RBGO Eissn 1806-9339 Gynecology & Obstetrics

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Revista Brasileira de Ginecologia e Obstetrícia Number 1 • Volume 41 • Pages 1–66 • January 2019 Show your true contributions to science Track and verify your peer review

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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

Andréa da Rocha Tristão Gerson Botacini das Dores Luiz Gustavo Oliveira Brito Universidade Estadual Paulista Gustavo Salata Romão Universidade de São Paulo, "Júlio de Mesquite Filho", Universidade de São Paulo, Ribeirão Preto, Campinas, SP, Brazil Botucatu, SP, Brazil SP, Brazil Maria Celeste Osório Wender Ana Katherine da Silveira Gonçalves Helena von Eye Corleta Universidade Federal do Rio Grande do Sul, Universidade Federal do Rio Grande do Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil Norte, Natal, RN, Brazil Porto Alegre, RS, Brazil Omero Benedicto Poli Neto Agnaldo Lopes da Silva Filho Universidade de São Paulo, Universidade Federal de Minas Gerais, Ilza Maria Urbano Monteiro Ribeirão Preto, SP, Brazil Belo Horizonte, MG, Brazil Universidade Estadual de Campinas, Patrícia El Beitune Alessandra Cristina Marcolin Campinas, SP, Brazil Universidade Federal de Ciências da Saúde Universidade de São Paulo, José Geraldo Lopes Ramos Ribeirão Preto, SP, Brazil de Porto Alegre, RS, Brazil Universidade Federal do Rio Grande do Daniel Guimarães Tiezzi Paula Andrea de Albuquerque Salles Navarro Sul, Porto Alegre, RS, Brazil Universidade de São Paulo, Universidade de São Paulo, Ribeirão Preto, SP, Brazil José Guilherme Cecatti Ribeirão Preto, SP, Brazil Eddie Fernando Candido Murta Universidade de São Paulo, Campinas, Ricardo Carvalho Cavalli Universidade Federal do Triângulo Mineiro, SP, Brazil Universidade de São Paulo, Uberaba, MG, Brazil José Maria Soares Júnior Ribeirão Preto, SP, Brazil Edward Araujo Júnior Universidade de São Paulo, Rosana Maria dos Reis Universidade Federal de São Paulo, São Paulo, SP, Brazil Universidade de São Paulo, São Paulo, SP, Brazil Julio Cesar Rosa e Silva Ribeirão Preto, SP, Brazil Eliana Aguiar Petri Nahas Universidade de São Paulo, Rosiane Mattar Universidade Estadual Paulista Universidade Federal de São Paulo, “Júlio de Mesquita Filho”, Ribeirão Preto, SP, Brazil São Paulo, SP, Brazil Botucatu, SP, Brazil Lucia Alves da Silva Lara Rodrigo de Aquino Castro Fabrício da Silva Costa Universidade de São Paulo, Universidade Federal de São Paulo, Monash University, Melbourne, Ribeirão Preto, SP, Brazil São Paulo, SP, Brazil Victoria, Australia Lucia Helena Simões da Costa Paiva Silvana Maria Quintana Fernanda Garanhani de Castro Surita Universidade Estadual de Campinas, Universidade Estadual de Campinas, Universidade de São Paulo, Campinas, SP, Brazil Campinas, SP, Brazil Ribeirão Preto, SP, Brazil Fernando Marcos dos Reis Luiz Carlos Zeferino Sophie Françoise Mauricette Derchain Universidade Federal de Minas Gerais, Universidade Estadual de Campinas, Universidade Estadual de Campinas, Belo Horizonte, MG, Brazil Campinas, SP, Brazil Campinas, SP, Brazil

Editorial Board

Alex Sandro Rolland de Souza Aurélio Antônio Ribeiro da Costa Carlos Grandi Instituto de Medicina Integral Universidade de Pernambuco, Universidad de Buenos Aires, Prof. Fernando Figueira, Recife, PE, Brazil Recife, PE, Brazil Buenos Aires, Argentina Ana Carolina Japur de Sá Rosa e Silva Belmiro Gonçalves Pereira Cesar Cabello dos Santos Universidade de São Paulo, Universidade Estadual de Campinas, Universidade Estadual de Campinas, Ribeirão Preto, SP, Brazil Campinas, SP, Brazil Campinas, SP, Brazil Ana Katherine da Silveira Gonçalves Carlos Augusto Alencar Junior Délio Marques Conde Universidade Federal do Rio Grande do Universidade Federal do Ceará, Hospital Materno Infantil de Goiânia, Norte, Natal, RN, Brazil Fortaleza, CE, Brazil Goiânia, GO, Brazil Dick Oepkes Joshua Vogel Paulo Roberto Nassar de Carvalho University of Leiden, Leiden, Department of Reproductive Health and Instituto Fernandes Figueira-Fiocruz, The Netherlands Research, World Health Organization, Rio de Janeiro, RJ, Brazil Dino Roberto Soares de Lorenzi Geneva, Switzerland Renato Augusto Moreira de Sá Universidade de Caxias do Sul, Juvenal Soares Dias-da-Costa Universidade Federal Fluminense, Caxias do Sul, RS, Brazil Universidade Federal de Pelotas, Niterói, RJ, Brazil Diogo de Matos Graça Ayres Pelotas, RS, Brazil Rintaro Mori de Campos Laudelino Marques Lopes National Center for Child Health Universidade do Porto, Porto, Portugal University of Western Ontario, and Development, Tokyo, Japan Eduardo Pandolﬁ Passos London, Ontario, Canada Roberto Eduardo Bittar Universidade Federal do Rio Grande do Sul, Luciano Marcondes Machado Nardozza Universidade de São Paulo, Porto Alegre, RS, Brazil Universidade Federal de São Paulo, São Paulo, SP, Brazil Edmund Chada Baracat São Paulo, SP, Brazil Rosane Ribeiro Figueiredo Alves Universidade de São Paulo, Luis Otávio Zanatta Sarian Universidade Federal de Goiás, Goiânia, São Paulo, SP, Brazil Universidade Estadual de Campinas, GO, Brazil Eliana Martorano Amaral Campinas, SP, Brazil Roseli Mieko Yamamoto Nomura Universidade Estadual de Campinas, Luiz Claudio Santos Thuler Universidade Federal de São Paulo, Campinas, SP, Brazil São Paulo, SP, Brazil Instituto Nacional do Câncer, Rossana Pulcinelli Vieira Francisco Francisco Edson Lucena Feitosa Rio de Janeiro, RJ, Brazil Universidade Federal do Ceará, Fortaleza, Universidade de São Paulo, Luiz Henrique Gebrim CE, Brazil São Paulo, SP, Brazil Universidade Federal de São Paulo, George Condous Ruﬀ o de Freitas Junior São Paulo, SP, Brazil Nepean Hospital in West Sydney, Sidney, Universidade Federal de Goiás, Manoel J. B. Castello Girão, Australia Goiânia, GO, Brazil Universidade Federal de São Paulo, Giuseppe Rizzo Sabas Carlos Vieira São Paulo, SP, Brazil Università degli Studi di Roma Universidade Federal do Piauí, Teresina, Marcelo Zugaib “Tor Vergata”, Roma, Italy PI, Brazil Universidade de São Paulo, Gutemberg Leão de Almeida Filho Sebastião Freitas de Medeiros São Paulo, SP, Brazil Universidade Federal do Rio de Janeiro, Universidade Federal do Mato Grosso, Marcos Desidério Ricci Rio de Janeiro, RJ, Brazil Cuiabá, MT, Brazil Universidade de São Paulo, Iracema de Mattos Paranhos Calderon Selmo Geber São Paulo, SP, Brazil Universidade Estadual Paulista Universidade Federal de Minas Gerais, “Júlio de Mesquita Filho”, Botucatu, SP, Brazil Maria de Lourdes Brizot Belo Horizonte, MG, Brazil João Luiz Pinto e Silva Universidade de São Paulo, Silvia Daher Universidade Estadual de Campinas, São Paulo, SP, Brazil Universidade Federal de São Paulo, Campinas, SP, Brazil Marilza Vieira Cunha Rudge São Paulo, SP, Brazil João Paulo Dias de Souza Universidade Estadual Paulista Shaun Patrick Brennecke Universidade de São Paulo, “Júlio de Mesquita Filho”, University of Melbourne Parkville, Ribeirão Preto, SP, Brazil Botucatu, SP, Brazil Victoria, Australia João Sabino Lahorgue da Cunha Filho Newton Sergio de Carvalho Técia Maria de Oliveira Maranhão Universidade Federal do Rio Grande do Sul, Universidade Federal do Paraná, Universidade Federal do Rio Grande do Porto Alegre, RS, Brazil Curitiba, PR, Brazil Norte, Natal, RN, Brazil José Carlos Peraçoli Nuno Henrique Malhoa Migueis Clode Toshiyuki Hata Universidade Estadual Paulista Faculdade de Medicina de Lisboa, Lisboa, University Graduate School of Medicine, “Júlio de Mesquita Filho”, Botucatu, SP, Brazil Portugal Kagawa, Japan José Juvenal Linhares Olímpio Barbosa Moraes Filho Wellington de Paula Martins Universidade Federal do Ceará, Universidade de Pernambuco, Recife, Universidade de São Paulo, Campus de Sobral, Fortaleza, CE, Brazil PE, 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 (2018) Presidency and Executive Staﬀ

President Avenida das Américas, 8445 – sala 711 César Eduardo Fernandes (SP) Barra da Tijuca – Rio de Janeiro – RJ CEP: 22793-081 Brazil Administrative / Financial Director Phone.: (+55 21) 2487-6336 Corintio Mariani Neto (SP) Fax: (+55 21) 2429-5133 Scientiﬁ c Director www.febrasgo.org.br Marcos Felipe Silva de Sá (SP) [email protected] Professional Status Defence [email protected] Juvenal Barreto Borriello de Andrade (SP)

Vice-president of North Region RBGO Editorial Oﬃ ce Hilka Flávia Barra do E. Santo (AM) editorial.oﬃ [email protected] Vice-president of Northeast Region Flavio Lucio Pontes Ibiapina (CE) Vice-president of Middle West Region Alex Bortotto Garcia (SP) Vice-president of Southeast Region Agnaldo Lopes da Silva Filho (MG) Vice-president of South Region Maria Celeste Osório Wender (RS)

Volume 41, Number 1/2019 RBGO Gynecology and Obstetrics Revista Brasileira de Ginecologia e Obstetrícia

Editorial

1 The Need for a Competence Matrix in Delivery Rooms for the Proper Work of Multiprofessional Teams Marcos Felipe Silva de Sá and Gustavo Salata Romão

Original Articles

Obstetrics

4 Association between Dietary Glycemic Index and Excess Weight in Pregnant Women in the First Trimester of Pregnancy Thais Helena de Pontes Ellery, Helena Alves de Carvalho Sampaio, Antônio Augusto Ferreira Carioca, Bruna Yhang da Costa Silva, Júlio Augusto Gurgel Alves, Fabrício Da Silva Costa, Edward Araujo Júnior, and Maria Luísa Pereira de Melo

Fetal Medicine

11 Accuracy of Prenatal Diagnosis of Congenital Cardiac Malformations Diesa Oliveira Pinheiro, Bruna Boff Varisco, Marcelo Brandão da Silva, Rafaela Silva Duarte, Graciele Dequi Deliberali, Carlos Roberto Maia, Mirela Foresti Jiménez, and Patrícia El Beitune

Image

17 Assessment of Sensitivity and Speciﬁ city of Ultrasound and Magnetic Resonance Imaging in the Diagnosis of Placenta Accreta Elisa Santos Lopes, Francisco Edson de Lucena Feitosa, Antonio Viana Brazil, José Daniel Vieira de Castro, Jesus Irajacy Fernandes da Costa, Edward Araujo Júnior, Alberto Borges Peixoto, and Francisco Herlânio Costa Carvalho

Basic and Translational Science/Obstetrics

24 The Inﬂ uence of Light Exposure in Ambiance during Pregnancy in Maternal and Fetal Outcomes: An Experimental Study Vitor Coca Sarri, Beatriz Maria Ferrari, Larissa Fernandes Magalhães, Paula Almeida Rodrigues, Almir Coelho Rezende, and Marisa Afonso Andrade Brunherotti

General Gynecology

31 Association between col1a2 Polymorphism and the Occurrence of Pelvic Organ Prolapse in Brazilian Women Josyandra Paula de Freitas Rosa, Raphael Federicci Haddad, Fabiana Garcia Reis Maeda, Ricardo Peres Souto, Cesar Eduardo Fernandes, and Emerson de Oliveira

Gynecological Endocrinology

37 The Prevalence of Metabolic Syndrome in the Diﬀ erent Phenotypes of Polycystic Ovarian Syndrome Aleide Tavares and Romualda Castro Rêgo Barros

Thieme Revinter Publicações Ltda online www.thieme-connect.com/products RBGO Gynecology and Obstetrics Volume 41, Number 1/2019

Review Articles

44 Isthmocele: From Risk Factors to Management Piergiorgio Iannone, Giulia Nencini, Gloria Bonaccorsi, Ruby Martinello, Giovanni Pontrelli, Marco Scioscia, Luigi Nappi, Pantaleo Greco, and Gennaro Scutiero

53 Use of the Pessary in the Prevention of Preterm Delivery Thayane Delazari Corrêa, Ester Gomes Amorim, Jade Aimée Guimarães Tomazelli, and Mário Dias Corrêa Júnior

Case Reports

59 Lithopedion in a Geriatric Patient Andrés Ricaurte Sossa, Henry Bolaños, Andrés Ricaurte Fajardo, Ángela Camila Burgos, Valentina Garcia, Paola Muñoz, and Diego Rosselli

62 Ruptured Renal Artery Aneurysm in a Pregnant Woman: Case Report and Literature Review Adriane Castro de Souza, Caio Henrique Yoshikatsu Ueda, Denise Hiromi Matsubara, and João Raphael Zanlorensi Glir

Erratum

65 Erratum – Maternal Mortality in Brazil: Proposals and Strategies for its Reduction

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

Copyright © 2019 by Thieme Revinter Publicações Ltda Inc. RBGO Gynecology Revista Brasileiro de Ginecologia e Obstetrícia is an official publication of the and Obstetrics/Revista Brasileiro de Ginecologia e Obstetrícia is published Federação Brasileira das Associações de Ginecologia e Obstetrícia (Brazilian monthly by Thieme-Revinter Publicações Ltda., Rua do Matoso, 170, Rio de Federation of Association of Gynecology and Obstetrics, Febrasgo), It is Janeiro 20270-135, Brazil. listed in Isi - Web of Science, Web of Knowledge (Emerging), MEDLINE / Editorial comments should be sent to [email protected]. Articles may PubMed, Index Medicus, Scopus (Sci Verse), SCImago, SciELO (Scientific be submitted to this journal on an open-access basis. For further informa- Electronic Library Online), LILACS (Literatura Latino-Americana e do Caribe tion, please send an e-mail to [email protected]. The content of this em Ciências da Saúde, Index Medicus Latino Americano), and Portal de journal is available online at www.thieme-connect.com/products. Visit our Periódicos Capes (Coordenação de Aperfeiçoamento de Pessoal de Nível Web site at www.thieme.com and the direct link to this journal at www. Superior). Thieme Medical Publishers is a member of the CrossRef initiative. rbgo.com.br. ISSN 0100-7203

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Editorial The Need for a Competence Matrix in Delivery Rooms for the Proper Work of Multiprofessional Teams

A necessidade de uma matriz de competências da sala de parto para a atuação adequada de uma equipe multiproﬁssional

Marcos Felipe Silva de Sá1 Gustavo Salata Romão2

1 Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil 2 Universidade de Ribeirão Preto, Ribeirão Preto, SP, Brazil

Rev Bras Ginecol Obstet 2019;41:1–3.

The Brazilian Ministry of Health (MH) is, although belatedly, newborns). Other articles about good practices in delivery actually concerned about the quality of maternal and childcare can be found in some publications in the Brazilian care. Indeed, the Brazilian national indicators related to literature.3 maternal and child mortality, the low quality of prenatal In Brazil, governmental and nongovernmental organiza- care, illustrated by the sharp growth in the number of cases tions have proposed several actions to improve obstetric care of syphilis in pregnant women and congenital syphilis in and reduce C-section rates, with many programs currently in recent years, the high rates of cesarean sections (C-sections; progress. In 2011, the MH launched the ‘Rede Cegonha’ Brazil is the second country in C-section rates in the world), program, which is developed in hospitals linked to the and the poor quality of delivery care, so broadly and repeat- Brazilian Unified Health System (SUS, in Portuguese). The edly exposed in the media, are alarming. There is an endless objective of this program is to ensure that all women have number of failures that may be attributed to the poor access to comprehensive health care since pregnancy confir- performance of the Brazilian health system, including pri- mation up to the second year of life of the child. It implies the vate health insurance plans. guarantee of access and improvement in the quality of Regarding delivery care, it is widely known that it requires childbirth care.4 Recently, the ‘Parto Cuidadoso’ program, more attention, taking into account the situation of immi- whose objectives are humanizing care in public maternities, nent risk to which the mother and her fetus are exposed. The was linked to ‘Rede Cegonha,’ and, in addition to improving World Health Organization (WHO) has recently issued a the care offered to pregnant and parturient women, publication entitled Intrapartum Care for a Positive Childbirth its secondary goal is reducing C-section rates. Experience,1 with recommendations for care during labor In 2015, the ‘Parto Adequado’ project, which was devel- and delivery based on an extensive review of published oped by the Brazilian National Regulatory Agency for Private studies, as well as care protocols from several countries. Health Insurance and Plans (ANS, in Portuguese), Hospital These data were submitted to evaluation by an external Israelita Albert Einstein, and the Institute for Healthcare commission, which included experts from the International Improvement (US), was implemented, with the support of Federation of Gynecology and Obstetrics (known by its the MH, to identify innovative and feasible models of child- French acronym FIGO). The WHO document was analyzed birth care that value normal childbirth and promote a and endorsed by the Brazilian Federation of Gynecology and decrease in the percentage of C-sections. In the first stage, Obstetrics Associations’ (Febrasgo, in Portuguese) National 35 large hospitals and 19 health insurance operators were Specialized Commission for Childbirth and Postpartum selected for the program. In the second phase, which is Care.2 It establishes the recommended and non-recom- currently in progress, 137 private hospitals, 25 public hos- mended practices according to the 2018 WHO intrapartum pitals, 65 health insurance operators, and 73 associated care model (considering healthy mothers and fetuses or hospitals were involved in the program, with a significant reduction in the number of C-sections in the institutions in 5 ORCID ID is https://orcid.org/0000-0002-4813-6404. which it was applied.

Address for correspondence DOI https://doi.org/ Copyright © 2019 by Thieme Revinter Marcos Felipe Silva de Sá, PhD, 10.1055/s-0039-1677882. Publicações Ltda, Rio de Janeiro, Brazil Av. Bandeirantes 3900, Monte ISSN 0100-7203. Alegre, Ribeirão Preto, 14049-900, SP, Brazil (e-mail: [email protected]). 2 Editorial

At the SUS setting, the ‘Aprimoramento e Inovação no Non-medical professionals have been introduced in the Cuidado e Ensino em Obstetrícia e Neonatologia’ (Apice On, process of providing care to pregnant women and partu- in Portuguese) project, an initiative of the MH in partnership rients as a measure to ‘save the system.’ However, the with Empresa Brasileira de Serviços Hospitalares (EBSERH, in insertion of new professionals should necessarily be ac- Portuguese), Associação Brasileira de Hospitais Universitár- companied by an adjustment, with specifications of the ios e de Ensino (ABRAHUE, in Portuguese), the Brazilian assignments of each professional involved in the care of Ministry of Education (MEC, in Portuguese), and Instituto pregnant women, parturients, and newborns, and with Fernandes Figueira/Fundação Oswaldo Cruz (IFF/FIOCRUZ, in each professional doing their share in a coordinated way. Portuguese), was created in 2017, with Universidade Federal If the group of professionals works in unison, better results de Minas Gerais as the executing institution.6 According to are expected regarding the well-being of mothers and the MH, ‘Apice On proposes training in the areas of childbirth fetuses. By ‘forcing’ the insertion of non-medical profes- care, postpartum and postmiscarriage reproductive plan- sionals in delivery rooms without the previously-estab- ning, and care to women who have experienced sexual lished support of an obstetrician, the lives of pregnant violence, miscarriage or legal abortion, in teaching or uni- women and fetuses may be put at risk. The result of this versity hospitals, or in auxiliary teaching units, within the hasty action is a sequence of judicial conflicts that involve scope of “Rede Cegonha.” Its purposes are expanding the regional or federal councils of non-medical professionals reach of the activities developed by hospitals from the SUS with the Brazilian Federal Medical Council, a staunch network and reformulating and/or improving work process- defender of the Medical Act Law, the norms that regulate es and flows to adjust care access, coverage, and quality.’ medical practice in Brazil.7 These judicial conflicts become Consequently, with the objective to contribute to the more frequent, especially when the complications occur programs designed to improve obstetric care in Brazil and during childbirths assisted by non-medical professionals reduce C-section rates, Febrasgo has actively supported the and that demand the intervention of an obstetrician. Addi- ‘Parto Adequado’ and Apice On projects. We understand that, tionally, interpersonal conflicts often arise from the poor when proposing or implementing public policies for mater- integration among different professionals. nal and childcare, public managers must seek to establish Based on these facts and since many of these programs are communications with professionals in the area, in a coordi- developed in public hospitals and maternities, usually uni- nated way, so they can all participate in the formulation of versity institutions, in order to minimize these problems, we standards, ordinances, laws etc., engaging and encouraging suggest that the managers should formulate the program them to play a more active role in maternal and childcare. with the participation of representatives from all of the Obstetricians access the Febrasgo portal on a regular basis, professions involved, under the coordination of the clinical and periodically receive varied types of information: notices director of each hospital or maternity unit. Thus, a compe- of conferences, scientific texts, protocols, newsletters, direct tence matrix for the delivery room should be developed for mailing, and journals. Therefore, Febrasgo intends to be a this purpose. The role of each professional in the activities mediator partner in the actions of the MH in the women’s developed in this setting would be well-defined since the health area, that is, a real bridge joining the public managers arrival of the pregnant woman or parturient at the hospital, and the 16,000 gynecologist and obstetrician associate pro- the labor, the childbirth, the reception of the newborn and fessionals who care for patients at clinics, wards, offices, and the postpartum steps, up to hospital discharge. With this delivery rooms, public or not. They are the specialists that document, the hierarchical levels of competence of each push the health system forward regarding women’s health professional would be respected, in accordance with the programs. laws that regulate the involved professions. The work per- The Febrasgo, in consonance with the aforementioned formed by an interdisciplinary group of professionals has projects, has repeatedly expressed its support to the work greater chances of being successful and integrating the group performed by multiprofessional teams, including obstetri- better. cians, nurse midwives, anesthetists, neonatologists, social The Febrasgo has recently developed a competence matrix workers and others, in delivery rooms. However, in order for for training resident (R) physicians in gynecology and ob- this integrated work to be successful, the interaction of all of stetrics, based on The Obstetrics and Gynecology Milestone the participants in establishing a routine for the delivery Project, which was designed by the American Board of room is necessary. Obstetricians are the only professionals Obstetrics and Gynecology (ABOG) and the American College trained to act throughout all of the childbirth process, from of Obstetrics and Gynecology (ACOG);8 it establishes the conception to postpartum. Therefore, there is no reason to roles of R1, R2, and R3 in the service routine, by training fear conjoint work. On the contrary, interdisciplinary action level and technical qualification, and according to their allows obstetricians to work longer where their skills are knowledges, skills, and decision-making ability.9 The essential. The patients certainly will notice the better care. Febrasgo competence matrix contains an innovative axis This does not mean that physicians should refrain from the entitled ‘Professionalism,’ whose objective is to strengthen responsibility of following the childbirth process. By isolat- new frameworks in global health, humanization, and care ing themselves in the process, resisting to multiprofessional qualification, emphasizing teamwork, with professionals integration, obstetricians will keep losing their role in the who complete medical residency programs in the gynecolo- group, compromising care quality and safety. gy and obstetrics field.

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 Editorial 3

Based on that document, we suggested that the formulation carrying out an extensive reviewof the international literature, of the competence matrix in the delivery room take into the ACOG Committee has established a series of guidance account some requisites in the evaluation of medical or non- involving obstetricians, nurses, patients, and all of the profes- medical professional capacity, which may be essential and sionals that help obstetricians during childbirth. Its main should include key aspects such as: 1) understanding the roles objective, which is common to all of the professionals, is to of the care team members; 2) capacity to communicate assist labor and childbirth using techniques that require effectively within the team; 3) understanding the importance minimum interventions and result in patient satisfaction. of care duties (shift changes and referrals) and team meetings; We believe that all the efforts undertaken by the MH and 4) punctuality in the clinical activities; 5) proper and timely the other institutions that support programs and projects filling of administrative and medical records and reports; 6) whose objective is to improve the care offered to pregnant effective performance in interprofessional and interdisciplin- women and parturients will be successful only with perma- ary health teams; 7) effective communication with physicians nent investment, mainly regarding infrastructure and the and other healthcare professionals regarding the care provided overall development of qualified human resources, with to patients; 8) engagement in shared decision-making, taking continuing education programs and, most importantly, the into consideration the cultural characteristics of the patients integration of all of the professionals involved. and their families; 9) organization of and participation in guidance actions in multidisciplinary teams geared towards Conflicts of Interest the patients, their relatives, and the team members; 10) The authors have no conflicts of interest to declare.. acceptance of constructive feedback to improve workcapacity; and 11) compassion, honesty, and respect for other people. For these reasons, the technical knowledge of each member References per se is not enough in the training of multidisciplinary work 1 WHO Recommendations: Intrapartum Care for a Positive Child- teams if there is not a proper understanding of their role in the birth Experience. Geneva: World Health Organization; 2018 group. Being multidisciplinary is not enough. The team must to 2 Trapani Júnior ACuidados noTrabalho de Parto e Parto: Recomendações da OMS2018https://www.febrasgo.org.br/pt/noticias/item/556-cuid be integrated. Although different levels of those requisites can ados-no-trabalho-de-parto-e-parto-recomevndacoes-da-oms. be found among the members of the group, they can be trained Accessed November 21, 2018. and work in order adjust them to structure the team. 3 Petrucce LFF, Oliveira LR, Oliveira VR, Oliveira SR. Humanização no Once the team is formed, it is necessary to establish guide- atendimento ao parto baseada em evidências. Femina 2017;45 lines (protocols) for delivery rooms, which are essential. The (04):212–222 objectives of clinical practice protocols are establishing proper 4 Rede Cegonha.2011http://www.brasil.gov.br/cidadania-e-justica/ 2011/10/rede-cegonha. Accessed September 12, 2018. criteria and the algorithm for problem/diagnosis, whether 5 Ministério da Saúde. Agência Nacional de Saúde Suplementar. they refer to diseases or bureaucratic events, as well as their Projeto Parto Adequado.http://ans.gov.br/gestao-em-saude/pro- treatment or solution, and creating mechanisms to guarantee jeto-parto-adequado. Accessed September 12, 2018. safe and effective prescriptions and the supervision of possible 6 Ministério da Saúde. Secretaria de Atenção à Saúde. Departamento adverse effects. The documents must to contain technical de Ações Programáticas Estratégicas Coordenação Geral de Saúde information based on the best scientific evidence available das Mulheres. Apice On: Aprimoramento no Cuidado, Ensino em Obstetrícia e Neonatologia2017http://portalarquivos.saude.gov.br/ and obey some primordial principles aiming to improve care images/pdf/2017/agosto/18/Apice-On-2017-08-11.pdf. Accessed quality. They must be clear enough, thus preventing noncon- May 15, 2018. ventional procedures and behaviors that have not yet been 7 Lei n° 12.842, de 10 de julho de2013. Dispõe sobre o exercício da consolidated, those that are not accessible in Brazil, or those Medicina. http://www.planalto.gov.br/ccivil_03/_Ato2011-2014/ that have not been approved by the Brazilian National Health 2013/Lei/L12842.htm. Accessed August 09, 2018. 8 The Accreditation Council for Graduate Medical Education, The Amer- Surveillance Agency (ANVISA, in Portuguese) for their appli- ican Board of Obstetrics and Gynecology, The American College of cation. Since most programs are developed in university Obstetrics and Gynecology. The Obstetrics and Gynecology Milestone hospitals, the protocols must be not only the basis for deci- Project2015http://www.acgme.org/Portals/0/PDFs/Milestones/Obste- sion-making by the professionals involved, but also an instru- tricsandGynecologyMilestones.pdf. Accessed September 12, 2018. ment for professional training, excelling through ethical 9 Romão GS, Reis FJC, Cavalli RC, Silva-de-Sá MF. Matriz de Compe- aspects and the preservation of the relationship between tência em ginecologia e obstetrícia: um novo referencial para os programas de residência médica no Brasil. Femina 2017; professionals and patients. 45:173–177 We recommend, as a model, the recent publication of the 10 Committee on Obstetrics Practice. ACOG Committee Opinion No. 10 ACOG, which is supported by the American College of Nurse- 766: approaches to limit intervention during labor and birth. Midwives (ACOG COMMITTEE OPINION Number 766). After Obstet Gynecol 2019;133(02):e1–e10

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 THIEME 4 Original Article

Association between Dietary Glycemic Index and Excess Weight in Pregnant Women in the First Trimester of Pregnancy Associação entre o índice glicêmico dietético e o excesso de peso em gestantes no primeiro trimestre de gestação

ThaisHelenadePontesEllery1 Helena Alves de Carvalho Sampaio1 Antônio Augusto Ferreira Carioca2 Bruna Yhang da Costa Silva1,3 Júlio Augusto Gurgel Alves4 Fabrício Da Silva Costa5,6 Edward Araujo Júnior7,8 Maria Luísa Pereira de Melo1

1 Group of Research in Nutrition and Chronic Diseases, Universidade Address for correspondence Edward Araujo Júnior, PhD, Escola Estadual do Ceará, Fortaleza, CE, Brazil Paulista de Medicina, Universidade Federal de São Paulo, Rua 2 Department of Nutrition, Universidade de Fortaleza, Fortaleza, Botucatu, 720, 04023-062, Vila Clementino, São Paulo, SP, Brazil Ceará, Brazil (e-mail: [email protected]). 3 Department of Nutrition, Instituto Federal de Educação, Ciência e Tecnologia do Ceará, Limoeiro do Norte, CE, Brazil 4 Department of Maternal and Child, Universidade Federal do Ceará, Fortaleza, Ceará, Brazil 5 Department of Obstetrics and Gynecology, Ribeirão Preto Medical School, Universidade de São Paulo, Ribeirão Preto, SP, Brazil 6 Department of Obstetrics and Gynecology, Monash University, Faculty of Medicine, Nursing and Health Sciences, Clayton, Victoria, Australia 7 Department of Obstetrics, Paulista School of Medicine, Universidade Federal de São Paulo, São Paulo, SP, Brazil 8 Medicine Course, Universidade Municipal de São Caetano do Sul, São Paulo-SP, Brazil

Rev Bras Ginecol Obstet 2019;41:4–10.

Abstract Objective To assess the association between dietary glycemic index (GI) and excess weight in pregnant women in the first trimester of pregnancy. Methods A cross-sectional study in a sample of 217 pregnant women was conducted at the maternal-fetal outpatient clinic of the Hospital Geral de Fortaleza, Fortaleza, state of Ceará, Brazil, for routine ultrasound examinations in the period between 11 and 13 weeks þ 6 days of gestation. Weight and height were measured and the gestational body mass index (BMI) was calculated. The women were questioned about their usual body weight prior to the gestation, considering the prepregnancy weight. The dietary Keywords GI and the glycemic load (GL) of their diets were calculated and split into tertiles. ► pregnancy Analysis of variance (ANOVA) or Kruskal-Walls and chi-squared (χ2) statistical tests were ► glycemic index employed. A crude logistic regression model and a model adjusted for confounding ► glycemic load variables known to influence biological outcomes were constructed. A p-value < 0.05 ► excess weight was considered significant for all tests employed.

ORCID ID is https://orcid.org/0000-0001-7510-0485.

received DOI https://doi.org/ Copyright © 2019 by Thieme Revinter March 19, 2018 10.1055/s-0038-1676096. Publicações Ltda, Rio de Janeiro, Brazil accepted ISSN 0100-7203. October 10, 2018 published online December 12, 2018 Association between Dietary Glycemic Index and Excess Weight in Pregnant Women Ellery et al. 5

Results The sample group presented a high percentage of prepregnancy and gestational overweight(39.7%and40.1%,respectively).InthetertilewiththehigherGIvalue,therewasa lower dietary intake of total fibers (p ¼ 0.005) and of soluble fibers (p ¼ 0.008). In the third tertile, the dietary GI was associated with overweight in pregnant women in the first trimester of gestation, both in the crude model and in the model adjusted for age, total energy intake, and saturated fatty acids. However, this association was not observed in relation to the GL. Conclusion A high dietary GI was associated with excess weight in women in the first trimester of pregnancy.

Resumo Objetivo Avaliar a associação entre índice glicêmico (IG) dietético e presença de excesso de peso em gestantes no primeiro trimestre de gestação. Métodos Estudo transversal realizado com 217 gestantes atendidas no Ambulatório de Medicina Materno-Fetal do Hospital Geral de Fortaleza, Fortaleza, CE, para realização de exames ultrassonográficos de rotina no período entre 11 e 13 semanas e 6 dias de gestação. Peso e altura foram obtidos para o cálculo do índice de massa corporal (IMC) gestacional. As mulheres foram questionadas quanto ao peso corporal habitual anterior à gestação, considerado o peso pré-gestacional. O IG e a carga glicêmica (CG) das suas dietas foram calculados e divididos em tercis. As associações foram investigadas por análise de variância (ANOVA, na sigla em inglês) ou pelos testes Kruskal-Walls e qui-quadrado (χ2). Resultados O grupo tinha alto percentual de excesso de peso pré-gestacional (39,7%) e gestacional (40,1%). Houve menor consumo de fibras totais (p ¼ 0,005) e fibras insolúveis (p ¼ 0,008) no tercil de maior valor de IG. No terceiro tercil, o IG da dieta foi Palavras-chave associadoaoexcessodepesodasmulheresno primeiro trimestre de gestação, tanto no ► gestação modelobrutocomonomodeloajustadoparaidade,consumototaldeenergiaede ► índice glicêmico ácidos graxos saturados. No entanto, não se observou esta associação em relação à CG. ► carga glicêmica Conclusão O alto IG da dieta consumida foi associado ao excesso de peso das ► excesso de peso mulheres no primeiro trimestre da gestação.

Introduction 50 g of carbohydrates of a test-food, expressed as a percentage response to the same quantity of carbohydrate of a – Gestational weight gain is the focus of several studies,1 5 as a standard food, measured in the same individual.10 The – result of the worldwide epidemic of obesity1 3 and its glycemic load (GL) is a measure derived from the quantity importance in gestational outcomes.4,5 Excessive gestational and quality (GI) of dietary carbohydrates.11 weight gain has been associated with increased risk of large High-GI and/or high-GL diets are independently associat- infants for the gestational age (GA), preeclampsia, gestational ed with the development and with the progression of chronic diabetes, cephalopelvic disproportion, trauma, asphyxia, and diseases, particularly those associated with insulin resis- perinatal death.4,5 Excessive gestational weight gain is asso- tance.6,11 The hypothesis that there is an association be- ciated with postpartum weight retention.3 tween overall dietary GI, GL, and disease risk have been In the last few years, the relevance of the dietary glycemic inconsistent with this hypothesis.12,13 index (GI) for the development of obesity has been contro- Therefore, given the importance of the diet to the nutri- – versially debated.6 8 The GI is considered an important tional status and health of pregnant women, the objective of determinant of fasting glucose tolerance and of postprandial the present study was to evaluate the association of dietary – glycemic response.7 9 Mechanisms linking the habitual con- GI and GL during pregnancy with excess weight (overweight sumption of high-GI foods to body composition include and obesity) in women at prepregnancy and during the first reduced satiety signaling, enhanced carbohydrate oxidation, trimester of gestation. and decreased fat oxidation in response to habitual post- 8,9 prandial glycemia and insulinemia. Methods The GI quantifies the glycemic variations in response to the dietary carbohydrate consumption, and is defined as the A cross-sectional study, part of a larger prospective cohort area under the glucose response curve after the intake of entitled “Prediction of preeclampsia using the triple vascular

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test” was conducted at the maternal-fetal outpatient clinic of the Food and Agriculture Organization (FAO)/WHO,22 and the Hospital Geral de Fortaleza, Fortaleza, state of Ceará, the total energy intake/BMR ratio was calculated. Values Brazil. The study was approved by the Local Ethics Commit- < 1.5, which is the reference cutoff point, were considered tee (reference number 050309/09). All of the participants of indicative of under-reporting.23 the present study were informed of the purpose of the study The values for dietary intake and anthropometric varia- and of all the potential risks involved before signing a written bles were split into the GI tertiles. Analysis of variance consent form. (ANOVA) or the Kruskal-Walls and chi-squared (χ2)statistical The sample comprised 217 pregnant women that under- tests were employed. A crude logistic regression model and a went routine ultrasound scans at between 11 and 13 weeks model adjusted for confounding variables known to influ- þ 6 days of gestation. Weight and height were measured ence biological outcomes were constructed. A p-value during pregnancy using a Marte digital anthropometric scale < 0.05 was considered significant for all statistical tests (Marte Científica, São Paulo, SP, Brazil), with a capacity of used. The IBM SPSS for Windows, Version 20.0 (IBM Corp., 200 kg and 2 m, with a sensitivity of 50 g and of 0.50 cm, Armonk, NY, USA) was used for all analyses. respectively. The women were questioned about their usual body weight prior to the gestation, considering the prepreg- Results nancy weight. Their body mass index (BMI) was calculated as their weight in kilograms divided by their height in meters The majority (77.9%) of the participants of the present study squared (kg/m2). The prepregnancy BMI was classified were between 19 and 34 years old, and most patients (67.7%) according to the World Health Organization (WHO)14 criteria were married or living with a partner. The distribution of the as underweight (< 18.5 kg/m2), normal (18.5–24.9 kg/m2), women according to their reported race was predominantly overweight (25.0–29.9 kg/m2) and obese ( 30 kg/m2). The mixed (71.4%) and white (24.4%). The anthropometric data gestational BMI was classified using the table of Atalah from the pregnant women are presented in ►Table 1.The et al.15 Overweight or obese women were grouped together mean prepregnancy BMI of the population studied was into a category named excess weight. 24.5 kg/m2 ( 4.4). The prepregnancy BMIs showed that a Dietary intake data was collected through interviews that high percentage (39.7%) of the patients had excess weight were applied two the 24 hours dietary recall (24hDR) during (overweight and obese). The gestational BMIs (first trimester 2 non-consecutive days, including one weekend day. The of gestation) revealed that 40.1% of the women had excess pregnant women informed their daily food intake from the weight. The mean BMI of the population increased to 25.1 kg/ previous 24 hours in household measures and, subsequently, m2 ( 4.4). Weight gain occurred in most of the women we converted them into grams.16 Dietary data were input to (71.9%), with a mean weight increase of 3.1 kg ( 2.5). the DietWin Profissional 2.0 software (dietWin, Porto Alegre, The relationship between sociodemographic profile, GA, RS, Brazil), which calculated the nutritional composition of BMI, and food consumption with the GI tertiles are shown in the diets, along with the total daily energy intake in kilo- ►Table 2. There was a significant difference in the consump- calories (Kcal). The nutrients consumed were adjusted for tion of total (p ¼ 0.005) and insoluble fibers (p ¼ 0.008), energy using the residual method17 and were expressed in g/ with a lower intake of this nutrient in the highest GI tertile. 1,000 Kcal. The GL varied between the three tertiles (p ¼ 0.002) without Based on the information available for the chemical a specific pattern, but following the variation of carbohy- composition of the diets, the GI was determined using the drates, even though the latter did not give a difference table of Brand-Miller et al.18,19 For foods whose GIs were not between the tertiles. listed in the tables, the value was estimated based on foods with similar characteristics and carbohydrate levels. The daily GI was calculated by multiplying the GI of each food Table 1 Anthropometric assessment at prepregnancy and during (IGf) by the proportion of glycemic carbohydrate in the food the first trimester of pregnancy item (HCOgf ¼ HCOf – total fiber of food) regarding the amount of daily glycemic carbohydrate,P andP summing the Variable n (%) resultant values (daily GI ¼ (GIf x HCOgf)/ HCOgf).The Prepregnancy nutritional diagnosis daily GL was determined by adding the glycemic carbohy- Underweight 9 (4.1) drate of each food, in grams, multipliedP by its individual GI, 20 and dividing it by 100 (daily GL ¼ (GIf x HCOgf) / 100). Normal weight 122 (56.2) The daily GI and GL of each of the two recalls were calculated, Excess weight 86 (39.7) and an arithmetic mean of daily GI and GL for each individual Nutritional diagnosis during pregnancy was obtained. The usual intake of GI and GL was estimated by the multiple source method (MSM) to correct for interper- Underweight 34 (15.7) sonal variability.21 The mean values adjusted by the MSM Normal weight 96 (44.2) were split into tertiles. Excess weight 87 (40.1) In addition, the presence of under-reporting of dietary Total 217 (100.0) intake was analyzed. To this end, the basal metabolic rate (BMR) was estimated using the formulas recommended by Source: Rasmussen et al (2009)14 and Atalah et al (1997).15

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Table 2 Distribution of gestational and dietary intake characteristics according to the glycemic index

Variables GI p-value 54.1–57.4 (n ¼ 72) 57.5–58.2 (n ¼ 73) 58.3–60.5 (n ¼ 72) Dietary intake Energy, Kcal 1,950.7 (553.0) 1,963.7 (629.5) 1,743.6 (682.2) 0.061 Protein, g/1000 Kcal 44.7 (9.9) 41.9 (12.2) 46.1 (12.2) 0.093 Carbohydrate, g/1000 Kcal 128.8 (19.4) 129.1 (20.4) 123.2 (20.9) 0.150 Dietary fiber, g 20.0 (10.5) 19.7 (9.8) 15.1 (6.3) 0.005¥ Soluble fiber, g 6.9 (4.0) 6.4 (3.3) 5.4 (2.7) 0.071 Insoluble fiber, g 9.4 (5.9) 9.7 (6.6) 7.0 (3.7) 0.008¥ Lipids, g/1,000 Kcal 33.8 (6.7) 34.8 (7.3) 35.4 (8.7) 0.435 SFA, g/1,000 Kcal 10.8 (3.2) 9.8 (3.0) 9.8 (3.1) 0.065 PFA, g/1,000 Kcal 6.4 (3.7) 6.6 (3.4) 7.2 (3.7) 0.250¥ MFA, g/1,000 Kcal 8.8 (2.5) 8.6 (3.0) 9.3 (3.4) 0.354 Glycemic load 141.3 (26.1) 143.7 (38.4) 124.5 (32.2) 0.002¥ Energy under-reporting, % 44 (61.1) 49 (67.1) 53 (73.6) 0.279 Socioeconomic profile Age, years old 27.6 (6.3) 27.3 (7.2) 26.8 (6.9) 0.284 Marital Status, married (%) 45 (62.5) 55 (75.3) 47 (65.3) 0.311 Nutritional status Gestational age, weeks 12.6 (0.9) 12.8 (0.8) 12.6 (0.9) 0.307 Prepregnancy BMI,1 kg/m2 24.5 (3.7) 25.2 (4.1) 25.0 (4.6) 0.199 Gestational BMI,2 kg/m2 24.9 (3.2) 25.5 (4.2) 25.8 (4.6) 0.204 Pre-BMI,1 excess weight (%) 26 (36.1) 30 (41.1) 39 (54.2) 0.078 2 Gestational BMI, excess weight (%) 36 (50.6) 37 (50.7) 48 (66.7) 0.074

Abbreviations: BMI, body mass index; g, grams; GI, glycemic index; MFA, monounsaturated fatty acids; PFA, polyunsaturated fatty acids; SFA, saturated fatty acids. Source: #Rasmussen et al (2009)14 and ##Atalah et al (1997).15 ANOVA Test: p < 0.05. ¥Kruskal-Wallis and χ2: p < 0.05.

All of the dietary intake variables and gestational charac- but beginning the pregnancy with excess weight can lead to teristics were tested according to the GI and GL tertiles. an increase in body mass that can affect negatively the health Logistic regression models were constructed showing that of both the mother and the newborn.2,25 the high GI values in the third tertile were associated with Excess weight in the first trimester of pregnancy was excess weight (overweight and obesity) of the pregnant found in 40.1% of the women. This group may have included women in the first trimester in both the crude model and women with excess weight before pregnancy that continued in the model adjusted for age, total energy intake, saturated to gain weight. Excessive gestational weight gain has been fatty acids, and under-reporting. This association was not associated with an increased risk of large infants for the observed for the GL (►Table 3). GA,24,26 preeclampsia, gestational diabetes, cephalopelvic disproportion, trauma, asphyxia, and perinatal death.4,5 Discussion Excessive weight gain can lead to an increased risk of postpartum weight retention, influencing a potential obesity The results of the present study revealed a high rate of excess that may persist or worsen during the lifetime of the wom- weight (overweight and obesity) before pregnancy, showing an.1,27 Mattar et al1 observed that 50% of the overweight or the need for continuous monitoring of weight and food obese women had a higher than recommended weight gain, consumption.3,15 Adequate weight gain and nutrient intake and that > 70% of them maintained the excessive weight up to are fundamental for the gestational period, preventing com- 12 months postpartum, and 30% had a retention of 10 kg. plications in pregnancy outcomes.4,5,24 Prepregnancy excess Our results showed a greater risk of overweight in indi- weight is a risk factor for overweight and obesity during viduals who consumed diets with a higher GI. Sampaio et al6 pregnancy. Pregnant women gain weight during this period observed the consumption of foods with a high or moderate

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Table 3 Odds ratio of gestacional body mass index according the tertiles of glycemic index and glycemic load adjusted by the multiple source method

Gestational BMI (with and without excess weight) Crude model Model 1 Model 2 OR (95% CI) OR (95% CI) OR (95% CI) GI MSM 1st tertile (54.1–57.4) 1.00 1.00 1.00 2nd tertile (57.5–58.2) 1.028 (0.536–1.971) 0.992 (0.504–1.955) 0.993 (0.494–1.996) 3rd tertile (58.3–60.5) 2.000 (1.020–3.922) 1.988 (0.981–4.029) 2.204 (1.064–4.567) p-value 0.045 0.059 0.034 GL MSM 1st tertile (52.9–119.7) 1.00 1.00 1.00 2nd tertile (120.9–146.1) 1.147 (0.592–2.223) 1.216 (0.566–2.611) 1.201 (0.552–2.614) 3rd tertile (148.4–307.0) 0.756 (0.392–1.458) 1.149 (0.446–2.961) 1.645 (0.583–4.644) p-value 0.402 0.764 0.354

Abbreviations: BMI, body mass index; CI, conﬁdence interval; GI, glycemic index; GL, glycemic load; MSM, multiple source method; OR, odds ratio. First trimester; Adjusted for age (tertile) and total energy intake (tertile); Adjusted for age (tertile), total energy intake (tertile), saturated fatty acids (tertiles), and under-reporting (yes or no).

GI in 78.7% of an obese group, highlighting a high percentage GL quantifies the total effect of a given amount of carbohy- of individuals who consumed diets with inadequate GI at drate on plasma glucose, representing the GI product of a breakfast (82.9%), at afternoon snacks (60.0%), and at dinner food by its available carbohydrate content.7 The GL can (64.6%). provide a better reflection of the glycemic response of a The GI quantifies the glycemic variations in response to specific food than the GI. The glycemic effect of foods varies the dietary carbohydrate consumption. When diets with with the composition of the food and with the methods of high GI are consumed, a glycemic increase occurs due to preparation.7,20 In addition, under-reporting was found in the high level of glucose, leading to hyperinsulinemia.28 53% of the pregnant women, which directly impacts the GL Different sources of carbohydrates have varying absorption values. Usually, women with excess weight tend to not fully rates, and their effects on plasma concentrations of glucose disclose their food intake for several reasons, including fear and insulin vary accordingly.29,30 In the present study, both of exposing their poor eating habits.34 the intake of total fiber as well as of the insoluble fiber The level of GI necessary to affect body composition declined by the tertile. Diets containing a higher level of fiber remains unclear. Further elucidation of the mechanisms asso- retard the absorption of glucose by the organism, avoiding a ciated with the potential benefits of consuming carbohydrates, rapid increase in blood glucose and reducing the release of as measured by GI values, is essential before introducing this as insulin by the pancreas.7,30 a strategy for controlling obesity and its comorbidities, partic- Postprandial glycemia is modulated mainly by the speed ularly during pregnancy, when weight gain can be expected. of release of carbohydrates derived from the diet into the Moses et al32 found no significant differences in fetal and bloodstream after meals, by the clearance time of the obstetric outcomes between subjects who followed a low-GI carbohydrates through insulin secretion, and by peripheral diet versus a higher-GI diet. A randomized controlled trial35 tissue sensitivity to the action of this hormone.20,29 Thus, the reported no difference in birth weight of newborns of mothers type and amount of dietary carbohydrates are key factors consuming a low-GL diet, whereas the gestational period was that influence the glycemic response.30,31 Studies have 10 days longer in the same group, suggesting that this type of shown that pregnant women receiving advice and encour- diet may be an important factor for preventing prematurity. A agement to consume a low-GI diet have longer gestational meta-analysis that assessed 7 maternal and 11 newborn out- periods,32,33 as well as fewer preterm births, although no comes observed that low-GI diets may have beneficial effects effects of these diets on infant birth weight have been found on maternal outcomes for those at risk of developing high in groups at risk of macrosomia.33 glucose levels, without causing adverse effects on newborn Another aspect to consider is the GL, which is calculated outcomes.36 by multiplying the GI of foods by their glycemic carbohydrate content and reflects directly the quantity and quality of Conclusion dietary carbohydrates.7,10 The GL is one of the most representative characteristics of the overall diet because it indi- Based in the results of the present study, it can be concluded cates the dietary fiber intake.9,10 No difference was observed that high-GI diets were associated with excess weight in among the GL values in the GI tertiles, probably because the pregnant women in the first trimester of gestation.

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Therefore, individualized nutritional consultations are rec- 12 Nadeau KJ, Anderson BJ, Berg EG, et al. Youth-onset type 2 ommended in this group to promote dietary improvements. diabetes consensus report: current status, challenges, and prio- rities. Diabetes Care 2016;39(09):1635–1642 Doi: 10.2337/dc16- Contributors 1066 13 Giugliano D, Maiorino MI, Bellastella G, Esposito K. Comment on Ellery T. H. P., Sampaio H. A. C., Carioca A. A. F., Silva B. Y. C., American Diabetes Association. Approaches to Glycemic Treat- Alves J. A. G., Costa F. S., Araujo Júnior E. and Melo M. L. P. ment. Sec. 7. In Standards of Medical Care in Diabetes-2016. contributed with the project, the interpretation of data, Diabetes Care 2016;39(Suppl. 1):S52-S59. Diabetes Care 2016;39 the writing of the article, the critical review of the (06):e86–e87 Doi: 10.2337/dc15-2829 intellectual content, and with the final approval of the 14 Rasmussen KM, Yaktine AL. Institute of Medicine, National Research Council, Committee to Reexamine IOM Pregnancy version to be published. Weight Guidelines. Weight Gain During Pregnancy: Reexamin- ing the Guidelines. Washington, DC: National Academies Press; Conflicts of Interest 2009 The authors have no conflicts of interest to declare. 15 Atalah E, Castillo C, Castro R, Aldea A. [Proposal of a new standard for the nutritional assessment of pregnant women]. Rev Med Chil Acknowledgments 1997;125(12):1429–1436 The authors are grateful for the support of Coordenação de 16 Pinheiro ABV, Lacerda EMA, Benzecry EH, Gomes MCS, Costa VM. Tabela para Avaliação de Consumo Alimentar em Medidas Case- Aperfeiçoamento de Pessoal de Nível Superior (CAPES), iras. 5a ed. São Paulo, SP: Atheneu; 2008 ’ through the scolarship during the master s degree, to the 17 Willett WC, Howe GR, Kushi LH. Adjustment for total energy pregnant women and to the General Hospital of Fortaleza. intake in epidemiologic studies. Am J Clin Nutr 1997;65(4, Suppl) 1220S–1228S, discussion 1229S–1231S Doi: 10.1093/ajcn/ 65.4.1220S References 18 Brand-Miller J, Nantel G, Slama G, Lang V. Glycaemic Index and 1 Mattar R, Torloni MR, Betrán AP, Merialdi M. [Obesity and Health: the Quality of the Evidence. Paris: John Libbey Eurotex; pregnancy]. Rev Bras Ginecol Obstet 2009;31(03):107–110 Doi: 2001 10.1590/S0100-72032009000300001 19 Brand-Miller J, Foster-Powell K, Atkinson F. The Shopper’s Guide 2 Carvalhaes MA, Gomes CdeB, Malta MB, Papini SJ, Parada CM. to GI Values: The Authoritative Source of Glycemic Index Values [Prepregnancy overweight is associated with excessive weight for More Than 1,200 Foods. Boston, MA: Da Capo; 2015 gain during pregnancy]. Rev Bras Ginecol Obstet 2013;35(11): 20 Lau C, Faerch K, Glümer C, et al; Inter99 study. Dietary glycemic 523–529 Doi: 10.1590/S0100-72032013001100008 index, glycemic load, fiber, simple sugars, and insulin resistance: 3 Nast M, de Oliveira A, Rauber F, Vitolo MR. [Excessive gestational the Inter99 study. Diabetes Care 2005;28(06):1397–1403 weight gain is risk factor for overweight among women]. Rev Bras 21 Harttig U, Haubrock J, Knüppel S, Boeing H; EFCOVAL Consortium. Ginecol Obstet 2013;35(12):536–540 Doi: 10.1590/S0100- The MSM program: web-based statistics package for estimating 72032013001200002 usual dietary intake using the Multiple Source Method. Eur J Clin 4 Vernini JM, Moreli JB, Magalhães CG, Costa RAA, Rudge MVC, Nutr 2011;65(Suppl 1):S87–S91 Doi: 10.1038/ejcn.2011.92 Calderon IMP. Maternal and fetal outcomes in pregnancies com- 22 FAO/WHO. Human Energy Requirements: Report of a Joint FAO/ plicated by overweight and obesity. Reprod Health 2016;13(01): WHO/UNU Expert Consultation. Rome: Food and Agriculture 100–119 Doi: 10.1186/s12978-016-0206-0 Organization; 2004 5 Khan MN, Rahman MM, Shariff AA, Rahman MM, Rahman MS, 23 Goldberg GR, Black AE, Jebb SA, et al. Critical evaluation of energy Rahman MA. 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Boston, MA: Da and glycemic load on blood glucose and insulin responses in Capo; 1999 humans. Nutr J 2006;5:22 Doi: 10.1186/1475-2891-5-22 11 Atkinson FS, Foster-Powell K, Brand-Miller JC. International tables 29 DeFronzo RA, Ferrannini E. Influence of plasma glucose and of glycemic index and glycemic load values: 2008. Diabetes Care insulin concentration on plasma glucose clearance in man. Dia- 2008;31(12):2281–2283 Doi: 10.2337/dc08-1239 betes 1982;31(8 Pt 1):683–688 Doi: 10.2337/diab.31.8.683

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30 Sheard NF, Clark NG, Brand-Miller JC, et al. Dietary carbohydrate study): randomised control trial. BMJ 2012;345:e5605 Doi: (amount and type) in the prevention and management of dia- 10.1136/bmj.e5605 betes: a statement by the american diabetes association. Diabetes 34 Hill RJ, Davies PSW. The validity of self-reported energy intake as Care 2004;27(09):2266–2271 Doi: 10.2337/diacare.27.9.2266 determined using the doubly labelled water technique. Br J Nutr 31 McGowan CA, McAuliffe FM. The inﬂuence of maternal glycaemia 2001;85(04):415–430 Doi: 10.1079/BJN2000281 and dietary glycaemic index on pregnancy outcome in healthy 35 Rhodes ET, Pawlak DB, Takoudes TC, et al. Effects of a low- mothers. Br J Nutr 2010;104(02):153–159 Doi: 10.1017/ glycemic load diet in overweight and obese pregnant women: a S0007114510000425 pilot randomized controlled trial. Am J Clin Nutr 2010;92(06): 32 Moses RG, Luebcke M, Davis WS, et al. Effect of a low-glycemic- 1306–1315 Doi: 10.3945/ajcn.2010.30130 index diet during pregnancy on obstetric outcomes. Am J Clin 36 Zhang R, Han S, Chen GC, et al. Effects of low-glycemic-index diets Nutr 2006;84(04):807–812 Doi: 10.1093/ajcn/84.4.807 in pregnancy on maternal and newborn outcomes in pregnant 33 Walsh JM, McGowan CA, Mahony R, Foley ME, McAuliffe FM. Low women: a meta-analysis of randomized controlled trials. Eur J glycaemic index diet in pregnancy to prevent macrosomia (ROLO Nutr 2018;57(01):167–177 Doi: 10.1007/s00394-016-1306-x

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 THIEME Original Article 11

Accuracy of Prenatal Diagnosis of Congenital Cardiac Malformations Acurácia do diagnóstico pré-natal de cardiopatias congênitas

Diesa Oliveira Pinheiro1 Bruna Boff Varisco1 Marcelo Brandão da Silva2 Rafaela Silva Duarte1 Graciele Dequi Deliberali1 Carlos Roberto Maia1 Mirela Foresti Jiménez1 Patrícia El Beitune1

1 Department of Postgraduate Program and Obstetrics and Address for correspondence Patrícia El Beitune, PhD, Departamento Gynecology, Universidade Federal de Ciências da Saúde de Porto de Pós-Graduação em Obstetrícia e Ginecologia, Universidade Federal Alegre, Porto Alegre, RS, Brazil deCiênciasdaSaúdedePortoAlegre,RuaSarmentoLeite245,90050- 2 Fetal Medicine and Fetal Echocardiography Services, Irmandade 170, Porto Alegre, RS, Brazil (e-mail: [email protected]). Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, RS, Brazil

Rev Bras Ginecol Obstet 2019;41:11–16.

Abstract Objective To evaluate the accuracy of the diagnosis of fetal heart diseases obtained through ultrasound examinations performed during the prenatal period compared with the postnatal evaluation. Methods A retrospective cohort study with 96 pregnant women who were attended at the Echocardiography Service and whose deliveries occurred at the Complexo Hospitalar Santa Casa de Porto Alegre, in the state of Rio Grande do Sul, Brazil. Risk factor assessment plus sensitivity and specificity analysis were used, comparing the accuracy of the screening for congenital heart disease by means of obstetrical ultrasound and morphological evaluation and fetal echocardiography, considering p < 0.05 as significant. The present study was approved by the Research Ethics Committee of the Institution. Results The analysis of risk factors shows that 31.3% of the fetuses with congenital heart disease could be identified by anamnesis. The antepartum echocardiography demonstrated a sensitivity of 97.7%, a specificity of 88.9%, and accuracy of 93% in the diagnosis of congenital heart disease. A sensitivity of 29.3% was found for the obstetric ultrasound, of 54.3% for the morphological ultrasound, and of 97.7% for the fetal echocardiography. The fetal echocardiography detected fetal heart disease in 67.7% of the cases, the morphological ultrasound in 16.7%, and the obstetric ultrasound in 11.5% of the cases. Keywords Conclusion There is a high proportion of congenital heart disease in pregnancies with ► fetal heart disease no risk factors for this outcome. Faced with the disappointing results of obstetric ► fetal ultrasound for the detection of congenital heart diseases and the current unfeasibility echocardiography of universal screening of congenital heart diseases through fetal echocardiography, the ► morphological importance of the fetal morphological ultrasound and its performance by qualified sonography professionals is reinforced for a more appropriate management of these pregnancies.

ORCID ID is https://orcid.org/0000-0003-0431-0690.

received DOI https://doi.org/ Copyright © 2019 by Thieme Revinter April 7, 2018 10.1055/s-0038-1676058. Publicações Ltda, Rio de Janeiro, Brazil accepted ISSN 0100-7203. October 1, 2018 published online December 14, 2018 12 Accuracy of Prenatal Diagnosis of Congenital Cardiac Malformations Pinheiro et al.

Resumo Objetivo Avaliar a acurácia do diagnóstico de cardiopatias congênitas obtidos por meio das ecografias realizadas durante o pré-natal comparativamente à avaliação pós- natal. Métodos Estudo de coorte retrospectivo com 96 gestantes atendidas no Serviço de Ecocardiografia cujos partos ocorreram no Complexo Hospitalar Santa Casa de Porto Alegre, RS, Brasil. Utilizou-se a avaliação de fatores de risco e a análise de sensibilidade e especificidade, comparando-se a acurácia do rastreamento de cardiopatia congênita por meio da ecografia obstétrica, da avaliação morfológica e da ecocardiografia fetal, considerando-se como significativo um p < 0,05. O referido estudo foi aprovado pelo Comitê de Ética em Pesquisa da Instituição. Resultados A análise de fatores de risco demonstra que 31,3% dos fetos com cardiopatia congênita poderiam ser identificados pela anamnese. As ecografias anteparto possuem sensibilidade de 97,7%, especificidade de 88,9% e acurácia de 93,0% no diagnóstico da cardiopatia congênita. Ao se analisar cada tipo de ecografia separadamente, encontrou-se sensibilidade de 29,3% para a ecografiaobstétrica,de 54,3% para ecografia morfológica, e de 97,7% para ecocardiografia fetal. A ecocardiografia fetal definiu a cardiopatia fetal em 67,7% dos casos, a ecografiamorfológicaem 16,7%, e a ecografia obstétrica em 11,5%. Conclusão Demonstra-se uma elevada proporção de cardiopatia congênita em Palavras-chave gestações sem fatores de risco para esse desfecho. Frente aos resultados desanima- ► cardiopatia fetal dores da ecografia obstétrica para a detecção de cardiopatias congênitas e na atual ► ecocardiografia inviabilidade de rastreamento universal de cardiopatias congênitas por meio da fetal ecocardiografia fetal, reforça-se a importância da ecografia morfológica fetal e sua ► ecografia realização por profissionais qualificados para esse fimdeformaapermitiromanejo morfológica mais adequado destas gestações.

Introduction cardiologic anomalies in between 40 and 50% of the cases. Congenital cardiopathies are the most frequent malforma- Other factors, such as a metabolic disorder in the mother or a tions related to morbidity and mortality during infancy.1 family history of congenital cardiac disease are also reasons They present an incidence estimated at between 6 and 12 to perform the specific screening exam.2 In addition, the in each 1,000 newborns.2 The treatment of these malforma- effects of environmental exposures to elements such as tions represents the highest hospital cost for congenital lithium, alcohol and cigarette smoke may compromise the diseases in first world countries.1 Half of the incidence is development of the vascular system that, according to ani- formed by “minor” cardiopathies, considered not severe, mal-based hemodynamic studies performed on vitelline and being easily corrected through interventional catheteriza- placental circulations, had demonstrated a relationship with tion or surgery, and the other half by “major” cardiopathies, changes in normal heart and vascular development.5 defined as those that need surgical intervention in the first In the course of the last decade, there was an increase in year of life, being responsible for more than 50% of the deaths the prevalence of congenital cardiopathy diagnosed during due to congenital anomalies during infancy.3 A study con- prenatal period, especially due to the improvement of obste- ducted by Moons et al4 describes an incidence of 8.3% in tric screening.6 The diagnosis of congenital cardiopathy newborns and stillborns with a gestational age 26 weeks during prenatal is considered beneficial for the neonate, and without chromosomic alterations.4 allowing the preparation of the team and the immediate The indications for fetal echography are intimately related delivery of the newborn to specialized pediatric medical to the recognition of possible etiologic factors and of risk assistance, therefore decreasing the morbidity that occurs groups for congenital cardiopathy.2,3 because of metabolic alterations, acidosis, hypoxemia, and A vast number of factors is associated with the augmented target organ damage, besides preventing major emotional risk of the presence of a congenital cardiopathy, such as trauma in the parents, providing them with enough time to family history of cardiopathy, maternal diseases and/or fetal understand the disease and with a clear and real idea of the conditions. The main indication for echocardiographic fetal prognosis of the fetus.7 evaluation is the suspicion of structural abnormality in the Considering the importance of the prenatal cardiac diag- obstetric echography, which performs the diagnosis of fetal nosis, our study has the objective to evaluate the accuracy of

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 Accuracy of Prenatal Diagnosis of Congenital Cardiac Malformations Pinheiro et al. 13 echography scans performed during prenatal period in rela- anomalies, analyzing the accuracy according to the image tion to the outcomes found as neonatal cardiopathies. method that was used, either a conventional obstetric echography or a morphologic study, evaluating the agreement Methods between the diagnostic methods through the kappa coefficient. The association among the variables was evaluated by This is a study of a retrospective cohort with pregnant the Pearson chi-squared test. Values of p < 0.05 were con- women attended at the Irmandade Santa Casa de Porto sidered statistically significant. Alegre (ISCMPA, in the Portuguese acronym), in the Echo- cardiography Service at the Santo Antônio Hospital, in Porto Results Alegre, state of Rio Grande do Sul, Brazil, between March 2013 and December 2015, with data collected from Considering the analysis of risk factors, 20.8% of the eval- electronic records. The study was approved by the ethics uated expectant mothers were of advanced maternal age, of committee of the Institution/Brazil Platform, under the which 8.4% presented diabetes mellitus, while 2.1% pre- supervision of the Universidade Federal de Ciências da Saúde sented an obstetric or familial history of cardiopathy. As to de Porto Alegre (UFCSPA, in the Portuguese acronym) (pro- the moment of diagnosis, the cardiopathies were identified tocol n° 1375733), accepted in November 2015. in the second trimester of the pregnancy in 35.4% of the The study group comprised fetuses with altered exams, in cases, and in the third trimester in 64.6% of the cases. There which were included all cases of fetal cardiopathies diag- was an association with other non-cardiac malformations in nosed during the period covered by the research, amounting 30.2% of the cases. In 17.7% of the cardiopathy cases, the an initial sample of 148 cases. Obstetric or morphological pregnant women suffered from diabetes mellitus (DM), ultrasound was performed before the fetal echocardiogra- considering that, of these, 17.6% were type I; 29.4% suffered phy, and there was no influence of the echocardiography on from DM type II, and 52.9% suffered from gestational DM. The the obstetric or morphological ultrasound in the diagnosis of association between DM and other non-cardiac malforma- congenital cardiac malformation. The exclusion criteria were tions was not significant. ►Table 1 demonstrates the char- births outside the maternity of the hospital, twin gestations, acteristics of the study group according to the risk factors in and stillborn fetuses, with 52 cases excluded. Only the which the echocardiography was performed. From the 96 newborns who underwent neonatal exams in the hospital cases studied, 35 evolved to death after birth, bearing in were included. Neonatal echocardiography was considered mind that 82.9% of these deaths were caused by the cardio- the gold standard for congenital cardiopathy. The final pathy. Among the patients that passed away, the cardiopa- sample comprised 96 expecting women in the study group. thies were complex, the majority with multiple cardiac Other 90 pregnant women were included to form the control malformations (31%), hypoplasia of the left ventricle group, who underwent fetal echocardiography with normal (17.2%), and great vessels transposition (13.7%). results, to evaluate accuracy. The fetal and neonatal echo- Our study showed a sensitivity of 97.7%, a specificity of cardiography exams were performed by pediatric specialists 88.9%, and an accuracy of 93.0% in the diagnosis of congenital in fetal and neonatal echocardiography in the institution. cardiopathy during the prenatal period. Ninety-six percent of Other obstetric and morphologic exams came from several the pregnant women of the study underwent at least one places, such as clinics and public and private hospitals. obstetric echography, but only 36.5% underwent a morpholo- The study compared the diagnosis obtained through fetal gical echography. While analyzing each type of echography echography with the final diagnosis determined after birth, separately, we found a sensitivity of 29.3% for the obstetric obtaining through these analyses the accuracy of the ultra- echography, of 97.7% for the morphologic echography, and of sonography for diagnosing congenital cardiopathy, as well as 97.7% for the fetal echocardiography (p < 0.05). evaluating the frequency and the type of alterations that were found. Table 1 Characteristics of the study group according to the risk The estimates of the sample size were calculated using the factors in which the echocardiography was performed software WinPEPI (Programs for Epidemiologists for Win- Risk factors n (%) dows), version 11.43 (Brixton Health, Llanidloes, United King- dom, Wales), and were based on studies by Wald et al (2007)8 Advanced maternal age 20 (20.8) 9 fi and by Durand et al (2015). For a con dence level of 95%, and Diabetes 17 (17.7) an error margin of 10%, the minimum necessary total of 96 DM 1 (17.6) exams was obtained. The data analysis was made in IBM SPSS Statistics for DMG (52.9) Windows, Version 21.0 (IBM Corp, Armonk, NY, USA). The DM 2 (29.4) quantitative variables were described by average and stan- Cardiopathy in the family 2 (2.1) dard deviation (SD) or by median and interquartile range, Neonatal mortality 35 (36.5) and the qualitative variables through absolute and relative frequencies. The incidence was identified, with a confidence Associated non-cardiac malformation 29 (30.2) interval (CI) of 95% for the estimation of the population and Abbreviations: DM1, diabetes mellitus type 1; DM2, diabetes mellitus sensibility for each specific type of identified congenital type 2; DMG, gestational diabetes mellitus.

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 14 Accuracy of Prenatal Diagnosis of Congenital Cardiac Malformations Pinheiro et al.

Table 2 Characteristics of study group according to cardiopathies cardiopathy stand out. Our study shows that a high proportion identified in newborns of congenital cardiopathy cases detected in the prenatal period is diagnosed in women who do not present the known risk Cardiopathies identified in newborns n (%) factors.7 This finding corroborates to the performance of fetal Multiple cardiac malformations 21 (21.9) echocardiographic exams for the general population of preg- fi Hypoplastic left heart syndrome 14 (14.5) nant women despite the evidence yet insuf cient to include this conduct during prenatal period.18 Transposition of the great vessels 11 (11.5) The importance of the prenatal diagnosis is also shown in Tetralogy of Fallot 9 (9.4) the number of newborns that went to the neonatal ICU (87%), Atrioventricular septal defect 7 (7.3) plus the necessity of surgery (50%), allowing a better organiza- 1 Pulmonary valve atresia 4 (4.2) tion before the birth when the diagnosis is already known. Obstetric echography is not considered the ideal exam for Hypoplastic right heart syndrome 4 (4.2) detecting cardiopathies because a large number of cases is Aortic stenosis 2 (2.1) not detected through this exam.19 The low rate of detection Ebstein anomaly 2 (2.1) of cardiopathies in obstetric ultrasounds is found in other 20 Hypertrophic cardiomyopathy 2 (2.1) revisions, as cited by Khoo et al in their Australian study, in Ã which the detection of cardiac malformation in the obstetric Others 9 (9.4) ÃÃ Normal 11 (11.4) exam was of 22.5%, considering that, in this study, 96% of the patients underwent at least one obstetric echography. This Ã Others include one case for each of the cardiac pathologies listed below: same conclusion was reached in the United States, in Ohio, coarctation of the aorta, constriction of ductus arteriosus, cardiac tumor, where the rates of cardiac anomalies detection were < 50% ventricular septal defect, pulmonary stenosis, left isomerism, atrioventri- ÃÃ 21 cular block, common arterial trunk, Taussig-Bing anomaly; Congenital with obstetric echography. Previous studies emphasize the heart disease was not confirmed after birth (5 constriction of ductus importance of routine fetal tracking for cardiopathy through arteriosus, 4 ventricular septal defect, 1 coarctation of the aorta and 1 fetal echocardiography due to the fact that this exam is more – – – hypertrophic cardiomyopathy). sensitive and specific,1 8,11 14,22 26 which is in line with what has been found in our study, in which the sensitivity of The fetal echocardiography contributed to the diagnosis of fetal echocardiography was superior to other ultrasounds. the cardiopathy in 67.7% of the cases, the morphologic Despite the recommendation of the American Institute of echography in 16.7%, and the obstetric echography in Ultrasound in Medicine27 for sonographic cardiac screening 11.5% of the cases. The most frequent prenatal diagnosed examination including four-chamber view, left and right ven- pathologies were multiple cardiac malformations (18.8%), tricular outflow tracts, the report of the sonographic exam- major vessels transposition (11.5%), hypoplasia of the left ination should also document the nature of eventual technical ventricle (11.5%), tetralogy of Fallot (9.4%), atrioventricular limitations, such as increased maternal abdominal wall thick- septum defect (7.3%), and constriction of the arterial canal ness. We are not sure how the sonographic cardiac screening (6.3%). ►Table 2 demonstrates the characteristics of the examinationwasperformed, if it included in fact four-chamber study group according to the cardiopathies identified in view and ventricular outflow tracts. In general, obstetric the postnatal echocardiography. echography has a summarized description of the ultrasound report. This data is important because it actually expresses the Discussion real way how the description of the sonographic cardiac screening is obtained in the majority of the obstetric exams Nowadays, the indications to perform a fetal echocardiogra- in the daily assistance, which, in spite of its evolution in the last phy are restricted to some situations considered of risk. decade, it is still far from the ideal. However, the prenatal diagnosis of cardiopathies is of para- Our observation is similar to what has been reported in a mount importance to enable a better monitoring of the fetus, recent article that concludes that, despite revised obstetrical allowing to plan the birth of the cardiopathic fetus in a center guidelines highlighting the importance of outflow tract – – of reference, improving the survival of the newborn.1 3,10 14 imaging, referrals and prenatal diagnosis of these types of Studies have shown that there is a better survival rate after critical congenital heart disease remain low. Education of the surgical correction of the cardiopathy when the diagnosis obstetrical sonographers and practitioners who perform of the anomalies is performed during the pregnancy instead fetal anatomic screening is vital to increase referrals and of during the postnatal period.15,16 There is proof of a prenatal detection of critical outflow tract anomalies.28 decrease in costs considering the necessity of transportation In the present study, differently from international stu- to the intensive care unit (ICU) and the plan to use prosta- dies, the cardiac malformation diagnosis in most cases was glandin, which is highly utilized for opening the arterial obtained in the third trimester, which was possibly a reflex of canal.17 Other possible advantage comprises the prevention the health conditions in our region, where echography is of trauma in parents who need time to understand the performed later on, as well as the pregnancy diagnosis, also physiopathology of the disease and its outcome.7 making it difficult the access to tertiary services. Among the risk factors of congenital cardiopathy, advanced The detection rates of cardiopathies in routine obstetric age of the mother, use of medication, maternal or familial exams are low. However, fetal echocardiography is a

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 Accuracy of Prenatal Diagnosis of Congenital Cardiac Malformations Pinheiro et al. 15 sensitive and specific tool for the detection of these pathol- References ogies. Based on these findings, we stress the importance of a 1 Lopes L. Ecocardiografia Fetal. Rio de Janeiro, RJ: Revinter; 2016. detailed fetal morphological exam in an audited service, with 2 Donofrio MT, Moon-Grady AJ, Hornberger LK, et al; American properly trained echographists enabled to ratify the fetal Heart Association Adults With Congenital Heart Disease Joint Committee of the Council on Cardiovascular Disease in the Young echocardiography whenever facing an unsatisfactory exam and Council on Clinical Cardiology, Council on Cardiovascular during the prenatal evaluation, in order to facilitate the Surgery and Anesthesia, and Council on Cardiovascular and Stroke optimization in the rate detection of congenital fetal cardio- Nursing. 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Outcome after prenatal according to the following subdivision: high risk when the diagnosis of tricuspid atresia: a multicenter experience. Am Heart absolute risk is estimated > 2%, low risk when the absolute J 2007;153(05):772–778 risk is estimated between 1 and 2%, and absence of risk when 9 Durand I, Deverriere G, Thill C, et al. Prenatal detection of the absolute risk is < 1%, without indication for fetal echo- coarctation of the aorta in a non-selected population: a prospective analysis of 10 years of experience. Pediatr Cardiol 2015;36 cardiography in the last case.2 (06):1248–1254 In addition, according to updated guidelines, a fetal echo- 10 Crawford DC, Chita SK, Allan LD. Prenatal detection of congenital cardiogram should be performed if congenital heart defect is heart disease: factors affecting obstetric management and survi- suspected, if the normal four-chamber and outflow tract val. Am J Obstet Gynecol 1988;159(02):352–356 views cannot be obtained at the time of screening, or if 11 D’Alton ME, DeCherney AH. Prenatal diagnosis. N Engl J Med – recognized risk factors indicate an increased risk of conge- 1993;328(02):114 120 12 Obu HA, Chinawa JM, Uleanya ND, Adimora GN, Obi IE. Congenital nital cardiac anomalies.29 malformations among newborns admitted in the neonatal unit of a tertiary hospital in Enugu, South-East Nigeria–a retrospective Conclusion study. BMC Res Notes 2012;5:177 13 Ali A, Zahad S, Masoumeh A, Azar A. Congenital malformations In conclusion, based on the results shown in the present among live births at Arvand Hospital, Ahwaz Iran – a prospective – study, we highlight the limitation of screening based on a study. Pak J Med Sci 2008;24:33 37 14 Jaeggi ET, Sholler GF, Jones OD, Cooper SG. Comparative analysis strategy of risk factor evaluation for congenital cardiopathy of pattern, management and outcome of pre- versus postnatally to indicate fetal echocardiography, as well as discouraging diagnosed major congenital heart disease: a population-based results of exclusive monitoring through obstetric echogra- study. Ultrasound Obstet Gynecol 2001;17(05):380–385 phy, becoming morphological echography a better option 15 Tworetzky W, McElhinney DB, Reddy VM, Brook MM, Hanley FL, with eventual complementation by mean of fetal echocar- Silverman NH. Improved surgical outcome after fetal diagnosis of diography, in face of unsatisfactory results obtained in the hypoplastic left heart syndrome. Circulation 2001;103(09): 1269–1273 revision of fetal anatomy in a way that allows the adequate 16 Verheijen PM, Lisowski LA, Stoutenbeek P, et al. Prenatal diagnosis management of these gestations. of congenital heart disease affects preoperative acidosis in the newborn patient. J Thorac Cardiovasc Surg 2001;121(04): Contributors 798–803 Pinheiro D. O., Varisco B. B., Silva M. B., Duarte R. S., 17 Friedberg MK, Silverman NH, Moon-Grady AJ, et al. Prenatal detection of congenital heart disease. J Pediatr 2009;155(01): Deliberali G. D., Maia C. R., Jiménez M. F., and El Beitune 26–31, 31.e1 P. designed the study, analyzed and interpreted the data, 18 Randall P, Brealey S, Hahn S, Khan KS, Parsons JM. Accuracy of fetal wrote the article and approved the final version of the echocardiography in the routine detection of congenital heart manuscript for publication. disease among unselected and low risk populations: a systematic review. BJOG 2005;112(01):24–30 19 Buskens E, Grobbee DE, Frohn-Mulder IM, et al. Efficacy of routine Conflicts of Interest fetal ultrasound screening for congenital heart disease in normal The authors have no conflicts of interest to declare. pregnancy. Circulation 1996;94(01):67–72

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20 Khoo NS, Van Essen P, Richardson M, Robertson T. Effectiveness of 25 Queisser-Luft A, Stolz G, Wiesel A, Schlaefer K, Spranger J. Mal- prenatal diagnosis of congenital heart defects in South Australia: a formations in newborn: results based on 30,940 infants and population analysis 1999-2003. Aust N Z J Obstet Gynaecol 2008; fetuses from the Mainz congenital birth defect monitoring system 48(06):559–563 (1990-1998). Arch Gynecol Obstet 2002;266(03):163–167 21 Sekar P, Heydarian HC, Cnota JF, Hornberger LK, Michelfelder EC. 26 Trines J, Hornberger LK. Evolution of heart disease in utero. Diagnosis of congenital heart disease in an era of universal Pediatr Cardiol 2004;25(03):287–298 prenatal ultrasound screening in southwest Ohio. Cardiol Young 27 American Institute of Ultrasound in Medicine. AIUM practice 2015;25(01):35–41 guideline for the performance of obstetric ultrasound examina- 22 Sandor GG, Farquarson D, Wittmann B, Chow TC, Lau AE. Fetal tions. J Ultrasound Med 2013;32(06):1083–1101 echocardiography: results in high-risk patients. Obstet Gynecol 28 Sun HY, Proudfoot JA, McCandless RT. Prenatal detection of 1986;67(03):358–364 critical cardiac outﬂow tract anomalies remains suboptimal 23 Richmond S, Atkins J. A population-based study of the prenatal despite revised obstetrical imaging guidelines. Congenit Heart diagnosis of congenital malformation over 16 years. BJOG 2005; Dis 2018;•••:; 112(10):1349–1357 29 Carvalho JS, Allan LD, Chaoui R, et al; International Society of 24 Rajangam S, Devi R. Consanguinity and chromosomal abnorm- Ultrasound in Obstetrics and Gynecology. ISUOG Practice Guide- ality in mental retardation and or multiple congenital anomaly. lines (updated): sonographic screening examination of the fetal J Anat Soc India 2007;56:30–33 heart. Ultrasound Obstet Gynecol 2013;41(03):348–359

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 THIEME Original Article 17

Assessment of Sensitivity and Specificity of Ultrasound and Magnetic Resonance Imaging in the Diagnosis of Placenta Accreta Avaliação da sensibilidade e especificidade da ultrassonografiaeressonânciamagnéticano diagnóstico da placenta acreta

Elisa Santos Lopes1 Francisco Edson de Lucena Feitosa1 Antonio Viana Brazil1 José Daniel Vieira de Castro1 Jesus Irajacy Fernandes da Costa1 Edward Araujo Júnior2 Alberto Borges Peixoto3 Francisco Herlânio Costa Carvalho1

1 Department of Maternal and Child, Maternidade Escola Assis Address for correspondence Edward Araujo Júnior, PhD, Escola Chateaubriand,Universidade Federal do Ceará, Fortaleza, CE, Brazil Paulista de Medicina, Departamento de Obstetrícia, Universidade 2 Paulista School of Medicine, Department of Obstetrics, Universidade Federal de São Paulo, Rua Botucatu 720, 04023-062, Vila Clementino, Federal de São Paulo, SP, Brazil São Paulo, SP, Brasil (e-mail: [email protected]). 3 Department of Obstetrics and Gynecology, Universidade Federal do Triângulo Mineiro, Uberaba, MG, Brazil 4 Hospital Mário Palmério, Universidade de Uberaba, Uberaba, MG, Brazil

Rev Bras Ginecol Obstet 2019;41:17–23.

Abstract Objective To assess and compare the sensitivity and speciﬁcity of ultrasonography and magnetic resonance imaging in the diagnosis of placenta accreta in patients with placenta previa. Methods This retrospective cohort study included 37 women, and was conducted between January 2013 and October 2015; 16 out of the 37 women suffered from placenta accreta. Histopathology was considered the gold standard for the diagnosis of placenta accreta; in its absence, a description of the intraoperative ﬁndings was used. The associations among the variables were investigated using the Pearson chi-squared test and the Mann-Whitney U-test. Results The mean age of the patients was 31.8 7.3 years, the mean number of pregnancies was 2.8 1.1, the mean number of births was 1.4 0.7, and the mean number of previous cesarean sections was 1.2 0.8. Patients with placenta accreta Keywords had a higher frequency of history of cesarean section than those without it (63.6% ► placenta Previa versus 36.4% respectively; p < 0.001). The mean gestational age at birth among ► placenta accreta women diagnosed with placenta previa accreta was 35.4 1.1 weeks. The mean birth ► ultrasound weight was 2,635.9 374.1 g. The sensitivity of the ultrasound was 87.5%, with a ► magnetic resonance positive predictive value (PPV) of 65.1%, and a negative predictive value (NPV) of imaging 75.0%. The sensitivity of the magnetic resonance imaging was 92.9%, with a PPV of

ORCID ID is https://orcid.org/0000-0002-6145-2532.

received DOI https://doi.org/ Copyright © 2019 by Thieme Revinter May 29, 2018 10.1055/s-0038-1675803. Publicações Ltda, Rio de Janeiro, Brazil accepted ISSN 0100-7203. October 1, 2018 published online November 14, 2018 18 Assessment Sensitivity Specificity Ultrasound Magnetic Resonance Imaging Lopes et al.

76.5%, and a NPV of 75.0%. The kappa coefficient of agreement between the 2 tests was 0.69 (95% confidence interval [95%CI]: (0.26–1.00). Conclusion The ultrasound and the magnetic resonance imaging showed similar sensitivity and specificity for the diagnosis of placenta accreta.

Resumo Objetivo Avaliar e comparar a sensibilidade e especificidade da ultrassonografiaeda ressonância magnética no diagnóstico do acretismo placentário em pacientes com placenta prévia. Métodos Estudo de coorte retrospectivo com 37 mulheres, sendo 16 com acretismo placentário, realizado de janeiro de 2013 a outubro de 2015. Considerou-se padrão- ouro para o diagnóstico de acretismo placentário o exame anatomopatológico, sendo que, na sua ausência, a descrição do achado intraoperatório. As associações entre variáveis foram investigadas utilizando o teste qui-quadrado de Pearson e o teste U de Mann-Whitney. Resultados A idade média foi de 31,8 7,3 anos, o número médio de gestações foi de 2,8 1,1, o número médio da quantidade de partos foi de 1,4 0,7, e o número médio de cesáreas prévias foi de 1,2 0,8. O grupo do acretismo placentário apresentou antecedente de cesariana mais frequentemente do que o grupo sem acretismo (63,6% versus 36,4%, respectivamente; p < 0,001). A idade gestacional no parto em mulheres com diagnóstico de placenta prévia com acretismo foi de Palavras-chave 35,4 1,1 semanas. O peso ao nascer médio foi de 2.635,9 374,1 g. A sensibilidade ► placenta prévia do ultrassom foi de 87,5%, com valor preditivo positivo (VPP) de 65,1%, e valor preditivo ► acretismo negativo (VPN) de 75,0%. Para a ressonância magnética, a sensibilidade foi de 92,9%, placentário com VPP de 76,5% e VPN de 75,0%. O índice kappa para concordância entre os dois ► ultrassom testes foi de 0,69 (intervalo de confiança de 95% [IC95%]: 0,26–1,00). ► ressonância Conclusão O ultrassom e a ressonância magnética apresentaram sensibilidade e magnética especificidade semelhantes no diagnóstico do acretismo placentário.

Introduction cases of posterior placenta, for which visualization by US is difficult owing to fetal parts.6 Placenta accreta is characterized by an anomalous adherence Few studies compared the accuracy of the MRI and US in the of the placenta to the uterine wall. Based on the degree of antenatal diagnosis of placental accretism, and similar predic- – adhesion, placental invasion can be classified into accreta, tion results have been found for both methods.7 10 Satija et al8 increta, or percreta.1 The global incidence of placenta accreta concluded that the US remains the primary modality for the has been increasing over the years; this seems parallel to the evaluation of placental accretism, and the MRI should be increased rate of cesarean sections (C-sections). Wu et al2 reserved for inconclusive cases. Rezk and Shawky9 compared reported the global incidence of placenta accreta as 1:533 Doppler US and MRI in patients with placenta previa and pregnancies between 1982 and 2002, which is much higher uterine scarring. Even though these authors did not make than the incidences of 1:4,027 and 1:2,510 reported in the separate analyses for the placement of the placenta, they 1970s and 1980s. concluded that the MRI should be reserved to exclude accre- Ultrasound (US) criteria are used to diagnose placental tion in cases of posterior or lateral placental location.9 invasion, namely loss of the hypoechoic retroplacental myo- The objective of the present study was to assess and metrial zone, thinning or disruption of the uterine serosa– compare the sensitivity and specificity of the US and MRI bladder interface, presence of exophytic zones and large in the diagnosis of placenta accreta in patients with placenta sonolucent areas in the placenta, myometrial thickness < 1 previa. mm, and, in Doppler US, turbulent flow of placental lacunae 3–5 and bladder–uterine serosa interface hypervascularity. Methods Magnetic resonance imaging (MRI) has been incorporated in the obstetric practice for some cases of fetal, maternal, and The present study is a retrospective cohort study of diagnos- placental assessment in which soft tissues are clearly visible, tic assessment that was documented using data obtained thus enabling the assessment of the retroperitoneal space. from the records of patients hospitalized at the Department The MRI does not seem to increase the possibility of diag- of Fetal Medicine, Maternidade Escola Assis Chateaubriand, nosing anterior placenta accreta; therefore, it is indicated for Universidade Federal do Ceará, Fortaleza, Brazil, between

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January 2013 and October 2015. During this period, there progressed to vaginal birth, and 36 (97%), to C-section. Out of was a total of 13,226 births; 7,009 (53.0%) of these were C- the 36 patients who had a C-section, 16 (44.4%) underwent sections, and 6,217 (47%) were live births. The study protocol concurrent hysterectomy, and 14 (87.5%) of these had pla- was analyzed and approved by the Ethics in Research Com- centa accreta confirmed by histopathology. Out of the 20 mittee of Universidade Federal do Ceará (#1.471.764), with (55.6%) patients who had C-sections but no hysterectomy, 2 the need for informed consent waived owing to the study’s (10%) had placenta accreta confirmed by histopathology of retrospective nature. the uterus segment that was resected or of the curettage The initial sample was composed of all 41 patients admitted material in the adhered segment. to the institution during the study period with ultrasono- Out of the 16 women with placenta accreta, 11 (68.8%) had graphic diagnoses of placenta previa who had been examined anterior placentas, and 5 (31.2%) had posterior placentas. due to complaints of transvaginal bleeding. All of those Regarding the degree of placental invasion, 9 (56.3%) women patients were submitted to at least one US examination, had placenta accreta, 6 (37.5%) had placenta increta, and 1 and, if possible, a single MRI examination. Four patients (6.2%) had placenta percreta. The mean age was 31.8 7.3 were excluded due to incomplete information. Data from the years, the mean number of pregnancies was 2.8 1.1, and last US and MRI examinations performed on the last week the mean number of deliveries was 1.4 0.7. The mean before delivery were considered for the statistical analysis. number of abortions was 0.3 0.6, the mean number of The US diagnosis of placenta previa was considered when curettage procedures was 0.4 0.7, and the mean number of the placental mass reached the internal cervical os. Cases of previous C-sections was 1.2 0.8. low placental insertion were not included in this series. There As for women without a diagnosis of placenta accreta, were 21 cases (56.8%) of total placenta previa, 12 (32.4%) of the mean age was 31 6.8 years, the mean number of partial placenta previa, and 4 (10.8%) of marginal placenta pregnancies was 3.5 2.2, and the mean number of deliv- previa. For the diagnosis of placenta accreta using Doppler US, eries was 2 2. The mean number of abortions was we used at least 1 of the following criteria: 1) loss of the 0.5 0.7, the mean number of curettage procedures hypoechoic retroplacental myometrial zone; 2) disruption of was 0.5 0.7, and the mean number of previous C-sections the uterine serosa–bladder interface; 3) presence of exophytic was 0.5 0.7 (►Table 1). zones; 4) large sonolucent areas in the placenta; 5) myometrial The mean gestational age at birth for women with thickness < 1 mm; 6) turbulent blood flow in the placental placenta accreta was 35.4 1.1 weeks. There was no lacuna; and 7) hypervascularity of theuterine serosa–bladder need for maternal blood transfusion in any of the cases – interface.3 5 For the diagnosis of placenta accreta by MRI, we without placenta accreta; however, blood transfusion only used the following criteria: 1) presence of uterine bulging; 2) occurred in one case of placenta accreta. This patient heterogeneous signal intensity within the placenta; 3) dark showed bladder invasion with resection of a bladder wall intraplacental bands on T2-weighted sequences,; 4) abnormal segment. There was no pelvic organ injury in any other placental vascularity; 5) focal interruptions in the myometrial case. The mean weight of the newborns was wall; 6) tenting of thebladder; and 7) direct visualization of the 2,635.9 374.1 g, and the mean 1- and 5-minute Apgar invasion of adjacent organs.6 scores were 7.9 0.6 and 8.4 0.6 respectively. There The variables analyzed were: age; parity; number of C- were four complications in the newborns in this group. sections; number of abortions; number of curettage proce- Among the patients without placenta accreta, the mean dures; type of delivery; and the need for hysterectomy. The gestational age was 35.6 2.2 weeks, the mean birth placenta-related variables analyzed were: location of the weight was 2,486.9 559.6 g, and the mean 1- and 5- placenta; and extent of placenta adherence. The newborn- minute Apgar scores were 6.7 2.6 and 8.4 0.9 respec- related variables analyzed were: gestational age; birth tively. There was one death and complications in nine weight; 1- and 5-minute Apgar scores; neonatal complica- newborns in this group (►Table 2). All neonatal complications; and deaths. Histopathology was considered the gold tions were infection or jaundice. A total of two neonates in standard for the diagnosis of placenta accreta; the descrip- the accretism group, as well as two neonates in the group tion of the intraoperative findings was used in its absence. without accretism, needed blood transfusions. Continuous variables were expressed as means and stan- Among the 37 (100%) women who underwent the US, the dard deviations, whereas nominal variables were expressed as prevalence of placenta accreta was 20 (54.2%) (95% confi- absolute frequencies and percentages. The associations among dence interval [95%CI]: 40.8–67.3), and among the 21 (56.7%) the variables were investigated using the Pearson chi-squared who underwent the MRI, it was 66.7% (95%CI: 43.0–85.4). test and the Mann-Whitney U-test. The Statistical Package for The measurements of the accuracy of the US and MRI the Social Sciences (SPSS, IBM Corp., Armonk, NY, US) software, examinations in the diagnosis of placenta accreta are pre- version 22.0, was used for all statistical analyses. Values of sented in ►Table 3. p < 0.05 were considered statistically significant. There was a prevalence of accretism in anterior versus posterior placentas according to the US exams (41.7%; 95% Results CI: 22.11–63.36 versus 46.2%; 95%CI: 19.22–74.87). The measurements of the diagnostic accuracy of the US and Out of the 37 patients included in the study, 16 (43.2%) had MRI at insertions of placenta are presented in ►Tables 4 placenta accreta, whereas 21 (56.8%) did not. One case (3%) and 5.

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Table 1 Clinical and obstetric characteristics of the patients diagnosed with placenta previa with and without placenta accreta

Variable With placenta accreta Without placenta accreta p-value n ¼ 16 n ¼ 21 Age (mean SD), years 31.8 7.3 31 6.8 0.774 Pregnancies (mean SD) 2.8 1.1 3.5 2.2 0.387 Deliveries (mean SD) 1.4 0.7 2 2 0.715 Abortions (mean SD) 0.3 0.6 0.5 0.7 0.617 Curettage procedures (mean SD) 0.3 0.6 0.5 0.7 0.617 Previous cesarean sections (mean SD) 1.2 0.8 0.5 0.7 0.008 No 2 (13.3) 13 (86.7) < 0.001# Yes 14 (63.6) 8 (36.4) 1 10 (62.5) 6 (37.5) 2 3 (60) 2 (40) 31(100)0

Abbreviation: SD, standard deviation. Notes: Mann-Whitney U-test; #chi-squared test.

Table 2 Maternal and perinatal results of patients diagnosed with placenta previa with and without placenta accreta

Variable With placenta accreta Without placenta accreta p-value n ¼ 16 n ¼ 21 Gestational age at birth (mean SD), weeks 35.4 1.1 35.6 2.2 0.751 Hysterectomy No 2 (9.5) 19 (90.5) < 0.001# Yes 14 (87.5) 2 (12.5) Maternal hospital stay after delivery (days) 3.4 1.9 2.9 2.2 0.735 Birth weight (mean SD), grams 2,635.9 374.1 2,486.9 559.6 0.596 1-minute Apgar score 7.9 0.6 6.7 2.6 0.280 5-minute Apgar score 8.4 0.6 8.4 0.9 0.961 Neonatal complications 4 9 0.123# Neonatal hospital stay (days) 7.8 3.1 8.2 3.9 0.639 Perinatal death 0 1 0.245#

Abbreviations: SD, standard deviation. Notes: Mann-Whitney U-test; #chi-squared test.

Table 3 Measurements of the accuracy of ultrasound and magnetic resonance imaging in the diagnosis of placenta accreta in pregnancies with placenta previa

Measurement Ultrasound Magnetic resonance imaging n ¼ 37 n ¼ 21 Sensitivity (95%CI) 87.5 (71–96.5) 92.9 (66–99.8) Speciﬁcity (95%CI) 44.4 (25.5–64.7) 42.9 (9.9–81.6) Positive predictive value (95%CI) 65.1 (49.1–78.9) 76.5 (50.1–93.2) Negative predictive value (95%CI) 75 (47.6–92.7) 75 (19.4–99.4) Positive likelihood ratio (95%CI) 1.57 (1.10–2.26) 1.63 (0.84–3.10) Negative likelihood ratio (95%CI) 0.28 (0.10–0.77) 0.17 (0.02–1.33)

Abbreviation: 95%CI, 95% conﬁdence interval.

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Table 4 Measurements of the accuracy of ultrasound and magnetic resonance imaging in the diagnosis of anterior placenta accreta in pregnancies with placenta previa

Measurement Ultrasound Magnetic resonance imaging n ¼ 24 n ¼ 13 Sensitivity (95%CI) 100 (69.2–100) 100 (66.4–100) Speciﬁcity (95%CI) 71.4 (41.9–91.6) 33.3 (4.3–77.7) Positive predictive value (95%CI) 71.4 (41.9–91.6) 69.2 (38.5–90.9) Negative predictive value (95%CI) 100 (69.2–100) 100 (15.8–100) Positive likelihood ratio (95%CI) 3.5 (1.53–8.0) 1.5 (0.85–2.64) Negative likelihood ratio (95%CI)

Abbreviation: 95%CI, 95% conﬁdence interval.

Table 5 Measurements of the accuracy of ultrasound and magnetic resonance imaging in the diagnosis of posterior placenta accreta in pregnancies with placenta previa

Measurement Ultrasound Magnetic resonance imaging n ¼ 13 n ¼ 8 Sensitivity (95%CI) 66.67 (22.3–95.7) 80 (28.4–99.5) Speciﬁcity (95%CI) 100 (59.0–100) 100 (2.5–100) Positive predictive value (95%CI) 100 (39.7–100) 100 (39.7–100) Negative predictive value (95%CI) 77.8 (39.9–97.2) 50 (1.3–98.7) Positive likelihood ratio (95%CI) Negative likelihood ratio (95%CI) 0.33 (0.11–1.03) 0.20 (0.03–1.15)

Abbreviation: 95%CI, 95% conﬁdence interval.

Discussion deliveries, and abortions between the two groups. Our results do not corroborate the risk association reported in Placenta accreta is an obstetric condition; it can be fatal, and another study.12 Thus, because there was no significant often requires a multidisciplinary approach.11 At our depart- statistical difference between the two groups, our study ment, 100% of the patients with placenta accreta underwent contradicts aspects that have already been reported in the C-sections, whereas 14 (87.5%) underwent total abdominal reviewed literature. hysterectomy. In 2 (10%) cases, a point of cleavage was No statistically significant differences were observed in the observed, and the placenta could be removed without the comparison of newborn parameters between the two groups need for hysterectomy. This approach contributed to a very (with and without placenta accreta); According to our current favorable outcome, that is, the absence of maternal mortality institutional protocol, when placenta accreta is diagnosed by during the study period, and there was only one case of imaging during antenatal care, the proposed surgical proce- neonatal death. dure is the classic uterine incision with fetal extraction fol- A total of 11 (68.8%) out of the 16 patients with placenta lowed by hysterectomy without attempting to remove the accreta had anterior placenta, and 5 (31.2%) had posterior placenta from the uterine wall. Previously, each surgical placenta. This finding corroborates with those of other approach was decided by the obstetrical team at the time of studies, which reported a higher incidence of anterior pla- the C-section. In most cases, Pfannenstiel incisions in the skin, centa in confirmed cases of placenta accreta.12 transverse incisions in the uterus, and attempts to remove the The mean maternal age of the patients with placenta placenta were made. After this change in protocol, in addition previa accreta was 31.8 years; this finding corroborates those to better neonatal well-being assessed by higher Apgar scores, found in the literature,13,14 which show means of 31.6 and 32 we observed a marked decrease in the need for blood products years. Maternal age and number of children are also known for both the mother and the newborn.16 to be associated with a high risk of placenta previa.15 The The consequences of a late diagnosis of placenta accreta number of previous C-sections was higher in patients with can be severe; this emphasizes the importance of prior placenta accreta, thus suggesting a strong relationship be- detection during antenatal care. The first and most crucial tween prior uterine scars and the risk of invasion, a finding step must be early investigation, by asking women about confirmed by other authors as well.15 However, this was not their previous uterine surgeries and other possible factors observed in relation to the mean number of pregnancies, related to placenta accreta, such as endometrial ablation or

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the use of assisted reproduction techniques.17 Women with The calculation of positive and negative predictive values myometrial damage primarily caused by previous C-sections depends on the prevalence of the disease; therefore, the are at an increased risk of developing placenta accreta.11 prevalence for each diagnostic tool in the calculation of these Antenatal diagnosis of placenta previa, placenta accreta, measurements was taken into account. The prevalence of and its variants may reduce maternal and fetal morbidity and placenta accreta was identified separately for each diagnos- mortality, thus enabling the resolution of the pregnancy to tic tool. The prevalence was higher using the MRI, but not due be scheduled at tertiary institutions with multidisciplinary to the selection of cases. There were attempts to perform teams, neonatal intensive care units, and blood banks, among MRIs in all cases, but some patients were unable to undergo other resources available at the time of surgery. These this examination. measures can prove effective only if these conditions are The comparison of sensitivity and specificity between created in advance, and if the correct diagnosis is made.12 the US and the MRI in the diagnosis of placenta accreta The US remains the main imaging modality to screen for indicated that the US had a good sensitivity, thus confirm- abnormal placental implantation; however, the MRI is also a ing the data from the literature. This eliminates the need very useful complementary imaging resource in cases of for MRI in most cases, a factor that is particularly impor- inconclusive US or posterior placenta.18 The MRI is clearly tant in low-income countries with limited access to this indicated when the US results in ambiguous conclusions.19 examination.18 The accuracy of the US in the diagnosis of placenta accreta 20 may be biased, as stated in a study in which a significant Conclusion increase in the diagnostic accuracy was observed once the risk factors became known during the examination. In the In summary, regardless of the location of the placenta, the US same study,20 when a diverse group of patients with un- and the MRI had similar sensitivity and specificity for the known obstetric history was assessed, the diagnostic perfor- diagnosis of placenta accreta. mance characteristics of the US were shown to be less accurate. Contributors A meta-analysis21 failed to show any significant difference Lopes ES, Feitosa FEL, Brazil AV, Castro JDV, Costa JIF, between the US and the MRI for the diagnosis of placenta Araujo Júnior E, Peixoto AB and Carvalho FHC designed the accreta. Both methods are highly specific and sensitive in study, analyzed and interpreted the data, wrote the diagnosing or ruling out the presence of placenta accreta, article, and approved the final version of the manuscript with the US being the first choice in patients with limited for publication. time and lower income.21 Another study22 also affirmed the good sensitivity of the US, but it showed that, although the Conflict of Interests MRI was not as useful as initially expected, it still provided The authors have none to declare. additional information for women at risk. Another study23 has indicated the MRI as an excellent method for placenta assessment, particularly to investigate findings related to References placental diseases, thus contributing to the adequate and 1 Farquhar CM, Li Z, Lensen S, et al. Incidence, risk factors and timely care of pregnant women.23 perinatal outcomes for placenta accreta in Australia and New Zealand: a case-control study. BMJ Open 2017;7(10):e017713 Several examiners performed the US and MRI in the Doi: 10.1136/bmjopen-2017-017713 present study. The radiologists performing the MRI were 2 Wu S, Kocherginsky M, Hibbard JU. Abnormal placentation: blinded to the US results, except for the fact that the patients twenty-year analysis. Am J Obstet Gynecol 2005;192(05):1458- were diagnosed with placenta previa, and that the objective –1461 Doi: 10.1016/j.ajog.2004.12.074 was to assess the presence and degree of placental invasion, 3 Finberg HJ, Williams JW. Placenta accreta: prospective sono- which was one of the strengths of the study. However, during graphic diagnosis in patients with placenta previa and prior cesarean section. J Ultrasound Med 1992;11(07):333–343 Doi: the US examinations, which were usually serial, the radiol- 10.7863/jum.1992.11.7.333 ogists often became aware of the MRI results; this can be 4 Chou MM, Ho ES, Lee YH. Prenatal diagnosis of placenta previa considered a limitation of the US assessment. This fact may accreta by transabdominal color Doppler ultrasound. Ultrasound not be relevant because almost 50% of the patients did not Obstet Gynecol 2000;15(01):28–35 undergo an MRI; therefore, the examiners were blinded to 5 Wang Y, Gao Y, Zhao Y, Chong Y, Chen Y. Ultrasonographic the results. diagnosis of severe placental invasion. J Obstet Gynaecol Res 2018;44(03):448–455 Doi: 10.1111/jog.13531 The patient sampling started at the moment the MRI 6 Budorick NE, Figueroa R, Vizcarra M, Shin J. Another look at device was installed. During this period, the radiologists ultrasound and magnetic resonance imaging for diagnosis of wished to evaluate all cases of placenta previa without prior placenta accreta. J Matern Fetal Neonatal Med 2017;30(20): knowledge of the US result in the presence or absence of 2422–2427 placenta accreta, in an attempt to evaluate the previous 7 Maher MA, Abdelaziz A, Bazeed MF. Diagnostic accuracy of ultrasound and MRI in the prenatal diagnosis of placenta accreta. experience of the service in identifying this finding. There Acta Obstet Gynecol Scand 2013;92(09):1017–1022 Doi: were requests for MRI examinations; however, they were not 10.1111/aogs.12187 performed in all cases due to the occasional technical un- 8 Satija B, Kumar S, Wadhwa L, et al. Utility of ultrasound and availability of this examination in the institution. magnetic resonance imaging in prenatal diagnosis of placenta

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accreta: A prospective study. Indian J Radiol Imaging 2015;25 centa previa, placenta accreta, and vasa previa. Obstet Gynecol Surv (04):464–470 Doi: 10.4103/0971-3026.169456 2012;67(08):503–519 Doi: 10.1097/OGX.0b013e3182685870 9 Rezk MA, Shawky M. Grey-scale and colour Doppler ultrasound 16 Lima ER, Feitosa HN, Feitosa FEL, Carvalho FHC. Maternal and versus magnetic resonance imaging for the prenatal diagnosis of perinatal outcomes in pregnancies with placenta previa with and placenta accreta. J Matern Fetal Neonatal Med 2016;29(02): without accreta at a tertiary center. Rev Med UFC 2015;55:18–24 218–223 Doi: 10.3109/14767058.2014.993604 Doi: 10.20513/2447-6595.2015v55n1p18-24 10 Daney de Marcillac F, Molière S, Pinton A, et al. [Accuracy of 17 Comstock CH, Bronsteen RA. The antenatal diagnosis of placenta placenta accreta prenatal diagnosis by ultrasound and MRI in a accreta. BJOG 2014;121(02):171–181, discussion 181–182 Doi: high-risk population]. J Gynecol Obstet Biol Reprod (Paris) 2016; 10.1111/1471-0528.12557 45(02):198–206 Doi: 10.1016/j.jgyn.2015.07.004 18 Allen BC, Leyendecker JR. Placental evaluation with magnetic 11 Committee on Obstetric Practice. Committee opinion no. 529: resonance. Radiol Clin North Am 2013;51(06):955–966 Doi: placenta accreta. Obstet Gynecol 2012;120(01):207–211 Doi: 10.1016/j.rcl.2013.07.009 10.1097/AOG.0b013e318262e340 19 Baughman WC, Corteville JE, Shah RR. Placenta accreta: spectrum 12 CalìG,GiambancoL,PuccioG,Forlani F. Morbidly adherent of US and MR imaging findings. Radiographics 2008;28(07): placenta: evaluation of ultrasound diagnostic criteria and dif- 1905–1916 Doi: 10.1148/rg.287085060 ferentiation of placenta accreta from percreta. Ultrasound 20 Bowman ZS, Eller AG, Kennedy AM, et al. Accuracy of ultrasound Obstet Gynecol 2013;41(04):406–412 Doi: 10.1002/uog. for the prediction of placenta accreta. Am J Obstet Gynecol 2014; 12385 211(02):177.e1–177.e7 Doi: 10.1016/j.ajog.2014.03.029 13 Rac MW, Dashe JS, Wells CE, Moschos E, McIntire DD, Twickler 21 Meng X, Xie L, Song W. Comparing the diagnostic value of ultra- DM. Ultrasound predictors of placental invasion: the Placenta sound and magnetic resonance imaging for placenta accreta: a Accreta Index. Am J Obstet Gynecol 2015;212(03):343.e1–343.e7 systematic review and meta-analysis. Ultrasound Med Biol 2013;39 Doi: 10.1016/j.ajog.2014.10.022 (11):1958–1965 Doi: 10.1016/j.ultrasmedbio.2013.05.017 14 Sumano-Ziga E, Veloz-Martínez MG, Vázquez-Rodríguez JG, 22 Ueno Y, Kitajima K, Kawakami F, et al. Novel MRI finding for Becerra-Alcántara G, Jimenez Vieyra CR. [Scheduled hysterect- diagnosis of invasive placenta praevia: evaluation of findings for omy vs. urgent hysterectomy in patients with placenta accreta in 65 patients using clinical and histopathological correlations. Eur a high specialty medical unit]. Cir Cir 2015;83(04):303–308 Doi: Radiol 2014;24(04):881–888 Doi: 10.1007/s00330-013-3076-7 10.1016/j.circir.2015.01.001 23 Masselli G, Gualdi G. MR imaging of the placenta: what a radi- 15 Rao KP, Belogolovkin V, Yankowitz J, Spinnato JA II. Abnormal ologist should know. Abdom Imaging 2013;38(03):573–587 Doi: placentation: evidence-based diagnosis and management of pla- 10.1007/s00261-012-9929-8

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 THIEME 24 Original Article

The Inﬂuence of Light Exposure in Ambiance during Pregnancy in Maternal and Fetal Outcomes: An Experimental Study Inﬂuência da exposição da luz do ambiente no período gestacional e o resultado fetal: um estudo experimental

Vitor Coca Sarri1 Beatriz Maria Ferrari1 Larissa Fernandes Magalhães2 Paula Almeida Rodrigues1 Almir Coelho Rezende3 Marisa Afonso Andrade Brunherotti4

1 Department of Medicine, Universidade de Franca, Franca, SP, Brazil Address for correspondence Marisa Afonso Andrade Brunherotti, 2 Department of Veterinary Medicine, Universidade de Franca, Franca, PhD, Departamento de Promoc¸ão da Saude e Medicina, Universidade SP, Brazil de Franca, Avenida Doutor Armando de Sales Oliveira, 201, Franca, SP, 3 Department of Physical Therapy, Universidade de Franca, Franca, SP,Brazil 14404-600, Brazil (e-mail: [email protected]). 4 Department of Health Promotion and Medicine, Universidade de Franca, Franca, SP, Brazil Rev Bras Ginecol Obstet 2019;41:24–30.

Abstract Objective The aim of this study is to evaluate whether exposure to different environmental lighting conditions affects the reproductive parameters of pregnant mice and the development of their offspring. Methods Fifteen pregnant albino mice were divided into three groups: light/dark, light, and dark. The animals were euthanized on day 18 of pregnancy following the Brazilian Good Practice Guide for Euthanasia of Animals. Maternal and fetal specimens were measured and collected for histological evaluation. Analysis of variance (ANOVA) test was used for comparison of the groups considering p 0.05 to be statistically significant. Results There was no significant difference in the maternal variables between the three groups. Regarding fetal variables, significant differences were observed in the anthropometric measures between the groups exposed to different environmental lighting conditions, with the highest mean values in the light group. The histological evaluation showed the same structural pattern of the placenta in all groups, which was within the normal range. However, evaluation of the uterus revealed a discrete to moderate number of endometrial glands in the light/dark and light groups, which were Keywords poorly developed in most animals. In the fetuses, pulmonary analysis revealed ► circadian rhythm morphological features consistent with the transition from the canalicular to the ► pregnancy saccular phase in all groups. ► embryonic and fetal Conclusion Exposure to different environmental lighting conditions had no influence development on the reproductive parameters of female mice, while the offspring of mothers ► light exposed to light for 24 hours exhibited better morphometric features.

ORCID ID is https://orcid.org/0000-0002-8058-8523.

received DOI https://doi.org/ Copyright © 2019 by Thieme Revinter May 16, 2018 10.1055/s-0038-1675610. Publicações Ltda, Rio de Janeiro, Brazil accepted ISSN 0100-7203. September 20, 2018 published online November 14, 2018 The Influence of Light Exposure in Ambiance during Pregnancy Sarri et al. 25

Resumo Objetivo Avaliar se a exposição a diferentes luminosidades no ambiente afeta parâmetros reprodutivos de camundongos fêmeas prenhas e o desenvolvimento de sua prole. Métodos Foram selecionados para o estudo 15 camundongos fêmeas albinas prenhas. Os camundongos foram separados em grupos: luz/escuro, luz e escuro. As fêmeas foram eutanasiadas no 18° dia de gestação, seguindo as recomendações do Guia Brasileiro de Boas Práticas para a Eutanásia de animais. Tanto peças maternas como fetais foram mensuradas e coletadas para avaliação histológica. Foi utilizado o teste de Análise de variantes (Anova) para comparação dos grupos, considerando estatisticamente significativo o valor de p 0,05. Resultados Ao comparar as variáveis maternas entre os três grupos, não foi encontrada diferença estatística significativa. Em relação às variáveis fetais, houve diferenças estatísticas entre as medidas de antropometria dos grupos submetidos a diferentes luminosidades do ambiente, com melhores valores médios no grupo luz. Histologica- mente, a avaliação placentária evidenciou em todos os grupos o mesmo padrão estrutural, com todos dentro da normalidade. No entanto, a avaliação de úteros, tanto dogrupoluz/escuroquantodogrupoluz,mostrouquantidadediscretaamoderadade Palavras-chave glândulas endometriais, com pouco desenvolvimento na maioria dos animais. Nos ► ritmo circadiano fetos, análise pulmonar evidenciou características morfológicas compatíveis com a ► gravidez transição da fase canalicular para sacular em todos os grupos. ► desenvolvimento Conclusão As exposições a diferentes luminosidades no ambiente não influenciaram embrionário e fetal nos parâmetros reprodutivos das fêmeas, entretanto, a ninhada das mães que ► luz receberam luz em todo período apresentou melhores medidas morfométricas.

Introduction rhythm is transferred from the mother to the fetus through the placenta or maternal milk.7 Thus, exposure to light and the Light in the environment interferes with the biological func- consequent deregulation of the maternal circadian rhythm can tion of different systems, and circadian rhythm activities are possibly cause repercussions for the fetus. related to light variation. The periods of sleep and wakefulness The question proposed using an experimental animal mod- are directly associated with the circadian rhythm, and the el is whether different times of exposure to artiﬁcial light restriction of nocturnal sleep during pregnancy can affect environmental during pregnancy causes changes in morpho- hypothalamic hormones, plasma cortisol, and body weight.1,2 logical and histological parameters of mother and fetus. There The sleep-wake cycle may be altered by working shift, and are no evidences yet in literature to demonstrate the effect some health issues, such as reproductive success, mating and comparing luminosity differences in the ambiance throughout pregnancy problems are related to working at night or shift- the gestational period. Therefore, the objective of the present work. Alterations in the biological rhythm caused by shiftwork study is to evaluate whether different environmental lighting are intimately linked to changes in the female hormonal cycle, conditions affect the reproductive parameters of pregnant and consequently in reproductive function.2,3 Melatonin, an females and the development of their offspring. indolamine produced by the pineal gland, plays a key role in the regulation of the circadian rhythm. This hormone is Methods secreted during the night and its function in mammals is to mediate signals of darkness.4 Environmental light is the most This study was conducted at the Animal House of the Uni- important factor for the regulation of melatonin synthesis, versidade de Franca within the Maternal-Infant project of the responsible for circadian rhythm and its secretion. Exposure to Laboratory of Health Promotion Strategies. The study was light at night acutely inhibits the synthesis of melatonin; approved by the Ethics Committee on Animal Use of the however, darkness does not stimulate its production.5 It Universidade de Franca (Protocol number 015/15). Fifteen should be noted that the presence of light, even of low female albino Swiss Webster mice (Mus musculus) obtained intensity (50–300 lux) as found in residences, can inhibit the from the Animal House of the Universidade de São Paulo (USP, production of melatonin in humans. in the Portuguese acronym) in Ribeirão Preto were selected for Variations in serum melatonin levels are closely related to this study. They were 90 days of age and weighed 40 g. The ovulation disorders and the function of melatonin in the animals were kept under the following conditions: constant female ovarian cycle is associated with steroidogenesis.6 Mel- air renewal, ambient temperature of 22 2°C, and humidity atonin resulting from the production related to the circadian of 50%. Water and ration were available ad libitum. The females

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selected for this study were mated and divided into three Table 1 Characteristics of pregnant mice sample. groups: 1) light group, consisting of five pregnant mice kept in the presence of light for 24 hours; 2) dark group, consisting of Light Dark Light/dark p-value (n ¼ 5) (n ¼ 5) (n ¼ 5) five pregnant mice kept in the dark for 24 hours; 3) light/dark group, consisting of five pregnant mice kept under a 12/12- Final weight (g)

hours light/dark cycle, with lights on from 6 AM to 6 PM. Average 63.0 65.7 67.1 0.71 The animals were mated at a proportion of one male per SD 6.6 10.4 5.0 female, always in the morning (7 AM). Mating was confirmed CV (%) 10.4 15.9 7.4 by the inspection of the vaginal plug, always 2 hours after the female-male exposure, and according to the presence of Litter size (n) seminal fluid in the vagina, the test was considered positive Average 12.0 9.2 13.6 0.15 and considered day zero of pregnancy. The mice selected for SD 2.7 4.2 2.9 the study were nulliparous. CV (%) 22.8 46.3 21.8 The animals were kept in plastic cages (2 animals/cage) for a period of 18 days. Animals from the light/dark group Uterine weight (g) (12 hours light and 12 hours dark) were maintained on a Average 1.7 1.5 1.7 0.57 normal day/night cycle. The light group was exposed to SD 0.08 0.34 0.24 constant cold light in the room for 24 hours. Animals of CV (%) 4.8 22.8 14.4 the dark group were kept in a completely dark room for Resorption (n) 24 hours. For this purpose, the windows were covered with a double layer of brown paper, as were the shelves containing Mean 0 2.4 0.6 0.26 the cages. A FoxLux Timer (FoxLux Ltda., Pinhais, PR, Brazil) SD 0 3.9 0.5 was used for light control in a room with light-beige colored CV (%) 98.0 91.2 walls measuring 11 m2, with a rail containing two fluores- Placental weight (g) cent lamps and slate floor. The light intensity on a scale of 2,000 was: center of the room (2,000:180 lux), back Average 1.6 1.2 1.6 0.35 (2,000:56 lux), and front (2,000:65 lux). The experiments SD 0.4 0.6 0.3 were conducted in the center of the room. CV (%) 29.2 48.5 24.0 The animals were killed following the Brazilian Good Estimated litter (n) Practice Guide for Euthanasia of Animals.8 Female mice were killed by intraperitoneal injection of thiopental (150 mg/kg). Average 12.0 11.6 14.2 0.20 Their offspring were anesthetized by hypothermia (immersion SD 2.7 0.8 2.7 in ice for 20 minute), followed by decapitation with a sharp CV (%) 22.8 7.7 19.5 blade. Females were euthanized on day 18 of pregnancy. The fetus and placenta were immersed in saline 0.9% and trans- Abbreviations: CV, coefficient of variation; SD, standard deviation. p < ferred to absorbent paper towels for the complete removal of Analysis of variance followed by Tukey test, with 0.05 indicating statistical significance. fluid or any type of residue before measurements to avoid false results. The fetuses collected were weighed on a MARTE AL500 high-precision scale (Marte Científica, São Paulo, SP, Brazil), observed between groups. Analysis of the weight evolution of and their length was measured with a caliper (millimeter females during pregnancy showed a similar average weight scale). The fetal skull, chest and lungs, and maternal uterus gain and final weight in the three groups, with no statistically and placenta were fixed in 10% paraformaldehyde for 24 hours significant difference. However, weight gain was lower in and transferred to alcohol 70% before embedding them in females exposed to light for 24 hours compared with the other paraffin. Routine staining with hematoxylin and eosin (H&E) two groups, but no statistic difference was observed in weight was used for histological analysis. gain. The same was observed for litter size, with no significant The results were compared between groups using the difference between the three groups. However, a smaller litter analysis of variance (ANOVA) test, followed by the Tukey test. was found in the group submitted to light deprivation during A p-value 0.05 was considered statistically significant. The the experiment (average of 9.2 4.2 offspring per litter). The BioStart 5.0 (AnalystSoft Inc., Walnut, Canada) program was number of resorptions did not differ significantly between used for statistical analysis of the data. groups. However, no resorption was observed in the group exposed to light for 24 hours (►Table 1). Placental and uterine Results weights were also similar in the groups. The same trend was observed for uterine weight (►Table 1). The results have demonstrated that the difference of luminos- ►Table 2 shows significant differences in the fetal varia- ity in the ambiance seems to have no influence in the female bles between the groups exposed to different environmental reproductive parameters, however, they suggest that it has lighting conditions. Average fetal length (►Fig. 1) was sig- influence on the fetus morphometric parameters. ►Table 1 nificantly higher in the light group compared with the dark shows the maternal variables. No significant differences were group (p < 0.05) and light/dark group (p < 0.01). Fetal

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Table 2 Morphometric variables of the 134 fetuses of 15 albino light/dark groups. Analysis of fetal cranial measures showed Swiss Webster mice (Mus musculus). better average growth values in the light group. The anteroposterior and laterolateral lengths of the skull differed Variable Light Dark Light/dark significantly between light and light/dark groups (p < 0.01) (n ¼ 60) (n ¼ 46) (n ¼ 68) and between dark and light/dark groups (p < 0.01), while no Length (mm) difference was found between light and dark groups. Average Average 24.5 22.8 22.2 skull weight was significantly higher in the light group < SD 1.1 1.9 4.4 compared with the dark group (p 0.05) and the light/ dark group (p < 0.01), also, there was a difference between CV (%) 4.6 8.4 20.1 the dark and light/dark groups (p < 0.05; ►Table 2). Similar- Weight (g) ly, the average chest variables tended to be higher in the light Average 1.4 1.2 1.1 group (►Table 2). The mean superoinferior diameter of the SD 0.08 0.14 0.33 chest was significantly greater in comparison to the light and CV (%) 5.6 11.9 28.3 light/dark groups (p < 0.01) and to the dark and light/dark < Anteroposterior skull (mm) groups (p 0.05). The average laterolateral diameter was

similar in the three groups. Average 11.2 11.1 10.3 All placentas and uteruses were submitted to histological SD 0.5 0.5 1.2 analysis. Placental evaluation revealed the same normal struc- CV (%) 5.1 5.2 11.6 tural pattern in all groups, showing cellular features typical of Laterolateral skull (mm) the species (►Fig. 2). Evaluation of the uteruses showed a Average 7.4 7.1 6.7 discrete to moderate number ofendometrialglands in thelight/ dark and light groups, which were poorly developed in most SD 0.5 0.4 1.0 animals, except for one animal in the light group that presented CV (%) 7.3 6.0 16.0 well-developed endometrial glands. Neovascularization in the Skull weight (g) lamina propria was observed in all fragments (►Fig. 2). Average 0.33¥ 0.30ϕ 0.28 Histological parameters of the chest and lungs of the SD 0.06 0.3 0.04 fetuses were evaluated. Thorax assessment revealed the presence of skin, muscle, cartilage, vertebral bodies, spine, CV (%) 18.3 9.8 16.8 esophagus, trachea, thymus, heart, and lung in all groups. Superoinferior thoracic diameter (mm) Pulmonary analysis showed morphological features consis- Average 10.1 10.0 9.5 tent with the transition from the canalicular to the saccular SD 0.8 0.7 1.3 phase in all animals. Only one animal from the light group CV (%) 7.9 7.7 14.3 exhibited tubuloacinar structures in the absence of alveolar fi Laterolateral thoracic diameter (mm) expansion and undifferentiated septal cells, ndings suggestive of the pseudoglandular phase (►Fig. 3). Average 8.1β 7.7α 8.5 SD 0.5 0.6 0.9 Discussion CV (%) 6.2 7.8 11.0 Thorax weight (g) Considering the influence of environmental light, that is, light/ dark cycle, on the biological system, the findings for animals Average 0.47 0.40 0.39 submitted to a light/dark period are in concordance with the SD 0.05 0.04 0.05 literature regarding litter size and average final female weight. CV (%) 11.9 11.9 14.7 The litter of this study was composed by 113 pups, with an

Abbreviations: CV, coefficient of variation; mm, millimeters; SD, standard average of 13.6 pups per female. An average of 8 to 10 pups per deviation. litter was reported in a study investigating the control of Analysis of variance followed by Tukey test, with p < 0.05 indicating reproduction in animal houses conducted in 2002.8 statistical significance. In the present study, the best average maternal variables p < : 0.01 light group vs dark and light/dark groups. were found for the light/dark group. In this group, daytime : p < 0.01 light/dark group vs light and dark groups. fl ¥: p < 0.05 light group vs dark group, and p < 0.01 light group vs light/ and night-time periods were simulated, which in uences in dark group. an expected way the normal circadian rhythm of an individ- ϕ: p < 0.05 dark group vs light/dark group. ual who performs his/her activities during the day and rests β: p < 0.01 light group vs dark group, and p < 0.05 light group vs light/ at night. The secretion of hormones and melatonin follows dark group. the biological rhythm and does not affect the biological α: p < 0.01 dark group vs light/dark group. activities of the organism. The weight gain of females was higher in the light/dark weight was also higher in the light group compared with the group compared with the two other groups, since the other groups (p < 0.01). On the other hand, no significant animals’ normal routine was maintained in this group, difference in weight was observed between the dark and with melatonin secretion following the normal rhythm of

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Fig. 1 (A) Photograph of the morphometric evaluation of a mouse fetus of the control group. (B) Image of the uterus of a control mouse.

Fig. 2 (A) Photomicrograph of the hemotrichorial placenta in a mouse of the light/dark group. De: decidua; ZB: basal zone; ZL: labyrinth zone; PC: chorionic placenta; •: yolk sac; umbilical cord vessels. H&E, 2.5x. (B) Photomicrograph of the hemotrichorial placenta in a mouse of the light/dark group. &: Chorionic vessels in the chorionic plate. H&E,10x. (C) Photomicrograph of the hemotrichorial placenta in a mouse of the light/dark group. Note the three types of cells in the basal layer: trophoblast giant cells (black arrow) separating the basal zone (ZB) and decidua (De); glycogen cells (asterisk), and spongiotrophoblast cells (red arrow). H&E., 10x. (D) Photomicrograph of the uterus in a mouse of the light/ dark group. 1: Uterine lumen where the dark line indicates the endometrium and the red line the myometrium; ~: placental tissue; 2: uterine tube. H&E., 2.5x. (E) Photomicrograph of the uterus in a mouse of the light/dark group. 1: endometrium with a moderate number of glands. Note the eosinophilic content in the lumen of some glands. 2: Myometrium. H&E., 2.5x. (F) Photomicrograph of the uterus in a mouse of the light/dark group. Arrow: simple cylindrical epithelium; : eosinophilic content in some glands. H&E, 20x.

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Fig. 3 (A) Photomicrograph of a cross-section of the fetal chest in the light/dark group. &:Lungtissue;•:heart; :esophagus;~:vertebral body; : spine. H&E, 2.5x. (B) Photomicrograph of the fetal lung in the light/dark group. Black arrow: bronchioles; red arrow: expansion of the alveolar sacs containing red blood cells and a moderate amount of mesenchyme. H&E, 5x. (C) Photomicrograph of the fetal lung in the light/dark group. :Bronchioles;•:esophagus.(D) Photomicrograph of the fetal lung in the light/dark group. H&E, 20x. (E)Photomicrographofthefetal lung in the light/dark group. Note the difference in the amount of mesenchyme. H&E, 40x. (F) Photomicrograph of the fetal lung in the light/dark group. Arrows: type II pneumocytes. the organism. The biological rhythm of the animals was Melatonin receptors are found in the pineal gland, and also maintained close to normal. On the other hand, and in in other organs such as the reproductive organs of humans and contrast to the literature, a comparison of weight gain animals. Melatonin exerts action on the ovaries and uterus and between the light and dark groups showed a higher weight is also involved in placental implantation after mating.10,11 gain in animals deprived of light for 24 hours. Melatonin Light exposure for short periods is unable to cause changes in deprivation or a reduction in its production has been shown maternal development. Alterations have been reported when to induce higher weight gain and can possibly cause obesity.9 female mice are exposed to light for long periods before No histological placental alterations were observed in any mating.11 In our study, females were exposed after mating, a of the groups, suggesting that the exchange of nutrients after fact that may explain the normal development of pregnancy. the placenta formation in pregnant mice was not affected. On Alterations resulting from light exposure before mating, the other hand, histological analysis of the uteruses showed a particularly morphological changes, are caused by melato- reduction in the number of endometrial glands in the light/ nin. These alterations mainly occur in the ovarian tissue, dark and light groups. These glands are necessary to provide leading to the development of polycystic ovaries in some adequate nutrition to the embryo, especially early on the females. In the uterus, the changes are related to hypertrophy pregnancy, when the placental circulation is not fully estab- of the endometrial epithelium.11 lished. Despite the alterations in endometrial glands, the light/ Statistical analysis of fetal parameters showed a better dark group gave birth to the largest litter of the experiment. development of almost all parameters in the group exposed The largest number of resorptions was observed in the to light for 24 hours. This might be explained by the longer dark group. Resorptions are deﬁned as the cessation of period of maternal cortisol secretion. Since cortisol is regulated embryo development and are found after removal of the by the circadian rhythm,12 the peak production of this hormone uterus. They resemble the placenta but are smaller. Resorp- depends on the presence of light, and lower concentrations are tion can occur if the female is exposed to a male pheromone thus observed when the animal is deprived of light. The passage that differs from the mating pheromone within 24 hours of maternal cortisol to the fetus throughout pregnancy is well- after copulation.8 The environment of our study was con- established.13 Considering this maternal-fetal exchange, this trolled to avoid such exposure. Thus, the resorptions found pro-catabolic hormone can be related to greater structural were due to nutritional or structural deﬁcits caused by the development of the offspring, since the fetuses would be deregulation of the circadian rhythm of the animals. more exposed to its effects due to higher maternal secretion.

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Microscopic analysis of the fetal specimens in all groups References did not reveal major structural alterations. Except for one 1 Alóe F, Azevedo AP, Hasan R. [Sleep-wake cycle mechanisms]. Rev animal of the light group that exhibited a delayed pulmonary Bras Psiquiatr 2005;27(Suppl 1):33–39 Doi: 10.1590/S1516- development, the parameters were similar in the remaining 44462005000500007 2 Mahoney MM. Shift work, jet lag, and female reproduction. Int J 133 fetuses. This finding suggests that the exposure to Endocrinol 2010;2010:813764 fi different lighting conditions and the signi cant morphomet- 3 Gamble KL, Resuehr D, Johnson CH. Shift work and circadian ric alterations were not sufficient to cause changes at the dysregulation of reproduction. Front Endocrinol (Lausanne) cellular level in the animals studied. 2013;4:92 Doi: 10.3389/fendo.2013.00092 With these results, we can consider that shift factors must 4 Rocha RMP, Matos MHT, Lima LF, et al. Melatonina e reprodução animal: implicações na fisiologia ovariana. Acta Vet Bras. 2011; have attention to the pregnant women health as an employ- 5:147–157 ment risk factor. Thus, expanding to bigger interests in 5 Souza Neto JA, Castro BF. [Melatonin, biological rhythms investigation in ambiance and health investigation, provid- and sleep: a review of the literature]. Rev Bras Neurol 2008; ing action plans for prevention and health promotion. 44:5–11 6 Maganhin CC, Carbonel AAF, Hatty JH, et al. Efeitos da melatonina no sistema genital feminino: breve revisão. Rev Assoc Med Bras Conclusion (1992) 2008;54(03):267–271 Doi: 10.1590/S0104-42302008000 300022 The present results show that exposure to different lighting 7 Tenorio Fd, Simões MdeJ, Teixeira VW, Teixeira AA. Effects of conditions during pregnancy did not influence female repro- melatonin and prolactin in reproduction: review of literature. Rev ductive parameters, while pups exposed to light throughout Assoc Med Bras (1992) 2015;61(03):269–274 Doi: 10.1590/1806- pregnancy exhibited better morphometric measures. How- 9282.61.03.269 ever, variations in luminosity had no negative influence on 8 Santos BF. Criação e manejo de camundongos. In: Andrade A, Pinto SC, Oliveira RS, orgs. Animais de Laboratório: Criação e the pregnancy of mice. Experimentação. Rio de Janeiro: Editora FIOCRUZ; 2002:115–118 9 Amaral FG, Castrucci AM, Cipolla-Neto J, et al. Environmental Contributions control of biological rhythms: effects on development, fertility Sarri V. C., Ferrari B. M., Magalhães L. F., Rezende A. C. e and metabolism. J Neuroendocrinol 2014;26(09):603–612 Doi: Brunherotti M. A. A. contributed with the project and 10.1111/jne.12144 interpretation of data, writing of the article, critical review 10 Reiter RJ, Tan DX, Korkmaz A, Rosales-Corral SA. Melatonin and of the intellectual content, and final approval of the version stable circadian rhythms optimize maternal, placental and fetal physiology. Hum Reprod Update 2014;20(02):293–307 Doi: to be published. 10.1093/humupd/dmt054 Conflicts of Interest 11 Silva FCA, Teixeira AAC, Teixeira VW. Efeito da iluminação constante sobre a placenta de ratas: um estudo morfológico, morfométrico e None to declare. histoquímico. Arq Bras Med Vet Zootec 2015;67:698–706 Doi: 10.1590/1678-4162-7726 Acknowledgments 12 Skarke C, Lahens NF, Rhoades SD, et al. A pilot characterization of the We thank the São Paulo Research Foundation (FAPESP, in human chronobiome. Sci Rep 2017;7(01):17141 Doi: 10.1038/s415 98-017-17362-6 the Portuguese acronym) – number 15/17748–3 for the 13 Bird AD, McDougall ARA, Seow B, Hooper SB, Cole TJ. Glucocorti- support provided in this project and the National Council coid regulation of lung development: lessons learned from con- for Scientific and Technological Development (CNPq, in ditional GR knockout mice. Mol Endocrinol 2015;29(02):158–171 the Portuguese acronym), for a scientific initiation grant. Doi: 10.1210/me.2014-1362

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 THIEME Original Article 31

Association between col1a2 Polymorphism and the Occurrence of Pelvic Organ Prolapse in Brazilian Women Associação entre polimorﬁsmodogenecol1a2eaocorrênciado prolapso de órgãos pélvicos em mulheres brasileiras

Josyandra Paula de Freitas Rosa1 Raphael Federicci Haddad1 Fabiana Garcia Reis Maeda1 Ricardo Peres Souto1 Cesar Eduardo Fernandes1 Emerson de Oliveira1

1 Faculdade de Medicina do ABC, Santo André, SP, Brazil Address for correspondence Emerson de Oliveira, PhD, Av. Príncipe de Galés, 821, 09060-650, Santo André, SP, Brazil . Rev Bras Ginecol Obstet 2019;41:31–36. (e-mail: [email protected]).

Abstract Objective To evaluate the rs42524 polymorphism of the procollagen type I alpha (α) 2(COL1A2)geneasafactorrelatedtothedevelopment of pelvic organ prolapse (POP) in Brazilian women. Methods The present study involved 112 women with POP stages III and IV (case group) and 180 women with POP stages zero and I (control group). Other clinical data were obtained by interviewing the patients about their medical history, and blood was also collected from the volunteers for the extraction of genomic DNA. The promoter region of the COL1A2 gene containing the rs42524 polymorphism was ampliﬁed, and the discrimination between the G and C variants was performed by digestion of the polymerase chain reaction (PCR) products with the MspA1I enzyme followed by agarose gel electrophoresis analysis. Results A total of 292 women were analyzed. In the case group, 71 had the G/G genotype, 33 had the G/C genotype, and 7 had the C/C genotype. In turn, the ratio in the control group was 117 G/G, 51 G/C, and 11 C/C. There were no signiﬁcant differences between the groups. Conclusion Our data did not show an association between the COL1A2 polymorphism and the occurrence of POP.

Resumo Objetivo Avaliar o polimorfismo rs42524 do gene pró-colágeno tipo I alfa (α)2 (COL1A2) como fator relacionado ao desenvolvimento de prolapso de órgãos pélvicos (POP) em mulheres brasileiras. Keywords Métodos O estudo envolveu 112 mulheres com POP nos estádios III e IV (grupo caso) ► procollagen type I e 180 mulheres com POP nos estádios zero e I (grupo controle). Outros dados clínicos alpha (α)2gene foram obtidos por meio de entrevistas com as pacientes sobre seu histórico médico, e o ► polymorphism sangue das voluntárias também foi coletado para extração de DNA genômico. A região ► pelvic organ prolapse promotora do gene COL1A2 contendo o polimorfismo rs42524 foi amplificada, e a

ORCID ID is https://orcid.org/0000-0002-5261-5563.

received DOI https://doi.org/ Copyright © 2019 by Thieme Revinter July 13, 2018 10.1055/s-0038-1676599. Publicações Ltda, Rio de Janeiro, Brazil accepted ISSN 0100-7203. November 5, 2018 32 Association between col1a2 Polymorphism and the Occurrence of Pelvic Organ Prolapse Rosa et al.

discriminação entreas variantes G e C foi realizada por digestão dosprodutos de reação em cadeia da polimerase (RCP) com a enzima MspA1I, seguida de análise por eletro- forese em gel de agarose. Palavras-chave Resultados Foram analisadas 292 mulheres. No grupo caso, 71 tinham o genótipo G/G, ► gene pró-colágeno 33 tinham o genótipo G/C, e 7 tinham o genótipo C/C. Por sua vez, a relação no grupo tipo I alfa (α)2 controle foi de 117 G/G, 51 G/C e 11 C/C. Não houve diferenças significativas entre os ► polimorfismo grupos. ► prolapso de órgãos Conclusão Nossos dados não mostraram associação do polimorfismodogene pélvicos COL1A2 com a ocorrência de POP.

Introduction ments are formed predominantly by collagen type I and III, which enable the accommodation of the structures in cases Pelvic organ prolapse (POP) is a pathological condition such as sudden increased abdominal pressure and the pas- characterized by the displacement of pelvic viscera in the sage of a fetus. caudal direction, towards the genital hiatus. The standardi- In the case of collagen changes, the pelvis becomes more zation of its symptoms was updated in 2016 by the Interna- susceptible to genital prolapse, as the fascia and its ligaments tional Continence Society (ICS) and by the International are put under stress during periods of increased intra- Urogynecology Association (IUGA). They considered the abdominal pressure. Thus, it is believed that an abnormal following complaints to be related to POP: vaginal bulging, connective tissue metabolism may be associated with this pelvic or suprapubic pressure, bleeding, discharge and infec- gynecological condition.7 tions related to ulceration, need for manual maneuvers to The COL1A2 gene is located on the chromosome 7q22.1.8 It facilitate defecation or urination, and pain in the sacral spine contains 52 exons and non-coding portions (38 kb in size).9 region.1 It encodes the procollagen alpha 2 chain, a component of the The prevalence of POP varies between 8 and 41%, contrib- collagen type I molecule.10,11 uting substantially to the reduction of the quality of life of Each α-chain contains terminal propeptides in the C- the patients, as they experience physical symptoms, but also terminus (carboxy) and in the N-terminus (amino), and a to problems related to general health, personal relationships, core domain composed of 338 Gly-X-Y repeats, where X and and sexual function.2 In addition, POP is the main reason for Y exclude cysteine and tryptophan, and are often proline and surgery in aging women.3 hydroxyproline, respectively. Glycine, as the smallest amino The etiology of POP is considered multifactorial, and several acid, is the only residue capable of occupying the axial risk factors, such as advanced age, pregnancy, obesity, neurop- position of the triple helix, so that any change from a glycine athies, ethnicity, hysterectomy, instrumental delivery, and residue will entail disruption of the helical structure.12,13 menopause, have been identified. Recent evidence suggests Genetic polymorphism is the presence of variation in the the existence of a genetic component with a 3.2- to 2.4-fold DNA sequence found at a frequency of > 1% of the popula- increased risk for the mothers and sisters of affected women, tion. A single-nucleotide polymorphism (SNP) is a site in the respectively. The high prevalence of POP in patients with type I DNA where a single base pair or nucleotide varies from and III collagen disorders, such as Ehlers-Danlos and Marfan person to person. As genetic markers, SNPs can be used to syndromes, corroborates the importance of studying the track inheritance patterns of chromosomal regions from genetic background of patients with the disease.3,4 generation to generation. Although most of the polymor- Older age and parity are the most significant etiological phisms are inactive, some may influence the promoter factors, but they do not fully explain the origin and progres- activity or the conformation of DNA and pre-mRNA, which sion of pelvic floor dysfunction in all women, since POP has may result in a change in the amino acid sequence and in the been observed in nulliparous women and has been absent in protein function and, therefore, in the phenotypic expres- many multiparous women.5 The main mechanism of pelvic sion.6 The frequency of SNPs can be measured and has been floor dysfunction is the weakening of the structures that associated with different risks of development of diseases.14 support the pelvic organs: connective tissue in the form of Mutations that affect the COL1A2 gene reduce the biosyn- ligaments and endopelvic fascia, and the levator ani thesis of type I collagen and, consequently, could be involved muscles.6 in osteogenesis imperfecta.15 According to the literature, a The main protein structure of connective tissues is type I polymorphism of the COL1A2 is associated with vascular – collagen, a heterotrimer with two α-1 chains and one α-2 disease and osteoporotic fractures.16 18 A recent meta-anal- chain encoded by the procollagen type I alpha (α)1(COL1A1) ysis suggests that COL1A2 rs42524 is a significant risk factor and procollagen type I alpha (α)2(COL1A2) genes, respec- for intracranial aneurysm susceptibility, with an especially tively. This protein is physiologically important to support strong effect in Asian people.19 However, in our review, it the pelvic floor structures and to confer mechanical stability was not possible to find studies evaluating the relationship of to the genitourinary tract.7 The vaginal fascia and its liga- this polymorphism with POP.

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Given the aging of the Brazilian population, which is The exclusion criteria were: (1) lack of permission from the estimated to be predominantly composed of adults and the patient to perform blood collection after having been informed elderly, according to the Brazilian Institute of Geography and about the study in both groups; and (2) patients who under- Statistics (IBGE, in the Portuguese acronym), and considering went any type of prior vaginal surgery in the control group. the high morbidity of this gynecological condition and the In the medical interview, the following data were collected: high costs of its treatment, it can be concluded that POP is a age, ethnicity, body mass index (BMI), parity, place of birth and highly relevant problem for the global public health.20,21 delivery route, obstetric interventions (analgesia and episiot- Thus, an important goal on the agenda of the urogyne- omy), weight of the heaviest newborn, previous diseases cological scientific community is to develop tools and (diabetes, hypertension, dyslipidemia, chronic cough, and markers capable of predicting which women will develop constipation), life habits (physical activity with high physical POP, so that they receive adequate follow-up, particularly in exertion, and smoking), and previous hysterectomy. terms of obstetric care. For this purpose, the identification All of the women were weighed and measured for the of genetic polymorphisms, more or less frequent in women calculation of their BMI, followed by a gynecological exami- with POP compared with the general population, can be the nation, in which POP-Q staging was performed for the basis for an early disease risk assessment and is therefore quantification of genital prolapse.22 extremely important. For the extraction of genomic DNA, the illustra blood Therefore, the objective of the present work is to verify the genomicPrep Mini Spin Kit (GE Healthcare Life Sciences, Chi- association between COL1A2 polymorphisms (rs42524) with cago, IL, USA) was used, following the instructions of the POP. manufacturer. The amplification reaction was performed in 20 μL using an adequately diluted PCR Master Mix reagent Methods (Promega Corporation, Madison, WI, USA) and the primers described by Liu et al (2012): 23 5′-TACCTGAGGCTTTGAGAC- This is a cohort study with a total of 292 postmenopausal 3′ and 5′-GAAAATATAGAGTTTCCAGAG-3′. The amplification women. The patients were treated at the Department of protocol was as follows: initial incubation at 94° C for 5 minutes Urogynecology and Vaginal Surgery of the Department of followed by 45 cycles of 3 temperatures (94° C for 30 seconds, Gynecology and Obstetrics of a School of Medicine. To ensure 49° C for 30 seconds, 72° C for 60 seconds) and a final incuba- the rights and duties of the scientific community, of the tion at 72° C for 10 minutes. The samples were then kept at 10° C study population and of the State, the present study com- until the electrophoresis was performed. The polymerase chain plied with the guidelines of Resolution 196/96 of the Nation- reaction (PCR) products were digested with the restriction al Health Council (CNS, in the Portuguese acronym) and, endonuclease MspA1I for 16 hours and visualized on agarose therefore, was previously submitted to evaluation and ap- gel stained with ethidium bromide. The genotypes were deter- proval by the Research Ethics Committee of the Faculdade de mined by the observed pattern of the digestion bands: a single Medicina do ABC (FMABC, in the Portuguese acronym) under 427 base pair (bp) for homozygous CC (mutant homozygous the number 554.670/2014. All of the patients were informed genotype); two bands of 312 and 115 bp for homozygous GG about the study and signed a consent form for participation. (wild type genotype), and three bands of 427, 312 and 115 bp The inclusion criteria were: (1) diagnosis, by physical forheterozygous GC (mutantheterozygousgenotype)(►Fig. 1). examination, of POP stages III and IV in the case group, The normality of the quantitative data was verified using and of POP stages zero and I in the control group; (2) a history the Shapiro-Wilk test. The qualitative variables were com- compatible with postmenopause (absence of menstrual pared using the chi-squared and the Fisher exact tests. An bleeding for at least a year); and (3) no hormone therapy unpaired t-test was used to compare the quantitative variables. in the previous 6 months for both groups. The data were analyzed using GraphPad Prism 6.0 (GraphPad

Fig. 1 Representative results for rs42524 genotyping of the COL1A2 gene.

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Software, La Jolla, CA, USA) and IBM SPSS Statistics for Win- Table 1 Analysis of the clinical characteristics of women with dows, Version 23.0 (IBM Corp., Armonk, NY, USA). After the and without pelvic organ prolapse stratification of the groups, the influence of the clinical characteristics on the risk of POP was estimated using odds Variables Case group Control p-value (n ¼ 112) group ratios (ORs) obtained from the binary logistic regression mean or % (n ¼ 180) fi p < model. The adopted signi cance level was 5% ( 0.05), and mean or % the adopted confidence interval (CI) was 95%. Age, mean 68.4 57.8 < 0.0001a (years old) Results White 69.90% 64.80% 0.422b A total of 180 women with stage zero or I (control group) and Non-White 30.10% 35.20% 112 women with stage III or IV (case group) were selected for Body mass index 28.8 28.9 0.874a analysis. The groups were significantly different in terms of (kg/m2) age, parity, number of pregnancies, and number of vaginal Age of 48.8 46.6 0.07a deliveries and home deliveries (►Table 1). menopause The independent risk factors for the development of POP (years old) were determined by calculating the OR using the logistic Hormonal 10.70% 18.10% 0.09b regression model and are shown in ►Table 2. Following the therapy adjusted OR analysis, we found a statistical significance only Smoking 13.10% 20.10% 0.15b for the variables age 51 years old and home delivery. Arterial 57.80% 49.40% 0.186b There was a tendency for the Hardy-Weinberg equilibrium hypertension in both groups regarding the frequency of the genotypes Diabetes mellitus 24.50% 23.70% 0.888b studied (p ¼ 0.046). We did not have DNA amplification in b one patient in the case group and in another in the control Dyslipidemia 25.40% 24.70% 0.889 group, totaling two cases of non-amplified DNA. Conversely, Chronic cough 1.80% 6.80% 0.08b the presence or absence of COL1A2 gene polymorphisms was Constipation 14.30% 10.40% 0.35b not associatedwith the presence ofgenital prolapse (►Table 3). Pregnancy 5.6 3.5 < 0.0001a Parity 4.8 2.9 < 0.0001a Discussion Vaginaldelivery 4.1 2.3 < 0.0001a The identification of patients who are susceptible to the C-section 0.08 0.12 0.377a development of POP may lead to preventive treatment. a Weight of the 3,516 3,059 0.147 Several genetic studies have already been conducted, reveal- heaviest ing different candidate genes and chromosomal loci that are newborn (g) associated with the risk of POP. Episiotomy 8.30% 9.20% > 0.99b Pelvic organ prolapse affects negatively the quality of life Labor analgesia 3.70% 4.80% 0.768b of women, especially after the age of 50 years old; among < b these women, approximately 10% will require surgery by the Home birth 25.90% 3.05% 0.0001 age of 80 years old. The etiology of POP is multifactorial; of Hysterectomy 15.20% 15.60% > 0.99b 10,11 late, genetic factors have been extensively studied. Exaggerated 22.50% 14.10% 0.077b Our results demonstrated a higher, albeit not statistically physical exercise significant, prevalence of the COLIA2 polymorphism among aUnpaired t test; patients with advanced POP. Genetic polymorphisms in the bFisher exact test. genes encoding α-1 and α-2 chains of type I collagen and its influence on POP were studied in the world literature. A Brazilian study demonstrated that there were no differences It has recently been shown that a common coding poly- in the prevalence of the GT and TT genotypes of the COL1A1 morphism (rs42524) in the COL1A2 gene, which replaces gene between the groups even when we grouped patients alanine for proline at position Y of the helical region of alpha with at least one polymorphic allele (GT and TT) and com- 2 (I) collagen, could be a genetic risk factor for aneurysms.26 pared them with patients without the polymorphic allele This study was followed by several others studying the (GG). Moreover, the COL1A1 Sp1-binding site was not signif- association of this polymorphism with osteoporosis and icantly associated with genital prolapse among our study vascular disease. Lindahl et al (2009)18 showed that the subjects.24 Another study of particular interest was the heterozygote genotype had an increased risk of stroke, finding that the only case of polymorphic homozygosity myocardial infarction, and lower bone mineral density. In (TT) of the COL1A1 gene was found in the control group turn, Majchrzycki et al (2017)17 found that the COL1A2 gene (that is, women without POP), suggesting that the GT geno- polymorphism may be a genetic risk factor related to the type has a stronger association with POP than the TT development of osteoporosis; and, lastly, Meng et al (2017)16 genotype.25 observed in a meta-analysis that rs42524 in the COL1A2 gene

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Table 2 Logistic regression of factors associated with the risk was adequate, the PCR was always performed by the same of pelvic organ prolapse three observers, and their consensus was recorded. We believe that further studies that seek to establish Factors Crude OR p-value Adjusted OR genetic markers for POP are necessary and, therefore, the (95% CI) (95% CI) present study may be useful for future meta-analyses. We Age 51 15.57 < 0.0001 11.89 also think that we cannot extrapolate the conclusion for – – (4.73 51.2) (3.53 40) other populations based on these results. This study is Pregnancy 32.02 0.004 0.656 specially important because the capacity to identify individ- (1.24–3.28) (0.283–1.51) uals at greater risk of developing POP through genetic Vaginal 3.12 < 0.0001 1.91 screening could be useful in cases such as deciding the delivery 3 (1.86–5.23) (0.7–5.22) most appropriate delivery route for large fetuses. Parity 32.64 < 0.0001 2.01 Hopefully, focusing on the genetic susceptibility to POP (1.62–4.31) (0.665–6.1) will allow the stratification of risk for women who develop Home birth 11.1 < 0.0001 9.645 POP and thus establish strategies for its prevention and (4.14–29.7) (3.35–27.7) lifestyle changes. These interventions could reduce the need for corrective surgery and could improve the quality Abbreviations: CI, confidence interval; OR, odds ratio. of life of women with the most severe stages of genital prolapse. Table 3 Distribution of the frequencies of COL1A2 genotypes between cases and controls Conclusion COL1A2 Case group Control group p-value genotypes (n ¼ 111) (n ¼ 179) In conclusion, our data did not demonstrate an association between the COL1A2 polymorphism and the occurrence of GG 71 (63.9%) 117 (65.3%) 0.9705a POP. GC 33 (29.7%) 51 (28.5%) CC 7 (6.4%) 11 (6.2%) Acknowledgments COL1A2 The authors thank the FAPESP (Fundação deAmparo à aggregated Pesquisa do Estado de São Paulo) for financially support- genotypes ing this research under contract 2014/01107-6. GG 71 (63.9%) 117 (65.3%) 0.7105b Contributors GC þ CC 40 (36.1%) 62 (34.7%) Rosa J. P. F., Haddad R. F., Maeda F. G. R., Souto R. P., Abbreviations: CC, mutant homozygous genotype; GC, mutant het- Fernandes C. E. and Oliveira E. contributed with the erozygous genotype; GG, wild type genotype. project and the interpretation of data, the writing of the aChi-squared test; article, the critical review of the intellectual content, and bFisher exact test. with the final approval of the version to be published.

Conflicts of Interest was associated with a significant increase in the risk of The authors have no conflicts of interest to declare. intracranial aneurysms in Japanese patients (allelic model: OR ¼ 1.94; 95% CI: 1.03–3.64; p ¼ 0.04). References In our study, we investigated the possible association of the rs42524 polymorphism of the COL1A2 gene with the 1 Haylen BT, Maher CF, Barber MD, et al. An International Urogy- necological Association (IUGA) / International Continence Society occurrence of POP. This is a pioneer work in the literature, (ICS) Joint Report on the Terminology for Female Pelvic Organ and it failed to demonstrate the association of this polymor- Prolapse (POP). Neurourol Urodyn 2016;35(02):137–168. Doi: phism with POP. 10.1002/nau.22922 We acknowledge that among the limitations of our work is 2 Lince SL, van Kempen LC, Vierhout ME, Kluivers KB. A systematic the fact that our samples were not completely homogeneous review of clinical studies on hereditary factors in pelvic organ in terms of some clinical characteristics, likely because prolapse. Int Urogynecol J Pelvic Floor Dysfunct 2012;23(10): 1327–1336. Doi: 10.1007/s00192-012-1704-4 advanced degrees of prolapse are more frequent in older 3 Wang X, Li Y, Chen J, Guo X, Guan H, Li C. Differential expression women with more gestations and deliveries, who, in this profiling of matrix metalloproteinases and tissue inhibitors of case, correspond to those of the study group. Other limita- metalloproteinases in females with or without pelvic organ tions of our study are the fact that it only evaluated a single prolapse. Mol Med Rep 2014;10(04):2004–2008. Doi: 10.3892/ polymorphim and gene, as well as the miscegeneation of the mmr.2014.2467 4 Ferrari MM, Rossi G, Biondi ML, Viganò P, Dell’utri C, Meschia M. Brazilian population, as well as the lack of equilibrium of Type I collagen and matrix metalloproteinase 1, 3 and 9 gene Hardy-Weinberg. Regarding the latter, perhaps the small polymorphisms in the predisposition to pelvic organ prolapse. number of patients may be responsible for the absence of Arch Gynecol Obstet 2012;285(06):1581–1586. Doi: 10.1007/ the genic equilibrium. In order to ensure that the genotyping s00404-011-2199-9

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 36 Association between col1a2 Polymorphism and the Occurrence of Pelvic Organ Prolapse Rosa et al.

5 Swift SE, Pound T, Dias JK. Case-control study of etiologic factors 17 Majchrzycki M, Bartkowiak-Wieczorek J, Bogacz A, et al. The in the development of severe pelvic organ prolapse. Int Urogy- importance of polymorphic variants of collagen 1A2 gene necol J Pelvic Floor Dysfunct 2001;12(03):187–192. Doi: 10.1007/ (COL1A2) in the development of osteopenia and osteoporosis in s001920170062 postmenopausal women. Ginekol Pol 2017;88(08):414–420. Doi: 6 Bortolini MA, Rizk DE. Genetics of pelvic organ prolapse: crossing 10.5603/GP.a2017.0077 the bridge between bench and bedside in urogynecologic research. 18 Lindahl K, Rubin CJ, Brändström H, et al. Heterozygosity for a Int Urogynecol J Pelvic Floor Dysfunct 2011;22(10):1211–1219. coding SNP in COL1A2 confers a lower BMD and an increased Doi: 10.1007/s00192-011-1502-4 stroke risk. Biochem Biophys Res Commun 2009;384(04): 7 Skorupski P, Jankiewicz K, Miotła P, Marczak M, Kulik-Rechberger 501–505. Doi: 10.1016/j.bbrc.2009.05.006 B, Rechberger T. The polymorphisms of the MMP-1 and the MMP- 19 Gan Q, Liu Q, Hu X, You C. Collagen type I alpha 2 (COL1A2) 3 genes and the risk of pelvic organ prolapse. Int Urogynecol J Polymorphism contributes to intracranial aneurysm susceptibil- Pelvic Floor Dysfunct 2013;24(06):1033–1038. Doi: 10.1007/ ity: a meta-analysis. Med Sci Monit 2017;23:3240–3246. Doi: s00192-012-1970-1 10.12659/msm.902327 8 de Wet W, Bernard M, Benson-Chanda V, et al. Organization of the 20 Instituto Brasileiro de Geografia e Estatística. Fundo de População human pro-alpha 2(I) collagen gene. J Biol Chem 1987;262(33): das Nações Unidas. Indicadores Sociodemográficos Prospectivos 16032–16036 para o Brasil 1991–2030. Rio de Janeiro, RJ: Arbeit; 2006. http:// 9 Kataoka K, Ogura E, Hasegawa K, et al. Mutations in type I collagen www.ibge.gov.br/home/estatistica/populacao/projecao_da_popu genes in Japanese osteogenesis imperfecta patients. Pediatr Int lacao/publicacao_UNFPA.pdf. Accessed July 22, 2017 2007;49(05):564–569 21 Subak LL, Waetjen LE, van den Eeden S, Thom DH, Vittinghoff E, 10 De Vos A, Sermon K, Van de Velde H, et al. Two pregnancies after Brown JS. Cost of pelvic organ prolapse surgery in the United preimplantation genetic diagnosis for osteogenesis imperfecta States. Obstet Gynecol 2001;98(04):646–651. Doi: 10.1016/ type I and type IV. Hum Genet 2000;106(06):605–613. Doi: S0029-7844(01)01472-7 10.1007/s004390000298 22 Bump RC, Mattiasson A, Bø K, et al. The standardization of 11 Alanay Y, Avaygan H, Camacho N, et al. Mutations in the gene terminology of female pelvic organ prolapse and pelvic floor encoding the RER protein FKBP65 cause autosomal-recessive dysfunction. Am J Obstet Gynecol 1996;175(01):10–17. Doi: osteogenesis imperfecta. Am J Hum Genet 2010;86(04): 10.1016/S0002-9378(96)70243-0 551–559. Doi: 10.1016/j.ajhg.2010.02.022 23 Liu W, Pang B, Lu M, et al. The rs42524 COL1A2 polymorphism is 12 Cole WG. The Nicholas Andry Award-1996. The molecular pathol- associated with primary intracerebral hemorrhage in a Chinese ogy of osteogenesis imperfecta. Clin Orthop Relat Res 1997;(343): population. J Clin Neurosci 2012;19(12):1711–1714. Doi: 235–248 10.1016/j.jocn.2012.03.025 13 Byers PH, Wallis GA, Willing MC. Osteogenesis imperfecta: trans- 24 Rodrigues AM, Girão MJ, da Silva ID, Sartori MG, Martins KdeF, lation of mutation to phenotype. J Med Genet 1991;28(07): Castro RdeA. COL1A1 Sp1-binding site polymorphism as a 433–442. Doi: 10.1136/jmg.28.7.433 risk factor for genital prolapse. Int Urogynecol J Pelvic Floor 14 Romero AA, Jamison MG, Weidner AC. Are single nucleotide poly- Dysfunct 2008;19(11):1471–1475. Doi: 10.1007/s00192-008- morphisms associatedwith pelvic organ prolapse? J Pelvic Med Surg 0662-3 2008;14(01):37–43. Doi: 10.1097/SPV.0b013e3181637a49 25 Feiner B, Fares F, Azam N, Auslender R, David M, Abramov Y. Does 15 Gajko-Galicka A. Mutations in type I collagen genes resulting in COLIA1 SP1-binding site polymorphism predispose women to osteogenesis imperfecta in humans. Acta Biochim Pol 2002;49 pelvic organ prolapse? Int Urogynecol J Pelvic Floor Dysfunct (02):433–441 2009;20(09):1061–1065. Doi: 10.1007/s00192-009-0895-9 16 Meng Q, Hao Q, Zhao C. The association between collagen gene 26 Yoneyama T, Kasuya H, Onda H, et al. Collagen type I alpha2 polymorphisms and intracranial aneurysms: a meta-analysis. (COL1A2) is the susceptible gene for intracranial aneurysms. Stroke Neurosurg Rev 2017;•••;. Doi: 10.1007/s10143-017-0925-x 2004;35(02):443–448. Doi: 10.1161/01.STR.0000110788.45858.DC

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 THIEME Original Article 37

The Prevalence of Metabolic Syndrome in the Different Phenotypes of Polycystic Ovarian Syndrome A prevalência da síndrome metabólica nos diferentes fenótipos da síndrome do ovário policístico

Aleide Tavares1 Romualda Castro Rêgo Barros1

1 Universidade Federal de Pernambuco, Recife, PE, Brazil Address for correspondence Aleide Tavares, Master, Universidade Federal de Pernanbuco, Av. Prof. Moraes Rego, 1235, 50670-901, Rev Bras Ginecol Obstet 2019;41:37–43. Cidade Universitária, Recife, PE, Brazil (e-mail: [email protected]).

Abstract Objective To evaluate the prevalence of metabolic syndrome (MetS) in the phenotypes of polycystic ovarian syndrome (PCOS). Methods This was a cross-sectional study involving 111 women aged between 18 and 39 years old diagnosed with PCOS, according to the Rotterdam Criteria, and grouped into four phenotypes: A: ovulatory dysfunction þ hyperandrogenism þ polycystic ovaries; B: ovulatory dysfunction þ hyperandrogenism; C: hyperandrogenism þ polycystic ovaries; D: ovulatory dysfunction þ polycystic ovaries. To evaluate the presence of MetS, we measured serum triglyceride levels, HDL cholesterol, fasting blood glucose, blood pressure, and waist circumference. Results The prevalence of MetS found in this sample was 33.6%, and there was no statistically signiﬁcant difference (p < 0.05) among the 4 phenotypes. However, phenotype D presented a signiﬁcantly higher mean glucose level after fasting Keywords (93.6 mg/dL) and 2 hours after ingesting a solution with 75 g of anhydrous glucose (120 mg/dL), as well as the lowest mean level of high-density lipoprotein (HDL) ► polycystic ovarian cholesterol (44.7 mg/dL). The women in this group demonstrated a high prevalence of syndrome abdominal circumference 80 cm (68.2%), as well as the highest mean abdominal circumfer- ► phenotype ence (90.1 cm). Amongst the women with an abdominal circumference 80 cm, phenotype ► insulin resistance A increased approximately six-fold the chance of developing metabolic syndrome in relation to ► metabolic syndrome phenotype C. ► abdominal obesity Conclusion The four phenotypes of PCOS demonstrated similar prevalence rates of metabolic syndrome; abdominal obesity presented a relevant role in the development of metabolic alterations, regardless of the phenotype.

Resumo Objetivo Avaliar a prevalência da síndrome metabólica nos fenótipos da síndrome do ovário policístico. Métodos Trata-se de um estudo transversal envolvendo 111 mulheres com idade entre 18 e39anoscomdiagnósticodesíndromedoováriopolicístico, segundo os critérios de Roterdã,

ORCID ID is https://orcid.org/0000-0001-5010-7031.

received DOI https://doi.org/ Copyright © 2019 by Thieme Revinter June 18, 2018 10.1055/s-0038-1676568. Publicações Ltda, Rio de Janeiro, Brazil accepted ISSN 0100-7203. October 31, 2018 38 Prevalence of Metabolic Syndrome in the Different Phenotypes Tavares, Barros

e agrupadas em quatro fenótipos: A: Disfunção ovulatória þ hiperandrogenismo þ ovários policísticos; B: disfunção ovulatória þ hiperandrogenismo; C: hiperandrogenismo þ ovários policísticos; D: disfunção ovulatória þ ovários policísticos. Para avaliar a presença de síndrome metabólica, foram medidos os níveis séricos de triglicérides, colesterol HDL e glicemia de jejum, pressão arterial e circunferência da cintura. Resultados A prevalência de síndrome metabólica encontrada nesta amostra foi de 33,6%, e não houve diferença estatisticamente signiﬁcativa (p < 0,05) entre os quatro fenótipos. Entretanto, o fenótipo D apresentou um nível médio de glicose signiﬁca- tivamente mais alto após o jejum (93,6 mg/dL) e duas horas após a ingestão de uma solução com 75g de glicose anidra (120 mg/dL), bem como o menor nível médio de colesterol HDL (44,7 mg/dl). As mulheres deste grupo demonstraram alta prevalência de circunferência abdominal 80 cm (68,2%), bem como a maior média de circun- Palavras-chave ferência abdominal (90,1 cm). Entre as mulheres com circunferência ► síndrome do ovário abdominal 80 cm, o fenótipo A aumentou em aproximadamente 6 vezes a chance policístico de desenvolver síndrome metabólica em relação ao fenótipo C. ► fenótipo Conclusão Os quatro fenótipos da síndrome do ovário policístico demonstraram ► resistência a insulina taxas semelhantes de prevalência de síndrome metabólica; a obesidade abdominal ► síndrome metabólica apresentou papel relevante no desenvolvimento de alterações metabólicas, indepen- ► obesidade abdominal dentemente do fenótipo.

Introduction those considered as classic, followed by C (ovulatory), and – much less frequently, D (nonhyperandogenic).4,20 23 Polycystic ovarian syndrome (PCOS) is an endocrinopathy with The metabolic disorders presented in women with PCOS manifestations of heterogeneous clinical signs and symptoms, may make up metabolic syndrome (MetS), which is deﬁned such as hyperandrogenic disorders, oligomenorrhea or amen- as the coexistence of risk factors for cardiovascular diseases orrhea, infertility and obesity.1,2 Polycystic ovarian syndrome in the same individual, with impaired glucose tolerance, is a complex syndrome, which presents different phenotypes.2 dyslipidemia, and hypertension being the most relevant According to the Rotterdam diagnostic criteria, it is possible to factors. Obesity, which is present in 30 to 70% of the cases identify the composition of four PCOS phenotypes: A: oligo- of PCOS, presents an additive effect on metabolic risk factors, ovulation or anovulation þ clinical and/or biochemical hyper- due to an exacerbation of insulin resistance (IR).18 Insulin androgenism þ polycystic ovaries; B: oligo-ovulation or anov- resistance is considered to be a causal link between these ulation þ clinical and/or biochemical hyperandrogenism; C: factors and obesity, and is considered responsible for ampli- clinical and/or biochemical hyperandrogenism þ polycystic fying the reduction of tissue sensitivity to insulin.13,24 ovaries; D: oligo-ovulation or anovulation þ polycystic ova- It is essential to study the frequency of PCOS phenotypes, as ries. Environmental, cultural and genetic factors, as well as the well as their association with MetS in a given population group diagnostic criteria used, also affect the prevalence rates of in order to help produce measures for the prevention and early PCOS and its phenotypes. The literature states that the preva- treatment of cardiovascular diseases and type II diabetes. lence rates of PCOS vary between 2 and 20% in women of 3–8 reproductive age. Methods Many studies have demonstrated that women with PCOS generally have a greater risk of developing cardiovascular This was a descriptive, observational, cross-sectional study, disease and metabolic disorders when compared to control conducted between June 2015 and November 2016, in the city – groups.9 15 The metabolic disorders of PCOS are mainly of Recife, state of Pernambuco, Brazil. During this period, 163 related to hyperandrogenism and compensatory hyperinsu- women were referred from the primary health care services to – linemia, and occur independently of obesity.16 18 However, the outpatient clinics of the Hospital Geral of the Universidade little information is available as to whether cardiovascular Federal de Pernambuco (HC-UFPE, in the Portuguese acronym) risks are related with all the phenotypes of PCOS, the and of the Instituto de Medicina Integral Professor Feranando spectrum of which is broad and extends from women with Figueira (IMIP, in the Portuguese acronym), presenting with evident signs of hyperandrogenism and amenorrhea to those complaints of oligomenorrhea, when the menstrual cycle who do not present with hyperandrogenism or present with occurs at an interval 35 days, or secondary amenorrhea, regular cycles. It has recently been argued that, in terms of when there has been an absence of menstruation over three cardiovascular diseases and metabolic risks, not all women consecutive cycles or for 6 months, and/or signs of hyper- with PCOS should be considered equal.19 Metabolic disorders androgenism, considered as hirsutism. Of these, six were seem to be more prevalent in phenotypes A and B, that is, excluded because they presented other endocrinopathies:

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 Prevalence of Metabolic Syndrome in the Different Phenotypes Tavares, Barros 39 late-onset congenital adrenal hyperplasia (n ¼ 1), hyperthy- The selected patients were divided into four groups, roidism (n ¼ 2), hypothyroidism (n ¼ 1), hyperprolactinemia according to the phenotypes: A: oligo-ovulation or anovu- (n ¼ 2), and one because she was breastfeeding. Of these, 111 lation þ hyperandrogenism þ polycystic ovaries; B: oligo- women aged between 18 and 39 years old were diagnosed ovulation or anovulation þ hyperandrogenism; C: hyperan- with PCOS according to the Rotterdam Consensus, and agreed drogenism þ polycystic ovaries; D: oligo-ovulation or anov- to participate in the present research.2 Forty-five participants ulation þ polycystic ovaries. were lost because they did not perform all the laboratory tests The main objective of the present study was to evaluate and/or a pelvic ultrasound scan. the prevalence of MetS and its components in the different In the anamnesis, the characteristics of the menstrual phenotypes of PCOS. Metabolic syndrome was defined cycle were investigated, along with age, use of medications according to the consensus held in 2009 by several scientific and of contraceptive methods. Physical examinations were entities related to the study of cardiovascular diseases and performed at the first consultation by a single researcher, diabetes, which considered the diagnosis of MetS to be the and the same instruments/equipment (same manufacturers presence of at least three of the following criteria: abdominal and models) were used at both centers. The height in obesity (a waist 80 cm in women), hypertension (systolic centimeters (cm) and weight in kilograms (kg) of all the blood pressure 130 mmHg and/or diastolic 85 mmHg), patients were measured without shoes, in orthostatic posi- high levels of blood glucose (fasting level 100 mg/dL or a tion, with an anthropometric mechanical scale Filizola diagnosis of type 2 diabetes), high triglyceride levels ( 150 (Filizola, Parque Grajaú, SP, Brazil). During the physical mg/dL or in treatment), and a reduction in HDL cholesterol examination, the Waist Circumference (WC) was measured (< 50 mg/dL or in treatment).29 using a tape measure midway between the iliac crest and the Exclusion criteria were pregnant or lactating women, the lower costal border, and blood pressure was measured use of hormonal contraceptives or of any medications that according to the recommendations of the Seventh Brazilian could have interfered in the hormonal profile over the Guidelines for Hypertension.25 An evaluation of hirsutism previous 3 months, as well as the presence of other endo- was performed by the same researcher based on the presence crinopathies associated with anovulation. and distribution of terminal hair, according to the modified The calculation for the sample size proportions, a finite Ferriman-Gallwey scale (hirsutism was present with a score population equal to infinite, was carried out based on the 8).26 The women were evaluated after a pause in hair prevalence of a PCOS of 8.5%.30 According to these criteria, removal of at least 4 weeks, and none of the patients had the sample size for the study was 111 women. undergone permanent hair removal procedures. Data were entered into Excel 2010 (Microsoft Corpora- In the clinical laboratory at each center, blood was collected tion, Redmond, WA, USA) and analyzed in the R 3.3.1 from patients by venipuncture after fasting for at least 8 hours. statistical software (R Foundation, Vienna, Austria), which This sample was divided into 2 dry test tubes, centrifuged at is freely available at http://www.r-project.org. The graphs 3,500 revolutions per minute. In order to analyze the serum presented here were produced both in R and in Excel. hormone levels, one of the test tubes underwent a process of Initially, in the statistical analysis, a descriptive analysis of chemiluminescence using an Abbott Architect i2000 (Abbot the study variables was performed. For the continuous Laboratories, Chicago, IL, USA); and to evaluate levels of variables, we used the mean and median values as measures glycemia, triglycerides and high density lipoprotein (HDL) of central tendency, and the standard deviation (SD) as a cholesterol, the other test tube was processed by spectropho- measure of dispersion. Initially, in the univariate analyzes, tometry on the Beckman Coulter Au680 analyzer (Beckman the normality assumptions of the quantitative variables were Coulter, Brea, CA, USA). Blood levels were evaluated for glucose, evaluated with the Kolmogorov-Smirnov test. If the normal- triglycerides, HDL cholesterol, prolactin, 17-hydroxyproges- ity assumption was valid, the assumption of homogeneity terone, follicle stimulating hormone (FSH), luteinizing was evaluated by the Bartlett test, and in the absence of hormone (LH), thyroid stimulating hormone (TSH), free thy- normality, the modified Levene test was applied. A compari- roxine (T4), and β-hCG. The oral glucose tolerance test(OGTT) son of the variables among the four phenotypes of PCOS was was performed, which evaluates glycemia 2 hours after inges- performed using the analysis of variance (ANOVA) test, when tion of 75 g of glucose. The diagnosis of Impaired Glucose the normality and homogeneity assumptions were accepted, Tolerance was considered if the test value was greater than or and, in the absence of normality, by the Kruskal-Wallis non- equal to 140 mg / dL and less than 200 mg / dL.27 Insulin parametric test. The Fisher exact test was used for the resistance was also evaluated with homeostatic model assess- qualitative variables. The odds ratios (ORs) between the ment of insulin resistance (HOMA-IR), and IR was considered phenotypes for the development of MetS and of IR were as being present with a HOMA-IR 2.7.28 estimated with the multivariate analyzes. In order to identify All of the patients underwent ultrasound scans during any the possible factors associated with MetS and IR, we tested stage of the menstrual cycle; non-virgins underwent trans- the relationship between these outcomes and the study vaginal scans, and virgins underwent abdominal scans. The variables. The association was evaluated through the logistic imaging examinations were performed by the same profes- regression model under the stepwise regression forward sional in each service, who measured the ovarian volume, selection process. The variables were maintained in the final and if the value was > 10 cm3, classified it as polycystic model when they presented a p-value < 0.05, according to ovary.2 the maximum likelihood ratio test. Finally, the prevalence

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 40 Prevalence of Metabolic Syndrome in the Different Phenotypes Tavares, Barros

Table 1 The clinical, hormonal and metabolic characteristics of ratios for each of these variables were estimated with their patients with polycystic ovary syndrome. respective confidence intervals (CI), which were of 95%. All of the patients were informed of the risks and benefits Variables n % related to the procedures and the research, and together with Age (years old) the researcher, they read the Informed Consent Form (ICF). 18–20 16 14.4 The research was approved by the Research Ethics Commit- tee at IMIP. 20–25 23 20.7 – 25 30 37 33.3 Results 30–35 25 22.5 35–40 10 9.1 The clinical, hormonal and metabolic characteristics of the patients with PCOS are presented in ►Table 1. The prevalence BMI of each phenotype of PCOS presented the following distribu- < 2 25 kg/m 36 32.4 tion: 54.1% met the criteria of phenotype A; 11.7% of pheno- 25–30 kg/m2 26 23.4 type B; 14.4% of phenotype C; and 19.8% of phenotype D. 30 kg/m2 49 44.1 ►Table 2 presents the mean values of the continuous variables in relation to the phenotypes of PCOS, in which it Oligomenorrhea/amenorrhea 93 83.8 was identified that the mean values of fasting and 2 hours Hirsutism 87 78.4 after ingesting glucose (GTT) were higher in phenotype D, AC 80 cm 73 65.8 with values of 93.6 mg/dL and of 120.0 mg/dL, respectively. HDL < 50 mg/dL 60 54.1 The mean value of HDL cholesterol (44.7 mg/dL) was lower in phenotype D, whereas the mean triglycerides level (158 mg/ Triglycerides 150 mg/dL 39 35.1 dL) was higher in phenotype A. All of the four variables BP 130/85 mmHg 25 22.5 presented statistical significance (p < 0.05). Fasting glucose 100 mg/dL 8 7.2 ►Table 3 presents the prevalence of metabolic changes IR 44 39.6 among the phenotypes, and it may be observed that levels of < Impaired glucose tolerance 8 7.2 HDL cholesterol 50 mg/dL are more frequent in phenotype D, and were present in 77.3% of the women in this group. This Total testosterone 80 mg/dL 11 9.9 was the only variable with a statistically significant differ- PCO 98 83.3 ence (p < 0.05) among the phenotypes. Metabolic Syndrome 34 33.6 In the logistic regression analysis, the variables HOMA-IR, age, and body mass index (BMI) demonstrated an impact on Abbreviations: AC, abdominal circumference; BMI, body mass index; BP, the chance of developing MetS. The OR revealed that obesity blood pressure; HDL, high density lipoprotein; IR, insulin resistance; PCO, polycystic ovary. increased the chance of developing MetS by approximately 4.8 times (►Table 4).

Table 2 The mean (and standard deviation) of the continuous variables being studied

PCOS Phenotypes Variables A B C D p-value n ¼ 60 n ¼ 13 n ¼ 16 n ¼ 22 FG (mg/dL) 86.5 (8.8) 89.5 (10.8) 80.9 (9.1) 93.6 (16.4) 0.0207 HDL (mg/dL) 51.5 (14.2) 49.2 (9.4) 57.8 (12.3) 44.7 (11.7) 0.0251 Triglycerides (mg/dL) 158 (122.8) 98.4 (38.2) 132.2 (44.9) 117.5 (63.1) 0.0213 AC (cm) 85.2 (16.7) 82.5 (15.8) 83.9 (8.5) 90.11 (15.6) 0.5327 SBP (mmHg) 117 (16.8) 106.9 (18.4) 116.2 (10.2) 114.1 (13.0) 0.2944 DBP (mmHd) 74.8 (11.1) 70.8 (8.6) 76.2 (6.2) 74.3 (10.9) 0.4525 HOMA-IR 3.2 (2.3) 2.7 (2.5) 2.4 (1.5) 3.2 (2.2) 0.4157 OGTT (mg/dL) 112.7 (19.6) 107.9 (19) 102.6 (5.7) 120.0 (31.1) 0.0448 BMI (kg/m2) 29.34 (6.51) 27.08 (7.46) 29.15 (4.23) 29.10 (6.91) 0.5385

Statistically signiﬁcant comparisons (p < 0.05); Non-parametric Kruskal-Walls Test. Abbreviations: AC, abdominal circumference; BMI, body mass index; DBP, diastolic blood pressure; FG, fasting glucose; HDL, high-density lipoprotein; HOMA-IR, homeostatic model assessment of insulin resistance; OGTT, oral glucose tolerance test; PCOS, polycystic ovary syndrome; SBP, systolic blood pressure..

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 Prevalence of Metabolic Syndrome in the Different Phenotypes Tavares, Barros 41

Table 3 The number (and percentages) of metabolic syndrome, of each component of metabolic syndrome, of insulin resistance and of impaired glucose tolerance within each polycystic ovary syndrome phenotype

PCOS Phenotypes Variables A B C D p-value n ¼ 60 n ¼13 n ¼16 n ¼22 Metabolic syndrome 20 (33.3) 4 (30.8) 2 (12.5) 8 (36.4) 0.3811 FG 100 mg/dL 3 (5.0) 1 (7.7) 0.0 (0.0) 4 (18.2) 0.1225 HDL < 50 mg/dL 32 (53.3) 7 (53.8) 4 (25.0) 17 (77.3) 0.0155 Triglycerides 150 mg/dL 25 (41.7) 2 (15.4) 6 (37.5) 6 (27.3) 0.2826 AC 80 cm 38 (63.3) 7 (53.8) 13 (81.2) 15 (68.2) 0.4457 BP 130/85 mmHg 14 (23.3) 3 (23.1) 3 (18.7) 5 (22.7) 0.9844 IR 26 (43.3) 4 (30.8) 3 (18.7) 11 (50.0) 0.1943 Impaired GL tolerance 4 (6.7) 0.0 (0.0) 0.0 (0.0) 4 (18.2) 0.1541 Obesity 32 (53.3) 4 (30.8) 77 (43.7) 6 (27.3) 0.1403

Statistically signiﬁcant comparisons (p < 0.05); The Fisher exact test. Abbreviations: AC, abdominal circumference; BP, blood pressure; FG, fasting glucose; GL, glucose; HDL, high density lipoprotein; IR, insulin resistance; MetS, metabolic syndrome.

Table 4 The odds ratios and 95% conﬁdence intervals for Table 5 The risk ratio of developing metabolic syndrome predicting metabolic syndrome based on the logistic regression amongst the polycystic ovary syndrome phenotypes in the analyzes group of women with an abdominal circumference 80 cm

Variables Positive OR (95%CI) p-value AIC Phenotype x in relation to pheno- categories type y HOMA-IR 1.435 0.0120 xyOR 95% CI p-value (1.083–1.904) A B 0.833 (0.164–4.239) 0.8261 Age 1.159 0.0037 103.81 – (1.049–1.281) A C 6.111 (1.191 31.366) 0.0301 BMI 1.114 0.0290 A D 0.972 (0.294–3.220) 0.9632 – (1.011 1.227) B A 1.200 (0.236–6.105) 0.8261 IR HOMA-IR 2.595 0.0403 121.06 B C 7.333 (0.877–61.327) 0.0660 2.7 (1.043–6.459) B D 1.167 (0.191–7.116 0.8673 Obesity BMI 30 4.851 0.0009 (1.907–12.340) C A 0.164 (0.032–0.840) 0.0301 – Abbreviations: AIC, Akaike information criterion; BMI, body mass index; C B 0.136 (0.016 1.140) 0.0660 CI, confidence interval; HOMA-IR, homeostatic model assessment of C D 0.159 (0.026–0.978) 0.0473 insulin resistance; IR, insulin resistance; MetS, metabolic syndrome; OR, – odds ratio. D A 1.029 (0.311 3.407) 0.9632 D B 0.857 (0.141–5.228) 0.8673 In the logistic regression analysis, to evaluate the impact D C 6.286 (1.022–38.648) 0.0473 that each phenotype exerted over the chance of developing MetS, no statistically significant association was observed. Abbreviations: CI, confidence interval; OR, odds ratio. However, when evaluating the impact that each phenotype exerted on the risk of developing MetS in the group of women lence of phenotype D varies considerably among studies. In a with an AC 80 cm, the risk of developing MetS in pheno- study conducted by Ladrón de Guevara et al,20 who evaluated type A increased approximately six-fold in relation to phe- 220 Chilean women and 206 Argentinian women with PCOS, notype C (►Table 5). phenotype D (non-hyperandrogenic) was the least prevalent, and corresponded to 1% and to 10% in each country, 31 Discussion respectively. Clark et al encountered 11% of the participants with the D phenotype, while Diamanti-Kandarakis In the present study, it was identified that the classic et al32 discovered phenotype D in 6.78% of the participants. phenotypes, composed of A and B, were the most frequent, This variation in the prevalence of phenotype D (non- followed by the non-hyperandrogenic (D), and then by the hyperandrogenic) among studies may be due to the subjec- least frequent, the ovulatory (C), which is compatible with tivity involved in evaluating hirsutism, a relevant sign for results observed in other studies.3,10,16 However, the preva- evaluating clinical hyperandrogensim. The Ferriman and

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Gallwey scale presents low reproducibility with great inter- and the ovulatory (C). The prevalence of MetS and IR among observer variability, which may reach 50%, depending on the the PCOS phenotypes did not present statistically significant area being considered.33 However, it is a widely used instru- differences. Abdominal obesity played a significant role in ment in the clinical practice because it is easy to use and the the development of metabolic changes, irrespective of the costs involved are low.34 PCOS phenotype. Prospective studies are needed to identify The prevalence of MetS encountered in the present sample which clinical, hormonal and metabolic characteristics of was 33.6%, with no statistically significant difference between each phenotype in PCOS may be considered predictive the phenotypes. However, a lower prevalence was observed in factors for the onset of MetS. phenotype C (ovulatory). In the group of women with an AC 80 cm, we observed that in phenotype A, the risk of Contributors developing MetS increased approximately six-fold in relation Tavares A. and Barros R. C. R. contributed with the project to phenotype C (ovulatory), which is also corroborated in the and the interpretation of data, the writing of the article, literature.3,4,20 the critical review of the intellectual content and the final In the present study, the prevalence of IR in women with approval of the version to be published. PCOS was 39.6%, which is a comparable rate with that reported in the literature, which ranges from 25 to Conflicts of Interest 70%.9,16,17 However, when comparing the phenotypes, no The authors have no conflicts of interest to declare. statistically significant difference was observed in the prevalence of IR among the four groups. This finding differs from other studies, which report a higher frequency of IR in the classic phenotypes (A and B), attributing a relevant role to the References excess of androgen in the development of central obesity and 1 Fauser BC, Tarlatzis BC, Rebar RW, et al. Consensus on women’s 3,13,16,20–22,32,35 in an exacerbation of IR. health aspects of polycystic ovary syndrome (PCOS): the Amster- By evaluating each metabolic change separately, it may be dam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop observed that triglycerides 150 mg/dL were more prevalent Group. Fertil Steril 2012;97(01):28–38.e25. Doi: 10.1016/j. in phenotype A. We also identified that fasting glycemia 100 fertnstert.2011.09.024 2 Chang J, Azziz R, Legro R. Rotterdam ESHRE/ASRM-Sponsored mg/dL, decreasedglucose tolerance, HDL cholesterol < 50 mg/ PCOS Consensus Workshop Group (2004). Revised 2003 consen- dL, and IR were also found to be more frequent in phenotype D. sus on diagnostic criteria and long-term health risks related to With the exception of HDL cholesterol, the other variables did polycystic ovary syndrome. Fertil Steril 2004;81(01):19–25. Doi: not present statistical significance (p < 0.05). It should be 10.1016/j.fertnstert.2003.10.004 noted that the D phenotype group presented with a higher 3 Daan NM, Louwers YV, Koster MP, et al. Cardiovascular and fi prevalence of an increased AC, of which 68.2% demonstrated metabolic pro les amongst different polycystic ovary syndrome phenotypes: who is really at risk? Fertil Steril 2014;102(05): an AC 80 cm and presented the highest mean AC (90.1 cm), 1444–1451.e3. Doi: 10.1016/j.fertnstert.2014.08.001 which may justify the higher prevalence of metabolic changes 4 Yildiz BO, Bozdag G, Yapici Z, Esinler I, Yarali H. Prevalence, encountered within this group. This finding indicates the phenotype and cardiometabolic risk of polycystic ovary syn- preponderant role of abdominal obesity in developing meta- drome under different diagnostic criteria. Hum Reprod 2012;27 – bolic changes. The interrelations between PCOS and obesity (10):3067 3073. Doi: 10.1093/humrep/des232 5 Sirmans SM, Pate KA. Epidemiology, diagnosis, and management are complex. However, two important aspects may be of polycystic ovary syndrome. Clin Epidemiol 2013;6:1–13. DOI: – highlighted: 1 hyperandrogenism, which increases the ex- 10.2147/ CLEP.S37559 pression of genes involved in lipogenesis, with a predisposition 6 Dias JA, Cândido AL, Oliveira FR, Azevedo RCS, Rocha ALL, Reis FM. for fat accumulation, particularly in the abdominal cavity; 2 - LAP (produto da acumulação lipídica) e síndrome metabólica em IR with compensatory hyperinsulinemia, which stimulates pacientes com síndrome dos ovários policísticos. Reprod Clim. – androgen production in the ovaries and in the adrenal glands, 2015;30(03):127 131. Doi: 10.1016/j.recli.2015.11.005 7 Antunes MD, Ricci GCL, Macedo LC. Marcadores moleculares e thereby closing the feedback loop.17,19,36 A laboratory evalua- bioquímicos para a síndrome dos ovários policísticos. SaBios tion for hyperandrogenism was performed by determining the 2014;9:118–130 total blood levels of testosterone. Studies consider the mea- 8 Habib L, Gois M, Gilmar J, Santos C, Maria J, Dias G. A importância surement of free testosterone or free testosterone index as the da idade na síndrome metabólica em pacientes portadoras de most sensitive measures to assess hyperandrogenemia.2,34 To ovários policísticos. Int J Neurol 2016;9:199–208 evaluate the ultrasound scan of polycystic ovary, we only 9 Wiltgen D, Spritzer PM. Variation in metabolic and cardiovascular risk in women with different polycystic ovary syndrome pheno- considered an ovarian volume > 10 cm3. It was not possible types. Fertil Steril 2010;94(06):2493–2496. Doi: 10.1016/j. to obtain the follicular counting information, as recommended fertnstert.2010.02.015 2 by the Rotterdam Consensus. These characteristics may rep- 10 Freire GIM, Brito LMO, Chein MBC, Ribeiro ASS, et al. Síndrome dos resent methodological limitations of the present study. ovários policísticos em um serviço de referência: prevalência e risco cardiovascular associado. Rev Pesq Saúde. 2012;13:32–36 11 Martins WdeP, Soares GM, Vieira CS, dos Reis RM, de Sá MF, Conclusion Ferriani RA. [Cardiovascular risk markers in polycystic ovary syndrome in women with and without insulin resistance]. Rev The classic phenotypes of PCOS, composed of A and B, were Bras Ginecol Obstet 2009;31(03):111–116. Doi: 10.1590/S0100- the most frequent, followed by the non-hyperandrogenic (D) 72032009000300002

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12 Melo AS, Macedo CS, Romano LG, Ferriani RA, Navarro PA. licacoes.cardiol.br/2014/diretrizes/2016/05_HIPERTENSAO_AR- [Women with polycystric ovary syndrome have a higher fre- TERIAL.pdf. Accessed December 12, 2017 quency of metabolic syndrome regardless of body mass index]. 26 Cook H, Brennan K, Azziz R. Reanalyzing the modified Ferriman- Rev Bras Ginecol Obstet 2012;34(01):4–10. Doi: 10.1590/S0100- Gallwey score: is there a simpler method for assessing the extent 72032012000100002 of hirsutism? Fertil Steril 2011;96(05):1266–70.e1. Doi: 10.1016/ 13 Spritzer PM. Polycystic ovary syndrome: reviewing diagnosis and j.fertnstert.2011.08.022 management of metabolic disturbances. Arq Bras Endocrinol Meta- 27 Oliveira JEP, Vencio S, orgs. Diretrizes da Sociedade Brasileira de bol 2014;58(02):182–187. Doi: 10.1590/0004-2730000003051 Diabetes (2015–2016). São Paulo, SP A.C. Farmacêutica; 2016 14 Wild RA, Carmina E, Diamanti-Kandarakis E, et al. Assessment of 28 Geloneze B, Vasques AC, Stabe CF, et al; BRAMS Investigators. cardiovascular risk and prevention of cardiovascular disease in HOMA1-IR and HOMA2-IR indexes in identifying insulin resis- womenwith the polycystic ovary syndrome: a consensus statement tance and metabolic syndrome: Brazilian Metabolic Syndrome by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Study (BRAMS). Arq Bras Endocrinol Metabol 2009;53(02): Society. J Clin Endocrinol Metab 2010;95(05):2038–2049. Doi: 281–287. Doi: 10.1590/S0004-27302009000200020 10.1210/jc.2009-2724 29 Alberti KG, Eckel RH, Grundy SM, et al; International Diabetes 15 Wild RA, Rizzo M, Clifton S, Carmina E. Lipid levels in polycystic Federation Task Force on Epidemiology and Prevention; Hational ovary syndrome: systematic review and meta-analysis. Fertil Steril Heart, Lung, and Blood Institute; American Heart Association; 2011;95:1073–1079.e1–11. Doi: 10.1016/j.fertnstert.2010.12.027 World Heart Federation; International Atherosclerosis Society; 16 Moghetti P, Tosi F, Bonin C, et al. Divergences in insulin resistance International Association for the Study of Obesity. Harmonizing between the different phenotypes of the polycystic ovary syn- the metabolic syndrome: a joint interim statement of the Inter- drome. J Clin Endocrinol Metab 2013;98(04):E628–E637. Doi: national Diabetes Federation Task Force on Epidemiology and 10.1210/jc.2012-3908 Prevention; National Heart, Lung, and Blood Institute; American 17 Leão LM. Obesidade e síndrome dos ovários policísticos: vínculo Heart Association; World Heart Federation; International Ather- fisiopatológico e impacto no fenótipo das pacientes. Rev HUPE osclerosis Society; and International Association for the Study of 2014;13(01):33–37. Doi: 10.12957/rhupe.2014.9796 Obesity. Circulation 2009;120(16):1640–1645. Doi: 10.1161/ 18 Romano LG, Bedoschi G, Melo AS, et al. [Metabolic abnormalities circulationaha.109.192644 in polycystic ovary syndrome women: obese and non obese]. Rev 30 Gabrielli L, Aquino EM. Polycystic ovary syndrome in Salvador, Bras Ginecol Obstet 2011;33(06):310–316. Doi: 10.1590/S0100- Brazil: a prevalence study in primary healthcare. Reprod Biol 72032011000600008 Endocrinol 2012;10:96. Doi: 10.1186/1477-7827-10-96 19 Jovanovic VP, Carmina E, Lobo RA. Not all women diagnosed with 31 Clark NM, Podolski AJ,Brooks ED, et al. Prevalence ofpolycysticovary PCOS share the same cardiovascular risk profiles. Fertil Steril syndrome phenotypes using updated criteria for polycystic ovarian 2010;94(03):826–832. Doi: 10.1016/j.fertnstert.2009.04.021 morphology: an assessment of over 100 consecutive women self- 20 Ladrón de Guevara A, Fux-Otta C, Crisosto N, et al. Metabolic reporting features of polycysticovary syndrome. Reprod Sci 2014;21 profile of the different phenotypes of polycystic ovary syndrome (08):1034–1043. Doi: 10.1177/1933719114522525 in two Latin American populations. Fertil Steril 2014;101(06): 32 Diamanti-Kandarakis E, Panidis D. Unravelling the phenotypic 1732–9.e1, 2. Doi: 10.1016/j.fertnstert.2014.02.020 map of polycystic ovary syndrome (PCOS): a prospective study of 21 Carmina E, Chu MC, Longo RA, Rini GB,Lobo RA. Phenotypic variation 634 women with PCOS. Clin Endocrinol (Oxf) 2007;67(05): in hyperandrogenic women cardiovascular risk parameters. J Clin 735–742. Doi: 10.1111/j.1365-2265.2007.02954.x Endocrinol Metab 2005;90:2545–2549. Doi: 10.1210/jc.2004-2279 33 Marcondes JA, Barcellos CR, Rocha MP. Dificuldades e armadilhas 22 Kim JJ, Hwang KR, Choi YM, et al. Complete phenotypic and no diagnóstico da síndrome dos ovários policísticos. Arq Bras metabolic profiles of a large consecutive cohort of untreated Endocrinol Metabol 2011;55(01):6–15. Doi: 10.1590/S0004- Korean women with polycystic ovary syndrome. Fertil Steril 27302011000100002 2014;101(05):1424–1430. Doi: 10.1016/j.fertnstert.2014.01.049 34 Wild RA, Vesely S, Beebe L, Whitsett T, Owen W. Ferriman Gallwey 23 Oliveira EP, Lima Md, Souza MLA. Síndrome metabólica, seus self-scoring I: performance assessment in women with polycystic fenótipos e resistência à insulina pelo HOMA-RI. Arq Bras Endo- ovary syndrome. J Clin Endocrinol Metab 2005;90(07):4112–4114. crinol Metabol 2007;51(09):1506–1515. Doi: 10.1590/S0004- Doi: 10.1210/jc.2004-2243 27302007000900014 35 Carvajal GR, Herrera GC, Porcile JA. Espectro fenotípico del 24 Foss-Freitas MC, Gomes PM, Andrade RC, et al. Prevalence of the síndrome de ovario poliquístico. Rev Chil Obstet Ginecol 2010; metabolic syndrome using two proposed definitions in a Japa- 75(02):124–132. Doi: 10.4067/S0717-75262010000200009 nese-Brazilians community. Diabetol Metab Syndr 2012;4(01): 36 Anzai A. Análise Metabolômica e Histomorfométrica do Fígado de 38. Doi: 10.1186/1758-5996-4-38 Ratas Adultas em Modelo Experimental da Síndrome dos Ovários 25 Malachias M, Souza W, Plavnik F, et al. 7a Diretriz Brasileira de Policísticos Induzida por Exposição Neonatal a Esteroides Sexuais Hipertensão Arterial. Arq Bras Cardiol 2016;107:1–83http://pub- [dissertação]. São Paulo, Brasil: Universidade São Paulo; 2015

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 THIEME 44 Review Article

Isthmocele: From Risk Factors to Management Istmocele: de fatores de risco ao manejo

Piergiorgio Iannone1 Giulia Nencini1 Gloria Bonaccorsi1 Ruby Martinello1 Giovanni Pontrelli2 Marco Scioscia2 Luigi Nappi3 Pantaleo Greco1 Gennaro Scutiero1

1 Section of Obstetrics and Gynecology, Department of Morphology, Address for correspondence Piergiorgio Iannone, MD, Ginecologia e Surgery and Experimental Medicine, Azienda Ospedaliero- Ostetricia, Dipartimento di Morfologia, Chirurgia e Medicina Universitaria S. Anna, Università di Ferrara, Cona, Ferrara, Italy sperimentale, Azienda Ospedaliero-Universitaria S. Anna, Università di 2 Section of Obstetrics and Gynaecology, Policlinico di Abano Terme, Ferrara, Via Aldo Moro, 8, 44121 Cona, Ferrara, Italy Abano Terme, Padova, Italy (e-mail: [email protected]). 3 Department of Medical and Surgical Sciences, Institute of Obstetrics and Gynecology, University of Foggia, Foggia, Italy

Rev Bras Ginecol Obstet 2019;41:44–52.

Abstract Objective The aim of the present study was to perform a comprehensive review of the literature to provide a complete and clear picture of isthmocele—a hypoechoic area within the myometrium at the site of the uterine scar of a previous cesarean section—by exploring in depth every aspect of this condition. Methods A comprehensive review of the literature was performed to identify the most relevant studies about this topic. Results Every aspect of isthmocele has been studied and described: pathophysiology, Keywords clinical symptoms, classiﬁcation, and diagnosis. Its treatment, both medical and ► isthmocele surgical, has also been reported according to the actual literature data. ► niche Conclusion Cesarean section is the most common surgical procedure performed ► cesarean section scar worldwide, and one of the consequences of this technique is isthmocele. A single and defect systematic classiﬁcation of isthmocele is needed to improve its diagnosis and ► hysteroscopy management. Further studies should be performed to better understand its ► laparoscopy pathogenesis.

Resumo Objetivo O objetivo do presente estudo foi realizar uma revisão abrangente da literatura a fim de fornecer um quadro completo e claro da istmocele—uma área hipoecoica dentro do miométrio no local da cicatriz uterina de uma cesariana anterior— aprofundandotodososaspectosdestacondição Métodos Uma revisão abrangente da literatura foi realizada para identificar os estudosmaisrelevantessobreestetema. Palavras-chave Resultados Todososaspectosdaistmoceleforamestudadosedescritos:fisiopato- ► istmocele logia, sintomas clínicos, classificação e diagnóstico. Os tratamentos médico e cirúrgico ► nicho também foram relatados de acordo com os dados reais da literatura. ► defeito cicatricial de Conclusão A cesárea é o procedimento cirúrgico mais comum realizado em todo o cesariana mundo, e uma das consequências desta técnica é a istmocele. Uma classificação única e ► histeroscopia sistemática da istmocele é necessária para melhorar seu diagnóstico e manejo. Novos ► laparoscopia estudos devem ser realizados para melhor entender sua patogênese.

ORCID ID is https://orcid.org/0000-0001-9485-0126.

received DOI https://doi.org/ Copyright © 2019 by Thieme Revinter August 14, 2018 10.1055/s-0038-1676109. Publicações Ltda, Rio de Janeiro, Brazil accepted ISSN 0100-7203. October 10, 2018 Isthmocele: From Risk Factors to Management Iannone et al. 45

1,6,11 Introduction chronic pelvic pain, dyspareunia, and infertility. They may also be responsible for future obstetrical complications, Cesarean section (CS) is one of the most common surgical such as ectopic pregnancy, uterine rupture, and placental operations performed worldwide.1 Nevertheless, the per- anomalies (for example, placenta accreta).11 The objective of centage of CS deliveries has dramatically increased in most the present review was to give awide and complete overviewof developed countries in the last decades, which has given rise the current literature by describing every aspect of this condi- to a great concern.2,3 According to the latest data from 150 tion, deeply analyzing its risk factors, its diagnosis, and its countries, CS rates range from 6 to 27.2%.3,4 A higher mater- surgical and medical management. nal socioeconomic status seems to be associated with a 5 greater likelihood of CS. The World Health Organization Methods (WHO) states that the optimal CS rate is around 15%.6 Cesarean incisions usually heal without consequences, but A review of the literature was conducted to identify the most there is always the possibility of complications. Lately, the relevant studies reported in the English language. We have increasing rate of CSs has increased the interest in the short- searched the PubMed MEDLINE electronic database, the and long-term morbidity of cesarean scar defect.7 International Prospective Register of Systematic Reviews Cesarean scar defect—also called isthmocele, niche, diver- (PROSPERO) database, the Cochrane Database, the Centre ticulum or pouch—was first described by Poidevin in 19618 for Reviews and Dissemination (CRD) database, the Database as a wedge-shaped defect in the uterine wall. Due to the of Abstracts of Reviews of Effects (DARE), and the National variety of names, we prefer to refer to this defect as isthmo- Institute for Health Research (NHS) database and studied all cele, which, we think, gives a better idea of the anatomical the articles published until October 2017. The keywords used defect described. were: isthmocele, niche, cesarean section defect, cesarean Isthmocele can be defined as a hypoechoic area within the section scar, cesarean section diverticulum,andcesarean myometrium of the lower uterine segment, reflecting a section pouch. Different combinations of the terms were discontinuation of the myometrium at the site of the uterine used. The filters used were studies conducted in humans, scar of a previous CS.6,7 systematic reviews, trials, meta-analyses, and multicentric Bij de Vaate et al9 definedisthmoceleasananechoicareaat trials. Moreover, the references in each article were searched the site of the cesarean scar with a depth of at least 1 mm. The in order to identify potentially missed studies. prevalence of isthmocele is difficult to quantify, ranging between 24 and 70% using transvaginal ultrasound, and between Results 56 and 84% using sonohysterography (SHG).1,10 In > 50% of the women with a history of CS, isthmocele can be observed when The research led to the retrieval of 105 articles; other 3 examined by SHG between 6 and 12 months after the CS.7 articles and 1 book were added manually. Thirty articles Cesarean section defects can be asymptomatic. However, in were excluded from our research. The exclusion criteria many cases, they can lead to a series of gynecological symp- were: articles not in English, not relevant to the review, toms, such as abnormal uterine bleeding, dysmenorrhea, and abstracts. ►Fig. 1 shows the selection process.

Fig. 1 Flowchart of the article selection process.

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 46 Isthmocele: From Risk Factors to Management Iannone et al.

Fig. 2 Classiﬁcation of studies according to Oxford Centre for Evidence et al. based Medicine.

We have divided the articles following the grades of rec- recent research also observed that the incidence of cesarean ommendations and levels of evidence proposed by the Oxford scar formation and niche depth was independent of the Centre for Evidence-Based Medicine, as shown in ►Fig. 2. hysterotomy closure technique used.20 In a recent meta-analysis, Di Spiezio Sardo et al7 reported that women who received a Discussion single-layer uterine closure had a similar incidence of uterine scar defects as women who received a double-layer closure. Pathophysiology Ceci et al,21 however, observed that patients who received a The pathophysiology of the development of isthmocele is locked continuous single-layer suture compared with the still unclear, although many authors have studied the asso- interrupted single-layer suture group showed a defect area ciated risk factors.2,6,11 However, data available in the cur- statistically larger on ultrasound and hysteroscopy evaluation, rent literature are very poor due to the lack of evidence. probably due to an ischemic effect on the uterine tissue.21,22 Nevertheless, the pathophysiology may be related both to the The hypothesis might be that not closing the deeper mus- surgery technique and to patient factors. cular layer leads to a disrupted myometrium and to the development of isthmocele.6 However, due to missing data, fi Risk Factors: Surgery and Patient a speci c surgical technique for uterine closure cannot be recommended yet.7 Surgery Technique Factors Another proposed hypothesis is the surgery itself.6 It is well Very low uterine incisions are reported to be independent risk known that surgery can lead to the development of adhesion, factors for the development of isthmocele.12 A higher preva- and that many factors may influence this process, such as lence of CS defects has been observed in those patientswitha CS inflammation, tissue ischemia, tissue manipulation, and inad- performed during active labor with cervical effacement.13 equatehemostasis.23 Theformation of adhesion between the CS Vikhareva Osser et al14 described an increased development scar and the abdominal wall might be a cause of the develop- of isthmocele in case of a cervical dilatation > 5 cm or of a labor ment of isthmocele. Vervoort et al6 hypothesized that the duration of > 5 hours. Moreover, isthmocele was observed in retraction of the scar tissue might pull the uterine scar toward theupper two-thirds of thecervix inwomenwith anelective CS, the abdominal wall, inducing the development of isthmocele. while, in the case of CSs performed after cervical dilatation, the niche was in the lower part of the cervical canal.15 An explana- Patient Factors tion to this phenomenon might be that lower incisions through Patient factors may play a role in isthmocele and in the CS the cervical tissue, which contains mucus-producing glands, healing process, due to individual differences.6 Some studies might interfere negatively with the wound healing process.6 have observed the association between the development of Another plausible factor is the closure technique, that is, scar defects and patient factors, such as retroflexed uterus, double- versus single-layer closure.2,6,7 These techniques vary multiple CSs, body mass index (BMI), and hypertension, but among countries and have changed over the years. For example, its mechanism of action remains unclear.2,6 in some European countries, such as Belgium and the We still do not know why some patients develop caesare- Netherlands, the single-layer closure technique is the most an scar defects while others do not. Probably, a single performed, while in the United Kingdom, double-layer closure individual genetic predisposition along with other unknown is the recommended technique.6,16 The CORONIS17 and the factors might be the key to this phenomenon. Further studies CAESAR18 trials evaluated maternal outcomes after 6 weeks in are needed to answer this question. patients undergoing CS with either the double- or the single- layer technique. Both trials observed no significant differences Clinical Symptoms in terms of maternal outcomes in both surgical methods. A As first described by Morris in 1995,24 cesarean scar defects 2014 review by Roberge et al19 also found no difference in the may be associated with clinical symptoms. The most frequent development of scar defects among the techniques used. A complaints reported by the patients is abnormal uterine

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 Isthmocele: From Risk Factors to Management Iannone et al. 47 bleeding (AUB), in particular postmenstrual spotting.11,25 defect.9 The residual myometrium is the vertical distance Abnormal uterine bleeding was found to be present in be- between the serosal surface of the uterus and the apex of tween 28.9 and 82% of the studied cases, and it seems that the defect.9,11 there is a correlation between the size of the cesarean defect The residual myometrium thickness is the most useful and the symptoms.1,25,26 The pathogenesis of AUB following discriminating measurement in the evaluation of isthmo- the development of isthmocele remains unexplained.27 It has cele.35 The residual myometrium appears thinner on ultra- been hypothesized that menstrual blood can accumulate in the sound inwomenwho received a single-layer closure compared pouch defect and then seep out slowly over the days after with those who received a double-layer closure.7 Moreover, menses.11 Thurmond et al28 also suggested that the disorder the scar is less thick in patients with two or more previous CSs, results from impaired uterine contractility at the scar area. and thicker in patients who underwent the last of the previous Several authors have reported and observed a connection CS > 2 years earlier.36 Large scar defects have been linked to an between isthmocele, dysmenorrhea, and pelvic pain. The increased risk of uterine rupture, although the real risk of presence of these symptoms might be related to the size of isthmocele remains unexplained.37 Some authors have pro- the defect.1 Some plausible explanations have been proposed, posed a cutoff of residual myometrium for risk of uterine as the presence of lymphocytic infiltration and anatomical rupture, varying between 2.5 mm and 3 mm.35 distortion, or of abnormal myocontracture due to the contin- Another important concept is the deficiency degree, in- uous efforts of the uterus to empty the contents of the troduced by Ofili-Yebovi et al,38 which is described as the isthmocele.11,25 ratio between the myometrial thickness at the scar and the Infertility may also represent a big issuefor patients with CS thickness of the adjacent myometrium. A deficiency rate defects. The lower fertility rate might be related to the persis- of < 50% was described as severe.38 tence of menstrual blood in the pouch, which affects the Since first described by Zilberman et al,39 saline infusion cervical mucus, as well as sperm motility and implantation.2,25 SHG has been widely used to assess the uterine cavity in Infertility might also be caused by an inflammatory condition, patients with suspected endometrial or intracavitary disease as it is already known in pathologies characterized by chronic for whom the TVUS might not give a defined diagnosis.39,40 inflammatory states and oxidative stress, such as endometri- Moreover, SHG increases the sensitivity and the specificity for – osis or endometritis.29 31 In isthmocele, the presence of the detection of CS scars by enhancing the defect.11 The residual menstrual blood might also lead to an environment prevalence of cesarean scar defects in randomly selected of chronic inflammation, thus affecting fertility.11 women appears to be higher in SHG compared with in TVUS Even though it is rare, isthmocele might lead to the (56–84% versus 24–70%), and the defect seems to be deeper or formation of an abscess due to the collection of mucus and larger in the SHG.1,25 The increased prevalence and scar size, menstrual blood, which act as an infection-promoting fac- when using SHG, is due to an exaggeration of the size of the tor.32 Another reported complication is caesarean scar ec- defect caused by the increased intrauterine pressure.1 topic pregnancy, with an incidence of 1 in 1,886 to 2,216 Isthmocele may also be diagnosed by hysterosalpingogra- pregnancies.25 With the development of the fetus and of the phy as an extension of contrast into the myometrial defect at gestational sac, the walls of the isthmocele might rupture, the site of a previous cesarean hysterotomy.11 Magnetic reso- leading to the known severe complications related to an nance imaging (MRI) represents another valuable tool that ectopic pregnancy.11,25 may be helpful to diagnose and characterize isthmocele.11,25 Magnetic resonance imaging is useful to evaluate the thickness Classification and Diagnosis of the lower uterine segment, the depth of the isthmocele, and Since 1990, when first described by Chen et al,33 ultrasound, the content of the endometrial and defect cavities.25 in particular transvaginal ultrasound (TVUS) has been used This imaging method, MRI, may clearly define the defect to evaluate caesarean scar defects. Nowadays, TVUS can be and enable a faster diagnosis when patients complain of considered the most common initial technique to identify otherwise unexplainable AUB.11,41 isthmocele in patients with a history of previous CS.11 Some authors suggest that the ideal moment to perform this Treatment diagnostic exam is during the early follicular phase, assum- The treatment of isthmocele is performed to relieve symp- ing that the endometrium may improve the identification of toms. Consequently, the asymptomatic cases should not be the defect and the measurement of its depth and size.9 treated.42 The treatment can be medical, although surgery is Isthmocele has been reported with several descriptions: as the most common treatment of choice, based on different a triangular anechoic area, as a filling defect on the anterior approaches: hysteroscopy, laparoscopy (including robotic isthmus, or as cystic mass between the lower uterine segment laparoscopy), laparotomy, vaginal repair, and combined and the bladder.11,34 Bij de Vaate et al9 proposed a more techniques. As it is well known, every surgical treatment systematic classification using six shapes to describe the has its own specific complications, such as infections, blad- defect: triangle, semicircle, rectangle, circle, droplet, and in- der and bowel injuries, and hemorrhage.43 clusion cysts. In this study, during a TVUS exam, the uterus was examined for isthmocele: position, length, width, depth, and Medical Treatment residual myometrium were recorded. A depth of at least 1 mm Many authors describe the effectiveness of oral contraceptives – is the vertical distance between the base and apex of the in reducing bleeding disorders correlated to isthmocele.44 46

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The mechanism ofaction of hormonal treatment may be due to the symptoms was associated not only with the removal of a regulatory effect on the endometrium.44 Tahara et al46 the scar diverticulum, in which the menstrual blood tends to demonstrated a diminution and cessation of the spotting after be retained, but also with the fulguration of dilated vessels three cycles of treatment with oral contraceptive pills in that constitute a potential additional source of non-men- studied patients, and also observed a disappearance of scar strual bleeding.50 dehiscences smaller than 3 mm after the treatment. Good outcomes were also found regarding infertility: the Florio et al44 compared the effectiveness of hysteroscopic majority of patients who desired to get pregnant conceived correction and of hormonal treatment to improve symptoms spontaneously between 12 and 24 months after the associated with isthmocele. They showed that, compared isthmoplasty.54,55 with hormonal treatment, resectoscopic correction is more According to Zhang et al,45 the comparison between effective in shortening the duration of postmenstrual AUB hysteroscopy and medical treatment, intrauterine device and in reducing the prevalence of pelvic pain.44 (IUD), laparoscopy, and vaginal repair showed that hystero- Zhang et al45 evaluated operative and non-operative scopic surgery offered the advantages of shorter operation therapies, considering laparoscopy, vaginal repair, hysteros- time, reduced blood loss, decreased length of hospital stay, copy, oral contraceptives, and levonorgestrel intrauterine and lower hospital fees. However, one of the limitations of system (LNG-IUS). All of the methods investigated, except the resectoscopic treatment is the impossibility of the perfor LNG-IUS, are useful in reducing the menstruation length formance of sutures.59 This is why the scar defect could in symptomatic patients.45 enlarge further, and the myometrial thickness at the level of Therefore, oral contraceptive pills might represent a valid the uterine isthmus could further decrease, increasing the option for symptomatic women who do not want to get risk of uterine rupture during future pregnancies.60 pregnant and prefer a conservative therapy. In the last few years, the development of new technologies applied to hysteroscopy have led to new interesting thera- Hysteroscopy peutic applications of minimally invasive surgery for the – Hysteroscopy is the gold standard procedure for uterine treatment of many pathologies.61 63 Therefore, these new cavity and cervical canal exploration and is the investigation advances could change the way to approach the repair of – of choice for AUB.47 49 During the hysteroscopy, the isthmo- isthmocele. cele appears as a bulging on the anterior wall of the cervical canal, easy to be localized on the isthmus site.34 Vaginal Repair Once diagnosed, an operative hysteroscopy can be per- Isthmocele vaginal repair has been evaluated by many formed totreat the defect, with atechnique called isthmoplasty. authors.45,56,59,64,65 After identifying the defect as a small According to the literature, the essential parameter to hollow area or depression at the uterine isthmus, thanks also perform hysteroscopy is the residual myometrial thickness; to the guidance of a probe in the uterus, Chen et al65 performed indeed, with the hysteroscopic approach, there is a risk of a transverse incision at the most prominent area of the bulge; bladder injury and uterine perforation if the myometrium afterwards, the isthmocele was removed, and the edges of the thickness at the site of the defect is < 3 mm.50 Some authors incision were trimmed to repair it. Then, the myometrial and suggest hysteroscopy to women with a residual myometrial vaginal defects were closed. The median operation time was thickness > 2 to 2.5 mm or with a scar defect size to myo- 33.6 minutes.65 Clinical improvement was observed in be- metrial thickness ratio < 5 0% and with no desire to get tween 85.9 and 92.9% of the patients: the prolonged menstrual – pregnant.51 53 symptoms were improved after the surgery, and a significant There is no homogeneous method to perform isthmo- difference was found between the mean preoperative and plasty, but almost every author uses a 9 mm resectoscope postoperative menstruation length.59,65 Isthmocele transva- and unipolar electrical current. Gubbini et al54 performed a ginal repair is comparably effective to the laparoscopic repair, resection of the defect by removing the isthmocele edges and but the surgical time is significantly shorter and the hospitali- by putting its wall in continuity with the cervical canal wall. zation expenses are lower.45 Fabres et al55 resected one edge of the scar and coagulated the thinnest part of the defect, allowing menstrual flow Laparotomy drainage to the cervix. Xie et al,56 who published one of With laparotomy, a complete resection of the dehiscent myo- the largest studies on isthmoplasty, performed it by simply metrium and an accurate uterine reconstruction can be per- removing the fibrotic tissue under the defect. As reported by formed.25,60,66 Pomorski et al66 proposed a minilaparotomy to Abacjew-Chmylko et al,50 some authors prefer to perform patients who fulfilled three criteria: presence of symptoms, resectoscopy under ultrasonographic guidance, but this ap- refusal of hormonal therapy, and residual myometrial thick- proach is not related to a lower morbidity rate. ness < 2.2 mm (this value increases the risk of uterine scar According to the literature, the mean time for resecto- dehiscence or of rupture in a subsequent pregnancy). This scopic treatment varies from 8 to 25 minutes.15,51,56 Gubbini cutoff value was chosen because if the thickness was larger, a et al57 and Florio et al58 found an association between the less invasive method was to be preferred. The minilaparotomy duration of the isthmoplasty and the size of the niche. of Pomorski et al66 was performed at the site of a previous CS. The total amount of successful outcomes of isthmoplasty After the scar defect was identified, it was excised up to the – is 85.5% (59.6–100%).15,27,51 55,58 An evident attenuation of endometrial layer of the anterior uterine wall, and, after that,

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 Isthmocele: From Risk Factors to Management Iannone et al. 49 the incision was closed. Shepker et al60 report a similar surgical ening the myometrial wall. In fact, Api et al79 analyzed the technique but using a double-layered interrupted suture for myometrial thickness, finding a mean value of 2 mm (0.7–6.2 uterine closure. Shepker et al60 recommend a complete ab- mm) before the laparoscopy and of 9.8 mm (2.5–13.1 mm) dominal resection of the niche and a reconstruction of the after the surgery. Vervoort et al78 published the first large uterus by an exact adaptation of the margins of the wound in prospective cohort study that evaluated the effect of laparo- order to minimize the risk of subsequent uterine rupture.60 scopic isthmocele resection on symptoms, on fertility, and on Laparotomy correction was successful in relieving postmenst- ultrasound findings, evaluating 101 women. In this study, rual spotting and abdominal pain, and a significant improve- Vervoort et al78 showed that the laparoscopic approach ment in residual myometrial thickness was observed: reduces postmenstrual spotting and its correlated discom- preoperatively, the mean thickness was 1.9 mm, and 2 to fort, reduces dysmenorrhea, and enlarges the residual myo- 3 days after surgery, the mean thickness was 8.8 mm.60,66 metrial thickness 6 months after the intervention. The Jeremy et al67 described a pregnancy rate of 71% following pregnancy rate after the laparoscopic approach is estimated the laparotomy procedure. to be 44%, as reported by Donnez et al.35

Laparoscopy Conclusion Since Jacobson et al68 first described the laparoscopic isthmocele resection in 2003, several authors adopted and Aunified definition of CS defects should be formulated to – described this surgical approach.35,45,51,64,68 79 Laparoscopy have a unique, international terminology in order to avoid is a technique that has to be preferred especially if the confusion in the literature. However, the main question of residual myometrial thickness is < 3mm.78 which surgical technique of CS diminishes the risk of scar A skilled laparoscopic surgeon can use conventional lap- development and its symptoms will probably remain unan- aroscopy or robotic-assisted surgery to correct the isthmo- swered. The clinical importance of isthmocele, however, cele.25 After the defect is identified, it is cut open and the relies on the diagnosis improvement with imaging tools. isthmocele and the surrounding fibrotic tissue are trimmed Every time we suspect the presence of isthmocele in a patient carefully and removed from the edges of the defect to access with at least one CS in her history, the first diagnostic the healthy myometrium.71 Before closing, Donnez et al35 approach should be performed with TVUS and SHG, espe- insert a Hegar probe into the cervix to preserve the continu- cially in those patients with AUB, pelvic pain, infertility, and ity of the cervical canal with the uterus and perform a dysmenorrhea. Isthmocele treatment should be based on the double-layer closure with separate sutures. history of the symptoms of the patient, on, the desire of The critical step of the laparoscopic procedure is to future pregnancy, and on the characteristics of the isthmo- correctly identify the isthmocele.25 This can be done using cele. Therefore, it is very important to discuss the manage- various techniques: easily laparoscopic visualization after ment with the patient, although it is not possible to speculate dissecting the uterovesical peritoneum; hysteroscopy per- which treatment appears to be superior to the other. It is formed at the same time of the laparoscopy to evaluate the important to highlight that treatment should be proposed uterine cavity and the defect; moreover, the hysteroscopic only to symptomatic patients. Isthmocele is a very fertile and transillumination better reveals the edges of the de- actual field of research due to its increased rate. Further fect.35,51,74 Klemm et al64 recommended that if the scar studies are needed to prevent its development and to in- was not immediately identifiable after the dissection of the crease the efficacy of its management. uterovesical fold, a transvaginal sonography under laparo- Conflicts of Interest scopic view could be performed. Akdemir et al76 reported a fl case in which, during laparoscopy, a Foley catheter was used The authors have no con icts of interest to declare. to identify the defect. The Foley catheter was inserted into the uterine cavity through the cervical canal, then it was filled at the lower uterine segment and, in this way, the References fi 76 79 isthmocele was clearly identi ed. Api et al described a 1 Tulandi T, Cohen A. Emerging manifestations of cesarean scar technique named the “slip and hook technique”: since the defect in reproductive women. J Minim Invasive Gynecol 2016;23 defect could not be identified by laparoscopy and the light (06):893–902 Doi: 10.1016/j.jmig.2016.06.020 source of the laparoscope could not recognize the transillu- 2 Bij de Vaate AJ, van der Voet LF, Naji O, et al. Prevalence, potential risk factors for development and symptoms related to the pre- mination of the hysteroscopic light through the scar, a Hegar sence of uterine niches following Cesarean section: systematic probe was placed in the cervical canal and then slipped review. Ultrasound Obstet Gynecol 2014;43(04):372–382 Doi: forward blindly at the level of the uterine isthmus, bulging 10.1002/uog.13199 out the niche on the uterine wall. The continuing pressure on 3 Indraccolo U, Scutiero G, Matteo M, Indraccolo SR, Greco P. the defect led to a “hooking effect”, allowing its perforation Cesarean section on maternal request: should it be formally – under laparoscopic visualization.79 The surgical time varies prohibited in Italy? Ann Ist Super Sanita 2015;51(02):162 166 Doi: 10.4415/ANN_15_02_15 between 42 and 90 minutes, and 240 minutes were needed 4 Betrán AP, Ye J, Moller AB, Zhang J, Gülmezoglu AM, Torloni MR. The 51,70,75,79 for the robotic excision. increasing trend in caesarean section rates: global, regional and The laparoscopic approach treats symptoms by eliminat- national estimates: 1990–2014. PLoS One 2016;11(02):e0148343 ing the reservoir effect of the defect, concomitantly strength- Doi: 10.1371/journal.pone.0148343

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The pathogenesis of endometrial polyps: a systematic semi- section diverticulum: a novel surgical treatment. Med Sci Monit quantitative review. Eur J Gynaecol Oncol 2013;34(01):5–22 2014;20:1395–1399 Doi: 10.12659/MSM.890642 49 Scutiero G, Nappi L, Matteo M, Balzano S, Macarini L, Greco P. 66 Pomorski M, Fuchs T, Rosner-Tenerowicz A, Zimmer M. Sono- Cervical pregnancy treated by uterine artery embolisation com- graphic evaluation of surgical repair of uterine cesarean scar bined with office hysteroscopy. Eur J Obstet Gynecol Reprod Biol defects. J Clin Ultrasound 2017;45(08):455–460 Doi: 10.1002/ 2013;166(01):104–106 Doi: 10.1016/j.ejogrb.2012.10.013 jcu.22449 50 Abacjew-Chmylko A, Wydra DG, Olszewska H. Hysteroscopy in 67 Jeremy B, Bonneau C, Guillo E, et al. [Uterine ishtmique trans- the treatment of uterine cesarean section scar diverticulum: A mural hernia: results of its repair on symptoms and fertility]. systematic review. Adv Med Sci 2017;62(02):230–239 Doi: Gynécol Obstét Fertil 2013;41(10):588–596 Doi: 10.1016/j. 10.1016/j.advms.2017.01.004 gyobfe.2013.08.005 51 Li C, Guo Y, Liu Y, Cheng J, Zhang W. Hysteroscopic and laparo- 68 Jacobson MT, Osias J, Velasco A, Charles R, Nezhat C. Laparoscopic scopic management of uterine defects on previous cesarean repair of a uteroperitoneal fistula. JSLS 2003;7(04):367–369 delivery scars. J Perinat Med 2014;42(03):363–370 Doi: 69 Donnez O, Jadoul P, Squifflet J, Donnez J. Laparoscopic repair 10.1515/jpm-2013-0081 of wide and deep uterine scar dehiscence after cesarean sec- 52 Chang Y, Tsai EM, Long CY, Lee CL, Kay N. Resectoscopic treatment tion. Fertil Steril 2008;89(04):974–980 Doi: 10.1016/j. combined with sonohysterographic evaluation of women with fertnstert.2007.04.024 postmenstrual bleeding as a result of previous cesarean delivery 70 Yalcinkaya TM, Akar ME, Kammire LD, Johnston-MacAnanny EB, scar defects. Am J Obstet Gynecol 2009;200(04):370.e1–370.e4 Mertz HL. Robotic-assisted laparoscopic repair of symptomatic Doi: 10.1016/j.ajog.2008.11.038 cesarean scar defect: a report of two cases. J Reprod Med 2011;56 53 Feng YL, Li MX, Liang XQ, Li XM. Hysteroscopic treatment of (5-6):265–270 postcesarean scar defect. J Minim Invasive Gynecol 2012;19(04): 71 Liu SJ, Lv W, Li W. Laparoscopic repair with hysteroscopy of 498–502 Doi: 10.1016/j.jmig.2012.03.010 cesarean scar diverticulum. J Obstet Gynaecol Res 2016;42(12): 54 Gubbini G, Casadio P, Marra E. Resectoscopic correction of the 1719–1723 Doi: 10.1111/jog.13146 “isthmocele” in women with postmenstrual abnormal uterine 72 Bakavičiūtė G, Špiliauskaitė S, Meškauskienė A, Ramašauskaitė D. bleeding and secondary infertility. J Minim Invasive Gynecol Laparoscopic repair of the uterine scar defect - successful treat- 2008;15(02):172–175 Doi: 10.1016/j.jmig.2007.10.004 ment of secondary infertility: a case report and literature review. 55 Fabres C, Arriagada P, Fernández C, Mackenna A, Zegers F, Fer- Acta Med Litu 2016;23(04):227–231 Doi: 10.6001/actamedica. nández E. Surgical treatment and follow-up of women with v23i4.3424 intermenstrual bleeding due to cesarean section scar defect. 73 van der Voet L, Vervoort A, Veersman S. BijdeVaate A, Brolmann H, J Minim Invasive Gynecol 2005;12(01):25–28 Doi: 10.1016/j. Huirne J. Minimally invasive therapy for gynaecological symp- jmig.2004.12.023 toms related to a niche in the cesarean scar: a systematic review. 56 Xie H, Wu Y, Yu F, He M, Cao M, Yao S. A comparison of vaginal BJOG 2014;121:145–156 Doi: 10.1111/1471-0528.12537 surgery and operative hysteroscopy for the treatment of cesar- 74 Suarez Salvador E, Haladjian MC, Bradbury M, et al. 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75 Urman B, Arslan T, Aksu S, Taskiran C. Laparoscopic repair of repair. Curr Opin Obstet Gynecol 2017;29(04):257–265 Doi: cesarean scar defect “isthmocele”. J Minim Invasive Gynecol 2016; 10.1097/GCO.0000000000000380 23(06):857–858 Doi: 10.1016/j.jmig.2016.03.012 78 Vervoort A, Vissers J, Hehenkamp W, Brölmann H, Huirne J. The 76 AkdemirA,SahinC,AriSA,ErgenogluM,UlukusM,Karadadas effect of laparoscopic resection of large niches in the uterine N. Determination of isthmocele with using a foley catether caesarean scar on symptoms, ultrasound ﬁndings and quality of during laparoscopic repair of caesarean scar defect. J Minim life: a prospective cohort study. BJOG 2018;125(03):317–325 Doi: Invasive Gynecol 2018;25(01):21–22 Doi: 10.1016/j. 10.1111/1471-0528.14822 jmig.2017.05.017 79 Api M, Boza A, Gorgen H, Api O. Should cesarean scar defect be 77 Sipahi S, Sasaki K, Miller CE. The minimally invasive approach to trated laparoscopically? A case report and review of literature. the symptomatic isthmocele - what does the literature say? A J Minim Invasive Gynecol 2015;22(07):1145–1152 Doi: 10.1016/j. step-by-step primer on laparoscopic isthmocele - excision and jmig.2015.06.013

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 THIEME Review Article 53

Use of the Pessary in the Prevention of Preterm Delivery Usodopessárionaprevençãodepartopretermo

Thayane Delazari Corrêa1 Ester Gomes Amorim1 Jade Aimée Guimarães Tomazelli1 Mário Dias Corrêa Júnior1

1 Departament of Obstetrics and Gynecology, Universidade Federal de Address for correspondence Mário Dias Corrêa Júnior, MD, PhD, Minas Gerais, Belo Horizonte, MG, Brazil Departamento de Obstetrícia e Ginecologia, Universidade Federal de Minas Gerais, Av. Prof. Alfredo Balena, 110, 30130-100, Santa Eﬁgênia, Rev Bras Ginecol Obstet 2019;41:53–58. Belo Horizonte, MG, Brazil (e-mail: [email protected]).

Abstract Objective The gestational complication most associated with perinatal mortality and morbidity is spontaneous preterm birth with gestational age < 37 weeks. Therefore, it is necessary to identify its risk factors and attempt its prevention. The benefits of the pessary in prematurity are under investigation. Our objective was to analyze the use of the pessary in the prevention of preterm births in published studies, and to compare its efficacy with other methods. Methods Randomized clinical trials published between 2010 and 2018 were selected from electronic databases. Studies on multiple gestations were excluded. Results Two studies were in favor of the pessary as a preventive method, one study was contrary to the method and another two showed no statistically significant Keywords difference. The meta-analysis showed no statistical difference with the use of a cervical ► pessary pessary in the reduction of births < 37 (odds ratio [OR]: 0.63; confidence interval [95% ► preterm birth CI]: 0.38–1.06) and < 34 weeks (OR: 0.74; 95% CI: 0.35–1.57) ► delivery Conclusion The pooled data available to date seems to show a lack of efficacy of the ► premature cervical pessary in the prevention of preterm birth, although the heterogeneity of the ► short cervix studies made comparisons more difficult.

Resumo Objetivo O parto com idade gestacional < 37 semanas é a complicação gestacional mais associada à mortalidade e morbidade perinatal, sendo necessária a identificação de seus fatores de risco e a tentativa de sua prevenção. Os benefícios do pessário na prematuridade estão sendo investigados. Nosso objetivo foi analisar os estudos publicados sobre uso do pessário na prevenção do parto pretermo e comparar sua Palavras-chave eficácia perante outros métodos. Métodos ► pessário Foram selecionados estudos clínicos randomizados publicados entre 2010 e ► nascimento 2018, extraídos de bases eletrônicas de dados. Estudos de gestações múltiplas foram prematuro excluídos. Resultados ► parto Dois estudos se mostraram a favor do pessário como método preventivo, ► prematuridade um estudo foi contrário ao método, e outros dois não demonstraram diferença fi fi ► colo curto estatisticamente signi cativa. A meta-análise não mostrou diferença signi cativa no

ORCID ID is https://orcid.org/0000-0003-4198-0546.

received DOI https://doi.org/ Copyright © 2019 by Thieme Revinter August 15, 2018 10.1055/s-0038-1676511. Publicações Ltda, Rio de Janeiro, Brazil accepted ISSN 0100-7203. October 22, 2018 54 Use of Pessary in the Prevention of Preterm Delivery Corrêa et al.

usodopessárionareduçãodenascimentos < 37 (razão de chance [RC]: 0,63; intervalo de confiança [IC 95%]: 0,38–1,06) e < 34 semanas (RC: 0,74; IC 95%: 0,35–1,57). Conclusão Os dados agrupados disponíveis até o momento parecem mostrar uma falta de eficácia do pessário cervical na prevenção do parto pretermo, embora a heteroge- neidade dos estudos tenha dificultado as comparações.

Introduction Cervical cerclage is a surgical procedure first introduced by Shirodkar and McDonald in the mid-1950s, currently used Nearly 15 million preterm births occur annually worldwide. prophylactically for women with second-trimester repetitive Delivery at a gestational age < 37 weeks is the gestational loss suggestive of cervical insufficiency. A history of previous complication more closely associated with perinatal mortality preterm birth and of cervical changes in the ongoing gestation and morbidity.1 Children born prematurely still have a high risk indicatedby ultrasonography (cervical length < 25 mm before of complications and hospital readmissions throughout life.2,3 24 weeks) and altered physical examination (cervical dilatation The etiology of preterm birth is multifactorial, and the perceived inthe physical examination before 24weeks) are also history of preterm delivery is the most significant risk factor. recognized indications in the literature. Cervical cerclage con- Another important factor is the presence of a short cervix (< sists of a suture of the uterine cervix, performed preferably at 25 mm) identified by transvaginal ultrasonography between the beginning of the gestation (8–14 weeks), which acts as a 20 and 24 weeks of gestation.2,4 physical barrier, as well as a biochemical one, by protecting the A large reduction in mortality rates and in neonatal membranes from ascending pathogens.2,6 morbidity resulting from preterm deliveries will only be An alternative approach could be the pessary, which is a achieved with greater accuracy after the proper identifica- device that has been used for the past 50 years.7 The pessary is tion of women with risk factors for this complication and the a conical ring of silicone that is introduced inside the vagina development of efficient prevention strategy.2 until it encircles the entire cervix, closing the cervical canal One of the prevention strategies considered is the use of and preventing its dilatation or shortening.1,8,9 It promotes a progesterone. Progesterone acts reducing the contractions of change in the cervical angle, reducing the direct pressure of the the uterine smooth muscle and decreasing the inflammatory uterine contents in the canal, and may be a safer alternative to process involved in the onset of labor. Progesterone is consid- surgical cerclage because it is easily removable and does not ered a key hormone for pregnancy maintenance, and if a require anesthesia.3,7,9 This device can be used from the decline of progesterone action occurs in the midtrimester, diagnosis of a short cervix, usually around between 18 and cervical shortening may occur, which would predispose the 22 weeks of gestation, and is withdrawn by the obstetrician at patient to preterm delivery. A blockade of progesterone action between 36 and 37 weeks of gestation, at which age the fetus can lead to the clinical, biochemical and morphologic changes has better clinical and physiological conditions for survival.7 associated with cervical ripening.5 Progesterone has been The ARABIN Cerclage Pessar Perforiert pessary (Dr. Ara- shown to be effective in reducing the preterm delivery and bin GmbH & Co., Witten, Germany)10 has three different neonatal mortality rates when compared with placebo.3,4 diameters to better suit the uterine cervix. It has been

Fig. 1 Picture of the ARABIN Cerclage Pessar Perforiert pessary.10

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Fig. 2 Picture of the PESSÁRIO AM INGÁMED11. released for use in Brazil about two years ago and we have The assessment of the quality of the included studies and an authorized representative in Brazil (►Fig. 1). The AM of their risk of bias was performed according to the criteria Ingámed pessary (Ingámed, Maringá, PR, Brazil)11 is devel- outlined in the Cochrane Handbook for Systematic Reviews oped by a Brazilian company, made of silicone in order to of Intervention.13 The results are shown on ►Fig. 3. better adapt to the cervix (►Fig. 2). We do not have studies Two types of comparisons were made among these comparing the differences between the two types. In Brazil, publications: the P5 study is underway to compare vaginal progesterone versus pessary and progesterone in patients with short cervix diagnosed by ultrasound, using the Ingámed pessary. The use of a cervical pessary in conjunction with intra- vaginal progesterone is shown to be a safe and feasible method for the prevention of preterm birth in women with a short midtrimester cervix. Moreover, this combined treatment has led to a pregnancy prolongation of 13.5 weeks, according to recent studies.12 Since it is a less invasive preventive method than cerclage, not dependent on hormonal supplementation, the pessary is assuming an important role in the medical practice among obstetricians.2 The present article aims to review the latest advances in the efﬁcacy of this method in the management of patients at risk of preterm birth.

Methods

Trials were identified by searching the literature in the PubMed, Scielo, EMBASE and Cochrane databases, between 2010 and 2018. The keywords used were pessário and pessário cervical and their correspondents in English, pessary and cervical pessary. The inclusion criteria were: articles with randomized controlled trials randomized clinical trials (RCTs) that evaluated the use of the pessary in the prevention of preterm births. Twenty-eight articles were found, and the ones that did not meet the criteria of the present study were excluded. The exclusion criteria were: articles published outside the period described, and those referring to the use of pessaries in multiple gestations. The final review was based on 5 articles from RCTs analyzing the efficacy of the pessary in preventing preterm birth in single pregnancies, in which the expected primary Fig. 3 Summary of the risk of bias for each trial: minus sign: high risk 34 and 37 weeks. of bias; plus sign: low risk of bias; blank space: unclear risk of bias.

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Two studies, Saccone et al (2017)1 and Karbasian et al (2016)4 compared the association of the pessary with vaginal progesterone with the use of progesterone alone. Although the studies have similar outlines, their results were different. Saccone et al (2017)1 observed a twofold lower preterm delivery rate with pessary use than in the progesterone-only group (7.3% for pessary associated with progesterone, and 15% for progesterone). Karbasian et al (2016)4 did not observe a statistically significant difference in the preterm delivery rates between the two groups (19.7% for pessary associated with progesterone, and 16.4% for progesterone alone). Studies comparing the use of pessary with expectant management also showed different outcomes. Nicolaides et al (2016)3 did not observe statistically significant differences when comparing the use of the pessary with expectant management (12% of premature parturition with pessary use, and 10.8% without any intervention). Hui et al (2013)9 observed a 4.1% higher rate in the outcome of births before 34 weeks with the use of the pessary (9.4% in the pessary group, and 5.5% in the control group). Fig. 4 Flow diagram of identified studies. On the other hand, Goya et al (2012)2 observed in their study a 4.5-fold lower rate of preterm delivery with pessary 1) Vaginal progesterone versus pessary associated with use versus expectant behavior (6% and 27% of births before vaginal progesterone. 34 weeks, respectively). 2) Pessary versus expectant management. It is important to note that, in all of the studies, there was no significant difference between maternal or infant perina- The data analysis was completed independently by two tal morbidity and mortality rates as a function of the choice authors (Corrêa Júnior, M. D., and Corrêa T. D.), using the of prevention method. Review Manager (RevMan), Version 5 software (Cochrane Vaginal discharge as the main side effect was found in four Collaboration, Copenhagen, Denmark). The summary meas- studies. Goya et al (2012)2 observed 100% of vaginal discharge ures were reported as relative risk (RR) with a 95% confi- in the cervical pessary group, and 46% in the expectant dence interval (CI). management group. Hui et al (2013)9 observed 47% of vaginal discharge in the cervical pessary group, and 21.8% in the 3 Results control group. Nicolaides et al (2016) observed vaginal discharge in 46.8% of the pessarygroupversus 13.8% of the control ►Fig. 4 shows the flow diagram of the information through group, and a high vaginal swab was obtained for bacteriologic the different phases of the review. Thirteen studies were examination; if the results showed infection, appropriate screened; eight trials including multiple gestations were antibiotic therapy was administered. Saccone et al (2017)1 excluded. Five RCTs were therefore included in the meta- found vaginal discharge as a side effect in 8.7% of the pessary analysis. group, and in 46% of the control group. Karbasian et al (2016)4 Blinding was considered not methodologically feasible, do not describe vaginal discharge as a side effect. ►Table 1 given the type of intervention, and none of the studies summarizes the main findings of the analyzed studies. included was double-blinded. All of the five studies used The comparison between these studies is difficult due to the ARABIN Cerclage Pessar Perforiert.10 the methodologies used: pessary versus absence of

Table 1 Main results of the analyzed studies

Author N Prematurity rate RR P-value Pessary Control Goya et al (2012)2 380 6% 27% 0.18 (0.08–0.37) < 0.0001 Hui et al (2013)9 108 9.4% 5.5% 1.04 (0.94–1.12) 0.46 Karbasian et al (2016)4 144 19.7% 16.4% 1.20 (0.60–2.41) 0.60 Nicolaides et al (2016)3 924 12% 10.8% 1.12 (0.75–1.69) 0.57 Saccone et al (2017)1 300 7.3% 15.3% 0.48 (0.24–0.95) 0.04

Abbreviation: RR, relative risk.

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Fig. 5 Meta-analysis of included studies for delivery < 37 weeks.

Fig. 6 Meta-analysis of included studies for delivery < 34 weeks. intervention or vaginal progesterone. This difficulty is even progesterone in the study by Nicolaides et al (2016)3 in greater when we consider that progesterone was also used in pregnant women with cervical length 15 mm may have the group randomized to the use of the pessary in some attenuated the benefit of the pessary in this group. studies, at the discretion of the attending physician. With There were more women with previous preterm deliveries this limitation in mind, we have performed a meta-analysis (16.5%) in the study by Nicolaides et al (2016),3 compared with of the included studies, as shown in ►Figs. 5 and 6. the study by Goya et al (2012)2 (10.8%), which raises the The meta-analysis showed no statistically significant dif- question of whether the pessarycan be effective only inwomen ference in the use of the pessary with or without the with a short cervix, but without a prior preterm delivery association of vaginal progesterone compared with the history. However, this issue could not be further analyzed group that did not use the pessary when the birth is < 37 due to the the fact that none of these trials reported prior weeks (RR: 0.63; 95% CI: 0.38–1.06), or < 34 weeks (RR: spontaneous preterm birth or no prior spontaneous preterm 0.74; 95% CI: 0.35–1.57). birth as subgroups. Saccone et al (2017)1 performed the only trial involving Discussion women with asymptomatic singleton pregnancies without prior spontaneous preterm birth, but with short cervical length Goya et al (2012)2 and Saccone et al (2017)1 obtained different detected by transvaginal ultrasound. The other four studies results, concluding that the pessary could prevent preterm analyzed the same sample of patients with and without a history birth in a population of at-risk women, suitably selected by of prematurity, which may have influenced their outcome. cervical screening on transvaginal ultrasonography performed The differences presented between the analyzed studies during prenatal care obtained similar results. However, in the show that a better evaluation is necessary before we gener- study by Goya et al, only 11% of the population was at high risk alize the favorable outcome of the pessary in the reduction of of spontaneous preterm birth due to previous history. preterm delivery, considering, for example, low-risk women The divergence between the studies by Nicolaides et al or different ethnic groups in the analysis. (2016)3 and by Saccone et al (2017)1 raise the question of For example, a more in-depth assessment is needed to whether cervical pessaries can only be effective at a very low clarify whether the study by Goya et al (2012)2 recruited cervix length cutoff, since the mean cervical length in the women with additional risk factors that could be responsible study by Saccone et al (2017),1 which demonstrated a for such a high baseline preterm rate (27%) compared with favorable outcome to the use of the pessary, was 12 mm, the study by Hui et al (2013)9 (9.4%). Perhaps the differences whereas in the study by Nicolaides et al (2016),3 the mean in the basal characteristics of the participating women could cervical length was 20 mm. In addition, the use of clarify this question.

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Similarly to our analysis, a systematic review and meta- 2 Goya M, Pratcorona L, Merced C, et al; Pesario Cervical para Evitar analysis by Saccone et al (2017)14 found that the ARABIN Prematuridad (PECEP) Trial Group. Cervical pessary in pregnant Pessary10 does not reduce the rate of spontaneous preterm women with a short cervix (PECEP): an open-label randomised controlled trial. Lancet 2012;379(9828):1800–1806. Doi: 10.1016/ delivery or improve the perinatal outcome, despite not having S0140-6736(12)60030-0 included the two studies included our analysis improve the 3 Nicolaides KH, Syngelaki A, Poon LC, et al. A randomized trial of a perinatal outcome. cervical pessary to prevent preterm singleton birth. N Engl J Med The cervical pessary was not associated with any harmful 2016;374(11):1044–1052. Doi: 10.1056/NEJMoa1511014 effects but was associated with a higher rate of vaginal 4 Karbasian N, Sheikh M, Pirjani R, Hazrati S, Tara F, Hantoushzadeh discharge. Although significantly more patients in the pessary S. Combined treatment with cervical pessary and vaginal progesterone for the prevention of preterm birth: A randomized group commonly reported side effects, especially an increase clinical trial. J Obstet Gynaecol Res 2016;42(12):1673–1679. Doi: in vaginal discharge, the rates of cervicovaginal infection did 10.1111/jog.13138 not differ significantly between the groups in the study by 5 Cruz-Melguizo S, San-Frutos L, Martínez-Payo C, et al. Cervical Nicolaides et al (2016),3 which was the only trial that used a pessary compared with vaginal progesterone for preventing early high vaginal swab for bacteriological examination. preterm birth: a randomized controlled trial. Obstet Gynecol 2018;132(04):907–915. Doi: 10.1097/AOG.0000000000002884 According to Alfirevic et al (2013),15 cerclage, vaginal 6 Suhag A, Berghella V. Cervical cerclage. Clin Obstet Gynecol 2014; progesterone, and the pessary appear to have similar effec- 57(03):557–567. Doi: 10.1097/GRF.0000000000000044 tiveness as management strategies in women with a single- 7 Cross RG. Treatment of habitual abortion due to cervical incom- ton pregnancy, previous spontaneous preterm birth, and a petence. Lancet 1959;274:127. Doi: 10.1016/S0140-6736(59) short cervix. However, Norman et al (2016)16 performed the 92242-1 largest randomized trial of vaginal progesterone for the 8 Abdel-Aleem H, Shaaban OM, Abdel-Aleem MA. Cervical pessary for preventing preterm birth. Cochrane Database Syst Rev 2013; prevention of preterm birth in high-risk women, and found (05):CD007873. Doi: 10.1002/14651858.CD007873.pub3 no difference between vaginal progesterone and placebo, 9 Hui SYA, Chor CM, Lau TK, Lao TT, Leung TY. Cerclage pessary for concluding that the efficacy of progesterone in improving preventing preterm birth in women with a singleton pregnancy outcomes is either non-existent or weak. However, this study and a short cervix at 20 to 24 weeks: a randomized controlled included a very heterogeneous group of patients and was trial. Am J Perinatol 2013;30(04):283–288. Doi: 10.1055/s-0032- underpowered to detect a meaningful difference. In another 1322550 10 ARABIN® Cerclage Pessar perforiert. https://dr-arabin.de/produkt/ study performed by Hassan et al (2011),17 it was found that arabin-cerclage-pessar-perforiert/. Accessed September 25, 2018 the administration of vaginal progesterone to women with a 11 Pessário Parto Prematuro. 2015. http://www.ingamed.com.br/pro- short cervix was associated with a reduction in the rate of dutos-detalhe/51/pessario-parto-prematuro. Accessed September preterm delivery < 33 weeks, < 35 weeks, and < 28 weeks 25, 2018 of gestation. Although there is a small number of publica- 12 Daskalakis G, Zacharakis D, Theodora M, et al. Safety and efficacy tions on the use of the pessary, with a diversity of results, of the cervical pessary combined with vaginal progesterone for the prevention of spontaneous preterm birth. J Perinat Med 2018; indicating the need for more research, the use of this non- 46(05):531–537. Doi: 10.1515/jpm-2017-0009 hormonal, accessible, and less invasive method for the 13 Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of pregnant woman, which is easily removable when necessary, Interventions Version 5.10. The Cochrane Colaboration; 2011. http:// has been gaining space in the medical practice.1,18 handbook-5-1.cochrane.org/. Accessed September 15, 2018 14 Saccone G, Ciardulli A, Xodo S, et al. Cervical pessary for preventing preterm birth in singleton pregnancies with short cervical Conclusion length: a systematic review and meta-analysis. J Ultrasound Med 2017;36(08):1535–1543. Doi: 10.7863/ultra.16.08054 From the analyzed studies, we can conclude that the cervical 15 Alfirevic Z, Owen J, Carreras Moratonas E, Sharp AN, Szychowski pessary seems to show a lack of efficacy in the prevention of JM, Goya M. Vaginal progesterone, cerclage or cervical pessary for preterm birth. However, it is not possible to determine its preventing preterm birth in asymptomatic singleton pregnant inferiority in the reduction of preterm births when com- women with a history of preterm birth and a sonographic short cervix. Ultrasound Obstet Gynecol 2013;41(02):146–151. Doi: pared with other methods due to the heterogeneity of the 10.1002/uog.12300 existing studies. Its association with progesterone also 16 Norman JE, Marlow N, Messow CM, et al; OPPTIMUM study group. requires a better evaluation. Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial. Lancet 2016; Conflicts of Interest 387(10033):2106–2116. Doi: 10.1016/S0140-6736(16)00350-0 The authors have no conflicts of interest to declare. 17 Hassan SS, Romero R, Vidyadhari D, et al; PREGNANT Trial. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double- References blind, placebo-controlled trial. Ultrasound Obstet Gynecol 2011; 38(01):18–31. Doi: 10.1002/uog.9017 1 Saccone G, Maruotti GM, Giudicepietro A, Martinelli P; Italian 18 Arabin B, Halbesma JR, Vork F, Hübener M, van Eyck J. Is treatment Preterm Birth Prevention (IPP) Working Group. Effect of cervical with vaginal pessaries an option in patients with a sonographi- pessary on spontaneous preterm birth in women with singleton cally detected short cervix? J Perinat Med 2003;31(02):122–133. pregnancies and short cervical length: a randomized clinical trial. Doi: 10.1515/JPM.2003.017 JAMA 2017;318(23):2317–2324. Doi: 10.1001/jama.2017.18956

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 THIEME Case Report 59

Lithopedion in a Geriatric Patient

Andrés Ricaurte Sossa1 Henry Bolaños1 Andrés Ricaurte Fajardo2 Ángela Camila Burgos3 Valentina Garcia2 Paola Muñoz4 Diego Rosselli2

1 Department of Obstetrics and Gynecology, Hospital Universitario Address for correspondence Diego Rosselli, MD, EdM, MSc, Medical Departamental de Nariño, San Juan de Pasto, Colombia School, Pontiﬁcia Universidad Javeriana, Carrera 7 No. 40 - 62, Bogota, 2 Medical School, Pontiﬁcia Universidad Javeriana, Bogota, Colombia Colombia (e-mail: [email protected]). 3 Medical School, Universidad Cooperativa de Colombia, San Juan de Pasto, Colombia 4 Department of Surgery, Hospital Universitario Departamental de Nariño, San Juan de Pasto, Colombia

Rev Bras Ginecol Obstet 2019;41:59–61.

Abstract Lithopedion (lithos ¼ rock and paidion ¼ child) is a rare condition that only occurs in 1.5 to 1.8% of extrauterine pregnancies and in 0.00045% of all pregnancies. It consists Keywords of an ectopic pregnancy in which the fetus dies but cannot be reabsorbed by the ► lithopedion mother’s body, which then coats it in a calcium-rich substance. We present the case of a ► ectopic pregnancy 77-year-old woman with an incidental diagnosis of a lithopedion, which had been ► geriatric retained in her left pelvis for presumably 40 years.

Introduction calcium-rich substance that will eventually mummify and petrify the fetus body.8,9 Abdominal ectopic pregnancy, defined as implantation of the In the medical literature, there are 300 reported cases of fertilized ovum in the peritoneal cavity, excluding tubal, lithopedion.6,7 Lithopaedion was first described during the 10th ovarian or intraligamentary implantations, is an uncommon century by an Arab physician. However, the most famous case type of extrauterine pregnancy. It has an estimated incidence was described by Jean d’Ailleboust, in 1582 inThe Lithopaedion of of 1 per 10,000 to 25,000 live births and leads to high Sens, which describes a female lithopedion retained for 28 years, maternal and fetal mortality.1,2 Most of these pregnancies discovered during the necropsy of a 68-year-old woman.10 occur after tubal rupture, with a subsequent reimplantation Kuchenmeister11 describes three types of lithopedion in the peritoneal cavity. However, it can also occur that the according to the calcified structures. The first one, litokeliposis, zygote passes through the fallopian tube and is primarily presents calcification of the membranes without the calcifica- – implanted in the peritoneal cavity.3 5 Extrauterine pregnan- tion of the fetal body. The second one, litokelitopedion, is the cies are sometimes not identified and may resolve sponta- calcification of the membranes and the fetus. The third one is neously, even when gestation is advanced. true lithopedion, in which the fetus is infiltrated with calcium An extrauterine pregnancy that has calcified over time is salts, but the calcification of the membranes is negligible.7,8 known as lithopedion.6 The estimated incidence of lithope- The duration of lithopedion retention has been described to dion is 1.5 to 1.8% of extrauterine pregnancies. It usually be between 4 and 60 years. For lithopedion development, the occurs when a fertilized ovum attaches outside the uterus fetus has to remain alive for more than 12 weeks. Additionally, and the fetus starts to grow but cannot survive and dies.7,8 If the ectopic pregnancy has to escape medical detection, and the the dead fetus is too large to be reabsorbed by the mother’s fetus has to remain in aseptic conditions and in a favorable body, it is recognized as a foreign object by the mother’s environment for calcification.7,12 Detection can be difficult, immune system, which reacts by coating the fetus in a and most cases are found incidentally during surgery, radio- graphic images or autopsy. It can be suspected in patients with persistent or recurrent abdominal pain, chronic constipation, ORCID ID is https://orcid.org/0000-0003-0960-9480. intestinal obstruction or obstructive uropathy.9,13

received DOI https://doi.org/ Copyright © 2019 by Thieme Revinter September 17, 2018 10.1055/s-0038-1676038. Publicações Ltda, Rio de Janeiro, Brazil accepted ISSN 0100-7203. October 2, 2018 published online December 12, 2018 60 Lithopedion in a Geriatric Patient Ricaurte Sossa et al.

Computed tomography (CT), magnetic resonance imaging was performed finding a mummified fetus with 41 mm and barium enema have been described to be performed based biparietal diameter (BPD), adhered to the greater omentum, on the patient’s symptoms and are useful to plan the surgical which was dissected and extracted in block (►Fig. 2). Subse- approach. The treatment of these patients should be indivi- quently, a right hemicolectomy was performed. She was then dualized, considering maternal age, presentation and symp- transferred to the intensive care unit (ICU), where she required toms. Main complications include intestinal obstruction, pelvic ventilatory and vasopressor support. After two days in the ICU abscess, cephalopelvic disproportion in future pregnancies, and a favorable evolution, she was transferred to the general extrusion of fetal parts through the abdominal wall, rectum ward and after resolution of thesymptoms, she was discharged – and vagina; fistula formation and tubal infertility.10,13 16 with no further complication. We present the case of a 77-year-old patient with an abdominal lithopedion suspected to be 40 years old, inci- Discussion dentally discovered. Lithopedion is a rare entity with a variable clinical course. It Case Description may be asymptomatic for many years or, less frequently, it may present with persistent or recurrent abdominal pain, chronic A 77-year-old female patient from Tumaco, in the Pacific coast constipation, intestinal obstruction or obstructive uropa- of Colombia, presented with 8 days of generalized abdominal thy.9,13 It can also present with complications such as pelvic pain associated with symptoms of absent peristalsis. She abscess; cephalopelvic disproportion in future pregnancies16; referred 4 pregnancies, of which she had had 3 normal vaginal extrusion of fetal parts through the abdominal wall, rectum or deliveries and 1 miscarriage (40 years prior), which was vagina; fistula formation or tubal infertility.10,13 recognized by the patient as her last pregnancy. Additionally, With the advances in antenatal diagnostic techniques of she mentioned a family history of colon cancer. Upon admis- different fetal conditions, lithopedion is much less frequent. sion to the emergency department, she was hemodynamically However, in neglected regions with difficult access to basic stable, with no signs of peritoneal irritation but a positive health services, as in the case presented, the timely identi- ascitic wave. There were no palpable masses, and symptomatic fication of infrequent antenatal conditions might be diffi- treatment was initiated. Blood tests were requested, which cult.14 Since the literature on this subject is mostly based on were not suggestive of intrabdominal infection. Plain abdom- case reports, it is not clear what might be the best diagnostic inal X-rays did not show any significant finding; abdominal tools or the most appropriate therapeutic approach. How- ultrasound documented a narrow hepatic angle and thickness ever, surgery has been the selected treatment option in most in the right colon mucosa. Given that imaging findings were of the reported cases. not conclusive, a contrasted abdominal CT was performed, In this case, a lithopedion suspected to be 40 years old revealing thickening of the ascending colon walls, signs of was found by means of a contrasted abdominal CT scan. In ileocolic intussusception and heterogeneous calcifications in case it is not possible to correctly measure the length of the the lower left pelvis compatible with a mummified fetus long bones, which is usually presented as anthropometric (►Fig. 1). After these findings, a diagnostic laparoscopy was data, BPD is accepted as the most reliable measurement. In performed with no relevant findings. Therefore, laparotomy this case, it corresponded to a gestational age of at least

Fig. 1 (A) Abdominal computed tomography evidencing the mummiﬁed fetus (B) Computed tomography imaging of the abdomen with 3D reconstruction.

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 LithopedioninaGeriatricPatient Ricaurte Sossa et al. 61

Fig. 2 Mummiﬁed fetus extracted during laparotomy.

15 18 weeks. The intestinal obstruction that led to the 5 Cunningham FG, Leveno KJ, Bloom SL, et al. Ectopic pregnancy. In: request for intraabdominal images and, therefore, to the Cunningham FG, Leveno KJ, Bloom SL, et al. Williams Obstetrics. diagnosis of lithopedion had no relation to the intraabdom- 25th ed. New York, NY: McGraw-Hill; 2018:371–387 inal fetus. In its absence, the diagnosis could have remained 6 Massinde AN, Rumanyika R, Im HB. Coexistent lithopedion and live abdominal ectopic pregnancy. Obstet Gynecol 2009;114(2 Pt unnoticed. 2):458–460 Doi: 10.1097/AOG.0b013e31819ecc82 7 Lachman N, Satyapal KS, Kalideen JM, Moodley TR. Lithopedion: a Conﬂicts of Interest case report. Clin Anat 2001;14(01):52–54 Doi: 10.1002/1098- None to declare. 2353(200101)14:1<52:AID-CA1009>3.0.CO;2-H 8 Martínez Abreu J, Flores Iríbar A. Litopedion y embarazo ectópico: – Acknowledgments presentación de un caso. Rev Méd Electrón 2012;34:591 598 9 Ede J, Sobnach S, Castillo F, Bhyat A, Corbett JH. The lithopedion - We would like to thank Juliana Collante for translating this an unusual cause of an abdominal mass. S Afr J Surg 2011;49(03): paper to English. We also wish to express our thank you to 140–141 the radiology and technology departments at the Hospital 10 Iregui Ceballos CL, Borbón Garzon A, Cerquera Cabrera F, García CJ. Universitario Departmental de Nariño for helping us to Litopedio. Diagnóstico por TC multicorte: reporte de un caso. Rev – obtain the images related to this case. Colomb Radiol 2009;20:2594 2597 11 Kuchenmeister F. Ueber Lithopädien. Arch Gynakol 1881;17:153–252 12 Fagan CJ, Schreiber MH, Amparo EG. Lithopedion: stone baby. Arch Surg 1980;115(06):764–766 Doi: 10.1001/archsurg.1980. 01380060062018 References 13 Burger NZ, Hung YE, Kalof AN, Casson PR. Lithopedion: laparoscopic 1 Gutiérrez YJ, Alvir Alvaro A, Campillos Maza JM, Garrido Fernández P, diagnosis and removal. Fertil Steril 2007;87(05):1208–1209 Doi: Rodríguez Solanilla B, Castán Mateo S. Embarazo ectópico abdom- 10.1016/j.fertnstert.2006.11.065 inal. Diagnósticoy tratamiento médico con metotrexato. Prog Obstet 14 Passini R Jr, Knobel R, Parpinelli MA, et al. Calciﬁed abdominal Ginecol 2011;54:257–260 Doi: 10.1016/j.pog.2011.02.017 pregnancy with eighteen years of evolution: case report. Sao 2 Vargas-Hernández VM, Hernandez Fierro MJR, Ventura Quintana Paulo Med J 2000;118(06):192–194 Doi: 10.1590/S1516-318020 V, Tovar Rodríguez JM. Embarazo ectópico abdominal: presenta- 00000600008 ción de un caso y revisión de la literatura. Rev Chil Obstet Ginecol 15 Hadlock FP, Deter RL, Harrist RB, Park SK. Fetal biparietal dia- 2017;82:338–344 Doi: 10.4067/s0717-75262017000300338 meter: a critical re-evaluation of the relation to menstrual age by 3 Atrash HK, Friede A, Hogue CJ. Abdominal pregnancy in the United means of real-time ultrasound. J Ultrasound Med 1982;1(03): States: frequency and maternal mortality. Obstet Gynecol 1987; 97–104 Doi: 10.7863/jum.1982.1.3.97 69(3 Pt 1):333–337 16 Leke RJ, Nasah BT, Shasha W, Monkam G. Cephalopelvic dispro- 4 Worley KC, Hnat MD, Cunningham FG. Advanced extrauterine preg- portion at term involving a lithopedion: a case report. Int J nancy: diagnostic and therapeutic challenges. Am J Obstet Gynecol Gynaecol Obstet 1983;21(02):171–174 Doi: 10.1016/0020-7292 2008;198(03):297.e1–297.e7 Doi: 10.1016/j.ajog.2007.09.044 (83)90057-7

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 THIEME 62 Case Report

Ruptured Renal Artery Aneurysm in a Pregnant Woman: Case Report and Literature Review Ruptura de aneurisma de artéria renal em gestante: relato de caso e revisão da literatura

AdrianeCastrodeSouza1,2 Caio Henrique Yoshikatsu Ueda2 Denise Hiromi Matsubara2 João Raphael Zanlorensi Glir2

1 Department of Obstetrics and Gynecology, Hospital Santa Cruz, Address for correspondence AdrianeCastrodeSouza,MD, Curitiba, PR, Brazil Universidade Positivo, Rua Prof. Pedro Viriato Parigot de Souza, 2 Universidade Positivo, Curitiba, PR, Brazil 5300, 81280-330, Curitiba, PR, Brazil (e-mail: [email protected]). Rev Bras Ginecol Obstet 2019;41:62–64.

Abstract Renal artery aneurysms (RAAs) are rare and usually asymptomatic; 90% of them are unilateral. Once diagnosed during pregnancy, they may rupture, presenting a high Keywords maternal-fetal risk. The present study reports the case of a 32-year-old pregnant ► renal artery aneurysm woman with a 30-week gestational age and a ruptured unilateral RAA. ► aneurysm in pregnant women ► broken aneurysm ► gestation ► renal aneurysm rupture

Resumo Os aneurismas de artéria renal (AAR) são raros, normalmente assintomáticos, e 90% Palavras-chave dos casos são unilaterais. Uma vez diagnosticados durante a gestação, estes podem se ► aneurisma de artéria tornar predisponentes a rotura e apresentar elevado risco materno-fetal. O presente renal artigo relata o caso de uma gestante de 32 anos, com idade gestacional de 30 semanas ► aneurisma nas e quadro de AAR unilateral roto. gestantes ► aneurisma roto ► gestação ► ruptura de aneurisma renal

Introduction The most accepted etiology is that the disease results from the loss of elastic ﬁbers and from the decrease of the smooth Renal artery aneurysm (RAA) is a rare and asymptomatic muscle tissue of the middle layer.1 Pregnancy has character- condition in the general population and, although some risk istics that may contribute to the increased size and rupture of factors can be recognized, its etiology is still controversial. RAAs, such as the hyperdynamic state and increased intraabdominal pressure.2 ORCID ID is https://orcid.org/0000-0003-3312-4440.

received DOI https://doi.org/ Copyright © 2019 by Thieme Revinter July 9, 2018 10.1055/s-0038-1676057. Publicações Ltda, Rio de Janeiro, Brazil accepted ISSN 0100-7203. October 5, 2018 published online December 12, 2018 Ruptured Renal Artery Aneurysm in a Pregnant Woman Souza et al. 63

The rupture of RAAs may cause symptoms that can be confused with other common conditions during pregnancy. It is an emergency and a complication that has an unfavorable prognosis for both the pregnant woman and the fetus. The present study reports the case of a pregnant woman who presented tothe emergency roomwith symptoms that initially suggested pyelonephritis. However, as the case evolved, the patient was diagnosed with a ruptured renal artery.

Case Description

A 32-year-old female, previously healthy, with history of 1 previous caesarian section and 30 weeks pregnant at admittance, presented to the emergency room with lower back and abdominal pain associated with vomiting that had begun 1 hour before. At admittance, the vital signs were: blood pressure of 90/45 mm Hg, temperature of 36.2° C, and oxygen saturation of 98%. During the initial examination, pain upon palpation of the iliac fossa and hypogastrium was observed, with no signs of peritoneal irritation, and positive Giordano test on the left side of the back. Furthermore, during the Fig. 1 Arteriography demonstrating extravasation of contrast by the obstetric gynecological examination, it was observed that ruptured aneurysm. the fetal heart rate was present and that the cervix was thick, long, posterior, and impervious. Due to the initial hypothesis of the VAD, and to the sedoanalgesia, with progressive improve- pyelonephritis associated with septic shock, blood culture and ment of the condition of the patient. After the 7th day in the laboratory tests were performed. An obstetric ultrasonogra- ICU, the patient was discharged and was referred the hospital phy (USG) and a room in the intensive care unit (ICU) were also ward. On the 3rd day after the discharge from the ICU, the requested, and ceftriaxone and fluid stat were initiated. condition of the patient evolved with a large amount of fecal As a result of the worsening of the hemodynamic state, the discharge through the surgical drain, which was associated patient was transferred to the ICU 2 hours after admittance. At with tachycardia, tachypnea, and hypoxemia. The patient was that time, the obstetric USG exam demonstrated the absence of referred back to the ICU with secondary peritonitis due to a fetal movements and cardiac activity, in addition to a large probable enteric fistula. New imaging tests were requested, amount of thick fluid in the abdominal cavity, suggestive of which showed pleural effusion and a subphrenic abscess on hemoperitoneum, which was subsequently confirmed by an the right region, pneumoperitoneum, and sigmoid colon fis- abdominal USG. A red blood cells transfusion and an emer- tula. Owing to this complication, a new abdominal approach gency cesarean section were then performed, the latter of was required for surgical drainage of the abdominal abscess, as which confirmed fetal death and hemorrhage, resulting in a well as a thoracoscopy for chest drainage. The patient large amount of blood in the retroperitoneum. The general remained in the ICU for 15 days to control the abdominal surgeon opted for damage control with retroperitoneal tam- infection and was stable and without new organ dysfunctions. ponade and a reapproach within between 48 and 72 hours due The patient was then transferred to the hospital ward so that to the hemodynamic instability. Owing to the critical situation, her nutritional status could be monitored and for the control it was necessary to use vasoactive drugs (VADs), orotracheal and correction of the fistula. After 15 days, the patient showed intubation (OTI), and sedation (►Fig. 1). clinical improvement and was then discharged. Once the patient was stable, an emergency arteriography showed contrast extravasation by the left renal peripheral Discussion branch located in the inferolateral region (►Fig. 1), and a super selective catheterization with embolization was requested. Renal artery aneurysms are defined as a localized dilation of However, an abdominal USG exam evidenced a large amount the renal artery or of its branches.3 It is a rare pathology with of blood in the abdominal cavity, and owing to the risk of an incidence close to 0.1% in the general population, and the Disseminated intravascular coagulation (DIC), a new approach rupture of these aneurysms is even less frequent, occurring to cavity lavage was discussed with the general surgeon. In this in 2% of this population.4,5 However, the prognosis of a approach, there was the presence of blood in the abdominal ruptured RAA is not favorable, mainly for pregnant women, cavity that culminated in a new retroperitoneal tamponade with maternal death rates varying between 50 and 92%, and and in a reapproach in between 48 and 72 hours. The patient fetal death rates ranging between 82 and 100%.6 remained in ICU care, still with VAD and OTI, for 2 days, when a The most common RAA etiology is that the disease results new approach was taken; an ischemic lesion in the sigmoid from the loss of elastic fibers and from the decrease of the was found, thus requiring sigmoidectomy. During the follow- smooth muscle tissue of the middle layer1 The risk factors ing days, there were adjustments to the antibiotic therapy, to include systemic arterial hypertension (SAH), atherosclerosis,

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 64 Ruptured Renal Artery Aneurysm in a Pregnant Woman Souza et al.

fibromuscular dysplasias, changes in collagen metabolism, instability. An emergency cesarean section should be per- inflammatory diseases, penetrating or blunt trauma, female formed to avoid fetal death, followed by a surgical approach gender, being 60 years old, and pregnancy.3,4 It is believed for hemorrhage control. Subsequently, an endovascular cor- that the increase of plasma volume, intra-abdominal pressure, rection with embolization can be performed or, in situations hormonal-metabolic changes, and hyperdynamic state in where there is no hemodynamic services available, nephrec- pregnancy may be contributing factors not only for the in- tomy may be selected. creased size but also for the rupture of these aneurysms. However, there seems to be no relation between the number Final Considerations of pregnancies and RAAs.2 Most patients have saccular and asymptomatic aneur- Although rare, RAAs may evolve unfavorably, especially in ysms. Pain, hypertension, and hematuria may be observed in pregnancy. The present case report demonstrates the com- symptomatic cases. Symptoms like murmur and palpable plexity and difficulty associated with the clinical assessment abdominal mass are non-specific and unreliable signs during of ruptured RAAs and their complications, even in assisted pregnancy. The main complication of RAA is its rupture, and patients. Therefore, a fast and correct diagnosis, associated in such cases, the patient may have sudden and non-specific with assessment techniques and commitment of the medical abdominal or lumbar pain, usually in the costovertebral team are fundamental so that the morbimortality of these angle, hypovolemic shock, gross hematuria, or complications cases is as low as possible. owing to the risk of embolization of thrombi arising from the aneurysm. This makes it difficult to distinguish it clinically Conflicts of Interest from other conditions, such as the causes of acute abdomen The authors have no conflicts of interest to declare. aetiology (infection, inflammation, vascular occlusion or obstruction), pyelonephritis, or ectopic pregnancy.4,7,8 Acknowledgments As most RAAs are asymptomatic, the diagnosis is usually We thank the patient who agreed to have her case reported made incidentally through imaging tests. Angiography is and, as a way to protect her rights, we wrote a free and considered the gold standard, owing to its diagnostic capac- informed consent form (TCLE, in the Portuguese acronym) ity, preoperative analysis, and the possibility of immediate and filed it with the hospital. In addition, we thank the correction through embolization. Otherwise, a computed Hospital Santa Cruz, Curitiba, in the state of Paraná, Brazil, tomography (CT) exam can be performed because it is a for allowing us to publish the case report and assisting us in sensitive examination, and, in an emergency case, the bene- contacting the patient. fits are worth the risk. Ultrasonography is an examination that does not pose maternal-fetal risks and can be performed References in hemodynamically unstable patients; however, it does not 1 Ferreira J, Pires V, Sousa P. Correção endovascular de aneurisma da always identify the aneurysm. Magnetic resonance imaging artéria renal com a técnica de Moret: caso clínico. Angiol Cir Vasc (MRI) is not recommended in cases of instability. Laparosco- 2014;10:159–162 Doi: 10.1016/j.ancv.2014.08.001 py may have its diagnostic value compromised in pregnant 2 Stanley JC, Henke PK. Renal artery aneurysms. In: D’Sa AABB, women, mainly after the second trimester, when the size of Chant ADB, eds. Emergency Vascular and Endovascular Surgical Practice. London: Hodder Education; 2005:315–324 the uterus may be a limiting factor for the method.3,5 3 Schulte W, Rodriguez-Davalos M, Lujic M, Schlosser F, Sumpio B. The treatment for pregnant women with RAA is quite Operative management of hilar renal artery aneurysm in a pregnant controversial in the literature, and the conduct depends on patient. Ann Vasc Dis 2015;8(03):242–245 Doi: 10.3400/avd.cr.15- the following factors: size and location of the aneurysm, 00026 presence or absence of symptoms, and the existence of 4 Coleman DM, Stanley JC. Renal artery aneurysms. J Vasc Surg – renovascular hypertension and calcifications.6 2015;62(03):779 785 Doi: 10.1016/j.jvs.2015.05.034 5 Maughan E, Webster C, Konig T, Renfrew I. Endovascular manage- To quantify the risk of rupture of these aneurysms, ment of renal artery aneurysm rupture in pregnancy - A case report. 9 González et al suggest that RAAs pose risks ranging from Int J Surg Case Rep 2015;12:41–43 Doi: 10.1016/j.ijscr.2015.05.011 low risk of rupture (calcified aneurysms with a diameter 6 Cohen JR, Shamash FS. Ruptured renal artery aneurysms during of < 1.5 cm) to those with > 20% chance of rupture (non- pregnancy. J Vasc Surg 1987;6(01):51–59 Doi: 10.1067/mva.1987. calcified saccular aneurysms associated with SAH). Thus, avs0060051 – RAAs, in general, should be treated in the following situa- 7 Moreira J, Nunes P,Antunes L, et al. Aneurisma da artéria renal caso clínico. Rev Angiol Cir Vasc 2011;7:215–218 tions: when the lesions measure > 2 cm in diameter, when 8 Rodrigues RG, Lucas ELO, Pereira ALBM, et al. Ruptura espontânea they show documented growth, when they are symptomatic, da veia renal em gestante: um relato de caso. Rev Fac Ciênc Méd before documented distal embolization, when they are as- Sorocaba 2016;18:228–230 Doi: 10.5327/Z1984-4840201626449 sociated with significant stenosis and poor renal perfusion, 9 González J, Esteban M, Andrés G, Linares E, Martínez-Salamanca and in women of childbearing age with a desire of future JI. Renal artery aneurysms. Curr Urol Rep 2014;15(01):376 Doi: 10.1007/s11934-013-0376-z pregnancies or pregnant women.9,10 10 Metzger PB, Kambara AM, Barbato HA, Rossi FH, Izukawa NM. The conduct in the case of a ruptured renal aneurysm in a Endovascular approach of a patient with bilateral renal artery pregnant woman is based primarily on clinical suspicion and fibrodysplasia associated with a massive renal aneurysm. Rev Bras on a rapid diagnosis with the control of hemodynamic Cardiol Invasiva 2015;23:145–147 Doi: 10.1016/j.rbciev.2015.12.015

Rev Bras Ginecol Obstet Vol. 41 No. 1/2019 THIEME Erratum 65

Erratum – Maternal Mortality in Brazil: Proposals and Strategies for its Reduction Mortalidade materna no Brasil: propostas e estratégias para sua redução

Rodolfo Carvalho Pacagnella1 Marcos Nakamura-Pereira2 Flavia Gomes-Sponholz3 Regina Amélia Lopes Pessoa de Aguiar4 Gláucia Virginia de Queiroz Lins Guerra5 Carmen Simone Grilo Diniz6 Brenno Belazi Nery de Souza Campos7 Eliana Martorano Amaral1,7 Olímpio Barbosa de Moraes Filho8

1 Universidade Estadual de Campinas, Campinas, SP, Brazil 2 Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira, Rio de Janeiro, RJ, Brazil 3 School of Nursing, Universidade de São Paulo, Ribeirão Preto, SP, Brazil 4 Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil 5 Instituto de Medicina Integral Professor Fernando Figueira, Recife, PE, Brazil 6 Universidade de São Paulo, São Paulo, SP, Brazil 7 Faculdade de Medicina São Leopoldo Mandic, Campinas, SP, Brazil 8 Universidade de Pernambuco, Recife, PE, Brazil

Rev Bras Ginecol Obstet 2019;41:65.

ERRATUM Rio de Janeiro, December 11, 2018

Dear readers,

In the E-Poster Maternal Mortality in Brazil: Proposals and Strategies for its Reduction (Rev Bras Ginecol Obstet 2018;40.09: 501-506_4010ed. DOI: 10.1055/s-0038-1672181.), published online in Rev Bras Ginecol Obstet in September 2018, where it reads:

Brenno Belazi Nery de Souza Campos7 Eliana Martorano Amaral1,7

It should read:

Brenno Belazi Nery de Souza Campos1,7 Eliana Martorano Amaral1

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*JCR stands for Journal Citation Reports Instructions to Authors

Scope and policy • Confl icts of interest: authors should report any potential confl icts All content of the journal, except where otherwise noted, is licensed under of interest whether political, economic, of resources for research a Creative Commons License. execution or intellectual property; The material submitted for analysis cannot be simultaneously submitted for • Acknowledgements: restricted to people and institutions that contrib- publication in other journals or previously published. In the selection of man- uted to research development in a relevant way. Any fi nancial support uscripts for publication, are evaluated the originality, relevance of the theme, provided by development agencies or private companies should be men- quality of the methodology used, and adequacy to the editorial standards tioned in the section Acknowledgments. For Brazilian authors, RBGO re- adopted by the journal. The published material becomes intellectual prop- quests the citation of CNPq, Capes, FAPESP and other fi nancing agencies, erty of the Brazilian Journal of Gynecology and Obstetrics and Febrasgo. together with the number of research process or granted scholarships. • Contributions: according to the criteria for scientifi c authorship of the Manuscripts evaluation International Committee of Medical Journal Editors (ICMJE), authorship The manuscripts submitted to the journal are received by the Editorial credit must be based on three conditions met in full: 1. Substantial Offi ce that checks the mandatory documentation and examines if the edi- contributions to conception and design, data collection or analysis, and torial norms contained in the Instructions to Authors have been fulfi lled. If interpretation of data; 2. Writing of the article or critical review of the in- the process is in compliance, the manuscript is sent to the Editor-in-Chief, tellectual content; and 3. Final approval of the version to be published. who will make a merit evaluation of the material. If the Editor-in-Chief Manuscript concludes the work is in favorable scientifi c and technical conditions, the Instructions to Authors manuscript is forwarded to the Associate Editors, who will designate re- The Brazilian Journal of Gynecology and Obstetrics publishes the follow- viewers (double mind process) to evaluate it. Then, the reviewers’ opin- ing categories of manuscripts: ions and editor’s instructions are sent to authors to inform them about changes to be made. Then, the authors resubmit the text with the sug- Original Articles, complete prospective, experimental or retrospec- gested changes within the requested deadline. When resubmitting the tive studies. Manuscripts containing original clinical or experimental manuscript, the requested corrections should be highlighted in yellow. research results have priority for publication. In cases of disagreement with the suggestions, observations should be Case Reports, of great interest and well documented from the clinical included in the comments balloons. Be assertive and punctual with the and laboratorial point of view. In the letter of referral, authors should in- inquiry, and support the hypothesis with references. dicate new or unexpected aspects in relation to already published cases. The text of Introduction and Discussion sections should be based on an IMPORTANT! Authors must comply with the deadlines, since non-attend- updated bibliographic review. ance will result in delay of manuscript publication or even archiving of the process. At any point in the process of analysis and editing of the text, Review Articles, including comprehensive reviews, meta-analysis or the authors may request the process suspension and withdrawal of the systematic reviews. Spontaneous contributions are accepted. The meth- manuscript, except when it is accepted for publication. The concepts and ods and procedures adopted for obtaining the text should be described, statements contained in the articles are of the authors’ responsibility. and based on recent references, including the current year. As this subject is still subject to controversy, the review should discuss the trends Preparing a manuscript for submission and lines of research under way. In addition to the text of the review, there should be an abstract and conclusions. See the ‘Instructions to Mandatory submission documents Authors’ section for information on the text body and title page; When submitting a manuscript to RBGO, attach the documents listed Letters to the Editor, dealing with editorial matters or not, but presenting below on the ScholarOne submission platform. Note that not attach- relevant information to readers. Letters can be summarized by the editor, ing the documents will result in cancellation of the submitted process. but maintaining the main points. In case of criticism to published works, the Mandatory documentation for online submission: letter is sent to the authors so their reply can be published simultaneously; • Authorization of copyright transfer signed by all authors (scanned Editorial, only at the publisher’s invitation. and attached as supplementary document) Model; • In accordance with chapter XII.2 of Res. CNS 466/2012, in Brazil, Title research involving human subjects needs to inform the registration When writing a scientifi c article, the researcher should focus on the number referring to the Certifi cate of Ethical Assessment (CAAE) manuscript title, which is the business card of any publication. It should or the approval number of the research (CEP/CONEP) in the Ethics be elaborated very carefully, and preferably written only after the article Committee. International manuscripts must present local ethical fi nalization. A good title adequately describes the manuscript content. documentation to proceed with the submission process; Generally it is not a phrase, because it does not contain the subject, only • Cover Letter: written to justify the publication. The authors should verbs and arranged objects. Titles rarely contain abbreviations, chemical be identifi ed, together with the title of the team that intends to pub- formulas, adjectives, names of cities, among others. The title of manu- lish, origin institution of the authors and intention of publication; scripts submitted to RBGO must contain a maximum of 18 words. • Title page; Abstract • Manuscript. The abstract should provide the context or basis for the study, establish the objectives, basic procedures, main outcomes and key fi ndings. It Title Page should emphasize new and important aspects of the study or observa- • Title of the manuscript in English with a maximum of 18 words; tions. Since the abstract is the only substantive part of the article in- • Authors’ full name without abbreviations (maximum six); dexed in many electronic databases, authors should ensure it refl ects • Corresponding author (full name, professional mailing address and the article content in an accurate and highlighted manner. Do not use contact email); abbreviations, symbols and references in the abstract. In case of original • Institutional affi liation of each author. Example: Faculty of Medicine, articles from clinical trials, authors must inform the registration number University of São Paulo, Ribeirão Preto, SP, Brazil; at the end of the text. Informational abstract of structured type of original articles which it was performed); sample of participants; data collection; in- Abstracts of original articles submitted to RBGO must be structured in tervention to be evaluated (if any) and the alternative intervention; four sections and contain a maximum of 250 words: statistical methods used and the ethical aspects of the study. When Objective: What was done; the question posed by the investigator. thinking about the writing of the study design, refl ect if it is appropriate to achieve the research objective, if the data analysis refl ects the Methods: How it was done; the method, including the material used to design, and if what was expected with use of the design was achieved achieve the objective. to research the theme. Following, the guidelines used in clinical or epi- Results: What was found, the main fi ndings and, if necessary, the sec- demiological research that should be included in the section Methods ondary fi ndings. of manuscripts sent to RBGO: Conclusion: The conclusions; the answer to the question asked. Informational abstract of structured type of systematic review articles Types of study (adapted from Pereira, 2014*): Among the included items are the review objective to the question Case Report (Case study): In-depth investigation of a situation in which asked, data source, procedures for selecting the studies and data collec- one or a few people are included (usually up to ten); tion, the results and conclusions. The abstracts of systematic review ar- Case series: A set of patients (for example, more than ten people) with ticles submitted to RBGO must be structured in six sections and contain the same diagnosis or undergoing the same intervention. In general, these a maximum of 250 words: are consecutive series of patients seen in a hospital or other health institu- Objective: Declare the main purpose of the article. tion for a certain period. There is no internal control group formed simul- Data sources: Describe the data sources examined, including the date, taneously. The comparison is made with external controls. The name of indexing terms, and limitations. external or historical control is given to the group used to compare the results, but that was not constituted at the same time within the study: for Selection of studies: Specify the number of studies reviewed and the example, the case series is compared with patients from previous years. criteria used in their selection. Transversal (or Cross-sectional) study: Investigation to determine Data collection: Summarize the conduct used for data extraction and prevalence; examine the relationship between events (exposure, dis- how it was used. ease, and other variables of interest) at any given time. Cause and eff ect Data synthesis: State the main results of the review and the methods data are collected simultaneously: for example, the case series is com- used to obtain them. pared with patients from previous years. Conclusions: Indicate the main conclusions and their clinical usefulness. Case-control study: Particular form of etiological investigation of ret- Informational abstract of unstructured type of review articles, except rospective approach in which the search of causes starts from the ef- systematic reviews and case studies fects. Groups of individuals, respectively with and without a particular It shall contain the substance of the article, covering the purpose, method, health problem are compared in relation to past exposures in order to results and conclusions or recommendations. It exposes enough details test the hypothesis that exposure to certain risk factors is the contrib- so readers can decide on the convenience of reading the full text (Limit of uting cause of the disease. For example, individuals affl icted with low words: 150). back pain are compared with an equal number of individuals (control Keywords group) of the same sex and age, but without low back pain. The keywords of a scientifi c paper indicate the thematic content of Cohort study: Particular form of investigation of etiological factors in the text they represent. The main objectives of the aforementioned which the search of eff ects starts from the cause; therefore, the oppo- terms are the thematic content identifi cation, indexing of the work in site of case-control studies. A group of people is identifi ed, and perti- databases, and rapid location and retrieval of contents. The keyword nent information on the exposure of interest is collected, so the group systems used by RBGO are DeCS (Health Sciences Descriptors - Lilacs can be monitored over time, checking those who do not develop the Indexer) and MeSH (Medical Subject Headings - MEDLINE-PubMed disease in focus, and if the prior exposure is related to occurrence of Indexer). Please choose fi ve descriptors that represent your work on disease. For example, smokers are compared to nonsmoker controls; the these platforms. incidence of bladder cancer is determined for each group. Manuscript body (Manuscripts submitted to RBGO must have a Randomized study: This has the connotation of an experimental study maximum of 4000 words. Note that tables, charts and fi gures in the to evaluate an intervention hence the synonym of intervention study. Can Results section and References are not counted). be performed in a clinical setting; sometimes referred to simply as clinical trial or clinical study. It is also conducted at the community level. In Introduction clinical trials, participants are randomly assigned to form groups called The Introduction section of a scientific article has the purpose of in- study (experimental) and control (or testimony), whether submitted or forming what was researched and the reason for the investigation. This not to an intervention (for example, a drug or vaccine). Participants are part of the article prepares the reader to understand the investigation monitored to verify the occurrence of outcome of interest. This way, and justification of its realization. The content informed in this sec- the relationship between intervention and eff ect is examined under tion should provide context or basis for the study (i.e. the nature of controlled observation conditions, usually with double-blind evaluation. the problem and its importance); state the specific purpose, research In the case of a randomized study, inform the number of the Brazilian objective, or hypothesis tested in the study or observation. The study Registry of Clinical Trials (REBEC) and/or the number of the International objective usually has a more precise focus when formulated as a ques- Clinical Trials Registration Platform (ICTRP/OMS) on the title page. tion. Both the primary and secondary objectives should be clear, and Ecological study: Research performed with statistics: the unit of observa- any analyzes in a pre-specified subgroup should be described; provide tion and analysis is not constituted of individuals, but of groups of individuals strictly relevant references only and do not include data or conclusions hence the synonyms: study of groups, aggregates, clusters, statistics or com- of the work being reported. munity. For example, research on the variation of mortality coeffi cients for Methods diseases of the vascular system and per capita consumption of wine among According to the Houaiss dictionary, Methods “is an organized, logical European countries. and systematic process of research”. The method comprises the ma- Systematic Review and Meta-analysis: Type of review in which there is terial and procedures adopted in the research in order to respond to a clearly formulated question, explicit methods are used to critically iden- the central research question. Structure the Methods section of RBGO tify, select and evaluate relevant research, and also to collect and analyze starting with the study design; research scenario (place and period in data from the studies included in the review. There is use of strategies to limit bias in the localization, selection, critical evaluation and synthesis of present the results in logical sequence in the text, tables and illustrations, fi rst relevant studies on a given topic. Meta-analysis may or may not be part mentioning the most important fi ndings. Do not repeat all information of the of the systematic review. Meta-analysis is the review of two or more stud- tables or illustrations in the text. Emphasize or summarize only important ob- ies to obtain a global, quantitative estimate of the question or hypothesis servations. Additional or supplementary materials and technical details may investigated; and employs statistical methods to combine the results of be placed in an appendix where they will be accessible without interrupting the studies used in the review. the fl ow of the text. Alternatively, this information may be published only in Source: *Pereira MG. Artigos Científi cos – Como redigir, publicar e avaliar. the electronic version of the Journal. When data are summarized in the results Rio de Janeiro: Guanabara-Koogan; 2014. section, provide numerical results not only in derived values (eg. percentages), Script for statistical review of original scientifi c papers but also in absolute values from which the derivatives were calculated, and Study objective: Is the study objective suffi ciently described, including specify the statistical methods used for their analysis. Use only the tables and pre-established hypotheses? fi gures necessary to explain the argument of the work and evaluate its foundation. When scientifi cally appropriate, include data analysis with variables Design: Is the design appropriate to achieve the proposed objective? such as age and sex. Do not exceed the maximum limit of fi ve tables, fi ve Characteristics of the sample: Is there a satisfactory report on the charts or fi ve fi gures. Tables, charts and/or fi gures should be included in the selection of people for inclusion in the study? Has a satisfactory rate body of the manuscript and do not count the requested limit of 4000 words. of responses (valid cases) been achieved? If participants were followed up, was it long and complete enough? If there was a pairing (eg. of cas- ATTENTION! es and controls), is it appropriate? How did you deal with missing data? In Case Studies, the Methods and Results sections should be Data Collection (measurement of results): Were the measurement replaced by the term Case Description. methods detailed for each variable of interest? Is there a description of Discussion comparability of the measurement methods used in the groups? Was there In the Discussion section, emphasize the new and important aspects consideration of the validity and reproducibility of the methods used? of the study and the conclusions derived therefrom. Do not repeat Sample size: Has adequate information on sample size calculation been details of data or other information presented in the introduction or provided? Is the logic used to determine the study size described, includ- results sections. For experimental studies, it is useful to begin the ing practical and statistical considerations? discussion by briefly summarizing the main findings, comparing and Statistical Methods: Was the statistical test used for each comparison contrasting the results with other relevant studies, stating the limita- informed? Indicate if the assumptions for use of the test were followed. tions of the study, and exploring the implications of the findings for Was there information about the methods used for any other analysis? future research and clinical practice. Avoid claiming precedence and For example, subgroup analysis and sensitivity analysis. Are the main referring to incomplete studies. Do not discuss data not directly related results accompanied by accuracy of the estimate? Inform the p value to the results of the presented study. Propose new hypotheses when and confi dence interval. Was the alpha level informed? Indicate the al- justifiable, but qualify them clearly as such. In the last paragraph of pha level below which the results are statistically signifi cant. Was the the Discussion section, cite which information of your work contributes beta error informed? Or indicate the statistical power of the sample. Has relatively to advancement of knowledge. the adjustment been made to the main confounding factors? Were the reasons that explained the inclusion of some and the exclusion of oth- Conclusion ers described? Is the diff erence found statistically signifi cant? Make sure The Conclusion section has the function of relating the conclusions to the there are suffi cient analyzes to show the statistically signifi cant diff er- objectives of the study, but authors should avoid unfounded statements ence is not due to any bias (eg. lack of comparability between groups and conclusions not adequately supported by data. In particular, authors or distortion in data collection). If the diff erence found is signifi cant, should avoid making statements about economic benefi ts and costs unless is it also relevant? Specify the clinically important minimal diff erence. their original includes economic analysis and appropriate data. Make clear the distinction between statistically relevant diff erence and References relevant clinical diff erence. Is it a one- or two-tailed test? Provide this information if appropriate. What statistical program is used? Inform the A study is based on the results of other research that preceded it. Once reference where to fi nd it, and the version used. published, it becomes support for future work on the subject. In the Abstract: Does the abstract contain the proper article synthesis? report of their research, authors state the references of prior works consulted that they deem pertinent to inform readers, hence the im- Recommendation on the article: Is the article in acceptable statistical stand- portance of choosing good References. Properly chosen references lend ard for publication? If not, can the article be accepted after proper review? credibility to the report. They are a source for convincing readers of the Source: *Pereira MG. Artigos Científi cos – Como redigir, publicar e avaliar. validity of facts and arguments presented. Rio de Janeiro: Guanabara-Koogan; 2014. Attention! For manuscripts submitted to RBGO, authors should num- IMPORTANT! ber the references in order of entry into the manuscript and use those RBGO joined the initiative of the International Committee of Medical Journal numbers for text citations. Avoid excessive references by selecting the Editors (ICMJE) and the EQUATOR Network, which are aimed to improve the most relevant for each statement and giving preference to the most presentation of research results. Check the following international guides: recent work. Do not use hard-to-reach quotations, such as abstracts Randomized clinical trial: of papers presented at congresses, theses or restricted publications http://www.consort-statement.org/downloads/consort-statement (non-indexed). Seek to cite the primary and conventional references (ar- Systematic reviews and meta-analysis: http://www.scielo.br/pdf/ress/ ticles in scientifi c journals and textbooks). Do not use references such v24n2/2237-9622-ress-24-02-00335.pdf as ‘unpublished observations’ and ‘personal communication’. Authors’ publications (self-citation) should be used only if there is a clear need Observational studies in epidemiology: strobe-statement.org/fi lead- and relationship with the topic. In this case, include in bibliographical min/Strobe/uploads/checklists/STROBE_checklist_v4_combined.pdf references only original works published in regular journals (do not cite Qualitative studies: http://intqhc.oxfordjournals.org/content/19/6/349.long chapters or revisions). The number of references should be 35, in ex- Results ception review articles. Authors are responsible for the accuracy of data The purpose of the Results section is to show the study fi ndings. It is the contained in the references. original data obtained and synthesized by the author with the aim to answer Please check the American Medical Association (AMA) Citation Style to the question that motivated the investigation. For the writing of the section, format your references. *The Instructions to Authors of this journal were elaborated based in the Revista Brasileira de Ginecologia e Obstetrícia literary work Artigos Científi cos: Como redigir, publicar e avaliar de Address: Brigadeiro Luiz Antonio Avenue, 3421, 01401-001, 903 Maurício Gomes Pereira, Editora Guanabara Koogan, 2014. room, Jardim Paulista, São Paulo, SP, Brazil. Phone: + 55 11 5573.4919 Submission of papers E-mail: editorial.offi [email protected] The articles must, necessarily, be submitted electronically, accord- Home Page: https://www.thieme.com/rbgo ing to the instructions posted on the site: http://mc04.manuscriptcentral.com/rbgo-scielo There is no fee for submission and review articles.

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