of persistent post-partum glucose metabolism disorders in women with gestational diabe- diagnosisofGDinthefirst trimester of pregnancy. Excessive tes mellitus. Acta Diabetol. 2018;55(03):243–251. Doi: 10.1007/ weight gain during pregnancy was not associated with PH. s00592-017-1090-y 13 Durnwald CP, Downes K, Leite R, Elovitz M, Parry S. Predicting Contributions persistent impaired glucose tolerance in patients with gestational P. M. R. had the idea and P. M. R., A. B. P. and B. G. P. diabetes: The role of high sensitivity CRP and adiponectin. conceived the study. A. B. P., R. O. M. B. A., J. A. P. M. D., N. L. Diabetes Metab Res Rev. 2018;34(02):e2958. Doi: 10.1002/ dmrr.2958 C. F., A. C. R. B., and A. F. D. collected the data. A. B. P. and P. 14 Sudasinghe BH, Wijeyaratne CN, Ginige PS. Long and short-term fi M. R. analyzed the data. A. B. P. wrote the rst version of outcomes of Gestational Diabetes Mellitus (GDM) among South the manuscript. All the authors contributed with amend- Asian women - A community-based study. Diabetes Res Clin ments and suggestions. Pract. 2018;145:93–101. Doi: 10.1016/j.diabres.2018.04.013

15 Rayanagoudar G, Hashi AA, Zamora J, Khan KS, Hitman GA, with recent gestational diabetes mellitus: association with Thangaratinam S. Quantiﬁcation of the type 2 diabetes risk in changes in weight, adiponectin, and C-reactive protein. Diabetes women with gestational diabetes: a systematic review and meta- Care. 2010;33(02):396–401. Doi: 10.2337/dc09-1493 analysis of 95,750 women. Diabetologia. 2016;59(07):1403- 17 Bellamy L, Casas JP, Hingorani AD, Williams D. Type 2 diabetes –1411. Doi: 10.1007/s00125-016-3927-2 mellitus after gestational diabetes: a systematic review and meta- 16 Xiang AH, Kawakubo M, Trigo E, Kjos SL, Buchanan TA. Declining analysis. Lancet. 2009;373(9677):1773–1779. Doi: 10.1016/ beta-cell compensation for insulin resistance in Hispanic women S0140-6736(09)60731-5

Risk Factors for Postpartum Hemorrhage and its Severe Forms with Blood Loss Evaluated Objectively – A Prospective Cohort Study Fatores de risco para hemorragia pós-parto e suas formas graves com perda sanguínea avaliada objetivamente – Um estudo de coorte prospectivo Anderson Borovac-Pinheiro1 Filipe Moraes Ribeiro1 Rodolfo Carvalho Pacagnella1

1 Department of Obstetrics and Gynecology, Universidade Estadual de Address for correspondence Anderson Borovac-Pinheiro, MD, PhD, Campinas, Campinas, SP, Brazil Cidade Universitária Zeferino Vaz, Barão Geraldo, Campinas, SP, 13083-970, Brazil (e-mail: [email protected]). Rev Bras Ginecol Obstet 2021;43(2):113–118.

Abstract Objective To identify risk factors related to postpartum hemorrhage (PPH) and severe PPH with blood loss quantiﬁed objectively. Methods This is a complementary analysis of a prospective cohort study that included pregnant women delivering vaginally. The total blood loss was obtained through the sum of the volume collected from the drape with the weight of gauzes, compresses and pads used by women within 2hours. Exploratory data analysis was performed to assess mean, standard deviation (SD), frequency, percentage and percentiles. The risk factors for postpartum bleeding were evaluated using linear and logistic regression. Results We included 270 women. The mean blood loss at 120 minutes was 427.49 mL (335.57 mL). Thirty-one percent (84 women) bled > 500 mL and 8.2% (22 women) bled > 1,000 mL within 2 hours. Episiotomy, longer second stage of labor and forceps delivery were related to blood loss > 500 mL within 2 hours, in the univariate analysis. Keywords In the multivariate analysis, only forceps remained associated with bleeding > 500 mL ► risk factors within 2 hours (odds ratio [OR] ¼ 9.5 [2.85–31.53]). Previous anemia and episiotomy ► postpartum were also related to blood loss > 1,000mL. hemorrhage Conclusion Prolonged second stage of labor, forceps and episiotomy are related to ► maternal mortality increased incidence of PPH, and should be used as an alert for the delivery assistants for early recognition and prompt treatment for PPH.

Resumo Objetivo Identiﬁcar os fatores de risco para hemorragia pós-parto e hemorragia pós- parto grave com o sangramento pós-parto avaliado objetivamente. Métodos Trata-sedeumaanálisecomplementardeumestudodecoorteprospectivo que incluiu somente mulheres que evoluíram para parto vaginal. O total de perda sanguínea foi avaliado objetivamente durante 24 horas pós-parto através da soma da

received DOI https://doi.org/ © 2021. Federação Brasileira das Associações de Ginecologia e January 28, 2020 10.1055/s-0040-1718439. Obstetrícia. All rights 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 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 114 Risk factors for postpartum hemorrhage and its severe forms Borovac-Pinheiro et al.

quantidade de sangue mensurada através de um coletor de sangue pós-parto somado ao peso de compressas, gases e absorventes utilizados no período pós-parto. Análises exploratórias dos dados foram realizadas através do cálculo de médias, desvio-padrão (DP), frequência, porcentagem e percentis. Os fatores de risco foram avaliados através de regressão linear e logística. Resultados Foram incluídas 270 mulheres. A média de perda sanguínea pós-parto após 120 minutos foi de 427.49 mL (335.57 mL). Trinta e um por cento (84 mulheres) sangraram > 500 mL e 8,2% (22 mulheres) sangraram > 1.000 mL em 2 horas. Episio- tomia, segundo período do parto prolongado e uso de fórceps estiveram associados a perda sanguínea > 500 mL em 2 horas. Na análise multivariada, somente fórceps manteve-se entre os fatores de risco para sangramentos superiores a 500 mL em 2 Palavras-chave horas (odds ratio [OR] ¼ 9.5 [2.85–31.53]). Anemia prévia e episiotomia estiveram ► fatores de risco associadas com perda sanguínea > 1.000 mL. ► hemorragia pós- Conclusão Segundo período do parto prolongado, fórceps e episiotomia estão parto associados a aumento da incidência de hemorragia pós-parto e devem ser usados ► mortalidade como um alerta para os proﬁssionais de saúde para o reconhecimento precoce e materna tratamento imediato da patologia.

Introduction pregnant women with gestational age > 34 weeks delivering vaginally at the Women’s Hospital (Hospital da Mulher J.A In spite of the efforts to decrease maternal mortality world- Pinotti, Campinas, São Paulo, Brazil) between 1 Febru- wide, every day 800 women die due to complications related to ary 2015 and 31 March 2016. The exclusion criteria were pregnancy and childbirth.1 Behind the numbers, these prema- the presence of one or more of these conditions: gestational ture deaths lead to an impact on families, societies and econo- age < 34 weeks, hypertension, hypo or hyperthyroidism mies and basically, for the children, mean the loss of a caregiver without treatment, coagulopathy, antepartum hemorrhage, and nurturing figure.2 At least for the past 25 years, maternal any cardiac disease and infections with fever or sepsis. hemorrhage remains the leading cause of maternal mortality During the labor, at the obstetric ward, women were worldwide and the majority of deaths occur at the postpartum invited to participate in the study, and if accepted, they period in low sociodemographic index countries.3,4 signed an informed consent form. A data collection form Postpartum hemorrhage (PPH) is defined by the World was filled with information from the women’s interview Health Organization (WHO) as bleeding > 500 mL within added with information from the medical records. The 24 hours after delivery and severe PPH as bleeding > 1,000 mL hemoglobin level was checked in prenatal records. If the during the same period.5 last dosage had been made before 3 months, we collected a For the last years, PPH and severe PPH is increasing around new blood count before delivery. Previous anemia was the world, even in developed countries.6,7 To recognize defined as hemoglobin levels < 11 g/dL. If the women pro- women at risk who could potentially develop PPH is the first gressed to C-section they were excluded from the study. action to prompt treatment to avoid deaths and near-misses Immediately after the fetal delivery, trained research due to PPH. assistants placed a calibrated drape under the women’s Nevertheless, several studies have shown conflicting risk buttocks (BRASSS_V drape_Maternova_Providence, RI, USA – factors for PPH based on visual estimation of blood loss.6 10 – ►Fig. 1). The total blood loss was obtained through the sum While some studies identified age < 20 years old, hyperten- of the volume collected from the drape with the weight of sion and multiple gestations6,8 as a risk factor for PPH, others gauzes, compresses and pads (subtracting the dry weight) did not find the relationship among these potential risk used by women within 2 hours. For volume estimation, we factors and postpartum bleeding.7,9,11 The fact is that the considered the density of blood to be 1 g/mL.15 majority of the studies evaluate PPH using a visual estimative For the statistical analyses, we identified the possible risk of blood loss, a low accuracy method to measure postpartum factors that could be related to PPH and severe PPH. There- – bleeding.12 14 fore, we performed exploratory data analysis to assess mean, The present study aimed to identify risk factors related to standard deviation (SD), minimum, median, maximum, fre- PPH and severe PPH with blood loss quantified objectively. quency, percentage and percentiles. The risk factors for postpartum bleeding were evaluated using linear and logis- Methods tic regression. All statistical analysis was made using SAS 9.4 (SAS Institute Inc., SAS São Paulo, São Paulo, Brazil) and we This is a complementary analysis of a prospective cohort defined a significance level of 5%. study designed to identify if shock index and other vital signs The Institutional Review Board (IRB of the Universidade could be useful to predict PPH (not published). It included de Campinas, Campinas, SP, Brazil) approved the main study,

Table 1 Sociodemographic and Obstetrics characteristics

Characteristics n Mean SD Age (years old) 270 24.67 6.2 BMI (antepartum) a 244 28.85 4.6 Parity 270 0.80 1.10 Gestational age (in weeks) 270 38.93 1.47 Education (in years) b 231 9.91 2.5 Time to second stage 223 32.47 34.7 (in minutes) c Initial Hb (in g/dL) d 260 11.45 0.1 Ethnicity - white e 178 (67%) Previous C-Section 42 (15.5%) Spontaneous onset of labor 203 (75.2%) Anesthesia/analgesia (yes) 170 (63%) Mode of delivery vaginal 247 (91.5%) forceps 23 (8.5%) Fig. 1 Calibrated drape used to measure objectively blood loss after Episiotomy (yes) 96 (36%) fetal delivery (BRASSS_V drape_Maternova_Providence, RI, USA). Laceration ( grade 2) 155 (57.1%) Blood loss within 120 minutes which included evaluating the risk factors for PPH (CAEE: 500 mL 84 (31%) 26787114.3.0000.5404). Without any participation in plan- 1000 mL 22 (8.2%) ning, designing, implementing, collecting data, analysis and interpreting results, Centro de Pesquisas em Saúde Repro- Abbreviations: BMI, body mass index; Hb, hemoglobin. a b c d e a 2 dutiva de Campinas (CEMICAMP) and Fund for Support to Missing: 26; 39; 47; 10; 7; in Kg/m . Teaching, Research and Outreach Activities (Faepex-UNI- CAMP) supported the study. Previous anemia, longer second stage of labor and episi- Results otomy were also related to blood loss > 1,000 mL. Neverthe- less, the multiple analyses had not shown a risk factor related From the 319 eligible women, 8 denied participation and 41 to bleeding > 1,000mL within 2 hours after delivery. progressed to C-section. Therefore, we included 270 women. The mean blood loss at 120 minutes was 427.49 mL Discussion (335.57 mL). Thirty-one percent (84 women) of the sample bled > 500 mL and 8.2% (22 women) bled > 1,000mL within Our study aimed to evaluate risk factors for PPH and severe 2 hours. On the other hand, among those who bled less, 93 PPH within 2 hours after delivery with blood loss quantified women (34.4%) had blood loss 300 mL and 125 (46.3%) had objectively. Episiotomy, forceps and longer second stage of blood loss 400mL, below the mean blood loss. Forty-seven delivery were related to PPH, and episiotomy and previous women (17.4%) arrived at the hospital during the second anemia were related with severe PPH. stage of labor. Sociodemographic and obstetrics character- The actual research related to PPH is concerned with the istics are shown in ►Table 1. early identification of PPH in an attempt to promote, with the No women in our sample had intensive care unit (ICU) prompt and accurate treatment, the decrease of maternal admission or surgical procedures. Only four women received mortality and near-miss due to PPH. The identification of risk blood transfusions due to PPH. Among those who bled > 500 mL, factors could contribute as an adjunct for early recognition of 18 women (21.4%) had forceps delivery and 38 (45.2%) had an PPH.10,16,17 episiotomy. And among those who bled > 1,000 mL, 4 women The main contributors to developing PPH and severe PPH (18.2%) had forceps delivery, 11 (50%) had an episiotomy and 6 in our study were forceps, longer second stage of labor and (27.3%) had previous anemia. The logistic regression to evaluate episiotomy, which are frequently described in the literature; factorsrelatedtobloodlossafterdeliveryisshownin►Table 2. nevertheless, in our study, maternal age > 35 years, multi- Episiotomy, longer second stage of labor and forceps parity, induced labor and previous C-sections were not delivery were related to blood loss > 500mL within 2 hours. related to PPH and severe PPH, as they were found as risk – The multiple analysis (n ¼ 260) shows that forceps delivery factors for PPH in other several studies.6 9,18 had an odds ratio (OR) of 9.48 (95% confidence interval [CI]: Forceps delivery had an OR of 9.48 for the risk of developing 2.85–31.53) for bleeding > 500 mL within 2 hours. PPH, although our analysis does not show forceps as a risk

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. 116 Risk factors for postpartum hemorrhage and its severe forms Borovac-Pinheiro et al.

Table 2 Univariate and multivariate analysis of risk factors to blood loss 500mL and 1000mL in 2 hours

500 mL within 2 hours 1,000 mL within 2 hours nOR p-value OR p-value (95%CI) (95%CI) Univariate analysis Age 19 years old 63 1.51 0.172 1.60 0.329 (0.83 - 2.71) (0.62 - 4.11) 20–35 years old 191 Ref. 35 years old 16 1.00 0.990 1.67 0.516 (0.34 - 2.99) (0.35 - 7.87) Ethnicity white 178 Ref. non-white 85 0.83 0.534 2.24 0.085 (0.47 - 1.47) (0.89 - 5.61) Schooling (mean in years) 231 1.04 0.431 0.97 0.813 (0.93 - 1.17) (0.80 - 1.18) Overweight (BMIa 25) 104 1.36 0.272 0.94 0.900 (0.78 - 2.36) (0.34 - 2.55) Obesity (BMIa 30) 89 1.03 0.913 1.60 0.350 (0.58 - 1.82) (0.59 - 4.31) Multiparity (two or more previous deliveries) 53 0.65 0.227 0.87 0.817 (0.32 - 1.30) (0.28 - 2.70) Gestational age 34–40 weeks 146 0.92 0.764 1.64 0.277 (0.53 - 1.59) (0.67 - 4.03) 40 weeks 102 Ref. Previous C-section 42 1.13 0.731 1.65 0.351 (0.56 - 2.28) (0.57 - 4.75) Anemia (hemoglobin 11 g/dl) 43 1.60 0.175 2.82 0.037 (0.81 - 3.15) (1.06 - 7.47) Spontaneous labor 203 0.58 0.062 0.87 0.780 (0.32 - 1.03) (0.32 - 2.32) Duration of second-stage of labor 30 minutes 223 1.88 0.032 1.90 0.230 (1.05–3.37) (0.66–5.45) Anesthesia (yes) 168 1.225 0.458 1.068 0.886 (0.71–2.09) (0.43–2.64) Episiotomy (yes) 96 2.39 0.001 3.05 0.017 (1.39 - 4.10) (1.12 - 7.66) Laceration ( grade 2) 144 1.03 0.924 1.64 0.300 (0.60 - 1.74) (0.64 - 4.22) Forceps (yes) 23 9.87 <0.001 2.68 0.101 (3.53 - 27.65) (0.82 - 8.72) Multivariate analysis Forceps (yes) 260 9.48 <0.001 (2.85 - 31.53) Duration of second stage of labor 30 minutes 260 1.05 0.883 (0.57–2.10) Episiotomy (yes) 260 1.49 0.25 (0.75–2.96)

Abbreviations: BMI, body mass index; CI, conﬁdence interval; OR, odds ratio.

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. Risk factors for postpartum hemorrhage and its severe forms Borovac-Pinheiro et al. 117 factor for severe PPH as demonstrated in other studies.8,9 A. wrote the first version and all authors approved the Perhaps, this difference could be explained by the quantifying final version of the manuscript. method to measured postpartum bleeding or by the number of women with severe PPH in our study, as only 22 women had Conflict of Interests severe PPH, while other studies, which were population The authors have no conflict of interests to declare. studies, found > 3,000 women with severe PPH.8,9 Previous anemia (hemoglobin level < 11 g/dl) was found Acknowledgments to be a risk factor for severe PPH. This is in agreement with We thank the statistical group from the Faculdade de another study that found hemoglobin levels < 9g/dlasarisk Medicina of the Universidade de Campinas, Campinas, SP, factor for severe PPH, OR ¼ 2.20 (1.63–3.15).9 Our data shows Brazil for data analysis. CEMICAMP and Faepex - Unicamp the importance of adequate antenatal care with diagnosis funded the present research. and treatment of anemia as a changeable risk factor for PPH. Iron supplementation is a recommendation of the WHO during pregnancy and the postpartum period19,20 and could References decrease a part of the incidence of PPH. Also, the presence of 1 Kendall T, Langer A. Critical maternal health knowledge gaps in previous anemia may influence the recovery after bleeding. low- and middle-income countries for the post-2015 era. Reprod Comparing the objective method of measuring PPH, one Health. 2015;12:55. Doi: 10.1186/s12978-015-0044-5 2 Knaul FM, Langer A, Atun R, Rodin D, Frenk J, Bonita R. Rethinking study from Uganda assessed postpartum bleeding using a maternal health. Lancet Glob Health. 2016;4(04):e227–e228. Doi: calibrated drape. The risk factors found by them were HIV 10.1016/S2214-109X(16)00044-9 11 positive, multiple pregnancy and macrosomia. Neverthe- 3 GBD 2015 Maternal Mortality Collaborators. Global, regional, and less, they had a very low frequency of PPH (9%) and severe national levels of maternal mortality, 1990-2015: a systematic analy- PPH (1.2%)11 compared with our data, which shows respec- sis for the Global Burden of Disease Study 2015. Lancet. 2016;388 – tively 31% and 8.2% of frequency. In our sample, only 11 (10053):1775 1812. Doi: 10.1016/S0140-6736(16)31470-2 4 Say L, Chou D, Gemmill A, Tunçalp Ö, Moller A-B, Daniels J, et al. women delivered babies > 4,000 g and 8 of them had post- Global causes of maternal death: a WHO systematic analysis. > partum bleeding 500mL. Lancet Glob Health. 2014;2(06):e323–e333. Doi: 10.1016/S2214- Our data showed that prolonged second-stage labor, 109X(14)70227-X forceps and episiotomy, which are very linked to each other, 5 Tunçalp O, Souza JP, Gülmezoglu MWorld Health Organization. are related to an increased incidence of PPH. In the modern New WHO recommendations on prevention and treatment of assistance to labor and delivery, it is recommended to respect postpartum hemorrhage. Int J Gynaecol Obstet. 2013;123(03): 254–256. Doi: 10.1016/j.ijgo.2013.06.024 the obstetrical physiological variations found among wom- 6 Bateman BT, Berman MF, Riley LE, Leffert LR. The epidemiology of 21 en. However, if an operative delivery or even episiotomy is postpartum hemorrhage in a large, nationwide sample of deliv- required, the team should be prepared for the possibility of eries. Anesth Analg. 2010;110(05):1368–1373. Doi: 10.1213/ facing a PPH, and these three risk factors should be used as an ANE.0b013e3181d74898 alert for the delivery assistants for early recognition and 7 Goffman D, Nathan L, Chazotte C. Obstetric hemorrhage: A global review. Semin Perinatol. 2016;40(02):96–98. Doi: 10.1053/j.sem- prompt treatment for PPH. peri.2015.11.014 Although our study has the strength of evaluating objec- 8 Kramer MS, Berg C, Abenhaim H, Dahhou M, Rouleau J, Mehrabadi tively the postpartum bleeding for 2 hours, a rare character- A, Joseph KS. Incidence, risk factors, and temporal trends in severe istic found in studies that evaluate risk factors, it has some postpartum hemorrhage. Am J Obstet Gynecol. 2013;209(05): limitations. Our sample size is limited, only 270 women were 449.e1–449.e7. Doi: 10.1016/j.ajog.2013.07.007 included, and we excluded pregnant women with hyperten- 9 Al-Zirqi I, Vangen S, Forsen L, Stray-Pedersen B. Prevalence and risk factors of severe obstetric haemorrhage. BJOG. 2008;115(10): sion, a known risk factor for PPH. Ideally, we should have 1265–1272. Doi: 10.1111/j.1471-0528.2008.01859.x divided the comparison of the second stage of labor between 10 Pacagnella RC, Borovac-Pinheiro A. Assessing and managing hypo- above and below 1 hour. However, our sample size was not volemic shock in puerperal women. Best Pract Res Clin Obstet sufficient for this. Future research with PPH should be done Gynaecol. 2019;61:89–105. Doi: 10.1016/j.bpobgyn.2019.05.012 evaluating postpartum bleeding objectively in a large sample 11 Ononge S, Mirembe F, Wandabwa J, Campbell OMR. Incidence and size and with no exclusion criteria. risk factors for postpartum hemorrhage in Uganda. Reprod Health. 2016;13:38. Doi: 10.1186/s12978-016-0154-8 12 Patel A, Goudar SS, Geller SE, Kodkany BS, Edlavitch SA, Patted SS, Conclusion et al. Drape estimation vs. visual assessment for estimating postpartum hemorrhage. Int J Gynaecol Obstet. 2006;93(03): Prolonged second stage of labor, forceps and episiotomy are 220–224. Doi: 10.1016/j.ijgo.2006.02.014 related to PPH, and should be used as an alert for the delivery 13 Toledo P, McCarthy RJ, Hewlett BJ, Fitzgerald PC, Wong CA. The accuracy of blood loss estimation after simulated vaginal delivery. assistants for early recognition and prompt treatment for PPH. Anesth Analg. 2007;105(06):1736–1740. Doi: 10.1213/01.ane.0000 286233.48111.d8 Contributions 14 Schorn MN. Measurement of blood loss: review of the literature. Borovac-Pinheiro A. and Pacagnella R. C. conceived and J Midwifery Womens Health. 2010;55(01):20–27. Doi: 10.1016/j. designed the study. Borovac-Pinheiro A. and Ribeiro F. M. jmwh.2009.02.014 collected the data. All authors were involved in data 15 MacLeod JH. Estimation of blood loss in a small community – analysis, interpretation, and writing. Borovac-Pinheiro hospital. Can Med Assoc J. 1966;95(03):114 117

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. 118 Risk factors for postpartum hemorrhage and its severe forms Borovac-Pinheiro et al.

16 Borovac-Pinheiro A, Pacagnella RC, Cecatti JG, Miller S, El Ayadi zation Multicountry Survey on Maternal and Newborn Health. AM, Souza JP, et al. Postpartum hemorrhage: new insights for BJOG. 2014;121(Suppl 1):5–13. Doi: 10.1111/1471-0528.12636 deﬁnition and diagnosis. Am J Obstet Gynecol. 2018;219(02): 19 World Health Organization. Daily iron and folic acid supplemen- 162–168. Doi: 10.1016/j.ajog.2018.04.013 tation during pregnancy. Geneva: WHO; 2016 17 Borovac-Pinheiro A, Ribeiro FM, Morais SS, Pacagnella RC. Shock 20 Peña-Rosas JP, De-Regil LM, Garcia-Casal MN, Dowswell T. Daily oral index and heart rate standard reference values in the immediate iron supplementation during pregnancy. Cochrane Database Syst postpartum period: A cohort study. PLoS One. 2019;14(06): Rev. 2015;(07):CD004736. Doi: 10.1002/14651858.CD004736.pub5 e0217907. Doi: 10.1371/journal.pone.0217907 21 National Institutefor Health and Care Excellence. Intrapartum carefor 18 Sheldon WR, Blum J, Vogel JP, Souza JP, Gülmezoglu AM, Winikoff healthy women and babies: clinical guideline [Internet]. 2017 [cited BWHO Multicountry Survey on Maternal and Newborn Health 2020 Jan 10]. Available from: https://www.nice.org.uk/guidance/ Research Network. Postpartum haemorrhage management, risks, cg190/resources/intrapartum-care-for-healthy-women-and-babies- and maternal outcomes: ﬁndings from the World Health Organi- pdf-35109866447557

Follicular Fluid from Infertile Women with Mild Endometriosis Impairs In Vitro Bovine Embryo Development: Potential Role of Oxidative Stress Fluido folicular de mulheres inférteis com endometriose leve prejudica o desenvolvimento in vitro de embriões bovinos: Potencial papel do estresse oxidativo Vanessa Silvestre Innocenti Giorgi1 Rui Alberto Ferriani1,2 Paula Andrea Navarro1,2

1 Human Reproduction Division, Department of Gynecology and Address for correspondence Vanessa Silvestre Innocenti Giorgi, PhD, Obstetrics, Faculdade de Medicina de Ribeirão Preto, Universidade Avenida Bandeirantes, 3900, Monte Alegre, Ribeirao Preto, SP, deSãoPaulo,RibeirãoPreto,SP,Brazil 14049-900, Brazil (e-mail: [email protected]). 2 Conselho Nacional de Desenvolvimento Cientíﬁco e Tecnológico, Brasília, DF, Brazil

Rev Bras Ginecol Obstet 2021;43(2):119–125.

Abstract Objective To investigate whether follicular ﬂuid (FF) from infertile women with mild endometriosis (ME) alters in vitro bovine embryo development, and whether the antioxidants N-acetyl-cysteine (NAC) and/or L-carnitine (LC) could prevent such damages. Methods Follicular ﬂuid was obtained from infertile women (11 with ME and 11 control). Bovine oocytes were matured in vitro divided in: No-FF, with 1% of FF from control women (CFF) or ME women (MEFF); with 1.5 mM NAC (CFF þ NAC, MEFF þ NAC), with 0.6 mg/mL LC (CFF þ LC, MEFF þ LC), or both antioxidants (CFF þ NAC þ LC, MEFF þ NAC þ LC). After in vitro fertilization, in vitro embryo culture was performed for 9 days. Results A total of 883 presumptive zygotes were cultured in vitro. No differences were observed in cleavage rate (p ¼ 0.5376) and blastocyst formation rate (p ¼ 0.4249). However, the MEFF group (12.5%) had lower hatching rate than the No-FF (42.1%, p ¼ 0.029) and CFF (42.9%, p ¼ 0.036) groups. Addition of antioxidants in Keywords the group with CFF did not alter hatching rate (p 0.56), and in groups with MEFF, just ► infertility NAC increased the hatching rate [(MEFF: 12.5% versus MEFF þ NAC: 44.4% (p ¼ 0.02); vs ► endometriosis MEFF þ LC: 18.8% (p ¼ 0.79); versus MEFF þ NAC þ LC: 30.8% (p ¼ 0.22)]. ► oocyte quality Conclusion Therefore, FF from infertile women with ME added to medium of in vitro ► N-acetyl-cysteine maturation of bovine oocytes impairs hatching rate, and NAC prevented these ► L-carnitine damages, suggesting involvement of oxidative stress in worst of oocyte and embryo quality of women with ME.

received DOI https://doi.org/ © 2021. Federação Brasileira das Associações de Ginecologia e March 18, 2020 10.1055/s-0040-1718443. Obstetrícia. All rights reserved. accepted ISSN 0100-7203. This is an open access article published by Thieme under the terms of the August 12, 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 120 Follicular Fluid from Infertile Women with Mild Endometriosis Giorgi et al.

Resumo Objetivo Investigar se o ﬂuido folicular (FF) de mulheres inférteis com endometriose leve (ME, na sigla em inglês) altera o desenvolvimento in vitro de embriões bovinos, e se os antioxidantes N-acetil-cisteína (NAC) e/ou L-carnitina (LC) poderiam prevenir possíveis danos. Métodos O FF foi obtido de mulheres inférteis (11 com ME e 11 controles). Oócitos bovinos foram maturados in vitro divididos em: sem FF (No-FF), com 1% de FF de mulheres controle (CFF) ou mulheres com ME (MEFF); com 1,5 mM de NAC (CFF þ NAC, MEFF þ NAC), com 0,6 mg/mL de LC (CFF þ LC, MEFF þ LC), ou ambos antioxidantes (CFF þ NAC þ LC, MEFF þ NAC þ LC). Depois da fertilização in vitro, o cultivo in vitro de embriões foi realizado por 9 dias. Resultados Um total de 883 zigotos presumidos foram cultivados in vitro. Nenhuma diferença foi observada na taxa de clivagem (p ¼ 0,5376) e na taxa de formação de blastocistos (p ¼ 0,4249). Entretanto, o grupo MEFF (12.5%) teve menor taxa de eclosão de blastocistos do que os grupos No-FF (42,1%, p ¼ 0,029) e CFF (42,9%, p ¼ 0,036).AdiçãodeantioxidantesnogrupocomCFFnãoalterouataxadeeclosão(p 0.56), e nos grupos com MEFF, somente a NAC aumentou a taxa de eclosão [(MEFF: Palavras-chave 12.5% versus MEFF þ NAC: 44.4% (p ¼ 0.02); versus MEFF þ LC: 18.8% (p ¼ 0.79); versus ► infertilidade MEFF þ NAC þ LC: 30.8% (p ¼ 0.22)]. ► endometriose Conclusão Portanto, o FF de mulheres inférteis com ME adicionado ao meio de ► qualidade oocitária maturação in vitro de oócitos bovinos prejudica a taxa de closão embrionária, e a NAC ► N-acetil-cisteína preveniu esses danos, sugerindo o envolvimento do estresse oxidativo na piora da ► L-carnitina qualidade oocitária e embrionária de mulheres com ME.

Introduction Previous studies demonstrated that follicular fluid (FF) from infertile women with mild endometriosis (ME), Endometriosis is a benign gynecological disease character- when added during in vitro maturation (IVM) causes ized by the presence and growth of endometrial tissue chromosome misalignment and meiotic spindle altera- (glands and stroma) outside the uterus.1 This disease is tions in bovine14,15 and murine16 oocytes. Alterations in associated with infertility: 30% of infertile women present oocytes during IVM may affect in vitro embryo develop- endometriosis2 and between 30 and 50% of women with ment.17,18 However, no study to date has evaluated the endometriosis have difficulties in becoming pregnant.3 effect of FF from infertile women with ME on embryo In cases with advanced endometriosis (moderate or development and the impact of antioxidants on this severe, stage III/IV), infertility could be due to pelvic ana- response. tomical alterations caused by lesions and adherences.4 On L-carnitine (LC) is a lysine derivative that clears hydrogen the other hand, minor endometriosis (minimal or mild, peroxide and products of lipid peroxidation.19 In mitochon- stage I/II) is not associated with marked changes in the dria, LC also facilitates the transport of fatty acids during β- pelvic anatomy (American Society for Reproductive Medi- oxidation, a major pathway for Adenosine Triphosphate (ATP) cine [ASRM], 1997)4 It is unclear whether, after assisted production.20 N-acetyl-cysteine (NAC) is an amino thiol with reproduction technologies (ART), endometriosis has a neg- immunomodulatory, anti-apoptotic, and antioxidant proper- – ative impact on clinical pregnancy and live birth rates.5 7 ties.21 N-acetyl-cysteine is a precursor of intracellular cysteine Findings from the most recent meta-analysis showed that and reduced glutathione (GSH), which also is and intracellular women with and without endometriosis have comparable antioxidant.22 ART outcomes in terms of live births, whereas those with As human oocytes and embryos are extremely rare, and severe endometriosis have inferior outcomes.6 On the other their use in invasive studies usually prevents their subsequent hand, classical studies assessing natural conception use in ART, studies using animal models may be useful for the reported lower cumulative pregnancy rate in women with elucidation of the mechanism by which endometriosis leads to early-stage endometriosis compared with women with infertility. Our hypothesis is that ME leads to OS, and this leads infertility of unknown cause.8,9 to infertility due to an impairment of oocyte and embryo In endometriosis women, menstrual reflux and macro- quality. Therefore, the aim of the present study was to evaluate phages have been implicated as potential inducers of oxida- the impact of adding FF from infertile women with ME and tive stress (OS)10,11 which, in turn, is involved in impairment without endometriosis (control), and antioxidants (NAC and/ of oocyte quality, and in compromising the reproductive or LC) to the IVM medium of bovine oocytes on in vitro embryo capacity of women with early-stage endometriosis.12,13 development (cleavage, blastocyst formation and hatching).

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. Follicular Fluid from Infertile Women with Mild Endometriosis Giorgi et al. 121

Methods onic gonadotropin (hCG) (Ovidrel, EMD Serono, Rockland, MA, USA). The present experimental study used an in vitro bovine Each patient received a daily subcutaneous injection of model. The present study was approved by the Ethics Com- 0.5 mg leuprolide acetate (Lupron; Abbott) starting 10 days mittee for Animal Experimentation of the Faculdade de after the ﬁrst ultrasound exam before COS. Recombinant FSH Medicina de Ribeirão Preto, Universidade de São Paulo (Gonal-F; Puregon, 200–225 units/day) was administered (FMRP-USP, in the Portuguese acronym) (n° 169/2008) and during ovarian stimulation, and follicular growth was moni- the Research Ethics Committee of the University Hospital, tored. Ovulation was triggered with Ovidrel, and oocytes FMRP-USP (n° 12201/2008). were retrieved between 34 and 36 hours later.

Patient Selection and Follicular Fluid Collection Collection and Processing of FF Samples Twenty-two FF samples were obtained between Febru- Follicular fluid was collected into individual sterile tubes ary 2009 and February 2011 from infertile women who preheated to 37°C in the absence of culture medium. The underwent ovarian stimulation for intracytoplasmic sperm sample was only from the first follicle (mean diame- injection (ICSI) at the Sector of Human Reproduction, De- ter 15 mm) of the first ovary punctured, with aspiration partment of Gynecology and Obstetrics of the FMRP-USP. of the full follicular content. Only FF with no blood contami- The endometriosis group consisted of patients with infer- nation upon visual inspection and with a mature oocyte was tility associated exclusively with ME, without other gyneco- used. The samples were centrifuged at 300 g for 10 minutes logical or clinical conditions. An experienced surgeon to remove the remaining cells, and the supernatant was diagnosed and classified these women by videolaparoscopy stored at - 80°C in two aliquots for future use. Follicular using the criteria of the American Society for Reproductive fluid was collected from 22 infertile women, 11 with ME and Medicine (1997).4 The control group consisted of women 11 with male and/or tubal infertility. with tubal or male factor infertility. All control women also We pooled the 11 FF samples of each group for experi- underwent videolaparoscopy as part of the protocol for ments because we had previously tested these samples investigation of marital infertility. None of the controls individually in a study of the role of FF from women with had endometriosis or any other gynecological diseases. infertility related to ME.14 The results of that study indicated The exclusion criteria were established to reduce con- no intragroup differences and a homogeneous response in all founding factors that could affect OS and/or oocyte quality. 11 samples from each group. This previous study14 also Thus, women with any of the following conditions were tested the effect of 4 different FF concentrations added to excluded: age 38 years old; body mass index (BMI) the IVM medium (1%, 5%, 10%, and 15%) and indicated no 30 kg/m2; serum concentration of follicle stimulating hor- dose-dependent effect. Thus, we used 1% FF concentration. mone (FSH) on the 3rd day of the menstrual cycle 10 mIU/ mL; chronic anovulation; presence of hydrosalpinx or chron- Chemicals and Reagents ic diseases such as diabetes mellitus or any other endocrin- All chemicals and reagents were purchased from Sigma opathy; cardiovascular disease; dyslipidemia; systemic Chemical Co (St. Louis, MO, USA), unless otherwise stated. lupus erythematosus or any other rheumatologic disease; HIV infection or any other active infection; smoking; and use Preparation of Antioxidant (N-acetyl-cysteine and of vitamins, hormonal or nonhormonal medications during L-carnitine) Solutions the 6 months before inclusion in the study. The solutions of both anti-oxidants were prepared at Comparison of the means and standard errors of the 100 (150 mM NAC and 60 mg/mL LC) using water after means (SEMs) indicated that the endometriosis and control passage through a filter with 0.22 μm pore. The NAC concen- groups had similar age (32.72 0.52 versus 30.63 1.36 tration used to supplement the IVM was 1.5 mM,23 and the years old), FSH concentration on the 3rd day of the menstrual LC concentration was 0.6 mg/mL.18 cycle (5.02 0.90 versus 5.79 0.62 mIU/mL), number of follicles measuring between 14 and 17 mm (10.09 1.43 Oocyte Collection versus 6.11 1.52 mm), and number of follicles of at least Bovine ovaries were collected immediately after slaughter 18 mm after ovarian stimulation (4.89 0.72 versus and transported in physiological saline maintained at be- 3.11 0.76 mm). tween 35 and 38.5°C. In the laboratory, the ovaries were washed with physiological saline supplemented with an Protocol of Controlled Ovarian Stimulation antibiotic, and follicles measuring 2 to 8 mm were aspirated Controlled ovarian stimulation (COS) was performed accord- by a 21-gauge needle mounted on a 10-mL syringe. Cumulus- ing to our institutional protocol (long protocol). Pituitary oocyte complexes (COCs), with homogeneous cytoplasm and blockade was performed by administering an agonist of at least 4 layers of cumulus oophorus cells, corresponding to gonadotropin releasing hormone (GnRH) (Lupron, Abbott, grades 1 and 2 as described previously,24 were selected São Paulo, SP, Brazil). Controlled ovarian stimulation was under a stereomicroscope and washed in holding medium performed by administering recombinant FSH (Gonal-F, (TCM-199 medium containing Hanks salts, HEPES buffer, and Serono, Geneva, Switzerland; Puregon, Organon, Oss, The L-glutamine (Invitrogen, Gibco Laboratories Life Technolo- Netherlands), and ovulation was induced with human chori- gies, Thermo Fisher Scientific, Waltham, MA, USA).

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. 122 Follicular Fluid from Infertile Women with Mild Endometriosis Giorgi et al.

In Vitro Maturation In Vitro Embryo Culture Selected COCs were cultured in plates containing 4 wells The presumptive zygotes were denuded from cumulus cells (NUNC, Thermo Fisher Scientific, Waltham, MA, USA) in groups by gentle pipetting and cultured in 50 μL droplets in CR2aa of 20 per well, with 400 µL of culture medium for IVM at 38.5°C, medium supplemented with 1 mg/mL BSA, 40 μg/mL sodium 17,25 95%humidity,and5%CO2 in a culture system without pyruvate, 5 mg/mL hemi-calcium, 20 μL/mL amino acid so- mineral oil for between 22 and 24 hours. The IVM medium was lution (0.09 μg/mL glutamine, 0.15 μg/mL alanine, and TCM-199 with Earle salts and bicarbonate (Invitrogen, Gibco 0.75 μg/mL glycine), 20 μL/mL Eagle Basal Medium (EBM), Laboratories Life Technologies, Thermo Fisher Scientific, Wal- 10 μL/mL Eagle Minimum Essential Medium (MEM) and 5% tham, MA, USA) supplemented with 0.4 mM sodium pyruvate, FBS, at 38.5°C in a humidified incubator in air with 5% CO2. 0.5µg/mLgentamicin,5µg/mLFSH,5mg/mLLH,1µg/mL The culture was maintained for 9 days after fertilization and estradiol, and 10% fetal calf serum (FCS) (Gibco Laboratories Life the medium was renewed every 2 days. Technologies, Thermo Fisher Scientific, Waltham, MA, USA) The number of cleaved embryos was recorded on day 3 (72 hours after insemination [HAIs]), blastocyst production In Vitro Fertilization was counted on day 7 (168 HAIs), and hatching of blastocysts In vitro matured oocytes were fertilized in vitro with frozen was checked on day 9 (216 HAIs). semen from a single bull (CRV Lagoa, SP, Brazil). Before addition, the frozen semen was thawed in 35°C water for 30 sec- Experimental Design onds. Swim-up was realized as described by Parrish et al.26,27 Immediately after selection, the COCs were subjected to IVM Briefly, the COCs were gently pipetted to remove adhering for between 22 and 24 hours, and divided in groups according granulosa cells and to break apart aggregations. The disag- to the supplementation of IVM medium with FF and antiox- gregated COCs were transferred into 50 μL microdrops of idants according to ►Figure 1 (►Fig. 1). After between 22 and fertilization medium (114 mM NaCl, 3.1 mM KCl, 25 mM 24 hours of IVM, IVF was performed as described above, and NaHCO3, 47 mg/L NaH2PO4.H2O, 10 mM HEPES, 10 mM embryos were cultured in vitro to assay cleavage, blastocyst sodium lactate 60%, 1.4 mM caffeine, 0.5 mM MgCl2.6H2O, formation, and hatching rates. 2 mM CaCl2.2H2O, 0.4 mM sodium pyruvate, 0.5 µg/mL gentamicin, 6 g/L BSA,10 µg/mL heparin, and 40 µL/mL Statistical Analysis each of penicillamine, hypotaurine, and epinephrine). Sperm Data were analyzed using RStudio software (R Foundation, (1 106/mL) was added and the medium was maintained for Vienna, Austria). Categorical variables (cleavage, blastocyst for- between 18 and 22 hours at 38.5°C in a humidified incubator mation and hatching) were expressed as percentage and they in air with 5% CO2. were compared by the chi-squared test, considering p < 0.05.

Fig. 1 Experimental design.

Results women with ME impairs bovine embryo development. Besides that, we observed that addition of NAC during IVM can prevent We performed IVF on 898 mature COCs and then cultured the compromised hatching rate promoted by MEFF. 883 presumptive zygotes in vitro. ►Table 1 shows preim- We observed that FF from ME women added to IVM plantation embryo development as cleavage rate, blastocyst medium of bovine oocytes did not alter cleavage and blastocyst formation rate and hatching rate of the different groups. formation rates, but decreased hatching rate. We expected to No differences were observed between groups in cleavage find impairment of cleavage in the group with MEFF due to (p ¼ 0.5376) and blastocysts formation (p ¼ 0.4249) rates damages on the meiotic spindle of oocytes.14,15,28 In vivo, (►Table 1). cleavage occurs during embryo transit between the oviduct However, in relation to the hatching rate, the groups and the uterus, and many factors can potentially interfere with without FF (No-FF: 42.10%) and with FF from control women this process.29 A study using time-lapse showed that meiotic (CFF: 42.86%) had a higher hatching rate than the group with spindle visualization of oocytes is not related to the morpho- FF from ME women (MEFF: 12.50%, versus No-FF: p ¼ 0.029; kinetic of in vitro embryo development, but it could be related versus CFF: p ¼ 0.036). to clinical pregnancy and live births in women with polycystic Addition of antioxidants in groups with FF from control ovarian syndrome.30 A recent study, assessing the impact of women did not alter the hatching rate [CFF versus CFF þ NAC endometriosis on embryo development and quality after ICSI, (50.0%, p ¼ 0.800), versus CFF þ LC (32.35%, p ¼ 0.557) and showed similar cleavage rates in groups of women with and versus CFF þ NAC þ LC (39.40%, p ¼ 0.990)]. without endometriosis, concordant with our findings.31 In Addition of NAC in groups with FF from ME women another recent study, Sanchez et al.31 did not find differences increased hatching rate (MEFF versus MEFF þ NAC: in the blastocyst formation rate comparing control and endo- p ¼ 0.020), being more efficient than the addition of LC metriosis groups undergoing ART. Thus, we hypothesize that (MEFF þ NAC versus MEFF þ LC: p ¼ 0.045). However, addition mild endometriosis may compromise oocyte quality,14,15,32 of LC and NAC þ LC did not alter the hatching rate in groups without interfering with cleavage and blastocyst rates, but with FF from ME women (MEFF versus MEFF þ LC [18.75%, reducing hatching rate, which could explain lower natural p ¼ 0.793] and versus MEFF þ NAC þ LC [30.77%, p ¼ 0.224]). fertility in some of these women.8,9 Hatching rates in the group with FF from ME women plus Corroborating our findings, Piromlertamorn et al.33 assessed the addition of LC or LC þ NAC were similar to the the impact of incubation of mouse oocytes with endometriotic groups without FF (No-FF versus MEFF þ LC: p ¼ 0.066 and fluid on early embryo in vitro development, and they also did versus MEFF þ NAC þ LC: p ¼ 0.511) and with FF from control not show differences in cleavage and blastocyst formation, but women (CFF versus MEFF þ LC: p ¼ 0.080 and versus they observed that endometriotic fluid impaired the hatching MEFF þ NAC þ LC: p ¼ 0.524). rate.33 Interestingly, a randomized clinical trial34 assessing assisted hatching in embryos from women with endometriosis Discussion reported higher implantation and clinical pregnancy rates in the group of women whose embryos had undergone laser-assisted The etiopathogenesis of ME-related infertility remains unclear. hatching after ICSI, suggesting that compromised hatching rate The present study is the first to show that FF from infertile may be involved in lower implantation rates in women with

Table 1 Embryo development after in vitro fertilization of bovine oocytes which underwent in vitro maturation in medium without follicular ﬂuid (No-FF), with 1% FF from infertile control women (CFF), or with 1% FF from infertile women with mild endometriosis (MEFF). The media with CFF and MEFF were supplemented with no antioxidants, 1.5 mM N-acetyl cysteine (NAC), 0.6 mg/mL L-carnitine (LC), or both antioxidants (NAC+LC)

No-FF CFF CFF+NAC CFF+LC CFF+NAC+LC MEFF MEFF+NAC MEFF+LC MEFF+NAC+LC p-value Presumptive 100 96 98 98 101 93 97 100 100 zygotes (n) Cleavage 65.00% (65) 61.46% (59) 57.14% 56.12% 60.40% 50.54% 57.73% 56.00% 51.00% p ¼ 0.5376 rate % (n) (56) (55) (61) (47) (56) (56) (51) Blastocysts 38.00% 29.17% 26.53% 34.69% 32.67% 25.81% 37.11% 32.00% 26.00% p ¼ 0.4249 formation (38) (28) (26) (34) (33) (24) (36) (32) (26) rate % (n) Hatching 42.10% 42.86% 50.00% 32.35% 39.40% 12.50% 44.44% 18.75% 30.77% avsNo-FF rate % (n) (16) (12) (13) (11) (13) (3)a (16) (6)b (8) p ¼ 0.029 vs CFF p ¼ 0.036 vs MEFF þ NAC p ¼ 0.020 bvsMEFFþ NAC p ¼ 0.045

Note: Data were obtained from 5 replicates. Letter indicate p value < 0.05 (chi-square test). aMEFF vs No-FF (p ¼ 0.029), vs CFF (p ¼ 0.036), vs MEFF+NAC (p ¼ 0.02). bMEFF+LC vs MEFF+NAC (p ¼ 0.045).

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. 124 Follicular Fluid from Infertile Women with Mild Endometriosis Giorgi et al.

endometriosis. A study, assessing embryo quality and implan- terms of improving natural fertility and/or implantation tation rate in infertile women undergoing ART, showed no rates in ME women with recurrent implantation failure. differences in the number of good quality embryos between women with and without endometriosis, but reported a sta- Conflict of Interests tistically significant decrease in implantation rate in the endo- The authors have no conflict of interests to declare. metriosis group.35 So, we question whether our findings could explain, at least in part, implantation failure in women with Contributions endometriosis and repeated implantation failure after IVF and Giorgi V.S.I.: Data collection, Data analysis, Manuscript embryo transfer, which needs further investigation. writing/editing. Ferriani R.A.: Manuscript writing/editing. Hatching is a prerequisite for embryo implantation in the Navarro P.A.: Project development, Data analysis, Manu- endometrium and depends on continuous expansion of the script writing/editing. blastocele and thinning and rupture of the zona pellucida.36 Goud et al.37 reported a correlation between follicular levels of Acknowledgments nitrate (an oxidative end product of nitric oxide) and zona The authors thank the staff of the Human Reproduction pellucida dissolution time (an indirect marker of thickness of Laboratory, University Hospital, Department of Gynecology the zona pellucida) of oocytes from a group of women with and Obstetrics at FMRP-USP, especially the embryologists endometriosis. So, we hypothesize that FF from women with Maria Cristina Picinato and Roberta Cristina Giorgenon for ME, due to OS, may cause alterations on the zona pellucida of the the collection of follicular fluid, and Suleimy Mazin for the oocyte,38 which compromises the normal hatching processes. statistical analysis. The present work was supported by the In relation to the addition ofantioxidants, NAC and/or LC did Foundation for Research Support of the State of Sao Paulo not alter cleavage and blastocyst rates in groups with FF from (Fundação de Amparo à Pesquisa do Estado de São Paulo – ME women and only NAC prevented reduced blastocyst hatch- FAPESP,grant number 2012/15070–1, Brazil)and Foundation ing rates. Thus, we hypothesize that NAC supplementation for Support of Education, Research and Service of the Hospi- prevented OS damages in meiotic spindle and on zona pellu- tal of Ribeirao Preto Medical School, University of Sao Paulo cida. N-acetyl-cysteine may also have reduced the disulfide (FAEPA). bonds in the zona pellucida and induced expansion of the zona pellucida39 culminating in hatching. However, a study using a References rat model demonstrated that intravenous NAC in high concen- 1 Burney RO, Giudice LC. Pathogenesis and pathophysiology tration (1000 mg.kg-1/day) promotes infertility probably due of endometriosis. Fertil Steril. 2012;98(03):511–519. Doi: to an exacerbated thinning of the zona pellucida.40 Thereby, 10.1016/j.fertnstert.2012.06.029 further studies using animal models are needed to evaluate the 2 Augoulea A, Alexandrou A, Creatsa M, Vrachnis N, Lambrinoudaki I. Pathogenesis of endometriosis: the role of genetics, inflamma- effect of different concentrations of NAC to determine its tion and oxidative stress. Arch Gynecol Obstet. 2012;286(01): fi ef cacy and safety for embryos before its effects can be 99–103. Doi: 10.1007/s00404-012-2357-8 evaluated in infertile women with endometriosis. 3 Bulletti C, Coccia ME, Battistoni S, Borini A. Endometriosis and Interestingly, but corroborating our previous study,15 con- infertility. J Assist Reprod Genet. 2010;27(08):441–447. Doi: comitant addition of NAC and LC had equal or inferior results 10.1007/s10815-010-9436-1 fi relative to NAC or LC alone. We can propose one hypothesis to 4 Revised American Society for Reproductive Medicine classi cation of endometriosis: 1996. Fertil Steril. 1997;67(05):817–821. explain this finding: an interaction of the reactive portions of Doi: 10.1016/s0015-0282(97)81391-x NAC and LC may have occurred when these antioxidants were 5 Barbosa MA, Teixeira DM, Navarro PAAS, Ferriani RA, Nastri CO, solubilized together in aqueous medium, thereby reducing the Martins WP. Impact of endometriosis and its staging on assisted efficacy of the clearance of free radicals. reproduction outcome: systematic review and meta-analysis. Ultra- Using bovine oocytes and FF from ME women, we aimed to sound Obstet Gynecol. 2014;44(03):261–278. Doi: 10.1002/uog.13366 6 Hamdan M, Omar SZ, Dunselman G, Cheong Y. Influence of mimetize what could happen in the follicular microenviron- endometriosis on assisted reproductive technology outcomes: a ment of women with mild endometriosis in natural cycles. systematic review and meta-analysis. Obstet Gynecol. 2015;125 However, data obtained from studies using animal models (01):79–88. Doi: 10.1097/AOG.0000000000000592 cannot necessarily be extrapolated to humans, and studies 7 Rossi AC, Prefumo F. The effects of surgery for endometriosis on evaluating in vitro development of embryos from ME women pregnancy outcomes following in vitro fertilization and embryo undergoing ART would be important to confirm our findings. transfer: a systematic review and meta-analysis. Arch Gynecol Obstet. 2016;294(03):647–655. Doi: 10.1007/s00404-016-4136-4 On the other hand, it is important to state that FF obtained 8 Bérubé S, Marcoux S, Langevin M, Maheux R; The Canadian from stimulated cycles not necessarily can represent FF from Collaborative Group on Endometriosis. Fecundity of infertile a natural cycle, which needs further investigation. women with minimal or mild endometriosis and women with Therefore, FF from infertile women with ME added to the unexplained infertility. Fertil Steril. 1998;69(06):1034–1041. medium of IVM of bovine oocytes did not interfere with Doi: 10.1016/s0015-0282(98)00081-8 cleavage and blastocyst rates, but impaired hatching rate. N- 9 Akande VA, Hunt LP, Cahill DJ, Jenkins JM. Differences in time to natural conception between women with unexplained infertility acetyl-cysteine prevented these damages, suggesting in- and infertile women with minor endometriosis. Hum Reprod. volvement of OS in the worst of oocyte and embryo quality 2004;19(01):96–103. 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The Effectiveness of Melissa Ofﬁcinalis L. versus Citalopram on Quality of Life of Menopausal Women with Sleep Disorder: A Randomized Double-Blind Clinical Trial

Mahboobeh Shirazi1,2 Mohamad Naser Jalalian2 Masoumeh Abed3 Marjan Ghaemi4

1 Maternal, Fetal & Neonatal Research Centre, Tehran University of Address for correspondence Marjan Ghaemi, MD, Valie-Asr Medical Sciences, Tehran, Iran Reproductive Health Research Center, (VRHRC), Tehran University of 2 Department of Obstetrics and Gynecology, Yas Hospital, Tehran Medical Sciences, Tehran, Iran University of Medical Sciences, Tehran, Iran (e-mail: [email protected]; [email protected]). 3 Department of Gynecology and Obstetrics, School of Medicine, Alborz University of Medical Sciences, Alborz, Iran 4 Valie-Asr Reproductive Health Research Center, Tehran University of Medical Sciences, Tehran, Iran

Rev Bras Ginecol Obstet 2021;43(2):126–130.

Abstract Objective The present study aimed to assess the effect of Melissa Officinalis L. (a combination of lemon balm with fennel fruit extract) compared with citalopram and placebo on the quality of life of postmenopausal women with sleep disturbance. Methods The present study is a randomized, double-blind, placebo clinical trial among 60 postmenopausal women with sleep disturbance who were referred to a university hospital from 2017 to 2019. The participants were randomized to receive M. Officinalis L. (500 mg daily), citalopram (30 mg) or placebo once daily for 8 weeks. The Menopause-Specific Quality of Life (MENQOL) questionnaire was self-completed by each participant at baseline and after 8 weeks of the intervention and was compared between groups. Results The mean for all MENQOL domain scores were significantly improved in the M. Officinalis L. group compared with citalopram and placebo (p < 0.001). The mean standard deviation (SD) after 8 weeks in the M. Officinalis L., citalopram and placebo groups was 2.2 0.84 versus 0.56 0.58 versus 0.36 0.55 in the vasomotor (p < 0.001), 1.02 0.6 versus 0.28 0.2 versus 0.17 0.1 in the psychomotor-social (p < 0.001), 0.76 0.4 versus 0.25 0.1 versus 0.11 0.1 in the physical and 2.3 1.0 versus 0.35 0.5 versus 0.41 0.5 in the sexual domain, respectively. Keywords Conclusions The results revealed that M. Officinalis L. may be recommended for ► melissa officinalis l. improving the quality of life of menopausal women with sleep disturbance. ► citalopram Trial registration The present study was registered by the name “Comparison of the ► menopause efficacy of citalopram and compound of Asperugo procumbens and foeniculum vulgare in ► quality of life treatment of menopausal disorders” with the code IRCT2013072714174N1 in the ► sleep disturbance Iranian Registry of Clinical Trials (IRCT).

received DOI https://doi.org/ © 2021. Federação Brasileira das Associações de Ginecologia e February 6, 2020 10.1055/s-0040-1721857. Obstetrícia. All rights 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. 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 The Effectiveness of Melissa Officinalis L. versus Citalopram Shirazi et al. 127

Introduction 1 year without menstrual cycle) along with confirming tests of menopause (follicle stimulating hormone Menopause is a physiologic phase characterized by the perma- (FSH) > 40 m IU/mL, and estradiol < 20pg/mL) who were nent cessation of ovulation.1 During this transitional period, poor sleepers according to the Pittsburgh Sleep Quality Index women experience quite a lot of physical, psychological, and (global score 5). The validity and reliability of the social symptoms such as hot flashes, mood variability, and Pittsburgh Sleep Quality Index questionnaire in Iran were sleep disturbance that may last for years.2 approved via the study by Nazifi et al.12 The exclusion criteria Sleep duration and quality in menopause may be were a history of hormone replacement therapy in the degraded when compared with premenopausal women, 6 weeks before the study, malignancies, thyroid disorders, which is presumably due to declines in the sex hormones.3 cardiovascular diseases, lipid abnormalities, diabetes melli- The symptoms can range from slight discomfort to intensive tus, and active psychiatric diseases. Indeed, we excluded the and debilitating marks such as insomnia and intermittent women who took the sleeping pills as well as other medi- sleep.2 Insomnia appears to be due to night sweats cations in the last 3 months, which may influence their sleep caused by the hormonal changes and lead to an increase habits. Within 8 weeks of the assessment, an independent in awakening.4 clinician, who was unaware of the allocated groups, Sleep disturbance can impact negatively on the quality of performed the assessments. After the enrolment was com- life and it seems that vasomotor symptoms are a key completed, randomization was done with an allocation sequence ponent of sleep disruption.5 generated by block randomization by the trial statistician. It is indicated that hormone replacement therapy can The participants were divided into 3 equal groups given a minimize estrogen deficiency, which may lead to an improve- block size of 20. The groups received citalopram (30 mg), an ment in quality of life in the physical, emotional, and sexual equal combinatorial capsule of lemon balm leaf and fennel aspects of life.6 However, due to its known side effects and fruit named as M. Officinalis L. (500 mg) or placebo capsule sometimes the contraindications, using alternative botanical (containing 500 mg starch) every day for 8 weeks. The therapies may be beneficial in this group of women.7 pharmaceutical products were packed into similar envelopes The extract of lemon balm and fennel as Melissa Officinalis L. and with the same appearance. The capsules were built in the is an Iranian herbal extract with an anxiolytic effect and has a faculty of Tehran Traditional Pharmacy. Participants and – positive impression on sleep disturbance.8 10 Phytochemical providers were blind to the treatment. In the first visit after investigations revealed that this plant contains volatile com- confirming their sleep disturbance, the participants were pounds, triterpenoids, phenolic acids and flavonoids and evaluated by asking their history, and physical examination effects on mood, cognition and memory.11 The present study was conducted for each subject. Then, they were asked to was conducted to determine the effects of this herbal ingredi- complete the Menopause-Specific Quality of Life Question- ent in improving postmenopausal women’s sleep disturbance naire and the demographic checklist including age, the age of and quality of life compared with citalopram and placebo. menarche, marital age, menopausal age, parity, and body mass index (BMI). Then the providers asked the participants Methods to administer 1 capsule daily for 8 weeks. There were no special requirements or lifestyle recommendations during Trial Registration this course. In the follow-up period, the participants were The present study was registered under the name “Compar- tracked for the incidence of any side effects. In their last ison of the efficacy of citalopram and compound of Asperugo follow-up visit after 8 weeks, they were requested to refill the procumbent and foeniculum vulgare in treatment of meno- questionnaire and report any probable side effects of the pausal disorders” with the code IRCT2013072714174N1 in drugs. the Iranian Registry of Clinical Trials (IRCT). Assessments Tool Ethics Statements The data were collected using a demographic checklist in the The protocol of the present study was approved by the ethical first visit and the Menopause-Specific Quality of Life Question- committee of the Tehran University of Medical Sciences with naire (MENQOL) in the first and last follow up. The MENQOL the code 89746. The participants subsequently submitted a wasself-administered and was used to investigate the women’s written consent form to participate in the trial. The present quality of life during the last month. This questionnaire con- trial was conducted according to the principles of the Hel- tained 29 items in the Likert form, including vasomotor (items sinki Declaration. 1–3), psychosocial (items 4–10), physical (items 11–26), and sexual (items 27–29) scales. Each question was scored from Study Overview zero (not annoying at all) to 6 (very annoying). Means were The present randomized double-blind placebo clinical trial computed by dividing the sum of the domain item by the was performed from April 2017 to November 2019 among 60 number of items within the domain.13 Ahigherscoreindicated postmenopausal women who were referred to the Women better quality of life. This questionnaire had good internal Hospital (a university hospital affiliated to the Tehran Uni- consistency in the Persian language in vasomotor, physical versity of Medical Sciences) due to sleeping disturbance. The and psychosocial domains, but not in the sexual domain.14 The inclusion criteria were all postmenopausal women (at least data were collected and analyzed in a secure framework.

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. 128 The Effectiveness of Melissa Officinalis L. versus Citalopram Shirazi et al.

Table 1 Baseline demographic characteristics by three allocated groups of the participants

Melissa Officinalis L. Citalopram Placebo Total p-value Age 51.7 3.3 52.6 3.5 51.4 3.3 51.9 3.4 0567 Age at menarche 13.2 2.4 12.8 2.6 12.9 2.5 12.9 2.3 0.890 Marital age 21.2 4.2 20.2 3.9 22.5 4.1 21.3 4.1 0.232 Menopausal age 50.6 1.4 49.2 1.7 50 1.5 49.9 1.6 0.154 Bdoy mass index 25.6 1.1 25.1 1.3 26.2 1.1 25.6 1.2 0.456 Parity 4.5 1.4 4.9 1.4 4.4 1.3 4.6 1.3 0.546

Mean standard deviation.

Statistics menarche, marital age and menopausal age as well as BMI The treatment groups were initially compared on baseline and parity between the three groups of the study. There was demographic variables with chi-squared tests and indepen- no significant difference between the demographic charac- dent samples t-tests. The one-sample Shapiro-Wilk test was teristics of the participants. used to test the normal distribution of the data. The Wilcoxon ►Table 2 indicates the baseline mean values score of signed-rank test was applied to compare the mean score of the MENQOL domains including vasomotor, psychomotor-social, variables before and after the interventions, and the Kruskal- physical and sexual domais, before the intervention. Diffi- Wallis test was applied for comparing the variables among the culty in sleeping had a worse score in all groups. Hot flashes three groups. Data were analyzed using Stata software version with mean SD ¼ 7.03 06.08 from the vasomotor domain 12 (Statacorp, College Station, TX, USA). P-values < 0.05 were were the second worst and facial hair from the physical considered statistically significant. domain had the best score (1.68 1.15). The total score of quality of life by MENQOL between groups was not signifi- Results cantly different before the intervention. The total score of MENQOL in the 3 groups got better In the present study, 60 postmenopausal women were compared with baseline (p 0.001). ►Table 3 indicates the recruited, and no participants left or withdrawed before mean and percentage of improving the score of MENQOL the termination of the study. There was no significant domains in participants of the three groups after the inter- difference between the mean of the Pittsburgh Sleep Quality vention. As shown in ►Table 3, improving the score of quality Index (PSQI) scores between the 3 groups (p ¼ 0.835). The of life in the M. Officinalis L. group was significant (p < 0.001) average age was 51.9 years old (minimum 43, maximum compared with the other groups, and its highest effect was 60 years old). ►Table 1 compares the mean of age, age of on the vasomotor domain, with a mean of 2.2 0.8. The

Table 2 Mean baseline score of MENQOL domains in participants of the three groups before intervention

Melissa Officinalis L. Citalopram Placebo p-value Vasomotor 5.83 1.3 5.85 1.3 5.95 1.2 0.749 Psychomotor-Social 3.84 1.5 3.96 1.6 3.93 1.4 0.661 Physical 3.06 1.0 3.52 1.1 3.08 0.9 0.760 Sexual 6.56 1.0 5.61 1.6 5.91 1.3 0.812

Higher index indicates worse quality of life. Mean standard deviation.

Table 3 Mean standard deviation change and percentage change ofMENQOLdomainsafter8weeksofintervention

Melissa Officinalis L. Citalopram Placebo p-value Mean SD Percentage Mean SD Percentage Mean SD Percentage change (%) change (%) change (%) Vasomotor 2.2 0.8 -38.0 0.56 0.5 -11.4 0.36 0.5 -5.7 < 0.001 Psychomotor-Social 1.02 0.6 -23.8 0.28 0.2 -6.8 0.17 0.1 -4.1 < 0.001 Physical 0.76 0.4 -23.6 0.25 0.1 -7.1 0.11 0.1 -4.0 < 0.001 Sexual 2.3 1.0 -34.5 0.35 0.5 -7.6 0.41 0.5 -6.4 < 0.001

Abbreviation: SD, standard deviation.

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. The Effectiveness of Melissa Officinalis L. versus Citalopram Shirazi et al. 129 citalopram group was also more effective than placebo in Our limitation was the small sample size and short dura- improving various domains of quality of life (p < 0.001). In tion of the study. Indeed, based on Ghazanfarpour et al.,30 we the present study, two participants in the citalopram group did not omit the “Vaginal dryness during intercourse” and reported nausea and one case reported headache, all of “weight gain” items from MENQOL due to missing the which were self-controlled. No adverse effect was reported consistency of the scores. in the M. Officinalis L. and placebo groups. Conclusion Discussion The present study demonstrates that M. Officinalis L. may Sleep disturbance is one of the critical symptoms in menopause improve the quality of life in menopausal women with sleep that influences quality of life.15 The main pathology of sleep disorders. Furthermore, no adverse effects were reported. It disruption may be vasomotor symptoms specially in the tran- is recommended that further research will be undertaken in sitional period.5 The result of the present study showed that this field with a larger sample size, longer follow-up, and M. Officinalis L. is more effective than citalopram and placebo in different racial populations. improving the quality of life of the participants. The vasomotor symptoms as well as the physical, psychomotor-social, and Contributions sexual domains of quality of life in the participants improved Shirazi M: study conception and design, analysis and more in the M.Officinalis L. compared with other groups. interpretation of data, critical revision; Jalalian M. N.: The average age of the participants with sleep disturbance analysis and interpretation of data; Abed M.: drafting of was near 52 years old, which may be due to the severity of the manuscript; Ghaemi M: analysis and interpretation of this problem in the transitional stage and early menopause.5 data, critical revision. All authors have read and approved It seems that citalopram compared with placebo may the manuscript. decrease insomnia symptoms and improve sleep quality16; but in some reviews, the selective serotonin reuptake inhib- Conflict of Interests itors (SSRIs) or citalopram for the treatment of major depres- The authors have no conflict of interests to declare. sion and anxiety disorders have noted that insomnia is a commonly reported adverse event.17,18 This conflict in effects Acknowledgments of specific SSRIs on self-reported sleep in women may be due The present research has been supported by the Tehran to several reasons including differences in the pharmacologic University of Medical Sciences & health Services grant 22189. properties of specific drugs, study populations, choice of sleep 16 outcome measures, and reporting of adverse events. References The global trend shows that the number of people prefer- 1 Greendale GA, Lee NP, Arriola ER. The menopause. Lancet. 1999; ring to use herbal ingredients instead of chemicals is grow- 353(9152):571–580. Doi: 10.1016/S0140-6736(98)0552-5 7,19 fi ing. M. Of cinalis L., as a botanical substance, has anxiolytic 2 Gibbs RS, Karlan BY, Haney AF, Nygaard IE. Danforth’s obstetrics effects and improves sleep quality in humans.20,21 It is also and gynecology. 10th ed. Philadelphia: Lippincott Williams & recommended in sleep disturbance in menopause.22 Indeed, Wilkins; 2008 this extract had been tested on animal models to decrease 3 Freedman RR. Menopause and sleep. Menopause. 2014;21(05): 534–535. Doi: 10.1097/GME.0000000000000243 anxiety and as an antioxidant.20,23,24 The mechanism of action 4 Krystal AD, Edinger J, Wohlgemuth W, Marsh GR. Sleep in peri- may be due to gamma-aminobutyric acid (GABA) elevation on menopausal and post-menopausal women. Sleep Med Rev. 1998; 22,25 the brain, because it is assumed that GABAergic neuro- 2(04):243–253. Doi: 10.1016/s1087-0792(98)90011-9 transmission has been associated with reductions in anxiety,20 5 Baker FC, Lampio L, Saaresranta T, Polo-Kantola P. Sleep and sleep but the extent of its therapeutic effects and amounts of various disorders in the menopausal transition. Sleep Med Clin. 2018;13 – constituents in the extract is unknown.18 (03):443 456. Doi: 10.1016/j.jsmc.2018.04.011 6 Steels E, Steele ML, Harold M, Coulson S. Efficacy of a proprietary M. Officinalis L. is a safe and well-tolerated ingredient, and Trigonella foenum-graecum L. de-husked seed extract in reducing no adverse event was reported due to the administration of menopausal symptoms in otherwise healthy women: a double- 26 500 mg of M. Officinalis L. in humans. In our study, no blind, randomized, placebo-controlled study. Phytother Res. participant reported adverse events or complications during 2017;31(09):1316–1322. Doi: 10.1002/ptr.5856 the trial, 7 Johnson A, Roberts L, Elkins G. Complementary and alternative medicine for menopause. J Evid Based Integr Med. 2019;24: The strength of our study may be due to the recommen- X19829380. Doi: 10.1177/2515690X19829380 dation of M. Officinalis L. to improve the quality of life of 8 Kennedy DO, Little W, Haskell CF, Scholey AB. Anxiolytic effects of menopausal women, which naturally declines in middle a combination of Melissa officinalis and Valeriana officinalis age.27 Besides, this ingredient did not have the same poten- during laboratory induced stress. Phytother Res. 2006;20(02): tial side effects as citalopram.28 96–102. Doi: 10.1002/ptr.1787 It seems that the placebo effect on health-related quality 9 Ranjbar M, Firoozabadi A, Salehi A, Ghorbanifar Z, Zarshenas MM, Sadeghniiat-Haghighi K, Rezaizadeh H. Effects of Herbal combi- of life is meaningful.29 In our study, we experienced a nation (Melissa officinalis L. and Nepeta menthoides Boiss. & placebo effect on quality of life. 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10 Miraj S, , Rafieian-Kopaei, Kiani S. Melissa officinalis L: a review 21 Shirazi M, Saedi N, Shariat M, Azadi F, Davari Tanha F. Comparison study with an antioxidant prospective. J Evid Based Complemen- of melissa with citalopram and placebo in treatment of sleep tary Altern Med. 2017;22(03):385–394. Doi: 10.1177/21565872 disorders in menopausal women: clinical trial. Tehran Univ Med J. 16663433 2016;74(08):562–568 11 Shakeri A, Sahebkar A, Javadi B. Melissa officinalis L. - A review of 22 Taavoni S, Nazem Ekbatani N, Haghani H. Valerian/lemon balm its traditional uses, phytochemistry and pharmacology. J Ethno- use for sleep disorders during menopause. Complement Ther Clin pharmacol. 2016;188:204–228. Doi: 10.1016/j.jep.2016.05.010 Pract. 2013;19(04):193–196. Doi: 10.1016/j.ctcp.2013.07.002 12 Nazifi M, Mokarami H, Akbaritabar A, Kalte HO, Rahi A. Psychometric 23 Taiwo AE, Leite FB, Lucena GM, et al. 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Effect of Preoperative Urodynamic Study on Urinary Outcomes after Transobturator Sling Efeito do estudo urodinâmico pré-operatório nos resultados pós-operatórios do sling transobturador Pedro Rincon Cintra da Cruz1,2 Aderivaldo Cabral Dias Filho2,3 Gabriel Nardi Furtado1 Rhaniellen Silva Ferreira1 CeresNunesResende1

1 Hospital Universitário de Brasília, Brasília, DF, Brazil Address for correspondence PedroRinconCintradaCruz,MD,Setor 2 Hospital de Base do Distrito Federal, Brasília, DF, Brazil de Grandes Áreas Norte 605, Asa Norte, Brasília, DF, 70840-901, Brazil 3 Universidade Estadual de Campinas, Campinas, SP, Brazil (e-mail: [email protected]).

Rev Bras Ginecol Obstet 2021;43(2):131–136.

Abstract Objective To evaluate whether performing preoperative urodynamic study inﬂuen- ces postoperative urinary symptoms of women with stress urinary incontinence that underwent transobturator sling. Methods Retrospective analysis of patients treated for stress urinary incontinence by transobturator sling from August 2011 to October 2018. Predictor variables included preoperative urodynamic study, age, incontinence severity, body mass index, preoperative storage symptoms and previous anti-urinary incontinence procedure. Outcome variables were postoperative subjective continence status, storage symptoms and complications. Logistic regression after propensity score was employed to compare outcomes between patients who underwent or not pre-operative urodynamic study. Results The present study included 88 patients with an average follow-up of 269 days. Most patients (n ¼ 52; 59.1%) described storage symptoms other than stress urinary incontinence, and 38 patients (43.2%) underwent preoperative urodynamic studies. Logistic regression after propensity score did not reveal an association between urinary continence outcomes and performance of preoperative urodynamic study (odds ratio 0.57; conﬁdence interval [CI]: 0.11–2.49). Among women that did not undergo Keywords urodynamic study, there was a subjective improvement in urinary incontinence in 92% of the cases versus 87% in those that underwent urodynamic study (p ¼ 0.461). ► urinary incontinence Furthermore, postoperative storage symptoms were similar between women who did ► urodynamic not undergo urodynamic study and those who underwent urodynamic study, 13.2% ► stress urinary versus 18.4%, respectively (p ¼ 0.753). incontinence Conclusion Preoperative urodynamic study had no impact on urinary incontinence ► transobturator cure outcomes as well as on urinary storage symptoms after the transobturator sling in suburethral tape women with stress urinary incontinence. ► propensity score

received DOI https://doi.org/ © 2021. Federação Brasileira das Associações de Ginecologia e May 20, 2020 10.1055/s-0040-1719148. Obstetrícia. All rights 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 132 Effect of Preoperative Urodynamic Study on Urinary Outcomes after Transobturator Sling da Cruz et al.

Resumo Objetivo Avaliar a inﬂuência do estudo urodinâmico pré-operatório nos resultados miccionais pós-operatórios em mulheres com incontinência urinária de esforço submetidas a sling transobturador. Métodos Análise retrospectiva de mulheres com incontinência urinária de esforço submetidas a sling transobturador entre agosto de 2011 e outubro de 2018. As variáveis preditoras pré-operatórias, entre outras, foram a realização do estudo urodinâmico, gravidade da incontinência e sintomas urinários de armazenamento. As variáveis de desfecho pós-operatórias foram o status subjetivo da continência, sintomas de armazenamento urinário e complicações cirúrgicas. A regressão logística após o escore de propensão foi empregada para comparar os resultados entre os pacientes que foram submetidos ou não ao estudo urodinâmico pré-operatório. Resultados Foram incluídas no presente estudo 88 pacientes com um seguimento médio de 269 dias. A maioria das pacientes apresentava sintomas miccionais de armazenamento (n ¼ 52; 59,1%) concomitantes à incontinência urinária de esforço. Um pouco menos da metade das pacientes (n ¼ 38; 43,2%) foram submetidas a estudo Palavras-chave urodinâmico pré-operatório. A regressão logística após o escore de propensão não ► incontinência urinária revelou associação entre os resultados de continência urinária e a realização de estudo ► urodinâmica urodinâmico pré-operatório (odds ratio 0,57; intervalo de conﬁança [IC]: 0,11–2,49). ► incontinência urinária Além disso, os sintomas de armazenamento urinário pós-operatórios foram similares de esforço entre as pacientes que não realizaram e aquelas que realizaram o estudo urodinâmico, ► sling suburetral 13,2% e 18,4% respectivamente (p ¼ 0,753). transobturatório Conclusão O estudo urodinâmico pré-operatório não teve impacto nos resultados de ► pontuação de continência urinária, bem como nos sintomas de armazenamento urinário após o sling propensão transobturatório.

Introduction Some doubts remain regarding the need to perform the Urinary incontinence (UI) is an important cause of social preoperative UDS and their real impact on postoperative isolation and poor quality of life among women. This is a urinary outcomes. Our hypothesis is that clinical history and common condition, with prevalence ranging from 15.7 to physical examination are sufficient for indicating surgical 49.6%.1,2 About half of incontinent women have stress uri- treatment in most women with UI and stress symptoms nary incontinence (SUI), which is, therefore, the main cause predominately. The aim of our study was to evaluate whether of UI in this population.2 performing preoperative UDS influences postoperative uri- Synthetic midurethral slings (MUS) have gradually nary symptoms of women with SUI who underwent the TOT replaced autologous fascial slings in the treatment of women procedure. with SUI.3 From studies developed by Ulmsten et al.4 and 5 Petros in the 1990’s, the tension-free vaginal tape (TVT) was Methods consolidated as the surgical procedure of choice in women with SUI. In 2001, the transobturator tension-free vaginal Study Design and Patient Eligibility tape (TOT) procedure emerged as an effective and technically After Institutional Board Review (CAAE: 27824819.3. simpler procedure than TVT with a lower rate of vascular, 0000.5558), we retrospectively identified and collected data bladder and intestinal injuries.6 from all consecutive patients treated for SUI by TOT procedure Urodynamic studies (UDS) are widely performed, but from August 2011 to October 2018 by the urology and gynecol- their role in the preoperative assessment of women candi- ogy team at our hospital. dates for the TOT procedure remains in dispute. Guidelines Patient assessment included urogynecological examina- from major urological societies indicate that UDS is not tion and supine stress test with variable bladder volume mandatory in women with uncomplicated SUI.7,8 Some stress tests. Patients with a high volume of urine loss or in authors, however, justify preoperative UDS in patients those in whom treatment with perineal physiotherapy was with SUI with the argument that it avoids unnecessary unsuccessful, who wished to progress to surgical treatment, operations and provides accurate information to patients preoperative UDS were performed. However, UDS were not about therapeutic outcomes.9,10 However, there is weak indicated for patients evaluated and operated by a single evidence that UDS improve clinical outcomes or that they surgeon who waived them in patients with SUI without prior predict the success of the surgery.11 incontinence surgery. That is, except when evaluated by this

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. Effect of Preoperative Urodynamic Study on Urinary Outcomes after Transobturator Sling da Cruz et al. 133 surgeon, all other patients underwent UDS before TOT derwent or not preoperative UDS. The variables used to placement. produce propensity scores were age, vaginal parity, preop- The TOTs were inserted by the out-inside route under erative storage symptoms, BMI, and incontinence severity, spinal anesthesia. Patients received first generation cepha- with missing values imputed via predictive mean matching. losporin as a prophylactic antibiotic. A low-cost 20 1.5 cm Outcomes were assessed by logistic regression models. polypropylene mesh, prepared by the surgeon himself, was used in all cases.12,13 Each end of the mesh was anchored Statistical Software with a zero polypropylene suture used to attach the tape to Statistical analysis was performed within the R language the helical needle. statistical environment (R Foundation, Vienna, Austria).14 Follow-up visits took place 1 month after the procedure and with 3-month intervals during 1 year, and yearly there- Results after. In these visits, clinical history was collected and the urogynecological examination and supine stress test was During the study period, 99 patients underwent the TOT performed. procedure. Eleven patients (11.1%) were excluded due to lack All patients who underwent TOT from August 2011 to of records for postoperative incontinence status, leaving 88 October 2018 were candidates for inclusion in the study, patients in our study population. The mean postoperative including those with preoperative storage symptoms as well follow-up was of 269 days. as those who underwent concomitant vaginal prolapse Overall characteristics of the patients are displayed repair. We excluded from analysis patients who did not in ►Table 1. The average age of the patients was 52.7 years return for postoperative follow-up in the 1st month and old and the average BMI was 29.67 Kg/m2. Most patients those in whom the continence status could not be recovered (n ¼ 52; 59.1%) described storage symptoms other than SUI. from their clinical records. Continence status was assessed The storage symptoms described were urinary urgency and according to the symptoms of the patient, classified as either increased daytime frequency. There were no cases of mixed cured/improved or unaltered/worsened, and by the average UI. A greater proportion (n ¼ 75; 85.2%) presented mild daily number of pads used by the patients stress incontinence, using at most one pad per day. Thirty- eight patients (43.2%) underwent preoperative UDS. Study Variables The patients who underwent preoperative UDS were not The predictor variables were: whether the patient under- significantly different with respect to age, BMI, number of went or not a preoperative urodynamic study; age in years; incontinence severity according to the average daily number Table 1 Overall patient characteristics (n ¼ 88) of pads used by the patients (1: 1 pad/day, 2: 2 or 3 > fi pads/day, 3: 3 pads/day); vaginal parity, de ned as the Variables Median (IQR) number of vaginal births; menopause status (yes or no); Continuous Age (years old) 51.1 (45.1, 59.4) body mass index (BMI) in Kg/m2; preoperative storage 2 symptoms, classified as absent, mild or moderate and wheth- BMI (kg/m ) 28.2 (26.5, 34.3) er the patient had a previous anti-urinary incontinence Ordinal Vaginal deliveries N (%) procedure (yes, no). 07(8) Outcome variables were postoperative subjective conti- 1–3 51 (58%) nence status at the last follow-up visit, classified as either > 4 30 (34.1%) cured/improved or unaltered/worsened; postoperative storage symptoms (present or absent) and postoperative Incontinence severity complications. 1 75 (85.2%) 2 11 (11.4%) Statistical Analysis 33(3.4%) N(%) Univariate and Bivariate Analysis Categorical Storage symptoms 52 (59.1%) Categorical and ordinal variables were described by their frequencies and continuous variables by their medians and Previous UI surgery 15 (17%) interquartile ratios (IQR). Differences between categorical DM 10 (11.4%) variables were assessed with the Pearson chi-squared and Smoking 14 (15.9%) Fisher exact tests, as appropriate. Differences between con- Preoperative UDS 38 (43.2%) tinuous variables were evaluated with the Kruskal-Wallis Synchronous prolapse surgery 32 (36.4%) test. Where appropriate, statistical significance was set at p < 0.05. Postoperative continence 80 (90.9%)

Abbreviations: BMI, body mass index; DM, diabetes mellitus; IQR, Propensity Score Matching and Logistic Regression interquartile ratio; n, number of patients; Preoperative UDS, preoper- Nearest neighbor propensity score 1:1 matching was ative urodynamic study; Previous UI surgery, previous urinary inconti- employed to compare outcomes between patients that un- nence surgery.

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. 134 Effect of Preoperative Urodynamic Study on Urinary Outcomes after Transobturator Sling da Cruz et al.

Table 2 Distribution of variables before and after nearest neighbor propensity score matching

Before matching After matching No UDS (n ¼ 50) UDS (n ¼ 38) p (test) No UDS (n ¼ 38) UDS (n ¼ 38) p (test) Age (years old) 49.6 (45.1, 56.1) 53.5 (47.4, 61.1) 0.188 (K) 50.60 (46.4, 58.1) 53.5 (47.4, 61.1) 0.496 (K) BMI (kg/m2) 29.3 (25.7, 32.3) 28.3 (26.9, 34.7) 0.870 (K) 29.65 (25.6, 34.0) 28.30 (26.9, 34.6) 0.852 (K) Vaginal deliveries 0 4 (8%) 3 (7.9%) 0.639 (K) 4 (10.5%) 3 (7.9%) 0.919 (K) 1–3 31 (62%) 20 (52.6%) 19 (50%) 20 (52.6%) > 4 15 (30%) 15 (39.5%) 15 (39.5%) 15 (39.5%) Incontinence severity 1 45 (90%) 30 (78.9%) 0.108 (K) 33 (86.8%) 30 (78.9%) 0.208 (K) 2 5 (10%) 5 (13.2%) 5 (13.2%) 5 (13.2%) 3 0 3 (7.9%) 0 3 (7.9%) Menopause 24 (48.8%) 24 (63.2%) 0.231 (C) 19 (50%) 24 (63.2%) 0.355 (C) DM 3 (6%) 7 (18.4%) 0.139 (F) 3 (7.9%) 7 (18.4%) 0.309 (F) Smoking 7 (14%) 7 (18.4%) 0.789 (C) 5 (13.2% 7 (18.4%) 0.753 (C) Previous UI surgery 4 (8%) 11 (28.9%) 0.021 (F) 4 (10.5%) 11 (28.5%) 0.100 (F) Preoperative storage symptoms 31 (62%) 21 (55.2%) 0.676 (C) 21 (55.3%) 21 (55.3%) 1.0 (C) Synchronous prolapse surgery 19 (38.0%) 13 (34.2%) 0.887 (C) 13 (34.2%) 13 (34.2%) 1.0 (C) Postoperative storage symptoms 6 (12.0%) 7 (18.4%) 0.591 (F) 5 (13.2%) 7 (18.4%) 0.753 (F) Postoperative continence 47 (94.0%) 33 (87%) 0.252 (C) 35 (92.1%) 33 (86.8%) 0.709 (C)

Abbreviations: BMI, body mass index; C, Pearson’s Chi-Squared test; DM, diabetes mellitus; F, Fisher exact test; IQR, interquartile ratio; K, Kruskal- Wallis test (followed by Dunn test as appropriate); n, number of patients; Preoperative UDS, preoperative urodynamic study; Previous UI surgery, previous urinary incontinence surgery.

vaginal deliveries, incontinence severity, and preoperative among women who underwent UDS, with no statistical storage symptoms. However, patients who had previous difference between groups (p ¼ 0.474). anti-incontinence surgery were more often submitted to In the follow-up, no patient required urethrolysis second- preoperative UDS than those who had no such history ary to urinary retention. There was only one mesh erosion in (28.9% versus 8.0%, p ¼ 0.021). The synchronous prolapse a patient who underwent a previous urodynamic study and surgeries performed were anterior vaginal repair, posterior who did not perform prolapse surgery concomitant with the vaginal repair and, in some cases, concomitant anterior and sling. posterior repair. The synchronous prolapse surgery performed was similar in the group that underwent UDS and Discussion in the group that did not undergo UDS (34.2% versus 38.0%, p ¼ 0,087). The distributions of the variables according to the Our study, which included 88 women with a mean age of 52.7 performance or not of preoperative UDS before and after years old and mean postoperative follow-up of 269 days, did matching are shown in ►Table 2. not indicate an association between the performance of pre- Logistic regression after propensity score did not reveal operative UDS and urinary continence outcomes for women an association between urinary continence outcomes and with SUI. In addition, postoperative storage symptoms were performance of preoperative UDS (odds ratio [OR] 0.57; similar between women who did not undergo UDS and those conﬁdence interval [CI]: 0.11–2.49). In addition, among who underwent UDS, 13.2% versus 18.4%, respectively women who did not undergo UDS, there was a subjective (p ¼ 0.753). It is important to note that 62% of the patients improvement in UI in 92% of the cases versus 87% in those in the group that did not undergo UDS and 55.2% in the group who underwent UDS (p ¼ 0.461). The vast majority of that underwent UDS had preoperative storage symptoms. patients had no postoperative urinary leakage, 84% (41/50) Our results are in line with recently published studies. In a in the non-UDS group and 76% (29/38) in the UDS group. large multicenter and randomized study, the Value study, Postoperative storage symptoms, urinary urgency and in- involving women with uncomplicated SUI, whose primary creased daytime frequency were similar between women outcome was treatment success, the results of the surgery who did not undergo UDS and those who underwent UDS, were compared between those who underwent and those who 13.2% versus 18.4%, respectively (p ¼ 0.753). In addition, did not undergo UDS in the preoperative period. The conclu- there were no cases of de novo storage urinary symptoms sion was that the basic ofﬁce evaluation is not inferior to that among women who did not undergo UDS, and only 2 cases associated with the performance of UDS in the preoperative

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. Effect of Preoperative Urodynamic Study on Urinary Outcomes after Transobturator Sling da Cruz et al. 135 period.15 A secondary analysis from the Value study indicated cause psychological discomfort, mainly through feelings of that preoperative UDS in women with uncomplicated SUI shame and anxiety, leads up to 20% of women to not want to increased costs and did not lead to better postoperative out- undergo the exam again.26 Finally, even if low, there is a comes.16 Rachaneni et al., in a 201517 meta-analysis, found possibility of lower urinary tract infection, with an incidence that in women with uncomplicated SUI or mixed urinary of 3%, even in healthy women.27 incontinence with predominantly stress symptoms, with pre- The present study has many methodological issues that served maximal bladder capacity and normal post-void resi- should be discussed. The group selection bias commonly due, preoperative UDS had no additional value. Finally, affects retrospective studies and ours was no different. It is recently, a Mayo Clinic retrospective study including 1,629 reasonable to question that patients who did not undergo women submitted to primary synthetic midurethral sling UDS preoperatively had mild UI and symptoms of pure SUI. placement did not uncover UDS parameters associated with Thus, as it was not a randomized study, to mitigate the the necessity for sling release.18 selection bias, we used propensity score matching to com- Despite the results of the studies cited above, many pare the groups, despite the overall characteristics of the authors have questioned the applicability of these findings patients being similar between the groups. in clinical practice. A large Italian multicenter retrospective It was not possible to apply objective questionnaires for study of 2,053 women showed that only 36% of the patients urinary continence assessment, and postoperative subjective with SUI could be classified as uncomplicated SUI. Moreover, parameters were used, which decreases the possibility of even in uncomplicated patients, UDS were able to diagnose replicability of our results. In addition, the postoperative voiding dysfunction in 13.4% of the cases and change the follow-up of our patients was not long, perhaps because, as management in 11% of the cases.19 In another Italian study, we are a tertiary hospital, many patients with good postop- with a cohort of 323 patients with SUI, the prevalence of erative evolution are referred early to follow-up at less uncomplicated SUI was 20.7%. Of these, 11.7% were excluded complex health units. from the diagnosis of uncomplicated SUI after UDS and 8.96% 20 had the surgical procedure canceled. Conclusion But is changing the therapeutic strategy of an uncomplicated SUI patient according to urodynamic findings a good The results of the present retrospective study suggest that strategy? In an interesting multicenter German study, van preoperative UDS had no impacton UI cure outcomes as well as Leijsen et al.21 evaluated patients with clinical diagnosis of on urinary storage symptoms after the transobturator tape uncomplicated SUI that differed from urodynamic diagnosis. procedure in women with UI and stress symptoms predomi- These women were randomized to surgical or clinical treat- nately. These data reinforce the hypothesis that perhaps UDS ment immediately after UDS. The conclusion was that from the are unnecessary in women with uncomplicated SUI. point of view of curing UI, the surgical procedure was not inferior to the individualized clinical treatment based on Contributors UDS.21 Furthermore, the effectiveness of TOT procedures has All of the authors contributed with the project and data been demonstrated in the literature for a long time. A prospec- interpretation, the writing of the article, the critical tive trial published in 2004 showed an objective cure rate for review of the intellectual content, and with the final TOT procedures of 90% and a subjective cure of 86.7%.22 A approval of the version to be published. systematic review of The Cochrane Database showed subjective cure rates with short, medium and long-term TOT proce- Conflict of Interests dures of 83.3%, 86.9% and 84.3%, respectively.23 Lastly, a recent The authors have no conflict of interests to declare. systematic review confirms the initial good results of the TOT procedure, with an average probability of improvement in UI References symptoms of 76.1%.24 These studies are in line with our results, 1 Nygaard I, Barber MD, Burgio KL, Kenton K, Meikle S, Schaffer showing subjective improvement rates of SUI symptoms be- JPelvic Floor Disorders Network. , et al; . Prevalence of symptom- tween 87 and 92%. atic pelvic floor disorders in US women. JAMA. 2008;300(11): The literature also shows good results with the use of low- 1311–1316. Doi: 10.1001/jama.300.11.1311 cost polypropylene mesh. Using the low-cost transobturator 2 Dooley Y, Kenton K, Cao G, et al. Urinary incontinence prevalence: vaginal tape inside-out technique, a prospective evaluation of results from the National Health and Nutrition Examination Survey. J Urol. 2008;179(02):656–661. Doi: 10.1016/j.juro.2007.09.081 59 women demonstrated 92% cure of SIU.13 In another work 3 Plagakis S, Tse V. The autologous pubovaginal fascial sling: An also using the low cost vaginal mesh, now using the outside-in update in 2019. Low Urin Tract Symptoms. 2020;12(01):2–7. Doi: 25 route, Elgamasy et al. achieved 87.5% cure for SUI. Given the 10.1111/luts.12281 evidence of safety and efficacy of using low-cost vaginal tape, 4 Ulmsten U, Henriksson L, Johnson P, Varhos G. An ambulatory these have proven to be a good alternative, especially in the surgical procedure under local anesthesia for treatment of female public health system with few financial resources, such as the urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct. 1996;7(02):81–85, discussion 85–86. Doi: 10.1007/BF01902378 hospital where our patients were operated. 5 Petros PP. The intravaginal slingplasty operation, a minimally fi The dispute about preoperative UDS is further justi ed invasive technique for cure of urinary incontinence in the female. due to it being an invasive, time-consuming examination Aust N Z J Obstet Gynaecol. 1996;36(04):453–461. Doi: 10.1111/ that can cause pain in the patient. Not least, its potential to j.1479-828X.1996.tb02192.x

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. 136 Effect of Preoperative Urodynamic Study on Urinary Outcomes after Transobturator Sling da Cruz et al.

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Doi: 10.1016/j. 44. Doi: 10.1186/s12894-019-0468-2 euf.2015.10.006 21 van Leijsen SA, Kluivers KB, Mol BW, Hout JIT, Milani AL, Roovers 10 Serati M, Braga A, Torella M, Soligo M, Finazzi-Agro E. The role of JWRDutch Urogynecology Consortium. , et al; . Value of urody- urodynamics in the management of female stress urinary incon- namics before stress urinary incontinence surgery: a randomized tinence. Neurourol Urodyn. 2019;38(Suppl 4):S42–S50. Doi: controlled trial. Obstet Gynecol. 2013;121(05):999–1008. Doi: 10.1002/nau.23865 10.1097/AOG.0b013e31828c68e3 11 Clement KD, Lapitan MC, Omar MI, Glazener CM. Urodynamic 22 deTayrac R, Defﬁeux X, Droupy S, Chauveaud-Lambling A, Calva- studies for management of urinary incontinence in children and nèse-Benamour L, Fernandez H. A prospective randomized trial adults: A short version Cochrane systematic review and meta- comparing tension-free vaginal tape and transobturator subure- analysis. Neurourol Urodyn. 2015;34(05):407–412. 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Malignant Uterine Neoplasms Attended at a Brazilian Regional Hospital: 16-years Proﬁle and Time Elapsed for Diagnosis and Treatment Neoplasias malignas do útero atendidas em hospital regional brasileiro: Perﬁl em 16 Anos e tempo dispendido até diagnóstico e tratamento Elaine Cristina Candido1 Nelio Neves Veiga Junior1 Monique Possari Minari1 Maria Carolina Szymanski Toledo1 Daniela Angerame Yela1 Julio Cesar Teixeira1

1 Department of Obstetrics and Gynecology, Faculty of Medical Address for correspondence Julio Cesar Teixeira, Department of Sciences, Universidade Estadual de Campinas, Campinas, SP, Brazil Obstetrics and Gynecology, Faculty of Medical Sciences, Universidade Estadual de Campinas, Rua Alexander Fleming, 101, Cidade Universitaria, Campinas, Rev Bras Ginecol Obstet 2021;43(2):137–144. SP 13083-881, Brazil (e-mail: [email protected]; [email protected]).

Abstract Objective The present study aims to evaluate the profile of endometrial carcinomas and uterine sarcomas attended in a Brazilian cancer center in the period from 2001 to 2016 and to analyze the impact of time elapsed from symptoms to diagnoses or treatment in cancer stage and survival. Methods This observational study with 1,190 cases evaluated the year of diagnosis, age-group, cancer stage and histological type. A subgroup of 185 women with endometrioid histology attended in the period from 2012 to 2017 was selected to assess information about initial symptoms, diagnostic methods, overall survival, and to evaluate the influence of the time elapsed from symptoms to diagnosis and treatment on staging and survival. The statistics used were descriptive, trend test, and the Kaplan- Meier method, with p-values < 0.05 for significance. Results A total of 1,068 (89.7%) carcinomas (77.2% endometrioid and 22.8% non- endometrioid) and 122 (10.3%) sarcomas were analyzed, with an increasing trend in the period (p < 0.05). Histologies of non-endometrioid carcinomas, G3 endometrioid, and carcinosarcomas constituted 30% of the cases. Non-endometrioid carcinomas and sarcomas were more frequently diagnosed in patients over 70 years of age and those on Keywords stage IV (p < 0.05). The endometrioid subgroup with 185 women reported 92% of ► endometrial abnormal uterine bleeding and 43% diagnosis after curettage. The average time neoplasms elapsed between symptoms to diagnosis was 244 days, and between symptoms to ► uterine sarcomas treatment was 376 days, all without association with staging (p ¼ 0.976) and survival ► epidemiology (p ¼ 0.160). Only 12% of the patients started treatment up to 60 days after diagnosis. ► neoplasm staging Conclusion The number of uterine carcinoma and sarcoma cases increased over the ► survival analysis period of 2001 to 2016. Aggressive histology comprised 30% of the patients and, for

received DOI https://doi.org/ © 2021. Federação Brasileira das Associações de Ginecologia e April 27, 2020 10.1055/s-0040-1718434. Obstetrícia. All rights 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 138 Malignant Uterine Neoplasms Attended at a Brazilian Regional Hospital Candido et al.

endometrioid carcinomas, the time elapsed between symptoms and diagnosis or treatment was long, although without association with staging or survival.

Resumo Objetivo O presente estudo avaliou o perﬁl dos carcinomas endometriais e sarcomas uterinos atendidos em um centro brasileiro de câncer no período de 2001 a 2016, e avaliou o impacto do tempo decorrido entre os sintomas até o diagnóstico ou tratamento no estadiamento e sobrevida pelo câncer. Métodos Estudo observacional com 1.190 casos que analisou o ano do diagnóstico, faixa etária, estágio e tipo histológico do câncer. Um subgrupo de 185 mulheres com histologia endometrioide e atendidas no período de 2012 a 2017 foi selecionado para avaliar informações sobre sintomas iniciais, métodos de diagnóstico, sobrevida global e para analisar a relação entre o tempo decorrido a partir dos sintomas até o diagnóstico e tratamento no estadiamento e sobrevida. Foram realizadas análises estatísticas descri- tiva, de tendência linear e de sobrevida pelo método de Kaplan-Meier, com valores de p < 0,05 para signiﬁcância. Resultados Os casos estudados de acordo com a histologia foram 1.068 (89,7%) carcinomas (77,2% endometrioides e 22,8% não endometrioides) e 122 (10,3%) sarcomas, com tendência crescente no período (p < 0,05). Histologias de carcinomas não endometrioides, G3 endometrioides e carcinossarcomas consistiram em 30% dos casos. Carcinomas não endometrioides e sarcomas foram mais frequentemente diagnosticados em pacientes acima de 70 anos de idade e em estágio IV (p < 0,05). O subgrupo com 185 mulheres com carcinoma endometrioide apresentou 92% de sangramento uterino Palavras-chave anormal e 43% de diagnóstico após curetagem. O tempo médio decorrido entre os ► neoplasias sintomas e o diagnóstico foi de 244 dias e entre os sintomas e o tratamento, 376 dias, endometriais todos sem associação com estadiamento (p ¼ 0,976) e sobrevida (p ¼ 0,160). Apenas ► sarcomas uterinos 12% das pacientes iniciaram o tratamento em até 60 dias após o diagnóstico. ► epidemiologia Conclusão O número de casos de carcinomas e sarcomas uterinos aumentaram no ► estadiamento de período de 2001 a 2016. A histologia agressiva compreendeu 30% dos pacientes e, no neoplasia caso dos carcinomas endometrioides, o tempo decorrido entre os sintomas e o ► análise diagnóstico ou tratamento foi longo, embora sem associação com estadiamento ou de sobrevivência sobrevida.

Introduction advanced age and previous radiotherapy can be associated Malignant uterine neoplasms are the most common type of with sarcoma development.4,5,8 gynecological cancers worldwide. Among the most frequent Staging and tumor histology are considered the main neoplasms, uterine cancer occupies the 6th position, with prognostic factors of malignant uterine neoplasms, with better 380 thousand new cases per year. Its incidence has increased prognosis described for endometrioid carcinomas. On the in recent decades, especially in developed countries.1 In other hand, poorly differentiated or non-endometrioid carci- Brazil, the estimated incidence for 2020 is 6,540 new cases, nomas and sarcomas have a worse prognosis.9,10 The gap with a higher expected incidence in the southeast region.2 between first symptoms and diagnosis or treatment onset These neoplasms are divided into two major categories: can modify the staging and therapeutic results, mainly for carcinomas and sarcomas. Endometrial carcinomas are re- worse prognosis cases. In less developed countries or regions – sponsible for 95% of all uterine malignancies.3 5 Risk with difficult access to health care, it is common to have delays factors for carcinomas are obesity, sedentary lifestyle, and in scheduling appointments, diagnostic investigation, and increased life expectancy, which are factors related to a referral to oncologic centers. However, this delay may be less higher Human Development Index.6,7 Conversely, regular relevant in neoplasms with slow evolution or a good prognosis. physical activity and proper use of hormonal therapies The present study aims to obtain information about the (estrogens associated with progestogens) can reduce the diagnosis profile of malignant uterine neoplasms diagnosed risk.6,7 In relation to uterine sarcomas, there is little infor- in women assisted in the public system of a regional cancer mation about risk factors. However, some studies show that center in Brazil, and the influence of the time elapsed

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. Malignant Uterine Neoplasms Attended at a Brazilian Regional Hospital Candido et al. 139 between the first symptoms to diagnosis or treatment in This study followed the recommendations of the National staging and survival of endometrioid carcinomas. Health Council of Brazil and was previously approved by the Ethics Committee of the University of Campinas (Certificate Methods of Ethical Assessment CAAE 48055015.3.0000.5404; approval number 1.760.085, October 4, 2016). An observational study was performed based on retrospective data extracted from the Hospital-Based Cancer Registries (HCR) Results system of the Women’s Health Hospital of the University of Campinas, from 2001 to 2016. We identified 1,243 records A total of 1,068 (89.7%) carcinomas (77.2% endometrioid and filtered by code C.54 (uterine body malignant neoplasia) from 22.8% non-endometrioid) and 122 (10.3%) sarcomas (►Table 1) the International Classification of Diseases, 10th edition (ICD- were analyzed. Considering only carcinomas with worse prog- 10).11 The included cases were from 90 cities (6.8 million nosis, such as non-endometrioid carcinomas, endometrioid inhabitants) that make up the Administrative Region of Cam- G3, and carcinosarcomas, we had 354 cases, or 29.8%. pinas (São Paulo, Brazil).12 A total of 51 cases from other cities, A trend toward increasing cases was registered in the one case with two synchronous neoplasms and one cervix evaluated period for carcinomas and sarcomas, with an addi- cancercasewereexcluded, resulting in1,190 cases. Information tional 10.8 cases of carcinomas (p ¼ 0.003) and 1.2 cases of was collected regarding the year of diagnosis, age, histological sarcomas (p ¼ 0.044) every 2 years. Between 2001 and 2002, 90 type, and staging according to the International Federation of carcinomas and 12 sarcomas were recorded, and this number Gynecology and Obstetrics (FIGO, 2009 for sarcomas and 2014 increased to 168 carcinomas and 20 sarcomas for the 2015 to for carcinomas).13,14 Tumor histology was defined according to 2016 biennium (►Fig. 1). The carcinomas and sarcomas diag- the pathologist’s final report and the International Histological noses’ proportions remained constant in the evaluated period, Classification of Tumors of the World Health Organization.15 around 90% of carcinomas and 10% of sarcomas. The main categories ofcarcinomaswere endometrioid types (or The mean age of the patients was 62 years, similar between Bokhman type I), non-endometrioid (or Bokhman type II, carcinomas and sarcomas. ►Table 2 shows the diagnoses including serous, serous-papillary, clear-cell, squamous-cell, distribution byage group, with 61 to 63% of the cases occurring mucinous, neuroendocrine or mixed histologies), and the in women aged 60 or over. Sarcomas were more diagnosed in poorly-differentiated or undifferentiated ones. Among neoplasms with a sarcomatous component (also called ‘sarcomas’), Table 1 Distribution of the histological types of 1,190 we found carcinosarcomas (including Mullerian tumors and malignant uterine neoplasms heterologous sarcomas), leiomyosarcomas, endometrial stromal sarcomas, and adenosarcomas.16 Thereafter, a subgroup Histological types n % with 185 women of up to 85 years of age, with endometrioid Carcinomas 1,068 89.7 histology and who had been attended from June 2012 to Endometrioid 825 77.2 June 2017, was selected to assess the association between Grade 1 (286) (34.7) the time elapsed from the onset of symptoms until diagnosis Grade 2 (485) (58.8) or treatment and the cancer stage and survival. The selection considered women from the region covered by the Regional Grade 3 (54) (6.5) Health Board VII - Campinas (42 cities and 4.43 million Non endometrioid 243 22.8 17 people). All of the 185 women had their medical records Serous or papillary (90) (37.0) reviewed, and information was collected about initial symp- Clear cells (48) (19.8) toms, diagnostic methods, and posttreatment outcomes, and Mucinous (24) (9.9) the interval between symptoms and diagnosis and between symptoms and treatment onset was calculated. Squamous cell (9) (3.7) Poor or undifferentiated (27) (11.1) Statistical Analysis Neuroendocrine (3) (1.2) The rates of diagnoses recorded between 2001 and 2016 Mixed (39) (16.1) were analyzed according to the biennial period, age group Other (3) (1.2) (< 50 years, 50–59, 60–69 years and > 70 years), staging (I– IV) and by histological types grouped into carcinomas Sarcomas 122 10.3 versus (versus) sarcomas and endometrioid carcinomas Carcinosarcoma (57) (46.7) (including the histological differentiation degree-G) versus Leiomyosarcoma (27) (22.1) non-endometrioid. The Chi-square, linear trend and Fisher Endometrial stromal sarcoma (20) (16.5) tests were used. Treatment outcomes were evaluated by Adenosarcoma (17) (13.9) Kaplan-Meier survival analyses and the Log-rank test. Sta- tistical analysis was made using the StatsDirect statistical Other (rhabdomyosarcoma) (1) (0.8) software v. 3.0 (StatsDirect, Cheshire, United Kingdom), and Degree of histological differentiation. p-values of less than 0.05 were considered statistically Carcinosarcomas were considered together with sarcomas, although significant. they follow the staging of carcinomas.

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. 140 Malignant Uterine Neoplasms Attended at a Brazilian Regional Hospital Candido et al.

Fig. 1 Biennial distribution of malignant uterine neoplasms according to the histological group, carcinomas (n ¼ 1,068), or sarcomas (including carcinosarcomas) (n ¼ 122).

Table 2 Distribution of malignant uterine neoplasms diagnosed in the period from 2001 to 2016 according to age group and stage

Variable Carcinomas (n ¼ 1,068) Sarcomas (n ¼ 122) Total (n ¼ 1,190) n%n%n% Age group (years) < 50 90 8.4 20 16.4 110 9.3 50–59 302 28.3 27 22.1 329 27.7 60–69 402 37.6 33 27.1 435 36.5 70 274 25.7 42 34.4 316 26.5 Stage I 615 57.7 54 42.2 669 56.2 II 126 11.8 13 10.7 139 11.7 III 250 23.4 29 23.8 279 23.5 IV 76 7.1 26 21.3 102 8.6 Miss information 1 1

Chi-square test: Age-group (p ¼ 0.001); Stage (p < 0.0001). Staging system according to FIGO-2014 for carcinomas and FIGO-2009 for sarcomas.

the extreme age groups, such as under 50 years old (16.4% Between endometrioid carcinomas versus non-endome- versus 8.4% for carcinomas) and 70 years old or more (34.4% trioid, signiﬁcant differences were observed in the mean versus 25.7% for carcinomas) (p ¼ 0.001). Concerning cancer ages (62.1 þ 10.3 years versus 65.6 þ 10.2 years, respectively, stage, stage I was mostly found in carcinomas (57.7% versus p < 0.001), and in the distributions by age groups or by staging 42.2%) and stage IV (21.3% versus 7.1%) was 3-fold more (►Fig. 2). Endometrioid carcinomas occurred in a greater frequent in sarcomas (p < 0.0001). proportion of younger age groups and stage I compared with

p<0.01 p<0.01 Endometrioid Non-endometrioid

Fig. 2 Distribution of uterine carcinomas by histology endometrioid (n ¼ 825) and non-endometrioid (n ¼ 243) according to age-group and neoplasia stage (FIGO-2014; there is no stage information for one case).

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. Malignant Uterine Neoplasms Attended at a Brazilian Regional Hospital Candido et al. 141 non-endometrioid types, which occurred in older patients and Table 4 The final stage according to the time elapsed (days) was diagnosed more often in stages II to IV (p < 0.01). from symptoms to diagnosis in 185 women with endometrioid The evaluation of the 185 women subgroup with endome- carcinomas trioid carcinoma exhibited a mean age (65.5 years; 54–83) and staging distribution (stage I ¼ 65.9%) similar to the main group Stage Symptom to diagnosis time (days) (p > 0.05), but with more cases of G3 neoplasms (G3 ¼ 22 or 90 91–180 181–365 > 365 p ¼ ¼ ¼ 11.9% versus 6.6%, 0.003; G1 44 or 24% and G2 119 or n% n% n% n% 64%). Overall five-year survival ratewas 76.9%, better for stage I I 2760.03368.73867.82466.7 (93.8% versus 43.0% for stages II–IV, p < 0.0001), and significantly worse for G3 carcinomas (49.9% versus 77.1% for G2 and II 7 15.6 7 14.6 8 14.3 5 13.9 89.4% for G1, p ¼ 0.012). ►Table 3 describes the symptom’s III and IV 11 24.4 8 16.7 10 17.9 7 19.4 pattern, diagnostic method, and time elapsed to diagnosis and Total 45 100 48 100 56 100 36 100 treatment for the 185-women subgroup. Three patients did p ¼ not receive treatment for advanced disease and died early. Staging system according to FIGO-2014; 0.976 (Chi-square test). Abnormal uterine bleeding was highlighted in 92.4% of the cases (as a unique symptom in 87.0% of the cases). Uterine curettage was the most used diagnostic method (43.2%), followed by hysteroscopy (36.2%) and endometrial biopsy Table 3 Pattern of symptoms, diagnostic method, and time (17.9%). The mean time elapsed between the onset of symp- elapsedtodiagnosisandtreatmentin185womenwith toms (or suspicion) and the cancer diagnosis was 244 days endometrioid carcinomas (24.3% up to 90 days, 25.6% between 91 and 180 days, 30.3% between 181 and 365 days, and 19.5% more than 365 days). Characteristic n % There was no association between the time elapsed and Symptom (sign) at diagnosis the final cancer stage (p ¼ 0.976) (►Table 4). Uterine abnormal bleeding 171 92.4 Among the 182 patients treated, the mean time elapsed between the onset of symptoms (or suspicion) and onset of Endometrial thickening (ultrasound) 7 3.8 treatment was 376 days, with 81.9% of the cases taking more Vaginal discharge 4 2.2 than 180 days, and there was no association between time Pelvic pain 2 1.1 elapsed and overall survival rate (►Fig. 3, p ¼ 0.160). The Abnormal clinical exam 1 0.5 Diagnostic method Dilation and curettage 80 43.2 Hysteroscopy 67 36.2 Aspiration biopsy 33 17.9 Hysterectomy 5 2.7 Symptom to diagnosis time (days) Mean (SD) 244 (44) 90 45 24.3 91–180 48 25.9 181–365 56 30.3 > 365 36 19.5 Diagnosis to treatment time (days) Mean (SD) 131 (71) 60 22 12.1 61–90 17 9.3 > 90 143 78.6 Symptom to treatment time (days) Mean (SD) 376 (49) 180 33 18.1 181–365 72 39.6 > 365 77 42.3

Abbreviation: SD, standard deviation. Fig. 3 Overall survival of 182 women with endometrioid carcinomas considered only the main one. according to time elapsed (days) from symptoms (or suspicion) to Three patients did not receive treatment for advanced disease and start treatment (upper chart), and from diagnosis to start treatment were early dead. (bottom chart).

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. 142 Malignant Uterine Neoplasms Attended at a Brazilian Regional Hospital Candido et al.

mean time interval between diagnosis and treatment onset better prognosis with a 5-year survival rate of 85%.16,20,21 was 131 days, with only 12.1% of the patients having started Relatively, non-endometrioid carcinomas affect older wom- treatment within 60 days of diagnosis (legal deadline accord- en, are associated with atrophic endometrium, high nuclear ing to current Brazilian legislation). There was no association grade, and poor cell differentiation, resulting in earlier between this time elapsed and the overall survival rate myometrial infiltration and lymph node involvement, with (p ¼ 0.345), as shown in the (►Fig. 3) bottom chart. shorter 5-year survival around 59%.16,20,21 Our results confirmed some differences between endo- Discussion metrioid and non-endometrioid carcinomas, such as twice as many endometrioid carcinomas in patients under 50 years The malignant uterine neoplasms new cases, including car- old (9.5% vs. 4.9%) and 34% of non-endometrioid recorded in cinomas and sarcomas, increased throughout th period from women aged 70 and over. Stage I prevailed among endome- 2001 to 2016. A rate of 90% of carcinomas and 10% of trioid cases (63.9%), while there were 3-fold more stage IV sarcomas was maintained in the period, with 60% of all cases non-endometrioid carcinomas (14.5% vs.5%)(p < 0.01). aged 60 years or more. Among the carcinomas, 77% were Analyzing the group of 185 women with endometrioid endometrioid type, and the most frequent sarcomas diag- carcinomas, 92.4% of them exhibited genital abnormal bleed- nosed were carcinosarcomas, with 46.7%, followed by leio- ing. Diagnosis accessing by hysteroscopy (36.2%) or outpa- myosarcomas (22.1%) and endometrial stromal sarcomas tient endometrial biopsy (17.9%) were not predominant. The (16.4%). Sarcomas were 3-fold more diagnosed in stage IV mean time elapsed from symptoms to diagnosis can be (disseminated disease). considered long, 244 days, with 75.7% of cases taking more The upward trend in the new cases attended of malignant than 90 days. Furthermore, the mean interval from symp- uterine neoplasms may be an effect of population growth, toms to treatment was longer and concerning, 376 days, with increased life expectancy, and due to greater request for the 81.8% over 180 days. unified health system (Sistema Único de Saúde – SUS, in Portu- The long periods observed waiting for a diagnosis can be guese), as observed in times of economic crisis. The Women’s associated with several factors, such as the lack of qualified Health Hospital is the main cancer center for gynecological gynecological care, the difficulty of accessing investigation oncologic care for a population of 6.5 million people, with 50% methods, and the lack of guidelines for the management of of SUS users.17 Notedly, for endometrioid carcinomas, obesity is suspected cases. This shows, in practice, the inefficient considered an important risk factor6,7 and this condition is assistance of the secondary level of the public health system gradually more frequent and associated with developed areas, in Brazil. Also, the cultural level and resignation of most SUS as well as the region where these cases came from. users, associated with a certain technical limitation of health The increase in the number of new cases of malignant professionals, contribute to this scenario. And, lastly, diffi- uterine neoplasms differs from American statistics for the culties continue for diagnosed neoplasia due to limited period of 2005 to 2014, according to which the rates have not assistance offered in the oncology centers of SUS. changed significantly,4 perhaps due to stable epidemiologi- Although the present study confirms the long waiting time cal factors for a longer time. for diagnosis and to start treatment, surprisingly and unex- As per the analysis by age group, these malignant uterine pectedly, there was no negative impact on the final staging or neoplasms predominated in the group above 60 years of age, overall survival. This may be related to the fact that endome- with 34% of sarcomas and 46.7% of carcinosarcomas being trioid carcinomas have a better prognosis. This histological diagnosed at 70 years old, highlighting the classic association type was analyzed in detail because they comprise a greater between aging and cancer.18 However, it is worth noting that proportion of cases, with early symptoms and better progno- 110 women (9.3%) presenting some of these neoplasms were sis, that is, cases in which the health care system must not fail. under 50 years old, which was twice more frequent in the The time elapsed between symptoms and diagnosis was longer sarcomas’ group (16.4% versus 8.4%, p ¼ 0.001). Among all 20 than diagnosis and treatment, pointing out the difficulties cases of sarcomas under 50 years of age, 9 were endometrial related to the current primary and secondary level of care in stromal sarcomas and 7 were leiomyosarcomas, which are the public health system. We planned to start a new study to estrogen-related neoplasms of younger women. No carcino- evaluate the relationship between the time elapsed for diag- sarcoma cases were observed in this age group since they are noses and non-endometrioid histology. related to elderly women.5,19 After the diagnosis, the limitation of the public system in Usually, carcinomas tend to be symptomatic earlier than providing care for women with gynecological cancer is clear, sarcomas, and sarcomas tend to have a faster and more as previously mentioned by other Brazilian authors,22 even aggressive progression. Thereafter, and according to our results, though the cases studied come from a high human develop- carcinomas were detected in a greater proportion in stage I ment index area. We noticed that only 12.1% of women were (57.7% versus 42.2%) and sarcomas were 3-fold more frequently able to start treatment within 60 days after diagnosis, as diagnosed in stage IV (21.3% versus 7.1%, p < 0.0001). determined by Brazilian Federal Law 12,732/12, valid since Comparing endometrioid and non-endometrioid carcino- 23/05/2013.23 About 80% of the cases waited for treatment mas, the etiological factors must be considered. The endo- for more than 90 days, confirming a deficiency in complying metrioid histology is related to endometrial hyperplasia due with the law. Although not shown in the results, most of the to the estrogenic effect, supporting an earlier diagnosis and time elapsed between diagnosis and treatment onset

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. Malignant Uterine Neoplasms Attended at a Brazilian Regional Hospital Candido et al. 143 occurred before the patients arrived at the cancer center, Conflict of Interests which, despite being overloaded, usually manages to start The authors have no conflict of interests to declare. the treatment available relatively quickly. Among the limitations of the present study, using a single institution as origin of the cases can lead to higher propor- References tions of more aggressive histological types. In the literature, 1 Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. the expected rate would be 3 to 5% for sarcomas and 15% for Global cancer statistics 2018: GLOBOCAN estimates of incidence – type-II carcinomas.3 5,24 However, we found 10% of sarco- and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(06):394–424. Doi: 10.3322/caac.21492 mas and 23% of non-endometrioid carcinomas. This situation 2 Ministério da Saúde Instituto Nacional de Câncer José Alencar fi is justi ed, in part, by the frequent management of endome- Gomes da Silva. Estimativa 2020: incidência de câncer no Brasil trioid carcinomas by general gynecologists since initial [Internet]. Rio de JaneiroINCA2019 [cited 2020 Jan 11]. Available stages exhibit better prognosis. Similar to our results, the from: https://www.inca.gov.br/sites/ufu.sti.inca.local/files//media/ literature shows that around 70% of the carcinomas are document//estimativa-2020-incidencia-de-cancer-no-brasil.pdf endometrioid type and a 5-year overall survival rate of 3 Boll D, Verhoeven RH, van der Aa MA, Pauwels P, Karim-Kos HE, Coebergh JWW, van Doorn HC. Incidence and survival trends of 90% for stage I cases.24 uncommon corpus uteri malignancies in the Netherlands, 1989- Conversely, the strength of the present study is the 2008. Int J Gynecol Cancer. 2012;22(04):599–606. Doi: 10.1097/ qualified information retrieved from HCR (accounts for igc.0b013e318244cedc 100% of the cases attended and with periodic review of 4 Jamison PM, Altekruse SF, Chang JT, Zahn J, Lee R, Noone AM, information) and the fact that this institution is a reference Barroilhet L. Site-specific factors for cancer of the corpus uteri center in gynecological cancer care with a specialized mul- from SEER registries: collaborative stage data collection system, version 1 and version 2. Cancer. 2014;120(Suppl 23):3836–3845. tidisciplinary team. It is also the main reference for cancer Doi: 10.1002/cncr.29054 care of SUS, in a wealthy developed area. Such characteristics 5 D’Angelo E, Prat J. Uterine sarcomas: a review. Gynecol Oncol. reflect the relevance of the data analyzed related as they 2010;116(01):131–139. Doi: 10.1016/j.ygyno.2009.09.023 show real-life scenarios. This study provides important 6 Felix AS, Yang HP, Bell DW, Sherman ME. Epidemiology of information that allows a review of assistance programs endometrial carcinoma: etiologic importance of hormonal and metabolic influences. Adv Exp Med Biol. 2017;943:3–46. Doi: offered to the population. The adequate protocol develop- 10.1007/978-3-319-43139-0_1 ment to care for symptomatic postmenopausal women, 7 Fortner RT, Hüsing A, Dossus L, Tjønneland A, Overvad K, Dahm stratified by levels of complexity, with accurate diagnosis CC, et al. Theoretical potential for endometrial cancer prevention methods, may shorten the waiting time to treatment onset. It through primary risk factor modification: Estimates from the is worth noting that 29.8% of the cases studied were consid- EPIC cohort. Int J Cancer. 2020;147(05):1325–1333. Doi: 10.1002/ ered to have a worse prognosis, and the impact of waiting ijc.32901 8 Travis LB, Ng AK, Allan JM, Pui CH, Kennedy AR, Xu XG, et al. time for them was not analyzed. Second malignant neoplasms and cardiovascular disease following radiotherapy. J Natl Cancer Inst. 2012;104(05):357–370. Doi: Conclusion 10.1093/jnci/djr533 9 AlHilli MM, Mariani A, Bakkum-Gamez JN, Dowdy SC, Weaver AL, In conclusion, the malignant uterine neoplasms occurrence Peethambaram PP, et al. Risk-scoring models for individualized increased over the period from 2001 to 2016, for both prediction of overall survival in low-grade and high-grade endometrial cancer. Gynecol Oncol. 2014;133(03):485–493. Doi: carcinomas and sarcomas. There are fewer cases of non- 10.1016/j.ygyno.2014.03.567 endometrioid carcinomas and sarcomas, which are more 10 Tropé CG, Abeler VM, Kristensen GB. Diagnosis and treatment of aggressive and present in higher proportion among women sarcoma of the uterus. A review Acta Oncol. 2012;51(06): over 70 years old and in stage IV. For endometrioid carcino- 694–705. Doi: 10.3109/0284186X.2012.689111 fi mas, the time elapsed between symptoms and diagnosis or 11 Organização Mundial de Saúde. CID-O: Classi cação Internacional de Doenças para Oncologia. 3a ed. São Paulo: Editora da Universi- beginning of treatment was long, although without associa- dade de São Paulo/Fundação Oncocentro de São Paulo; 2005 tion with worsening of staging or survival. 12 Governo do Estado de São Paulo. Regiões Administrativas do Estado de São Paulo: Região Administrativa Campinas [Internet]. Contributions 2018 [cited 2020 Apr 12]. Available from: https://www.desen- Each author has participated actively and sufficiently in volvesp.com.br/mapadaeconomiapaulista/ra/campinas/ this work and all had finalapprovalofthemanuscript 13 Prat J. FIGO staging for uterine sarcomas. Int J Gynaecol Obstet. 2009;104(03):177–178. Doi: 10.1016/j.ijgo.2008.12.008 version being submitted. E. C. contributed to conception 14 FIGO Committee on Gynecologic Oncology. FIGO staging for and design, data collection, interpretation of data, and carcinoma of the vulva, cervix, and corpus uteri. Int J Gynaecol writing of the article; N. V. J. contributed to conception, Obstet. 2014;125(02):97–98. Doi: 10.1016/j.ijgo.2014.02.003 data collection, and writing of the article; M. M. contrib- 15 Kurman RJ, Carcangiu ML, Herrington CS, Young RH, Eds. WHO uted to data collection and writing of the article; M. T. Classification of Tumours of Female Reproductive Organs. 4th ed. contributed to interpretation of data and writing of the Lyon: IARC; 2014 16 Bokhman JV. Two pathogenetic types of endometrial carcinoma. article; D. Y. contributed to conception and design, inter- Gynecol Oncol. 1983;15(01):10–17. Doi: 10.1016/0090-8258(83) pretation of data, and critical review of the article; and J. T. 90111-7 contributed to conception and design, data collection and 17 Secretaria de Estado da Saúde de São Paulo Mendes JDV, Cruz analysis, interpretation of data, and writing of the article. RMF, Portas SLC, organizadores. Plano Estadual de Saúde-PES:

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. 144 Malignant Uterine Neoplasms Attended at a Brazilian Regional Hospital Candido et al.

2016–2019 [Internet]. São Paulo: SES/SP; 2015 [cited 2020 Mar 21 Amant F, Mirza MR, Koskas M, Creutzberg CL. Cancer of the corpus 12]. Available from: http://www.saude.sp.gov.br/resources/ses/ uteri. Int J Gynaecol Obstet. 2018;143(Suppl 2):37–50. Doi: perﬁl/gestor/documentos-de-planejamento-em-saude/plano- 10.1002/ijgo.1261296–S104 estadual-de-saude-2016-2019-sessp/pessp_2017_11_01_17.pdf 22 Paulino E, Nogueira-Rodrigues A, Goss PE, Faroni L, Guitmann G, 18 Pérez-Mancera PA, Young AR, Narita M. Inside and out: the Strasser-Weippl K, et al. Endometrial cancer in Brazil: preparing activities of senescence in cancer. Nat Rev Cancer. 2014;14(08): for the rising incidence. Rev Bras Ginecol Obstet. 2018;40(10): 547–558. Doi: 10.1038/nrc3773 577–579. Doi: 10.1055/s-0038-1673644 19 Brooks SE, Zhan M, Cote T, Baquet CR. Surveillance, epidemiology, 23 Entra em vigor hoje a Lei dos 60 dias para tratamento do câncer and end results analysis of 2677 cases of uterine sarcoma 1989- [Internet]. 2013 [cited 2020 Apr 12]. Available from: http://www. 1999. Gynecol Oncol. 2004;93(01):204–208. Doi: 10.1016/j. blog.saude.gov.br/servicos/32374-entra-em-vigor-hoje-a-lei-dos ygyno.2003.12.029 -60-dias-para-tratamento-do-cancer 20 Felix AS, Weissfeld JL, Stone RA, Bowser R, Chivukula M, Edwards 24 Svanvik T, Sundfeldt K, Strömberg U, Holmberg E, Marcickiewicz J. RP, Linkov F. Factors associated with Type I and Type II endome- Population-based cohort study of the effect of endometrial cancer trial cancer. Cancer Causes Control. 2010;21(11):1851–1856. Doi: classiﬁcation and treatment criteria on long-term survival. Int J 10.1007/s10552-010-9612-8 Gynaecol Obstet. 2017;138(02):183–189. Doi: 10.1002/ijgo.12214

Transmediastinal Gunshot Wound in a Pregnant Patient with Stable Hemodynamics

Ozhan Ozdemır1 Cemal Resat Atalay2

1 Department of Obstetrics and Gynecology, Gulhane School of Address for correspondence Ozhan Ozdemir, Associate Professor, Medicine, University of Health Sciences, Ankara, Turkey Department of Obstetrics and Gynecology, University of Health 2 Department of Obstetrics and Gynecology, University of Health Sciences, Gulhane School of Medicine, Ankara, Turkey Sciences, Ministry of Health Ankara City Hospital, Ankara, Turkey (e-mail: [email protected]).

Rev Bras Ginecol Obstet 2021;43(2):145–147.

Abstract Transmediastinal gunshot wounds (TGWs) may lead to life-threatening injuries of vital organs such as large vessels, the esophagus, and lungs. Although they are not commonly encountered in pregnant women, additional caution should be given to these patients. Physical examination for the diagnosis and the choice of treatment modality contain controversial points in hemodynamically stable patients, and resuscitation has excessive importance due to physiological changes in pregnancy. We present a hemodynamically stable 26-week pregnant woman brought to the emer- Keywords gency department for TGW. She had a 1-cm diameter of bullet entrance hole on the ► gunshot right anterior 4th intercostal space, 2 cm lateral to the sternum, and a 3-cm diameter ► transmediastinal exit hole on the right posterior 12th intercostal space on the midscapular line. With our ► trauma conservative approach, she had an uncomplicated pregnancy period, and gave birth to ► pregnancy a healthy baby at term.

Introduction physiological and anatomical alterations during pregnancy Although the exact incidence of trauma during pregnancy is not require additional care for the evaluation and treatment of known, approximately every 1 pregnancy out of 12 is compli- these patients.3 Herein, we report a hemodynamically stable cated with trauma, and it is one of the leading reasons for 26-week pregnant woman with TGW in whom the pregnancy nonobstetric maternal death.1 Approximately 9% of all traumas terminated uncomplicated with conservative approach. during pregnancy is penetrant, and handguns, knives, and shot- 2 guns are the cause in 73%, 23%, and 4% of them, respectively. Case Report Maternal mortality due to penetrant traumas during pregnancy is between 3.9 and 7%, whereas fetal mortality is 73%.2 A 37-year-old, primiparous 26-week pregnant woman was Mediastinum is restricted with the sternum anteriorly, the brought to the emergency department with a gunshot wound. spine posteriorly, and the diaphragm inferiorly, and contains She had a 1-cm bullet entrance hole on the right anterior 4th vital organs such as the heart, the esophagus, large vessels, and intercostal space, 2 cm lateral to the sternum (►Fig. 1), and a 3- the tracheobronchial tree. Hence, the mediastinum should be cm exit hole on the right posterior 12th intercostal space on the evaluated carefully and systematically in patients with trans- midscapular line (►Fig. 2). She was brought to the hospital in mediastinalgunshot wounds (TGWs). In patients with gunshot 30 minutes following the gunshot, and she was conscious, wounds, the prediction of the direction of the bullet inside is oriented and cooperated when she arrived. She was hemody- difﬁcult, and the entrance hole does not give an adequate idea namically stablewitharterial blood pressure 110/70 mmHg, 89 about the location and extent of the wound. Furthermore, the pulses/minute, body temperature 36.7°C, respiration count 28/

received DOI https://doi.org/ © 2021. Federação Brasileira das Associações de Ginecologia e May 2, 2020 10.1055/s-0040-1715142. Obstetrícia. All rights reserved. accepted ISSN 0100-7203. This is an open access article published by Thieme under the terms of the June 29, 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 146 Transmediastinal Gunshot Wound in a Pregnant Patient with Stable Hemodynamics Ozdemir et al.

Fig. 1 The entrance hole of the bullet with 1cmdiameteronthe right anterior 4th intercostal space, 2 cm lateral to the sternum.

Fig. 3 Chest radiogram following tube thoracostomy.

ahealthy,3.700g-weighingchildinthe39th week by elective cesarean section due to cormical presentation.

Discussion

Gunshot wounds are the second most common traumas following traffic accidents in the general population, and penetrant wounds are extremely rare in pregnant women.4 As treatment is urgent in hemodynamically unstable patients with TGW, diagnostic tests are often emitted. In Fig. 2 The exit hole of the bullet with 3cmdiameterontheright hemodynamically stable patients, imaging techniques such posterior 12th intercostal space on the midscapular line. as ultrasonography, computed tomography (CT), esophagog- raphy or esophagoscopy, angiography, or bronchoscopy minute, and oxygen saturation 92%. Thoracentesis was per- should be performed when indicated, to determine the exact formed from the right midaxillary 6th intercostal space as no location of the injury.5 respiratory sound was heard on the right lung base, and Several patients with TGW succumb to death owing to defibrinated hemorrhagic fluid was aspirated. Following tube cardiac tamponade or acute fatal hemorrhage before they are thoracostomy, 700 mL of defibrinated hemorrhagic fluid was brought to the hospital. Approximately 43% of the patients are acutely drained. The chest radiograph after tube thoracostomy hemodynamically unstable when they arrive at the hospital revealed open bilateral sinuses and expanded parenchyma; and need urgent surgery. The remaining 57% of patients are however, increased density was present in right lower zones hemodynamically stable, and between 35 and 60% of them probably due to contusion (►Fig. 3). The echocardiography need urgent surgery.6 The mortality rate of patients with TGW revealed normal cardiac functions with no pericardial fluid. brought to hospital is 27%, and the majority of them are Similarly, free fluid was not seen in the abdominal ultrasonog- hemodynamically unstable. The mortality rate of hemody- raphy,andnoevidenceoflacerationoforgansorlargevessels namically stable patients is between 0 and 10%.6 However, was present. In obstetric ultrasonography, single fetus match- according to some authors, more than half of the patients with ing 26 weeks with positive fetal cardiac activity, normal amni- TGW are hemodynamically stable, and more than between 60 otic fluid index, and no placental pathology was seen. The and 70% of these patients do not need surgery, and are treated patient did not have any complaints about vaginal bleeding or with conservative approach.7 amniotic fluid loss, and cervical dilation and effacement was The approach to penetrant injury and resuscitation in not observed in the pelvic examination. Antibiotics and steroid pregnancy is of greater importance owing to the presence for fetal lung maturation were administered, and an additional of the fetus and physiological and anatomical gestational 100 mL defibrinated hemorrhagic fluid was drained from the alterations. The management of penetrant injury in preg- thoracostomy tube in the 1st hour. The patient was followed nancy requires a multidisciplinary approach comprising with stable vital signs and hemodynamics. As the drainagefrom the anesthesiologist, obstetrician, neonatologist and trau- the thoracostomy tube decreased in thefollow-up, the tube was ma surgeon. Moreover, it should be individualized accord- exerted on the 5th day, and the entrance and exit holes were ing to the entrance site of the wound and time of sutured after debridement. The patient was discharged from pregnancy.8 The primary aim in the management of trauma the hospital on the 7th day of her arrival. No obstetric compli- in a pregnant woman is to obtain maternal stabilization, cation was observed during her follow-up, and she gave birth to and the early and aggressive resuscitation of the pregnant

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira das Associações de Ginecologia e Obstetrícia. All rights reserved. Transmediastinal Gunshot Wound in a Pregnant Patient with Stable Hemodynamics Ozdemir et al. 147 woman is directly associated with fetal results.9 In addi- Conclusion tion, maternal physiological and anatomical alterations should be taken into account during resuscitation. For As a result, hemodynamically stable patients with TGW instance, a preservative environment is formed through should be evaluated for their need for adequate diagnostic physiological hemodilution and hypervolemia during preg- methods to determine the site and severity of the injury. In nancy, and maternal shock symptoms may not be observed patients who are chosen to be treated conservatively, the until 40% of the maternal blood volume is lost. Further- anatomical and physiological alterations during pregnancy more, maternal hemodynamic measurements may not be should be considered. able to correctly point out the state of uteroplacental circulation. Besides, as the buffering capacity also Conflicts of İnterests decreases in pregnancy, tendency to metabolic acidosis The authors have no conflict of interests to declare. may occur in case of hypoperfusion and hypoxia.9 The functional residual capacity of the lungs decreases during References pregnancy due to elevation of the diaphragm 4cmand 1 Mendez-Figueroa H, Dahlke JD, Vrees RA, Rouse DJ. Trauma in increase in chest diameter 2 cm, leading to an increase in pregnancy: an updated systematic review. Am J Obstet Gynecol. tendency to hypoxia. These alterations should be consid- 2013;209(01):1–10. Doi: 10.1016/j.ajog.2013.01.021 ered during interventions such as thoracostomy. If neces- 2 Petrone P, Talving P, Browder T, Teixeira PG, Fisher O, Lozornio A, sary, a thoracostomy tube should be placed through the Chan LS, et al. Abdominal injuries in pregnancy: a 155-month – intercostal space 1 or 2 above the classical 5th intercostal study at two level 1 trauma centers. Injury. 2011;42(01):47 49. Doi: 10.1016/j.injury.2010.06.026 space to prevent abdominal insertion.8 3 Buck DG, Zajko AB, Peitzman AB. Transected subscapular artery in Essential radiologic imaging techniques should promptly a transmediastinal gunshot wound presenting as a hemothorax: be performed if clinically indicated in traumas during preg- treatment with embolotherapy. J Trauma. 2000;48(02):322–324. nancy, and in this situation fetal effects may be ignored. The Doi: 10.1097/00005373-200002000-00024 gold standard diagnostic method for TGW in hemodynami- 4 Osnaya-Moreno H, Zaragoza Salas TA, Escoto Gomez JA, Mondragon cally stable patients is CT angiography.10 Fetal radiation Chimal MA, Torres Castaneda MdeL, Jimenez Flores M. Gunshot wound to the pregnant uterus: case report. Rev Bras Ginecol Obstet. exposure of CT is > 3.5 rad (0.035 Gy), and its potential 2013;35(09):427–431. Doi: 10.1590/s0100-72032013000900008 fi bene t should be considered in life-threatening injuries. 5 Stassen NA, Lukan JK, Spain DA, Miller FB, Carrillo EH, Richardson More importantly, fetal exposures < 5 rad (0.05 Gy) do not JD, Battistela FD. Reevaluation of diagnostic procedures for trans- lead to any increase in the risk of fetal anomaly, pregnancy mediastinal gunshot wounds. J Trauma. 2002;53(04):635–638, loss or growth retardation.1 In nonsensitized Rh negative discussion 638. Doi: 10.1097/00005373-200210000-00003 6 Nagy KK, Roberts RR, Smith RF, Joseph KT, An GC, Bokhari F, Barret pregnant women with major injuries, the Kleihauer-Betke J, et al. Trans-mediastinal gunshot wounds: are “stable” patients test should be performed to calculate the total Rh immuno- really stable? World J Surg. 2002;26(10):1247–1250. Doi: 11 globulin dose for prophylaxis. 10.1007/s00268-002-6522-2 10 Burack et al evaluated 207 patients with mediastinal pene- 7 Zarain Obrador L, Al-Lal YM, de Tomás Palacios J, Amunategui trant injury in the emergency department, and reported that 35 Prats I, Turégano Fuentes F. Transmediastinal and transcardiac and 65% of these patients were hemodynamically unstable and gunshot wound with hemodynamic stability. Case Rep Surg. 2014;2014:985097. Doi: 10.1155/2014/985097 stable, respectively. Twenty-six percent of hemodynamically 8 Brown HL. Trauma in pregnancy. Obstet Gynecol. 2009;114(01): unstable patients succumbed to death during medical interven- 147–160. Doi: 10.1097/AOG.0b013e3181ab6014 tions. The remaining 53 patients were submitted to urgent 9 Chulu A, Kuczkowski KM. Anaesthetic management of the parturient surgery and, among these, 32 patients survived. The CT angiog- with massive peripartum haemorrhage and fetal demise. Anaesthesia. raphy was normal in 80% of hemodynamically stable patients, 2003;58(09):933–934. Doi: 10.1046/j.1365-2044.2003.03362_30.x ’ and conservative treatment was preferred. In another 10 Burack JH, Kandil E, Sawas A, O Neill PA, Sclafani SJA, Lowery RC, Zenilman ME. Triage and outcome of patients with mediastinal study, > 60% of the patients with transmediastinal injury were penetrating trauma. Ann Thorac Surg. 2007;83(02):377–382, 12 hemodynamically stable and were treated conservatively. Both discussion 382. Doi: 10.1016/j.athoracsur.2006.05.107 these studies show that the conservative approach is adequate 11 American College of Obstetricians and Gynecologists. ACOG educa- for hemodynamically stable patients with transmediastinal in- tional bulletin. Obstetric aspects of trauma management. Number 251, jury. However, several patients who are stable at first will need September 1998 (replaces Number 151, January 1991, and Number 161, November 1991). Int J Gynaecol Obstet. 1999;64(01):87–94 surgery. The decision for surgery is made by the results of 12 Velmahos GC, Chahwan S, Falabella A, Hanks SE, Demetriades D. fl imaging studies and the amount of the uid draining from the Angiographic embolization for intraperitoneal and retroperito- thoracostomy tube. In our case, conservative treatment was neal injuries. World J Surg. 2000;24(05):539–545. Doi: 10.1007/ performed, and the pregnancy terminated successfully. s002689910087

Management of Ectopic Pregnancy and the COVID-19 Pandemic

Rujittika Mungmunpuntipantip1 Viroj Wiwanitkit1

1 Ajeenkya DY Patil University, Pune, Maharashtra, India Address for correspondence Rujittika Mungmunpuntipantip, Ajeenkya DY Patil University, Pune 412105, Maharashtra, India Rev Bras Ginecol Obstet 2021;43(2):148–149. (e-mail: [email protected]).

Dear Editor, Conﬂict of Interests We would like to share ideas on the publication “Medical The authors have no conﬂict of interests to declare. Treatment for Ectopic Pregnancy during the COVID-19 Pan- demic.” Elito Júnior and Araujo Júnior1 mentioned that the “clinical treatment of ectopic pregnancy by MTX or expectant References management is an alternative during the COVID-19 pandemic. 1 Elito Júnior J, Araujo Júnior E. Medical treatment for ectopic An early diagnosis and appropriate selection of treatment pregnancy during the COVID-19 pandemic. Rev Bras Ginecol Obstet. 2020;42(12):849–850. Doi: 10.1055/s-0040-1718438 options are critical for the success of the treatment.”1 In 2 Howard SC, McCormick J, Pui CH, Buddington RK, Harvey RD. fact, using methotrexate (MTX) as alternative treatment for Preventing and managing toxicities of high-dose methotrexate. ectopic pregnancy during COVID-19 is a useful approach, and Oncologist. 2016;21(12):1471–1482. Doi: 10.1634/theoncolo- can reduce risk as well as decrease the workload at the gist.2015-0164 hospital. The patient selection is very important. However, it 3 Sriwijitalai W, Wiwanitkit V. Coronavirus-antibody immune should be noted that MTX might cause renal impairment,2 complex: A nanostructure appraisal possible cause of nephropa- thology. Saudi J Kidney Dis Transpl. 2020;31(03):694–695. Doi: and COVID-19 has a trend to develop renal impairment due 3 10.4103/1319-2442.289457 to the immunopathological process of infection. Close 4 Nunes LLA, Lima TM. Use of medicines for covid-19 treatment in monitoring of the renal function is needed in MTX therapy, patients with loss of kidney function: a narrative review. J Bras and the adjustment of the dosage based on renal function is Nefrol. 2020;•••:S0101-28002020005044202. Doi: 10.1590/2175- important.4 8239-JBN-2020-0105 [ahead of print]

Author’s response

Reply to “Management of Ectopic Pregnancy and the COVID-19 Pandemic”

Júlio Elito Júnior1 Edward Araújo Júnior 1 1

1 Department of Obstetrics, Escola Paulista de Medicina, Universidade Address for correspondence Edward Araújo Júnior, Departmento de Federal de São Paulo, São Paulo, SP, Brazil Obstetrícia, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Botucatu 740, Vila Clementino, São Paulo, SP, 04023-062, Brazil Rev Bras Ginecol Obstet 2021;00:148–149. (e-mail: [email protected]).

DOI https://doi.org/ © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights 10.1055/s-0041-1725937. reserved. ISSN 0100-7203. This is an open access article published by Thieme under the terms of the 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 Editor 149

Dear Editor, However, close monitoring of the renal function is necessary Thank you for your comments. The most important in cases of non-tubal pregnancies submitted to the protocol message of this letter was the correct selection of patients of multiple doses of MTX. for the medical treatment with methotrexate (MTX). We mentioned in the third paragraph that one of the exclusion Conﬂict of Interests criteria was renal dysfunction. Therefore, before the treat- The authors have no conﬂict of interests to declare. ment, blood samples of every patient were collected for some exams, and one of them was creatinine. High levels of Reference creatine were an exclusion criterion for the MTX treatment. 1 Clark LE, Bhagavath B, Wheeler CA, Frishman GN, Carson SA. Role On the other hand, patients with normal levels of creatinine of routine monitoring of liver and renal function during treat- can be submitted to the medical treatment. For tubal preg- ment of ectopic pregnancies with single-dose methotrexate nancies, we recommend a single dose of MTX (50 mg/m2). protocol. Fertil Steril. 2012;98(01):84–88. Doi: 10.1016/j.fertn- The risk of renal impairment related to this dose is very rare.1 stert.2012.03.037

Rev Bras Ginecol Obstet Vol. 43 No. 2/2021 © 2021. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. FEBRASGO POSITION STATEMENT Vaccination in women with cancer Number 2 - February 2021 DOI: https://doi.org/10.1055/s-0041-1726075

The National Specialty Commission for Vaccines 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: • Cancer patients may be immunosuppressed due to their disease of origin or because of anticancer therapies. The degree and duration of immunosuppression varies according to the drug, dose and duration of treatment. • Immunization of patients with neoplasms must be considered from two points of view: the immunization of the patient herself, as well as the immunization of the family, health professionals and the patient’s caregivers. • The term “immunosuppressed” encompasses different types and degrees of immunosuppression, such as deficiencies in humoral, cellular, complement and phagocytosis immunity. Different impairments of the immune system influence the effectiveness of immunization and the risk of adverse effects. • Reference Centers for Special Immunobiologicals provide immunobiologicals for routine immunization schedules and special ones for patients in certain conditions. • Vaccination guidance should result from joint work between the patient’s attending physician and Reference Centers for Special Immunobiologicals, as both the vaccination schedule and its respective doses may not follow the usual recommendations. • Patients who received chemotherapy for the treatment of neoplasms could benefit from booster doses of vaccines, although there is still no defined approach for this situation.

Recommendations: • Whenever possible, the vaccination schedule should be updated in up to 14 days before the start of antineoplastic therapy. In this situation, the interval between vaccine doses may be shortened. • After the initiation of therapy that may cause immunosuppression, attenuated vaccines are contraindicated (for example: chickenpox, triple viral, yellow fever, oral polio, oral typhoid and anti-cholera vaccine). • Patients with neoplasia using immunosuppressive drugs, transplanted solid organs recipients and candidates for transplantation should receive routine vaccines (except attenuated vaccines) and vaccines against pneu- mococci (depending on the age group); Hib (Haemophilus influenzae type b) for patients up to 19 years; influenza, hepatitis B (regardless of age) and hepatitis A for susceptible individuals. • Vaccines given during the immunosuppression period need to be repeated after treatment is stopped and the patient is immunocompetent; usually three to six months after the end of treatment. • Ideal time for vaccination according to immunosuppressive therapies: live virus vaccines should be administered 14 to 30 days before the introduction of immunosuppressive therapy and only three to six months after the end of therapy; may be administered three months after chemotherapy, but at least six months after therapy with anti-B cell antibodies (rituximab). Patients receiving corticosteroids can be vaccinated one month after stopping the drug. • Children born to mothers who used immunomodulators during the last two trimesters of pregnancy must have the BCG vaccine postponed for 6 to 12 months of life. In this situation, the rotavirus vaccine is not contraindicated. • Patients who will receive anti-TNF (tumor necrosis factor) should be vaccinated for influenza, pneumococcus, hepatitis B, diphtheria and tetanus. The sooner the vaccination the better. • Patients susceptible to hepatitis B should be vaccinated before the introduction of rituximab (anti-B cells), because there is a greater risk of complications if this infection occurs. • In situations of high risk of exposure to the yellow fever virus, the vaccine can be administered to some patients, as long as they are not severely immunosupressed, after medical evaluation. The yellow fever vaccine is not contraindicated for people living with immunocompromised patients. The yellow fever vaccine is contraindicated in immunobiological therapies in which live organisms developed by genetic engineering are used to act on specific targets within the organism.

150 FEBRASGO POSITION STATEMENT Neves NA, Teixeira JC, Santos AL, Gonçalves MA, Fridman FZ, Roteli-Martins CM

Background this moment right after the diagnosis of the neopla- Over the past few decades, the number of immunocom- sia and before starting immunosuppressive therapy. promised patients has increased rapidly, although the Whenever possible, the vaccination schedule should be principles of the state of immunosuppression differ be- updated in up to 14 days before the start of immuno- tween different categories of patients. Cancer patients suppressive therapy. In this situation, the vaccination may be immunocompromised both because of their schedule may also be shortened. Whenever possible, neoplastic disease (such as in hematological neoplasms we should wait to start the cancer treatment, possibly or spinal infiltration by any malignant neoplasm) and by immunosuppressive; four weeks after application of antineoplastic treatment. Generally, immunosuppres- live vaccines and two weeks after application of inac- sion in cancer patients is secondary to changes in the tivated vaccines.(2) cellular and humoral immune response, temporary and The ideal is not to vaccinate during the maximum resulting from treatment. As this induced depression is period of immunosuppression in order to achieve the intense, in a way, it is predictable, hence, providing im- best immune response and avoid the risk of causing the munization before treatments with immunosuppressive disease by the vaccine agent. Live vaccines should not potential is a widely used strategy in oncology. be administered during this period. If there is a precise The immunization of cancer patients with a certain indication due to risky situations, inactivated vaccines degree of immunosuppression that tends to worsen with can be used during the chemotherapy, radiotherapy or treatment or by the pathology itself is important for the corticotherapy procedure, although reapplication after patient’s protection against infections. The family and immunosuppressive treatment will be necessary to en- health professionals who care for these patients also need sure an adequate immune response.(3) to be vaccinated against the main infectious agents. If the Three to six months after the end of the immuno- patient is already immunocompromised, vaccines with suppression condition, the woman can use live, bacteri- live or attenuated agents (e.g. the oral poliovirus vaccine) al or viral vaccines, depending on her clinical situation. cannot be used, including for contacts, to avoid the risk of Generally, there is no need to revaccinate the pa- causing a secondary infection in the patient.(1) tient after chemotherapy or radiotherapy if she has The vaccination of these women must be con- been vaccinated before starting treatment, except sidered according to the treatment they will undergo patients that received bone marrow transplants, who and the people with whom they live. Vaccine guid- must be revaccinated.(4-6) ance should result from a joint work between the patient’s attending physician and Reference Centers for Are vaccines safe and effective Special Immunobiologicals, because the vaccination for patients with cancer? schedule and vaccine doses may not follow the usual All inactivated vaccines can be administered to immu- recommendations. nocompromised patients, even if the vaccine is of re- In immunosuppression secondary to chemother- combinant subunit, fractionated or whole virus, toxoid, apy, radiotherapy or corticotherapy for cancer treat- polysaccharide or polysaccharide-conjugate. With the ment, the duration of the immunosuppression condi- exception of the inactivated influenza vaccine, vaccination and the vaccination history are important for the tion during chemotherapy or radiation therapy should patient’s evaluation. The degree of immunosuppres- be avoided, because the immune antibody response sion varies according to the type of immunosuppres- should be suboptimal. Patients who were vaccinated sive drug, dose and duration of treatment. within 14 days before the start of treatment or while The great challenge for specialists is to indicate receiving immunosuppressive therapy should be consid- vaccines for patients who will use new therapeutic mo- ered non-immunized and be revaccinated at least three dalities for the neoplasia, because so far, there are no months after the end of immunosuppressive treatment studies completely determining the safety and effec- and if immunological competence has been restored.(3) tiveness of vaccines under these conditions. Patients receiving immunoglobulin treatment As the group of cancer patients is very heteroge- should not receive live or inactivated vaccines due to neous and there are few defining studies on the safety low vaccine effectiveness. If they are receiving chemo- and effectiveness of vaccines in this group, most vac- therapy with anti-B cell antibodies (e.g. rituximab), they cination recommendations are based on the immune should wait at least six months after the end of treat- response and vaccine safety in general. ment and then, be vaccinated with inactivated vaccines. Patients with leukemia, lymphoma or other neo- When should the adult patient plasms in which disease is in remission, immunocom- with cancer be vaccinated? petence has been reestablished and chemotherapy has Ideally, the patient should update her vaccination ended at least three months earlier, can receive a live schedule and receive the other vaccines indicated for virus vaccine.(7)

FEBRASGO POSITION STATEMENT 151 Vaccination in women with cancer

Vaccination against herpes zoster is contraindi- • Immunosuppressed patients should also receive cated in patients with lymphoma, leukemia, tumors two doses of the Haemophilus influenzae type b involving the bone marrow and those undergoing che- (Hib) vaccine with a two-month interval between motherapy. This is a major concern, because the inci- doses. dence of this disease in patients with altered immuno- Vaccines indicated for updating the vaccination competence is significantly high.(8) schedule are: • Influenza: prefer the quadrivalent vaccine, as it What vaccines are recommended provides greater coverage of circulating strains. for adult cancer patients and their Single annual dose; contacts during treatment? • Hepatitis B: if not vaccinated, apply four doses The Advisory Committee on Immunization Practices (0-1-2-6 months) in a double dose for the age (ACIP), responsible for vaccination guidance of the group. Serology is required after 30 to 60 days. Centers for Disease Control and Prevention (CDC), rec- The person is considered vaccinated if anti-HBs ommends the following specific vaccines for cancer is greater than or equal to 10 IU/mL. If serology patients:(9) is negative, the vaccine schedule of four doses • Pneumococcal vaccines; with doubled volume should be repeated only • Hib vaccine (Haemophilus influenzae type b): pa- once more; tients under 60 who are undergoing chemother- • HPV: the three-dose vaccination schedule is man- apy or radiation therapy and have not previously datory for immunosuppressed people, regardless been vaccinated with Hib, and bone marrow trans- of age; plant patients of any age, regardless of the history • Triple bacterial: if already vaccinated, booster dose of Hib vaccination. every ten years. The National Immunization Program (NIP) is re- The vaccination of immunocompromised patient sponsible for recommending and acting on Brazilian contacts is highly recommended. Reference Centers public vaccination, and also recommends other vac- for Special Immunobiologicals provide influenza and cines for cancer patients, shown in Table 1, adapted chickenpox vaccines to these contacts. from the Manual of the Reference Centers for Special Chart 1. Vaccines recommended for patients with neoplasms Immunobiologicals-NIP-Ministry of Health.(10) undergoing chemotherapy, radiotherapy or corticotherapy and for Some vaccines outside the vaccination calendar re- people living with these patients lated to the age group are specifically indicated for immunosuppressed patients, such as the pneumococcal, Patient meningococcal and Hib for Haemophilus influenzae. Vaccine Before During Contact • There are two pneumococcal vaccines: 13-valent treatment treatment pneumococcal conjugate (VPC13) and 23-valent BCG No No polysaccharide pneumococcal (VPP23). VPC13 DTP Yes Yes is indicated for children from two months of age OPV No No No and elderly people from 60 years of age, but has IPV Yes Yes Yes a specific dose recommendation for patients of Hepatitis B Yes Yes any age with neoplasia. The VPP23 vaccine is also Triple viral Yes No Yes indicated routinely for children from two years Chickenpox Yes No Yes, if old and elderly people from 60 years old and has susceptible a specific recommendation of two doses (five- Yellow fever Yes No year interval) for patients from two years old Hib Yes, if <19 Yes, if <19 with neoplasia. The vaccination schedule should years years always be started with VPC13, followed by the Influenza Yes Yes Yes application of the VPP23 vaccine, respecting the Hepatitis A Yes Yes minimum two-month interval in between. After Meningococcal C Yes Yes five years, application of the VPP23 should be (2 doses) repeated. HPV (3 doses) Yes (9-26 Yes (9-26 • The meningococcal vaccine is indicated in two years) years) doses for immunosuppressed adult patients with Pneumococcal Yes Yes (according to a two-month interval. If immunosuppression per- age) sists, a booster dose should be applied every five PCV10 / PCV13 / years. Whenever possible, the ACWY meningococ- PPSV23 cal vaccine should be applied. Source: Ministry of Health (2019).(10)

152 FEBRASGO POSITION STATEMENT Neves NA, Teixeira JC, Santos AL, Gonçalves MA, Fridman FZ, Roteli-Martins CM

Which vaccines are contraindicated transplanted organ. Live virus vaccines should not be for cancer patients and contact administered within two months after the end of these persons during treatment?(2) drugs, but the herpes zoster vaccine can be adminis- • Live bacteria vaccines: BCG, adenovirus and tered one month after the end of drugs to prevent re- Salmonella typhi oral vaccine Ty21a. jection.(9) • Live virus vaccines: triple viral, oral polio, nasal flu, As the transplant may happen at any time, shorter yellow fever, herpes zoster, rotavirus, chickenpox, vaccination schedules against hepatitis B can be used. dengue and smallpox. The need to use a double dose should be evaluated The oral polio vaccine is contraindicated for con- according to the underlying clinical situation. Human tacts of immunosuppressed people and should be re- anti-hepatitis B immunoglobulin (IGHAB) for liver placed by the inactivated polio vaccine. transplant recipients who have AgHbs is regulated by Ordinance No. 86 of February 5, 2002, of the Health Are vaccination recommendations Assistance Secretariat and is not responsibility of the different depending on the type Reference Centers for Special Immunobiologicals. of cancer or therapeutic plan? Bone marrow transplantation (hematopoietic Immunosuppressive drugs (corticosteroids, immuno- stem cells): regardless of the type of transplant, the modulators, non-biological immunosuppressants, bio- hematopoietic stem cell is responsible for the recon- logical immunosuppressants): stitution of the immune system of the post-transplant The degree of immunosuppression varies ac- recipient. The post-transplant vaccination recommen- cording to the drug, dose and duration of treatment. dation is not different for recipients of autologous, Corticosteroids for oral use are considered immuno- allogeneic or syngeneic transplantation. Studies have suppressants at a dose ≥ 2 mg/kg/day of prednisone shown that hematopoietic stem cell transplant recipi- (<20 mg/day) or its equivalent. There is no evidence ents, both allogeneic and autologous, lose protective of immunosuppression with the use of topical (skin or immunity after transplantation. These individuals must eyes), inhalation or intra-articular corticosteroids and have their vaccination regimen redone after transplan- there is no contraindication for vaccination in these pa- tation.(4,5) tients. Patients receiving corticosteroids can be vaccinated one month after stopping them.(5) Final considerations Immunosuppressant doses of non-biological Gynecologists have been consolidating themselves as agents are:(10) the specialist medical assistants of women with the • Methotrexate: ≥0.4 mg/kg/week; most opportunity to fully assist them and diagnose • Cyclosporine:> 2.5 mg/kg/day; gynecological or other organ neoplasms. Women • Tacrolimus: 0.1 to 0.2 mg/kg/day; with malignancies will need special care to prevent • Mycophenolate mofetil: 3 g/day infectious diseases, including vaccination for various • Azathioprine: 1-3 mg/kg/day; agents, whether to update the vaccination schedule or • Cyclophosphamide: 0.5-2.0 mg/kg/day; receive new vaccines indicated because of the neopla- • Leflunomide: 0.25-0.5 mg/kg/day; sia diagnosis and consequent therapy. As these wom- • 6-mercaptopurine: 1.5 mg/kg/day. en must be vaccinated as soon as possible before the For biological immunosuppressive agents, any start of cancer treatment, the role of gynecologists is dose is considered immunosuppressive: infliximab (an- key. They will be able to quickly discuss with the on- ti-TNFα) and other anti-TNF; rituximab (anti-B cells); cologist and specialists of Reference Centers for Special abatacept (reduces T cell activation); tocilizumab (an- Immunobiologicals, speeding up the administration of ti-interleukin-6); eculizumab (reduces complement vaccines to the patient, their relatives and contacts. activation). References Transplants in oncology 1. Zuckerman MA, Brink NS, Kyi M, Tedder RS. Exposure Various oncological situations require transplants of ei- of immunocompromised individuals to health-care workers immunised with oral poliovaccine. Lancet. ther solid organs or bone marrow. 1994;343(8903):985-6. doi: 10.1016/s0140-6736(94)90114-7 Solid organ transplantation: the need for im- 2. Ljungman P. Vaccination of immunocompromised hosts. munization of candidates for recipients of solid organ In: Plotkin SA, Orenstein WA, Offit PA, Edwards KM, editors. transplants is justified by the immunosuppressive ac- Plotkin’s vaccines. 7th ed. Philadelphia: Elsevier; 2018. p. tivity of the underlying disease (for example, patients 1355-69. with chronic renal failure and patients with neoplasms) 3. Rubin LG, Levin MJ, Ljungman P, Davies EG, Avery R, Tomblyn M, and because they will undergo immunosuppressive et al. 2013 IDSA clinical practice guideline for vaccination of the therapy after transplantation to avoid rejection of the immunocompromised host. Clin Infect Dis. 2014;58(3):e44- 100. doi: 10.1093/cid/cit684

FEBRASGO POSITION STATEMENT 153 Vaccination in women with cancer

4. Ljungman P, Cordonnier C, Einsele H, Englund J, Machado CM, Storek J, et al. Vaccination of hematopoietic cell transplant Nilma Antas Neves1 recipients. Bone Marrow Transplant. 2009;44(8):521-6. doi: 1Universidade Federal da Bahia, Salvador, BA, Brasil. 10.1038/bmt.2009.263 2 5. American Academy of Pediatrics. Immunization in special Júlio César Teixeira 2 clinical circumstances. In: Pickering LK, Baker CJ, Kimberlin Universidade Estadual de Campinas, Campinas, SP, Brasil. DW, Long SS, editors. Red Book: 2009 report of the Committee André Luis Ferreira Santos3 on Infectious Diseases. 28th ed. Elk Grove Village: American 3Universidade de Taubaté, Taubaté, SP, Brasil. Academy of Pediatrics; 2009. p. 68-104. 4 6. Staples JE, Bocchini JA Jr, Rubin L, Fischer M; Centers for Disease Manoel Afonso Guimarães Gonçalves Control and Prevention (CDC). Yellow fever vaccine booster 4Pontifícia Universidade Católica do Rio Grande do Sul, Porto doses: recommendations of the Advisory Committee on Alegre, RS, Brasil. Immunization Practices, 2015. MMWR Morb Mortal Wkly Rep. Fabíola Zoppas Fridman5 2015;64(23):647-50. 5Hospital Femina Grupo Hospitalar Conceição, Porto Alegre, RS, 7. Marin M, Guris D, Chaves SS, Schmid S, Seward JF. Prevention Brasil. of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. Cecília Maria Roteli-Martins 2007;56(RR-4):1-40. 6Faculdade de Medicina do ABC, Santo André, SP, Brasil. 8. Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of Conflict of interest: none to declare. herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. National Specialty Commission for Vaccines of the Brazilian 2008;57(RR-5):1-30. Federation of Gynecology and Obstetrics Associations (FEBRASGO) 9. Centers for Disease Control and Prevention (CDC). Advisory Committee on Immunization Practices (ACIP). Altered President: immunocompetence: general best practice guidelines for Cecília Maria Roteli Martins immunization: best practices guidance of the ACIP [Internet]. Vice-President: 2020 [cited 2020 Nov 8]. Available from: https://www.cdc.gov/ Nilma Antas Neves vaccines/hcp/acip-recs/general-recs/immunocompetence. html Secretary: Susana Cristina Aidé Viviani Fialho 10. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Imunização e Doenças Transmissíveis. Members: Manual dos Centros de Referência de Imunobiológicos Especiais André Luís Ferreira Santos [Internet]. Brasília (DF): Ministério da Saúde; 2019 [cited 2020 Angelina Farias Maia Nov 8]. Available from: https://portalarquivos2.saude.gov.br/ Fabíola Zoppas Fridman images/pdf/2019/dezembro/11/manual-centros-referencia- Giuliane Jesus Lajos imunobiologicos-especiais-5ed.pdf Isabella de Assis Martins Ballalai Juarez Cunha Júlio Cesar Teixeira Manoel Afonso Guimarães Gonçalves Marcia Marly Winck Yamamoto de Medeiros Renata Robial Renato de Ávila Kfouri Valentino Antonio Magno

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