RBGO Eissn 1806-9339 Gynecology & Obstetrics

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

Revista Brasileira de Ginecologia e Obstetrícia Number 8 • Volume 39 • Pages 373–440 • August 2017

ISSN 0100-7203

RBGO Gynecology and Obstetrics Revista Brasileira de Ginecologia e Obstetrícia

Editor in Chief

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

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

Associated Editors

Agnaldo Lopes da Silva Filho Helena von Eye Corleta Maria Celeste Osório Wender Universidade Federal de Minas Gerais, Universidade Federal do Rio Grande do Sul, Universidade Federal do Rio Grande do Sul, Belo Horizonte, MG, Brazil Porto Alegre, RS, Brazil Porto Alegre, RS, Brazil Alessandra Cristina Marcolin Ilza Maria Urbano Monteiro Omero Benedicto Poli Neto Universidade de São Paulo, Universidade de São Paulo, Universidade de São Paulo, Ribeirão Preto, SP, Brazil Campinas, SP, Brazil Ribeirão Preto, SP, Brazil Daniel Guimarães Tiezzi José Geraldo Lopes Ramos Patrícia El Beitune Universidade de São Paulo, Universidade Federal do Rio Grande do Universidade Federal de Ciências da Saúde Ribeirão Preto, SP, Brazil Sul, Porto Alegre, RS, Brazil de Porto Alegre, RS, Brazil Eddie Fernando Candido Murta José Guilherme Cecatti Ricardo Carvalho Cavalli Universidade de São Paulo, Universidade de São Paulo, Universidade Federal do Triângulo Mineiro, Campinas, SP, Brazil Ribeirão Preto, SP, Brazil Uberaba, MG, Brazil José Maria Soares Júnior Rosiane Mattar Edward Araujo Júnior Universidade de São Paulo, São Paulo, Universidade Federal de São Paulo, Universidade Federal de São Paulo, SP, Brazil São Paulo, SP, Brazil São Paulo, SP, Brazil Julio Cesar Rosa e Silva 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 Alves da Silva Lara Silvana Maria Quintana Fernando Marcos dos Reis Universidade de São Paulo, Universidade de São Paulo, Universidade Federal de Minas Gerais, Ribeirão Preto, SP, Brazil Ribeirão Preto, SP, Brazil Belo Horizonte, MG, Brazil Lucia Helena Simões da Costa Paiva Sophie Françoise Mauricette Derchain Gerson Botacini das Dores Universidade de São Paulo, Universidade de São Paulo, University of Miami, Miami, USA Campinas, SP, Brazil Campinas, SP, Brazil Gustavo Salata Romão Luiz Gustavo Oliveira Brito Victor Hugo de Melo Universidade de São Paulo, Ribeirão Preto, Universidade de São Paulo, Universidade Federal de Minas Gerais, SP, Brazil Campinas, SP, Brazil Belo Horizonte, MG, Brazil Editorial Board

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

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50107-414946-Anuncio_Dialogo_Roche-210x280.indd 1 5/25/17 3:51 PM Volume 39, Number 8/2017 RBGO Gynecology and Obstetrics Revista Brasileira de Ginecologia e Obstetrícia

Editorial

373 Barriers to Implementing and Consolidating a Family Planning Program that would meet Brazilian Needs Luis Bahamondes, Arlete Fernandes, and Ilza Monteiro

Original Articles

Obstetrics

376 Trends in the Prevalence of Live Macrosomic Newborns According to Gestational Age Strata, in Brazil, 2001–2010, and 2012–2014 Maria Isabel do Nascimento, Daniele Francine Pereira, Calliana Lopata, Carina Ladeia Flores Oliveira, Ariane Arruda de Moura, Maria Júlia da Silva Mattos, and Lucas Saraiva da Silva

384 Food Insecurity, Prenatal Care and Other Anemia Determinants in Pregnant Women from the NISAMI Cohort, Brazil: Hierarchical Model Concept Fran Demétrio, Carlos Antônio de Souza Teles-Santos, and Djanilson Barbosa dos Santos

Human Reproduction

397 Proﬁ le of Reproductive Issues Associated with Diﬀ erent Sickle Cell Disease Genotypes Flávia Anchielle Carvalho, Ariani Impieri Souza, Ana Laura Carneiro Gomes Ferreira, Simone da Silva Neto, Ana Carolina Pessoa de Lima Oliveira, Maria Luiza Rodrigues Pinheiro Gomes, and Manuela Freire Hazin Costa

Gynecological Surgery and Urogynecology

403 Evaluation of Cases of Abdominal Wall Endometriosis at Universidade Estadual de Campinas in a period of 10 Years Daniela Angerame Yela, Lucas Trigo, and Cristina Laguna Benetti-Pinto

Lower Genital Tract Diseases

408 Detection of High-Risk Human Papillomavirus in Cervix Sample in an 11.3-year Follow-Up after Vaccination against HPV 16/18 Cirbia Silva Campos Teixeira, Julio Cesar Teixeira, Eliane Regina Zambelli Mesquita Oliveira, Helymar Costa Machado, and Luiz Carlos Zeferino

Sexuality

415 Survey on Aesthetic Vulvovaginal Procedures: What do Portuguese Doctors and Medical Students Think? Pedro Vieira-Baptista, Joana Lima-Silva, José Fonseca-Moutinho, Virgínia Monteiro, and Fernanda Águas

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Review Article

424 Physical Activity during Pregnancy: Recommendations and Assessment Tools Cibele Santini de Oliveira, Thiago dos Santos Imakawa, and Elaine Christine Dantas Moisés

Case Reports

433 Diﬀ erential Diagnosis between Bartholin Cyst and Vulvar Leiomyoma: Case Report Kelly Alessandra da Silva Tavares, Thomas Moscovitz, Marcos Tcherniakovsky, Luciano de Melo Pompei, and César Eduardo Fernandes

436 Cotyledonoid Dissecting Leiomyoma with Symplastic Features: Case Report Fatma Cavide Sonmez, Zeynep Tosuner, Ayse Filiz Gökmen Karasu, Dilek Sema Arıcı, and Ramazan Dansuk

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Editorial Barriers to Implementing and Consolidating a Family Planning Program that would meet Brazilian Needs Barreiras à implementação e consolidação de um programa de planejamento familiar que atenda às necessidades brasileiras

Luis Bahamondes1 Arlete Fernandes1 Ilza Monteiro1

1 Department of Obstetrics and Gynecology, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil

Rev Bras Ginecol Obstet 2017;39:373–375.

Around 50–55% of all births in Brazil are unplanned, and planned pregnancies and 1.47 million planned pregnancies these figures include both unwanted and mistimed pregnan- occur annually, with 351 maternal deaths, of which 49 (14%) cies.1,2 The overall rate of induced abortion is estimated at are attributed to abortions, and 302 to complications result- 1.5%, with all induced abortions resulting from unplanned ing from miscarriages and childbirth. The number of infant pregnancies culminating in an adjusted abortion rate of 2.7%. deaths in the first year of life is estimated at 32,864. The In many cases, unplanned pregnancies terminate in induced model estimates the number of preterm deliveries attributed abortions and, since abortion in Brazil is restricted and only to unplanned pregnancies at 122,523. The estimated number allowed under certain circumstances, many of these proce- of neonatal admissions associated with unplanned pregnan- dures are unsafe. Indeed, unsafe abortions are estimated to cies was 224,631 for 2010, including all preterm deliveries account for 13% of all maternal deaths.3,4 and 7.6% of all term deliveries.10 The cost of unplanned pregnancies weighs not only on the Consequently, the total annual costs attributed to un- healthcare system but also on society, and involves the cost planned pregnancies are estimated at R$4.1 billion or more, of abortion care and of unplanned childbirth. When the depending on the exchange rate. Approximately R$4.07 pregnancy is unplanned, the likelihood of preterm births billion (99.2%) of that total amount is attributed to childbirth and low birthweight infants increases, and this scenario and its resulting complications. Based on national cost implies high costs associated with neonatal care and long- estimates and the number of unplanned pregnancies per term disabilities.5,6 The total fertility rate in Brazil has fallen year, the cost per unplanned pregnancy is calculated at R significantly in recent decades, and today stands at 1.8 births $4,439. However, this is based only on cases occurring within per woman. Over the same period, the use of contraceptives the public healthcare system, with abortions paid for by has increased.7,8 individuals or clandestine cases not being included in this Preventing unplanned pregnancies through publicly calculation. This simple analysis highlights the considerable funded programs is a strategy that has proven to be effective cost savings that can be achieved by reducing the number of in significantly cutting costs for health services.9 In this unplanned pregnancies.10,11 There are many examples re- editorial, we will discuss the current situation in Brazil, garding the potential cost savings that can be made by providing an insight into the inequalities that exist in the preventing unplanned pregnancies. In the United States, provision of contraceptive methods, particularly long-acting for instance, it was estimated that every dollar spent on reversible contraceptive (LARC) methods, and highlighting preventing unplanned pregnancies results in savings of US the causes and consequences of unplanned pregnancies in $2.76 at 2 years and US$5.33 at 5 years following Brazil, where fertility planning services are vastly different to delivery.10,11 those provided in developed countries, and where abortion If most unplanned pregnancies can be avoided, why is the legislation is restrictive. unplanned pregnancy rate still so high in Brazil (50–55% of all The Brazilian National Healthcare Service (SUS, in the pregnancies) when contraceptive prevalence is high and the Portuguese acronym) covers the cost of around 70–75% of total fertility rate is in decline? The answer to this question is all procedures performed in the country, including those complex and depends on many factors. Scientific evidence related to reproduction. An estimated 1.79 million un- shows that the most effective approach to prevent unplanned

Address for correspondence DOI https://doi.org/ Copyright © 2017 by Thieme Revinter Luis Bahamondes, MD, PhD, Caixa 10.1055/s-0037-1604423. Publicações Ltda, Rio de Janeiro, Brazil Postal 6181, 13084-971, ISSN 0100-7203. Campinas, SP, Brazil (e-mail: bahamond@caism. unicamp.br). 374 Editorial

pregnancies is through education and contraceptive use, with right included in the Brazilian constitution? Yet another – LARC methods being the most effective intervention.12 16 obstacle is that the manufacturers of the LARC methods Many international and national agencies and societies, have done little to provide training to the thousands of including the Brazilian Federation of Associations of Gynecol- Brazilian gynecologists. ogy and Obstetrics (FEBRASGO, in the Portuguese acronym), Notwithstanding, many doctors who have actually been advocate the use of LARC methods as first-line. Long-acting trained refuse to provide copper IUDs to women at basic reversible contraceptive methods include intrauterine contra- health units. Why? In many cases, because they are over- ceptives, that is, the copper intrauterine device (IUD) and the whelmed with work and obliged to meet quotas in terms of levonorgestrel-releasing intrauterine system (LNG-IUS), and the number of consultations they perform daily. Another subdermal implants. However, the prevalence ofcontraceptive common situation is the physician refusing to insert an IUD if use in Brazil is based on combined oral contraceptives (COCs), the woman is not having her menstrual period at that time. which are associated with a failure rate of around 8/100 This is a major barrier, since it is often difficult to schedule an women-years, and tubal ligation2, which is in decline in this appointment within a few days of the onset of menstruation. country.17,18 In other cases, doctors prescribe a COC because it is simpler Conversely, the sales of LARC methods, the most effective than inserting an IUD, or because there is no adequate – contraceptive methods, have been very low,18 20 even during referral system in the event of complications, or even be- the recent Zika virus outbreak.21 This reflects the fact that cause the appropriate instruments are not available, such as most women are using contraceptive methods such as COCs, a Hartman forceps to remove IUDs in cases in which the progestin-only pills, injectable and emergency contracep- threads cannot be visualized. In addition to the difficulties tives, all of which are much less effective than LARC methods. involved in scheduling consultations, other barriers at ser- Moreover, there is an unmet need for family planning that is vice delivery points (SDPs) involve issues such as the fact that estimated at 8%, assuming that at least 22 million women LARC methods, when available, can only be inserted by need contraception to avoid an unwanted pregnancy. It was physicians, that the methods are sometimes allowed to recently calculated from current sales of contraceptives that remain on the shelves at the SDPs until their expiration almost 18 million women are protected; however, 90% of date has passed, and that healthcare providers are not given these are relying on methods for which the typical use updated information on the benefits and risks of LARC effectiveness is low.21 methods. Furthermore, there are the myths, misconceptions Several barriers have been identified that may limit the and misinformation that exist regarding these methods, and uptake of LARC methods. First, there are the public policies women’s fear of pain at insertion. for the provision of contraceptive methods. The Brazilian The lack of reimbursement or incomplete insurance cov- Ministry of Health recently refused FEBRASGO’s request to erage for LARC methods may result in the client having to pay introduce the LNG-IUS and contraceptive implants into high up-front costs. The high cost of LARC methods has public healthcare services, arguing that the cost of these already been shown to represent an important barrier to methods is high, and that the copper IUD is available within access these methods.22 A recent study conducted in the the public sector. Even though it is true that the copper IUD is clinic of our institution showed that providing women with available and cheaper than the other two methods, the the LNG-IUS at no cost proved successful in preventing reality is that it is used by no more than 1.8% of women of unwanted pregnancies, maternal morbidity and mortality, reproductive age. This situation could remain unchanged child mortality, and unsafe abortion.20 The SUS provides free even if the LNG-IUS and the implants were available; how- coverage to around 74% of the population, including the ever, many women are unable to use the copper IUD, or do provision of contraceptive methods at no cost, since family not like the method, and could benefit if the LNG-IUS and the planning is guaranteed under the Brazilian constitution. The implants were also available. On the other hand, reflecting LNG-IUS and the contraceptive implants, however, are not the current situation with the copper IUD, it is possible that, included in the contraceptive arsenal provided free of charge even if all the LARC methods were available in the public by the SUS, with only a few, very rare exceptions. sector, this would not necessarily increase the prevalence of A new model of family planning management needs to be the use of LARC methods or, consequently, lead to any developed urgently. It is not right that the unplanned preg- reduction in the unplanned pregnancy rate. nancy rate remains high despite high contraceptive preva- The lack of training of healthcare providers in LARC lence, nor that the prevalence of the use of LARC methods is placement is another factor that contributes to the low low. The availability of LARC methods must be increased, as rates of use of these methods. For one thing, many medical well as the access to and use of these methods. Task sharing is residency teaching programs in Obstetrics and Gynecology necessary, and a coordinated response is needed from the fail to provide any training on LARC placement, while federal, state and municipal governments; however, govern- hospitals run by the Catholic Church refuse to provide mental response alone will be insufficient. To ensure access any family planning methods at all. It could be argued to LARC methods, the academia must be involved, as well as that, in this particular case, they have the right to do so; professional and scientific organizations, private health in- however, why does the Brazilian Ministry of Education pay surance companies, policy makers, and all stakeholders. This for the training of medical residents who then fail to receive editorial may serve to initiate a debate on the subject, not adequate training in family planning, which is a human only in government offices but also among medical and

Rev Bras Ginecol Obstet Vol. 39 No. 8/2017 Editorial 375

nursing students, residents in Gynecology and Obstetrics and 9 Amaral G, Foster DG, Biggs MA, Jasik CB, Judd S, Brindis CD. Public family practice, and at scientific congresses and other appli- savings from the prevention of unintended pregnancy: a cost cable events. Brazil urgently needs to identify an appropriate analysis of family planning services in California. Health Serv Res 2007;42(05):1960–1980 and rapid solution to reduce the high rate of unplanned 10 Le HH, Connolly MP, Bahamondes L, Cecatti JG, Yu J, Hu HX. The pregnancies in the country and its consequences in terms of burden of unintended pregnancies in Brazil: a social and public maternal morbidity and mortality, as well as the high rate of health system cost analysis. Int J Womens Health 2014; unsafe abortions. 6:663–670 11 Pesquisa revela dados sobre parto e nascimento no Brasil [Re- search reveals data on labor and delivery in Brazil] [webpage on Conflicts of Interest the Internet]. Ministry of Health of Brazil; 2012. Available at: The authors declare no conflicts of interest. http://www.ensp.fiocruz.br/portal-ensp/informe/site/materia/ detalhe/29584. Accessed on April 24, 2017 12 American College of Obstetricians and Gynecologists. ACOG Acknowledgments Committee Opinion No. 392, December 2007. Intrauterine device This editorial was supported in part by Fundação de Apoio and adolescents. Obstet Gynecol 2007;110(06):1493–1495 à Pesquisa do Estado de São Paulo (FAPESP) (grant # 2015/ 13 American College of Obstetricians and Gynecologists Committee 20504–9). on Gynecologic Practice; Long-Acting Reversible Contraception Working Group. ACOG Committee Opinion no. 450: Increasing use of contraceptive implants and intrauterine devices to reduce unintended pregnancy. Obstet Gynecol 2009;114(06):1434–1438 References 14 Oringanje C, Meremikwu MM, Eko H, Esu E, Meremikwu A, Ehiri 1 Santelli J, Rochat R,Hatfield-Timajchy K, et al; Unintended Pregnancy JE. 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In: Hatcher RA, Trussell J, Nelson of Unsafe Abortion and Associated Mortality in 2008. 6th ed. AL, Cates W, Kowal D, Policar M (eds). Contraceptive Technology: Geneva: World Health Organization; 2011. Available at: http:// Twentieth Revised Edition. New York NY: Ardent Media; 2011 whqlibdoc.who.int/publications/2011/9789241501118_eng.pdf. 18 Bahamondes L, Bottura BF, Bahamondes MV, et al. Estimated Accessed on April 13, 2017 disability-adjusted life years averted by long-term provision of 4 Vlassoff M, Walker D, Shearer J, Newlands D, Singh S. Estimates of long acting contraceptive methods in a Brazilian clinic. Hum health care system costs of unsafe abortion in Africa and Latin Reprod 2014;29(10):2163–2170 America. Int Perspect Sex Reprod Health 2009;35(03):114–121 19 Secura GM, Madden T, McNicholas C, et al. Provision of no-cost, 5 Rocha RC, de Souza E, Soares EP, Nogueira ES, Chambô Filho A, long-acting contraception and teenage pregnancy. N Engl J Med Guazzelli CA. Prematurity and low birth weight among Brazilian 2014;371(14):1316–1323 adolescents and young adults. J Pediatr Adolesc Gynecol 2010;23 20 Ferreira JM, Monteiro I, Fernandes A, Bahamondes MV, Pitoli A, (03):142–145 Bahamondes L. Estimated disability-adjusted life years averted by 6 Born Too Soon: The Global Action Report on Preterm Birth. Geneva: free-of-charge provision of the levonorgestrel-releasing intrau- World Health Organization; 2012. Available at: http://www.who.int/ terine system over a 9-year period in Brazil. J Fam Plann Reprod pmnch/media/news/2012/introduction.pdf. Accessed on April 14, Health Care 2017:jfprhc-2016-101569 [Epub ahead of print] 2017 21 Bahamondes L, Ali M, Monteiro I, Fernandes A. Contraceptive 7 Potter JE, Schmertmann CP, Assunção RM, Cavenaghi SM. Map- sales in the setting of the Zika virus epidemic. Hum Reprod 2017; ping the timing, pace, and scale of the fertility transition in Brazil. 32(01):88–93 Popul Dev Rev 2010;36(02):283–307 22 Peipert JF, Madden T, Allsworth JE, Secura GM. Preventing unin- 8 Curtis SL. Contraceptive use dynamics research needs post ferti- tended pregnancies by providing no-cost contraception. Obstet lity transition. Rev Bras Estud Popul 2012;29:191–193 Gynecol 2012;120(06):1291–1297

Rev Bras Ginecol Obstet Vol. 39 No. 8/2017 THIEME 376 Original Article

Trends in the Prevalence of Live Macrosomic Newborns According to Gestational Age Strata, in Brazil, 2001–2010, and 2012–2014 Tendências na prevalência de recém-nascidos vivos macrossômicos, estratiﬁcadas por idade gestacional, Brasil, 2001–2010 e 2012–2014

Maria Isabel do Nascimento1 Daniele Francine Pereira2 Calliana Lopata2 Carina Ladeia Flores Oliveira2 Ariane Arruda de Moura2 Maria Júlia da Silva Mattos2 Lucas Saraiva da Silva2

1 Department of Epidemiology and Biostatistics, Instituto de Saúde Address for correspondence Maria Isabel do Nascimento, PhD, Coletiva, Universidade Federal Fluminense, Niterói, RJ, Brasil Hospital Universitário Antonio Pedro, Secretaria da Coordenação de 2 Medical Students, Faculdade de Medicina, Universidade Federal Medicina, Rua Marquês do Paraná, 303, Centro, Niterói (RJ), Brasil Fluminense, Niterói, RJ, Brasil (e-mail: [email protected]).

Rev Bras Ginecol Obstet 2017;39:376–383.

Abstract Purpose To describe the trends in the prevalence of macrosomia (birth weight 4,000 g) according to gestational age in Brazil in the periods of 2001–2010 and 2012–2014. Methods Ecological study with data from the Brazilian Live Birth Information System (SINASC, in the Portuguese acronym) regarding singleton live newborns born from 22 gestational weeks. The trends in Brazil as a whole and in each of its five regions were analyzed according to preterm (22–36 gestational weeks) and term (37–42 gestational weeks) strata. Annual Percent Changes (APCs) based on the Prais-Winsten method and their respective 95% confidence intervals (CIs) were used to verify statistically significant changes in 2001–2010. Results In Brazil, the prevalence of macrosomic births was of 5.3% (2001–2010) and 5.1% (2012–2014). The rates were systematically higher in the North and Northeast Regions both in the preterm and in term strata. In the preterm stratum, the North Region presented the highest variation in the prevalence of macrosomia (þ137.5%) Keywords when comparing 2001 (0.8%) to 2010 (1.9%). In the term stratum, downward trends ► macrosomia were observed in Brazil as a whole and in every region. The trends for 2012–2014 were ► prevalence more heterogeneous, with the prevalence systematically higher than that observed for ► trends 2001–2010. The APC in the preterm stratum (2001–2010) showed a statistically ► epidemiology significant trend change in the North (APC: 15.4%; 95%CI: 0.6–32.3) and South (APC: ► maternal health 13.5%; 95%CI: 4.8–22.9) regions. In the term stratum, the change occurred only in the ► child health Northregion(APC:-1.5%;95%CI:-2.5–-0.5).

received DOI https://doi.org/ Copyright © 2017 by Thieme Revinter January 8, 2017 10.1055/s-0037-1604266. Publicações Ltda, Rio de Janeiro, Brazil accepted ISSN 0100-7203. May 24, 2017 TrendsinthePrevalenceofLiveMacrosomicNewbor Nascimento et al. 377

Conclusion The prevalence of macrosomic births in Brazil was higher than 5.0%. Macrosomia has potentially negative health implications for both children and adults, and deserves close attention in the public health agenda in Brazil, as well as further support for investigation and intervention.

Resumo Objetivo Descrever tendências nas prevalências de macrossomia (peso ao nascer 4.000 g) segundo idade gestacional no Brasil em 2001–2010 e em 2012–2014. Métodos Estudo ecológico com dados do Sistema de Informação sobre Nascidos Vivos (SINASC), incluindo bebês nascidos vivos a partir de 22 semanas, de gestações únicas. As tendências no Brasil como um todo e nas suas cinco regiões foram analisadas nos estratos pré-termo (22–36 semanas de gestação) e termo (37–42 semanas de gestação). Mudanças percentuais anuais (APCs) baseadas nos modelos de regressão propostos por Prais-Winsten e intervalos de confiança (ICs) de 95% foram calculados para verificar diferenças estatisticamente significantes no período 2001–2010. Resultados No Brasil, a prevalência de macrossomia foi de 5,3% (2001–2010) e 5,1% (2012–2014). As frequências foram sistematicamente maiores nas regiões Norte e Nordeste, tanto no pré-termo quanto no termo. No pré-termo, a região Norte apresentou a variação mais importante na prevalência de macrossomia (þ137,5%) quando comparados o ano de 2001 (0,8%) e o de 2010 (1,9%). No termo, tendências declinantes foram observadas no Brasil e em todas as suas regiões. As tendências em 2012–2014 foram mais heterogêneas, com frequências maiores do que aquelas observadas em 2001–2010. As APCs no estrato pré-termo (2001–2010) mostraram Palavras-chave que as mudanças foram estatisticamente significantes no Norte (APC: 15,4%; IC95%: ► macrossomia fetal 0,6–32,3) e no Sul (APC: 13,5%; IC95%: 4,8–22,9). No termo, a mudança ocorreu ► prevalência apenas no Norte (APC: -1,5%; IC95%: -2,5–-0,5). ► tendências Conclusão A prevalência de macrossomia no Brasil foi maior do que 5,0%. A ► epidemiologia macrossomia tem implicações potencialmente negativas para a saúde da criança e ► saúde materna do adulto, e merece mais atenção das políticas de saúde pública no Brasil, bem como ► saúde da criança mais apoio para investigação e intervenção.

Introduction Besides the potential for immediate injuries to both the The term fetal macrosomia implies fetal growth beyond a mothers and the newborns, macrosomia is suspected to be specific weight, regardless of the fetal gestational age.1 related to long-term harmful health effects, such as increased However, there is little consensus on the cut-off weight risk of developing obesity during childhood9 and adulthood,10 that properly allows to classify newbornss as macrosomic.2 as well as cancer,11 diabetes,12 and other chronic diseases. Definitions based on percentiles are dependent on gestation- The conditions associated to macrosomia include pregesta- al age3 and regional features.4 These parameters increase the tional and gestational diabetes mellitus, maternal obesity, and complexity to estimate the fetus’ measures, and this limits gestational weight gain,2 which may be reasonably controlled their use in the obstetric practice. Simpler classifications via adequate prenatal care. Considering prenatal care as based only on the cut-off weight are commonly used, and universally offered in Brazil, and the scarce scientific literature macrosomic newborns are considered those who were born investigating macrosomia at the population level, this study with a birth weight 4,000 g5 or 4,500 g.3,6 aimed to describe trends in the prevalence of live newborns Even though low birth weight is an issue of major interest in weighing 4,000 g according to gestational age strata, in the specialized scientific literature focusing on unfavorable Brazil and in its five regions, in the periods of 2001–2010 perinatal outcomes, the effects of macrosomia are also adverse, and 2012–2014. with potentially serious consequences for the mothers and 3 newborns. Maternal problems include high frequency of Methods cesarean sections, perineum lacerations, postpartum hemor- rhage, prolonged hospitalization, and puerperal infections. This is an ecological study based on nationwide information The newborns are at risk of shoulder dystocia, fracture, intra- provided by the Department of Informatics of the Brazilian uterine hypoxemia, intensive care unit admission and death.7,8 Unified Healthcare System (DATASUS, in the Portuguese

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acronym), the main national vital statistics subsystems tical significance evaluated via the Durbin Watson test. The coordinator in Brazil. The Brazilian Live Births Information annual percent changes (APCs) and their respective 95% System (SINASC, in the Portuguese acronym) is the subsys- confidence intervals (95%CIs) were estimated as described tem that stores epidemiologic information on live births in by Antunes and Cardoso.15 The statistical procedures were Brazil, and it is the source of the variables (namely year of performed using The Microsoft Excel Software (Microsoft birth, number of live newborns, gestational age, and birth Corporation, Redmond, WA, US). weight) used in the present study. All live newborns from singleton pregnancies from 22 gestational weeks from 2001 Ethical Procedures to 2010 and from 2012 to 2014 were included in the study. This study followed the recommendations for scientific The data for 2011 were not used because the gestational research involving human subjects, and as it was conducted age field in the birth certificate form was modified in using de-identified secondary datasets publicly available on that year, and its inclusion could cause the erroneous the DATASUS website; therefore, it was exempt from formal classification of some babies in regard to gestational age. ethical procedures. The definition of macrosomia was based on the cut-off birth weight 4,000 g. Results Prevalence of macrosomic births in Brazil as a whole and in its five regions (North, Northeast, Midwest, Southeast and In Brazil, the number of live births after 22 gestational weeks South) was calculated for each year, for all live newborns reached over 30 million during 2001–2010, and over 8 from 22 gestational weeks, for preterm newborns (from 22 to million during 2012–2014. The number of newborns with 36 gestational weeks), and for term newborns (from 37 to 42 birth weight 4,000 g reached 1,606,330 (2001–2010) and gestational weeks). Considering the improvement in cover- 422,069 (2012–2014), determining an overall prevalence of age and data quality provided by the SINASC in more recent 5.3% (2001–2010) and 5.1% (2012–2014). This indicator years, a correction factor created by Szwarcwald et al13 was decreased slightly (8.9%) when comparing the frequency used to reduce the effect of underreported births only during obtained in 2001 (5.6%) and in 2010 (5.1%). There was no the 2001–2010 period, so as to more accurately represent the change in the 2012–2014 period (►Fig. 1). real number of live births in Brazil. Prevalence indicators showed distinct trends according to As differences between the SINASC data and the primary gestational age strata and time periods. Comparing the data studied by Silveira et al14 were more marked involving preterm strata rates observed in the 2001–2010 period, newborns weighing up to 3,000 g, with lower or no signifi- the prevalence of macrosomia increased both in Brazil as a cant difference above this weight group, no factor was used whole and in four of its five regions, with the Southeast to correct the birth weight 4,000 g in relation to gesta- Region registering a variation of zero. The highest increase tional age. occurred in the North Region (> 130.0%). In the 2012–2014 period, macrosomia preterm rates registered a slight nega- Secular Trends Analysis tive change. The highest reduction occurred in the South First, a trend assessment (increasing, decreasing, or station- Region (20.0%). ary) was visually obtained through the inspection of specific In the term strata, from 2001 to 2010, the prevalence rates graphs for Brazil as a whole. The dependent variable (preva- for macrosomia decreased in Brazil as a whole and in all lence of live newborns weighing 4,000 g) was placed on regions. In the 2012–2014 period, the frequency was some- the y-axis and correlated with the independent variable what heterogeneous. The prevalence of newborns born from (year of birth), which was placed on the x-axis. The analyses 37 gestational weeks and weighting 4,000 g decreased in were repeated for each of the five Brazilian regions. Brazil as a whole and in the South Region, but it increased in the North and Southeast Regions. There were no variations Trend Variation in the 2001–2010 Period in the Northeast and Midwest Regions (►Table 1). Anticipating that some random effects related to prevalence Pictorial representations of the time series allowed the variations over time would make it more difficult to interpret visualization of prevalence trends (solid lines) in Brazil and potential trends, a second step was taken with the plotting in every region separately for the 2001–2010 period. and reevaluation of smoothed prevalence rates using a third- Smoothed data (dotted lines) showed that preterm macro- order moving average. This step was only adopted for the somia prevalence rates changed harmonically during 2004– 2001–2010 period, as this statistical technique is not recom- 2005 (►Fig. 2). mended for analysis of historical data with less than 7 time The results indicate statistically significant elevation trends points.15 in preterm macrosomic births in the North and South Regions. Next, to address the residue autocorrelation effects deter- According to the APCs, the North Region had the most impor- mined by time frame proximity, a step-by-step procedure tant annual variation (APC: 15.4%; 95%CI: 0.6–32.3) followed proposed by Antunes and Cardoso15 was followed beginning by the South Region (APC: 13.5%; 95%CI: 4.8–22.9). In term with the ten-base logarithmic transformation of the preva- macrosomic births, the APCs suggest statistically significant lence rates. Finally, parameter estimations were made by declining trends only in the North Region (APC: 1.5%; 95%CI: generalized linear regression designated as autoregressive 2.5–0.5). In Brazil as a whole and in the other four regions, modeling, using the Prais-Winsten method, and with statis- the trends were stationary (►Table 2).

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Fig. 1 Birth of live newborns after 22 gestational weeks registered in the Brazillian Live Births Information System (SINASC, in the Portuguese acronym), and trends in the prevalence of macrosomic live newborns in Brazil, from 2001 to 2010, and from 2012 to 2014. The principal y-axis shows the total number of births. The secondary y-axis shows prevalence of macrosomic babies. The x-axis shows the year of birth.

Table 1 Prevalence of live macrosomic newborns ( 4,000 g) according to GW strata in Brazil and its regions, from 2001 to 2010 and from 2012 to 2014

Year Brazil North Northeast Midwest Southeast South

22 to 36 37 to 42 22 to 36 37 to 42 22 to 36 37 to 42 22 to 36 37 to 42 22 to 36 37 to 42 22 to 36 37 to 42 GW (%) GW (%) GW (%) GW (%) GW (%) GW (%) GW (%) GW (%) GW (%) GW (%) GW (%) GW (%)

2001 0.6 5.9 0.8 7.3 0.7 7.5 0.5 5.8 0.6 4.5 0.3 5.6

2002 0.4 5.6 0.7 6.9 0.3 7.1 0.5 5.5 0.5 4.4 0.2 5.3

2003 0.3 5.3 0.6 6.4 0.4 6.5 0.2 5.2 0.4 4.2 0.2 5.0

2004 0.3 5.5 0.6 6.5 0.2 6.7 0.3 5.3 0.4 4.4 0.2 5.3

2005 0.3 5.7 0.6 6.4 0.2 7.0 0.2 5.6 0.3 4.6 0.3 5.5

2006 1.0 5.7 2.5 6.5 1.5 7.1 0.8 5.6 0.7 4.6 0.5 5.3

2007 0.9 5.6 2.5 6.4 1.3 7.1 0.7 5.4 0.6 4.4 0.6 5.1

2008 0.9 5.7 1.9 6.4 1.4 6.9 0.9 5.4 0.6 4.6 0.6 5.5

2009 0.9 5.5 1.8 6.3 1.4 6.8 1.0 5.3 0.5 4.5 0.5 5.3

2010 0.9 5.4 1.9 6.1 1.2 6.7 0.8 5.1 0.6 4.4 0.6 5.1

Change 50.0 8.5 137.5 16.4 71.4 10.7 60.0 12.1 0.0 2.2 100.0 8.9 2001 to 2010

2012 2.0 5.6 2.8 6.4 2.7 6.9 1.8 5.0 1.4 4.6 1.5 5.3

2013 1.8 5.4 2.4 6.2 2.5 6.6 1.7 5.0 1.3 4.6 1.3 5.3

2014 1.8 5.5 2.5 6.5 2.6 6.9 1.5 5.0 1.2 4.7 1.2 5.2

Change 10.0 1.8 10.7 1.6 3.7 0.0 16.7 0.0 14.3 2.8 20.0 1.9 2012 to 2014

Abbreviation: GW, gestational weeks. Note: Change (%) after comparingthe prevalence of macrosomia in 2001with the prevalence of macrosomiain2010,and in 2012 with the prevalence in2014.

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Fig. 2 Trends in prevalence rates and in smoothed prevalence rates of macrosomic live newborns born between 22 to 36 and 37 to 42 gestational weeks, in Brazil and its regions, from 2001 to 2010. The y-axis shows the prevalence, and the x-axis shows the year of birth.

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Table 2 Trends and APCs in the prevalence of live born macrosomic newborns ( 4,000 g), Brazil and regions, 2001–2010

22 to 36 gestational weeks 37 to 42 gestational weeks Region APCs (%) and Trend APCs (%) and Trend 95%CI Interpretation 95%CI Interpretation Brazil 10.3 (2.1; 24.3) stationary 0.5 (–1.5; 0.5) stationary North 15.4 (0.6; 32.3) increasing 1.5 (2.5; 0.5) declining Northeast 16.8 (2.8; 40.6) stationary 0.8 (2.0; 0.5) stationary Midwest 12.2 (3.2; 30.0) stationary 1.1 (2.1; 0.0) stationary Southeast 3.1 (4.5; 11.4) stationary 0.2 (0.7; 1.0) stationary South 13.5 (4.8; 22.9) increasing 0.3 (1.2; 0.6) stationary

Abbreviations: 95%CI, 95% conﬁdence interval; APCs, annual percent changes.

Discussion more noticeable, comparing 2012–2014 to 2001–2010 in the present study. In the 2001–2010 period, the estimates were This study focused on large newborns ( 4,000 g) born from within the limits of prevalence of preterm newborns weighing 2001 to 2014 in Brazil, excluding the year 2011. The overall between 4,000 g and 5,000 g obtained with a correctional prevalence of macrosomic live births in the country as a equation provided by Silveira et al.14 For the 2012–2014 whole was of 5.3% (2001–2010) and 5.1% (2012–2014). This period, the estimates were higher than those found in the first frequency declined over the first period (2001–2010), and period, and this probably reflects the improvement in the remained relatively stationary in the more recent period quality of the data from SINASC. (2012–2014). The prevalence of macrosomia in the North In Denmark, a secular trend study involving all live new- and Northeast Regions was systematically higher than in borns born from 20 gestational weeks from 1973 to 2003 Brazil as a whole and in the other regions, both by gestational showed that the increase in mean birth weight was of 5.0 g age strata and by time period. per year both for boys and girls. Stratifying by gestational age, Over time, the macrosomia among preterm newborns the birth weight increased 3.5 g or 4.0 g per year among term showed an upward trend in Brazil and in its regions, except in newborns. However, stronger variations were seen among Southeast Region, where this problem kept a stationary preterm newborns, a group in which the mean birthweight trend. On the other hand, downward trends were found in rose 8.3 g or 9.0 g per year.18 the term strata (2001–2010). The macrosomia problem was The increase in the frequency of births of heavier preterm more heterogeneous in the 2012–2014 time period. newborns is a complex phenomenon for which there are no In Brazil, the general indicator of macrosomia was near the easy or obvious explanations. Although three major health lowest estimates found amongst high-income countries (5.0% conditions (diabetes, maternal obesity and maternal weight to 20.0%), but it was higher than the findings concerning term gain during the gestational period) may account for dispro- large newborns reported in a Brazilian research coordinated by portionate increases in fetal weight,19,20 they may also be the World Health Organization (WHO’s Global Survey on controlled via adequate prenatal care. Considering the wide Maternal and Perinatal Health) conducted by Koyanagi et al4 prenatal care coverage provided in Brazil as well as the high with 14,804 newborns (4.1%), and in another study conducted proportion of women attending six or more prenatal visits, a by Ye et al3 with 13,373 newborns (4.4%). The survey results question opportunely presented is: Why has the frequency of were restricted only to live births occurring in 3 maternity overweight involving preterm newborns increased in Brazil? hospitals between 2004 and 2005. Even though the maternity Labor induction and cesarean section indicated specifi- hospitals were randomly selected in the WHO study, the cally to deliver a fetus suspected to be overweight for outcomes presented in our study may be closer to true gestational age or macrosomic could partially explain the population parameters, since they reflect SINASC data of preterm births of those newborns who experienced higher almost all live births registered in Brazil. weight gain and faster intrauterine growth.21 In a way, this Reductions in macrosomia rates in Brazil resemble a trend could reflect in the decline in weight in the last gestational described in South Korea.16 Considering all live births in that weeks, as recorded in the United States. In that country, country, macrosomia dropped by almost half, going from Zhang et al22 reported that term and post-term macrosomia 6.7% to 3.5%, in the 1993–2010 period. The lowest rates were rates dropped from 2.2% to 1.6% respectively, from 1992 to correlated with improvements in pregnancy management, 2003, while the rates of labor induction and cesarean section particularly for gestational diabetes, considered to be one of increased from 14.3% to 27.0% and from 21.3% to 25.0% in the the leading causes of fetal macrosomia. same period respectively. Fetal growth is more prominent in the last month of Statistically significant findings in the term strata (2001– pregnancy.17 However, it was in the preterm strata before 2010) were observed only in the North Region, maybe as an the physiological weight gain acceleration expected in the last effect of the pattern of births of macrosomic newborns 4 gestational weeks that the macrosomia frequency became before 37 gestational weeks. In Beijing, China, the proportion

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of live newborns weighing 4,000 g increased from 6.6% in country via the PBF was almost double the amount received 1996 to 9.5% in 2000, and declined to 7.0% in 2010.23 This by those in the 10 richest states.29 trend was accompanied by gestational age shortening, and Dependence on the PBF benefit is greater in the North and by more premature newborns in 2010 (6.6%) than in 1996 Northeast compared with the Southeast Region. Such cir- (4.1%). According to Shan et al,23 the magnitude of the cumstance seems to be related to a high consumption in the prevalence of macrosomia could be reflecting an excessive former of unhealthy foods such as sugar, fat, coffee, beans maternal gestational weight gain, a situation maximized by and soft drinks.30 Moreover, an insufficient prenatal cover- both socioeconomic progress and increased consumption of age reduces the possibility of controlling the conditions highly caloric foods, which has been typical during these related to macrosomia, mainly among minorities living in nutritional transition years. socioeconomically disadvantaged areas. In view of these The smoothing statistical method eliminates some effects problems, the magnitude of the prevalence found in the related to random fluctuations and facilitates the visualization present study suggests the difficulty of tackling macrosomia of cyclical or seasonal components in time series studies.15 conditions in some Brazilian regions. Inflections coincided in the years 2004 and 2005. As descrip- Some limitations should be mentioned. This study was tive analyses are inappropriate to draw causal inferences, it developed with data from a secondary vital statistics source would be important to conduct further research to verify in which databases were fed with information collected by whether public policies to combat hunger and to improve healthcare workers on a day-to-day basis. However, SINASC income distribution, along with its resulting socioeconomic is an official live birth records system that covers all of the improvement, could partially explain the variations in macro- national territory, and it is the main source of birth data in somia rates found in Brazil. Brazil. Even though in this study the parameter was preva- It is noteworthy that there is evidence showing that the lence, inconsistent values present in large databases must be initiative entitled Family Grant Program (Programa Bolsa dealt with appropriately. However, no studies were found Família – PBF, in the Portuguese acronym) is associated to an regarding inconsistencies in large-newborn birth weight increase in the number of prenatal visits, and to a reduction in values in the SINASC database, or that recommended any low birth weight, particularly in the less-affluent regions, such data correction for the rates found therein. as the Northeast region of Brazil.24 Conditional money trans- Another limitation was that macrosomia was based on the fers via PBF were accelerated in the 2004–2005 biennium, and cut-off birth weight at 4,000 g, and this prevented com- they expanded rapidly throughout Brazil. The contingent of parisons with studies that used other definitions. Further- benefited families grew from 10 million to 12 million between more, changes in the gestational age calculation inserted in 2008 and 2009, reaching almost 13 million in 2011. The target the birth certificate form in 2011 hindered the development was the poorest people living in the North and Northeast of the secular analysis for the entire period (2001–2014). The Regions of the country, but PBF coverage currently reaches all prevalence was instead estimated for separate time periods Brazilian municipalities.25 The question was raised above (2001–2010 and 2012–2014). The performance of statistical because social investment in the country has aimed to achieve procedures was possible only for the first period (2001– the best results in terms of the improvement in quality of life of 2010), since only 3 time points were available in the final the poorest people in Brazil. Studies showed that the increase period (2012–2014). in fetal macrosomia followed a socioeconomic improvement in Finally, the prevalence of macrosomia was calculated in some regions of China,26 outlining a context that might relation to all live births from 22 gestational weeks, including resemble the changes that are happening in Brazil. newborns weighting 500 g. Even so, the prevalence was Fetal weight influences maternal and perinatal outcomes. higher than the estimates found in previous studies that only The North and Northeast Regions experienced higher macro- included live births of newborns weighing 1,000 g.3,4 somia prevalence, suggesting that regional inequalities may In conclusion, the prevalence of live newborns weighing be determining the worst results in those regions compared 4,000 g was higher than 5%, and the trends in Brazil were with Brazil as a whole and to the more affluent Southeast, heterogeneous. The upward trend in preterm macrosomic Midwest and South Regions. In accordance with data from births was a finding that may partially explain the downward the report Saúde Brasil 2013,27 only 57.0% and 67.0% of trend found among heavy newborns born from 37 gestational mothers from the North and Northeast Regions had 6 or weeks in 2001–2010. In the 2012–2014 period, the preterm more prenatal visits, in 2012 respectively. The frequency of rates weresystematically higher than in the 2001–2010 period, mothers who had up to 3 appointments was unacceptably although they were almost stationary among term newborns. high both in the North (21.0%) and in the Northeast (14.1%) Considering the causes and effects of macrosomia in maternal Regions. Considering that fetal weight gain is influenced in a and perinatal morbimortality, as well as their potential im- way by optimal prenatal care, this highlights the importance plications on the child’s and adult’s health, fetal macrosomia of improving the frequency of mothers attending six or more requires more attention in the Brazilian public healthcare prenatal visits in the North and Northeast Regions. agenda, and more support for investigation and intervention. Public policies focusing on the poorest people have relatively more positive impact on the income of people living in the poorest regions.28 For example, the per capita amount Conflicts of Interest received in 2006 by families in the 10 poorest states in the There are no conflicts of interest to declare.

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Financial Support 16 Kang BH, Moon JY, Chung SH, et al. Birth statistics of high birth The study did not receive any financial support. weight infants (macrosomia) in Korea. Korean J Pediatr 2012; 55(08):280–285 17 Filkaszova A, Chabada J, Stencl P, et al. Ultrasound diagnosis of References macrosomia. Bratisl Lek Listy (Tlacene Vyd) 2014;115(01):30–33 1 Chatfield J; American College of Obstetricians and Gynecologists. 18 Schack-Nielsen L, Mølgaard C, Sørensen TI, Greisen G, Michaelsen ACOG issues guidelines on fetal macrosomia. Am Fam Physician KF. Secular change in size at birth from 1973 to 2003: national data 2001;64(01):169–170 from Denmark. Obesity (Silver Spring) 2006;14(07):1257–1263 2 Aye SS, Miller V, Saxena S, Farhan M. Management of large-for- 19 Viecceli C, Remonti LR, Hirakata VN, et al. Weight gain adequacy gestational-age pregnancy in non-diabetic women. Obstet Gyne- and pregnancy outcomes in gestational diabetes: a meta-analysis. col 2010;12(04):250–256 Obes Rev 2017;18(05):567–580 3 Ye J, Torloni MR, Ota E, et al. Searching for the definition of 20 Walsh JM, McAuliffe FM. Prediction and prevention of the macro- macrosomia through an outcome-based approach in low- and somic fetus. Eur J Obstet Gynecol Reprod Biol 2012;162(02): – middle-income countries: a secondary analysis of the WHO Global 125 130 Survey in Africa, Asia and Latin America. BMC Pregnancy Childbirth 21 Donahue SM, Kleinman KP, Gillman MW, Oken E. Trends in birth 2015;15:324 weight and gestational length among singleton term births in the – 4 Koyanagi A, Zhang J, Dagvadorj A, et al. Macrosomia in 23 United States:1990-2005.Obstet Gynecol2010;115(2Pt 1):357 364 developing countries: an analysis of a multicountry, facility- 22 Zhang X, Joseph KS, Kramer MS. Decreased term and postterm based, cross-sectional survey. Lancet 2013;381(9865):476–483 birthweight in the United States: impact of labor induction. Am J – 5 Kc K, Shakya S, Zhang H. Gestational diabetes mellitus and macro- Obstet Gynecol 2010;203(02):124.e1 124.e7 somia: a literature review. Ann Nutr Metab 2015;66(Suppl 2):14–20 23 Shan X, Chen F, Wang W, et al. Secular trends of low birthweight and 6 Pía Juárez S. Quality of the Spanish Vital Statistics to estimate macrosomia and related maternal factors in Beijing, China: a long- perinatal health outcomes: small and large for gestational age. itudinal trend analysis. BMC Pregnancy Childbirth 2014;14:105 Rev Esp Salud Publica 2015;89(01):85–91 24 Santos LMP, Guanais F, Porto DL, et al. Peso ao nascer entre fi fi 7 Araujo Júnior E, Peixoto AB, Zamarian AC, Elito Júnior J, Tonni G. crianças de famílias de baixa renda bene ciárias e não bene - Macrosomia. Best Pract Res Clin Obstet Gynaecol 2017;38:83–96 ciárias do Programa Bolsa Família da Região Nordeste (Brasil): 8 World Association of Perinatal Medicine. Matres Mundi Interna- pareamento CadÚnico e Sinasc [Internet]. In: Brasil. Ministério da tional. Recommendations and Guidelines for Perinatal Medicine. Saúde. Secretaria de Vigilância em Saúde. Departamento de Barcelona: Matres Mundi; 2007 Análise de Situação em Saúde. Saúde Brasil 2010: uma análise 9 Qiao Y, Ma J, Wang Y, et al; ISCOLE Research Group. Birth weight da situação de saúde e de evidências selecionadas de impacto de and childhood obesity: a 12-country study. Int J Obes Suppl 2015; ações de vigilância em saúde. Brasília (DF): Ministério da Saúde; 5(Suppl 2):S74–S79 2011 [cited 2016 Abr 7]. p. 271–93. Available from: http://bvsms. 10 Schellong K, Schulz S, Harder T, Plagemann A. Birth weight and saude.gov.br/bvs/publicacoes/saude_brasil_2010.pdf long-term overweight risk: systematic review and a meta-analy- 25 Segura-Pérez S, Grajeda R, Pérez-Escamilla R. Conditional cash sis including 643,902 persons from 66 studies and 26 countries transfer programs and the health and nutrition of Latin American globally. PLoS One 2012;7(10):e47776 children. Rev Panam Salud Publica 2016;40(02):124–137 11 Smith NR, Jensen BW, Zimmermann E, Gamborg M, Sørensen TI, 26 Lu Y, Zhang J, Lu X, Xi W, Li Z. Secular trends of macrosomia in Baker JL. Associations between birth weight and colon and rectal southeast China, 1994-2005. BMC Public Health 2011;11:818 cancer risk in adulthood. Cancer Epidemiol 2016;42:181–185 27 Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. 12 Harder T, Rodekamp E, Schellong K, Dudenhausen JW, Plagemann Departamento de Análise de Situação em Saúde [Internet]. Saúde A. Birth weight and subsequent risk of type 2 diabetes: a meta- Brasil 2013: uma análise da situação de saúde e das doenças analysis. Am J Epidemiol 2007;165(08):849–857 transmissíveis relacionadas à pobreza. Como nascem os brasileiros. 13 Szwarcwald CL, Morais Neto OL, Frias PG, et al. Busca ativa de óbitos Brasília (DF): Ministério da Saúde; 2014 [cited 2016 Set 7]. Available e nascimentos no Nordeste e na Amazônia Legal: estimação das from: http://portalsaude.saude.gov.br/images/pdf/2015/janeiro/28/ coberturas do SIM e do Sinasc nos municípios brasileiros [Internet]. saude-brasil-2013-analise-situacao-saude.pdf In: Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. 28 CampelloT, Neri MC (org). Programa Bolsa família: uma década de Departamento de Análise de Situação de Saúde. Saúde Brasil 2010: inclusão e cidadania: sumário executivo. Brasília (DF): IPEA; 2014 análise da situação de saúde e de evidências selecionadas de [cited 2017 Maio 11]. Available from: http://repositorio.ipea.gov. impacto de ações de vigilância em saúde. Brasília (DF): Ministério br/bitstream/11058/2082/5/Sum%C3%A1rio_executivo-Livro- da Saúde; 2011 [cited 2016 Jan 20]. p. 79–98. Available from: http:// Programa_Bolsa_Fam%C3%ADlia-uma_d%C3%A9cada_de_inclus% bvsms.saude.gov.br/bvs/publicacoes/saude_brasil_2010.pdf C3%A3o_e_cidadania.pdf 14 Silveira MF, Matijasevich A, Horta BL, et al. [Prevalence of preterm 29 Silveira-Neto RM, Azzoni CR. Social policy as regional policy: birth according to birth weight group: a systematic review]. Rev market and nonmarket factors determining regional inequality. – Saude Publica 2013;47(05):992–1003 J Reg Sci 2012;52(03):433 450 15 Antunes JLF, Cardoso MRA. [Using time series analysis in epide- 30 de Bem Lignani J, Sichieri R, Burlandy L, Salles-Costa R. Changes in miological studies]. 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Rev Bras Ginecol Obstet Vol. 39 No. 8/2017 THIEME 384 Original Article

Food Insecurity, Prenatal Care and Other Anemia Determinants in Pregnant Women from the NISAMI Cohort, Brazil: Hierarchical Model Concept Insegurança alimentar, cuidado pré-natal e outros determinantes da anemia em mulheres grávidas da coorte Nisami, Brasil: modelo conceitual hierárquico

Fran Demétrio1 Carlos Antônio de Souza Teles-Santos2,3 Djanilson Barbosa dos Santos1

1 Centro de Ciências da Saúde, Universidade Federal do Recôncavo da Address for correspondence FranDemétrio,PhD,CentrodeCiências Bahia, Santo Antônio de Jesus, BA, Brazil da Saúde, Universidade Federal do Recôncavo da Bahia, Av. Carlos 2 Instituto de Saúde Coletiva, Universidade Federal da Bahia, Salvador, Amaral, n° 1015, Cajueiro, 44570-000 - Santo Antônio de Jesus, BA, BA, Brazil Brazil (e-mail: [email protected]; [email protected]). 3 Biostatistics and Molecular Epidemiology Laboratory, Centro de Pesquisas Gonçalo Moniz-Fiocruz, Salvador, BA, Brazil

Rev Bras Ginecol Obstet 2017;39:384–396.

Abstract Objective To identify the prevalence of anemia and its relation to food insecurity (FI) and other determinants in pregnant women. Methods A cross-sectional, cohort-nested study, with the participation of 245 pregnant women who were cared for at Family Health Units in the municipality of Santo Antônio de Jesus, Bahia, Brazil. The participants underwent blood tests for hemoglobin levels, anthropometric examinations, and answered a structured questionnaire. The hemoglobin (Hb) parameter (Hb < 11 g/dL) was used for the classification of the diagnosis of anemia. Food insecurity was evaluated using the North American short-scale food insecurity assessment. Logistic regression was adopted for the statistical analyses, based on a hierarchical conceptual model that enabled the measurement of the decomposition of the total effect of its non-mediated and mediated components using the proposed hierarchical levels. Results The prevalence of anemia in the studied population was of 21.8%, and the average hemoglobin was 12.06 g/dL (standard deviation [SD]: 1.27). Food insecurity was fi Keywords identi ed in 28.16% of the pregnant women. The average maternal age was 25.82 years (SD: 5.94). After ranking, the variables positively associated with anemia remained ► women’s health significant: FI (odds ratio [OR] ¼3.63; 95% confidence interval [95%CI]: 1.77–7.45); not ► pregnant women undergoing prenatal care (OR ¼ 5.15; 95%CI: 1.43–18.50); multiparity (OR ¼ 2.27; 95%CI: ► anemia 1.02–5.05); and non-supplementation of iron medication (OR ¼ 2.45; 95%CI: 1.04–5.76). ► prenatal care The results also indicated that the socioeconomic and environmental factors were largely ► food and nutrition mediated by food insecurity and factors regarding prenatal care. security

received DOI https://doi.org/ Copyright © 2017 by Thieme Revinter October 26, 2016 10.1055/s-0037-1604093. Publicações Ltda, Rio de Janeiro, Brazil accepted ISSN 0100-7203. March 31, 2017 published online June 30, 2017 Food Insecurity, Prenatal Care and Other Anemia Determinants Demétrio et al. 385

Conclusions In the present study, the chance of occurrence of anemia in pregnant women was signiﬁcantly higher, mainly among women: in situations of food insecurity, not undergoing prenatal care, not having received iron supplements, and who are multiparous.

Resumo Objetivo Identificaraprevalênciadeanemiaesuarelaçãocomainsegurança alimentar (IA) e outros determinantes em mulheres grávidas. Métodos Trata-se de estudo transversal aninhado a uma coorte, do qual participaram 245 gestantes atendidas em Unidades de Saúde da Família do município de Santo Antônio de Jesus-BA. As participantes foram submetidas a exame de sangue para dosagem de hemoglobina, exame antropométrico, e responderam a um questionário estruturado. Utilizou-se o parâmetro hemoglobina (Hb < 11 g/dL) para a classificação do diagnóstico de anemia. A IA foi avaliada por meio da escala curta norte-americana de avaliação da segurança alimentar. Para as análises estatísticas, adotou-se a regressão logística, tomando-se como base um modelo conceitual hierarquizado definido apriori, que possibilitou a mensuração da decomposição do efeito total em seus componentes não mediados e mediados nos níveis hierárquicos propostos. Resultados A prevalência de anemia na populaçãoestudadafoide21,8%,eamédia de hemoglobina foi de 12,06 g/dL (desvio padrão [DP]: 1,27). A IA foi identificada em 28,16% das gestantes. A média de idade materna foi de 25,82 anos (DP: 5,94). Após a hierarquização, permaneceram significativas as variáveis associadas positivamente à anemia: IA (razão de possibilidades [OR] ¼ 3,63; intervalo de confiança de 95% [IC95%]: 1,77–7,45); não realização de pré-natal (OR ¼ 5,15; IC95%: 1,43-18,50); Palavras-chave multiparidade (OR ¼ 2,27; IC95%: 1,02–5,05); e a não suplementação medicamentosa ► saúde da mulher de ferro (OR ¼ 2,45; IC95%: 1,04–5,76). Os resultados indicaram ainda que os fatores ► gestantes socioeconômicos e ambientais foram mediados em grande parte pela IA e pelos fatores ► anemia de cuidado pré-natal. ► cuidado pré-natal Conclusões Nesse estudo, a chance de ocorrência de anemia em gestantes foi signifi- ► segurança alimentar e cantemente maior, principalmente, entre aquelas que estavam em situação de IA, não nutricional realizaram o pré-natal, eram multíparas, e não fizeram a suplementação de ferro.

Introduction inflammatory or neoplastic processes) represent the most common types of iron metabolism disorders. Another type is Gestation is a period of physiological vulnerability in the life of anemia due to hemoglobinopathies.3,6 women, and it involves biological, physical and psychosocial In accordance with the World Health Organization changes.1 Accordingly, pregnant women form a priority group (WHO),3 iron-deficiency anemia is the most prevalent nutri- in the development of specific care, actions and policies by the tional deficiency condition in the world, and it mainly affects public healthcare system involving not only the health of the women of reproductive age, pregnant women and children. woman-mother, but also the health of the fetus.2,3 The global prevalence for this issue for pregnant women is Nevertheless, an elevated portion of women during the estimated at 41.8%, and at 29.1% for Brazil.3 During pregnan- pregnancy-puerperal phase expresses high rates of anemia, cy, mainly in the 2nd and 3rd quarters, 4 to 5 mg per day of even after the implementation of public health programs and iron is necessary to guarantee the balance of this nutrient.6 policies with the aim of controlling this problem, namely Iron-deficiency anemia is the result of an evolution due to during gestation. This can be observed, for example, with the successive stages of iron deficiency until the deficit of medicinal iron supplementation treatment and the enrich- hemoglobin3 is installed. Accordingly, WHO suggests anemia ment of wheat and corn flour, and the effectiveness of these as a proxy of iron-deficiency anemia, and the latter as an actions should be discussed.4,5 estimator of the general prevalence of iron deficiency in the Anemia is represented by a decrease in hemoglobin in the populations of underdeveloped and developing countries blood, and its main etiology is characterized by the abnormal that do not have any other important markers for anemia.3 biosynthesis of hemoglobin. Regarding this, iron-deficiency Notwithstanding the importance of this proposal by the anemia and anemia of chronic disease (present in infectious, WHO for the formulation of strategies for the control of

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anemia in pregnant women, some surveys have signaled that Methods the cases of anemia attributed to maternal iron deficiency were below what was expected, indicating the necessity of Study Design caution when using the prevalence of anemia as a proxy for A cross-sectional, cohort-nested study of pregnant women iron-deficiency anemia and the latter as an iron deficiency from the urban zone of the municipality of Santo Antônio de estimator in pregnancy.3,4 Jesus, Bahia, Brazil, performed between February 2014 and The occurrence of anemia during pregnancy is associated February 2015. The study integrated the more extensive to socio-environmental and economic conditions, prenatal survey entitled “Nutritional and Genetic Risk Factors during care, behavioral aspects and nutritional factors, especially Gestation Associated to Low Birth Weight/Prematurity: the the anthropometric nutritional state and food consumption NISAMI cohort”.a (namely dietary sources of iron or dietary sources that The municipality of Santo Antônio de Jesus has a territorial improve bioavailability).2,3,7 area of 261 Km2 and is located 187 Km from the city of In accordance with Fischer et al,8 women of reproductive Salvador, the capital of the state of Bahia, Brazil. The munici- age and pregnant women present higher chances of devel- pality has 90,949 inhabitants, 79,271 of whom residing in the oping anemia, mainly in the context of food insecurity (FI), urban area, and 11,676 in the rural area, comprising 47,963 which is marked by the decrease in quantity and quality of women and 42,986 men.12 It is considered the commercial and the food consumed. According to the results of the survey service hub of the south coast of Bahia (called Recôncavo in performed by these authors, the adjusted odds ratio (OR) for Portuguese). Most of the population of wage earners works in acquiring anemia was 31–43% higher among women living the local commerce. The human development index of the under FI conditions. municipality is of 0.700, and it occupies position 1,904 in the It is understood that awareness of these factors could national rank of municipalities with the best human develop- contribute toward the control of anemia during pregnancy, ment index.13 and mitigate the damages to the health and quality of life of A random sample of pregnant women aged between 14 and the women and of the fetus, such as the occurrence of 49 years was selected between January and February 2014. The cardiac and immunological impairments, thus reducing pregnant women were selected during prenatal consultations maternal and perinatal mortality, prematurity and low at the Family Health Unit (FHU) of the municipality. After this birth weight.2,3,6 phase, an interview was scheduled (by phone) at the homes of On the other hand, in Brazil there are few surveys that the pregnant women for the application of the assessmentscale investigated the relationship between FI and the prevalence for FI, which occurred between December and February 2015. of anemia in pregnant women, above all when analyzed in For effect of the sample power calculation of 80% for the conjunction with other determinants (socioeconomic, de- sample of 245 pregnant women used in this study, we used a mographic, environmental, prenatal care, behavioral and prevalence of anemia of 29.1%, estimated by the WHO3 for nutritional determinants) and, primarily, established by Brazil, with a sample error of 8% and a reliability of 95%. means of a hierarchical conceptual model. According to Teles-Santos,9 the hierarchical model could Selection Criteria constitute an applicable alternative to the epidemiological Pregnant women with and without associated morbidities studies with an elevated number of co-variables. Accord- were included, but only those with anemia, diabetes (gesta- ingly, the decision of including variables in a risk factor tional or clinical) and arterial hypertension (gestational or analysis for a certain outcome should not be exclusively clinical), residing in the urban zone of the municipality, ado- based on statistical significance; it should also consider the lescents and adults, with gestational ages of up to 32 weeks at hierarchical conceptual framework approach, which in- the moment of the collection of information, and attending the volves various levels.10 Thus, when investigating the factors prenatal care service at the FHU of the investigated municipal- associated to the genesis of cases of anemia during preg- ity were selected. Those with multiple gestations, or with nancy, it is possible to determine input levels for the health issues such as pre-eclampsia, renal problems or HIV different variables, always when there is an interrelation were not included in the survey. Therefore, these conditions among the variables at each level.10,11 were not identified among the selected pregnant women. For this purpose, assuming that anemia is not a nutritional or health condition determined only by biological factors, Conceptual Model but involving also a set of socioeconomic, demographic, For the study of the determinants of anemia, the hierarchical environmental, prenatal care and lifestyle determinants, conceptual model was established (►Fig. 1), which encom- among others, implies the consideration of the different passed the factors organized hierarchically in 3 levels accord- levels of determination.11 ing to the proximal-intermediary-distal relation for the In view of the exposed, the objective of this survey is to outcome under consideration (anemia). This strategy en- identify the prevalence of anemia and its relation to FI and abled the measurement of the breakdown of the non- other determinants in pregnant women, based on a hierarchical conceptual model that enables the measurement of a Cohort financed by Conselho Nacional de Desenvolvimento Cientí- the breakdown of the total effect in non-mediated compo- fico e Tecnológico (CNPq), process 481509/2012–7/ 2013. NISAMI nents (or direct). (Núcleo de Investigação em Saúde Materno-Infantil/UFRB).

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Socioeconomic and environmental factors

Income, receiving social welfare, schooling, marital status, position in the labor market, skin Block I color, number of residents in the household. Level 1

Food insecurity

Block II Level 2

a. b. c. Prenatal care factors Nutritional Lifestyle and Planned pregnancy, prenatal care, quarter factors maternal factors in which the prenatal care began, Received nutritional Alcohol consumption, Block III gestational period, number of prenatal Level 3 guidance, pregestational age consultations, parity, use of medicinal iron anthropometric nutritional supplementation status

Anemia Outcome

Fig. 1 Hierarchical conceptual model of the determinants of anemia in pregnant women.

mediated total (or direct) effect, as well as the study of the based on the parameters of the Institute of Medicine (IoM),16 mediated (or indirect) effect in the proposed hierarchical namely: low weight (BMI < 18.5), adequate weight (BMI levels.10,14 ¼ 18.5 to 24.9), and excess weight – overweight/obesity (BMI 25). Food insecurity was evaluated by means of the Variables of the Study short version of the United States Department of Agriculture A structured questionnaire was used to obtain information (USDA)12 Food Security Scale, which includes 6 questions related to the socioeconomic, demographic, biological, envi- related to food in the 12 months prior to the interview. This ronmental and prenatal care conditions. This questionnaire scale generates a score that ranges from 0 to 6 (►Table 1).12,17 was applied by a previously trained team composed of In four questions, each positive answer corresponds to one nutritionists and nutrition students. point, while in one of the questions the point is given to a The independent variables are represented by socioeco- negative answer and, in another one, it corresponds to the time nomic and environmental factors, food insecurity, and prenatal of exposure in which there was a decrease in the quantity of care variables such as: age, gestational age, number of prenatal food due to lack of money. The score is calculated from the sum consultations, folic acid and ferrous sulfate supplementation, of these points. Food safety is considered for those pregnant guidance during prenatal care, pregestational anthropometric women who score one point; food insecurity is considered for nutritional status, lifestyle, and maternal lifestyle and age. The pregnant women scoring two to four points, and hunger is pregestational weight was obtained from the file of the preg- considered for those with a score of five to six points.12 The nant woman, and when it was not available, the referred short scale was chosen due to the fact that it comprises a weight was registered. The height of the pregnant woman greater time interval in relation to the period of application was verified by previously trained researchers and students of (the last twelve months prior to the interview). In the present the Nutrition Course of one of our institutions. To verify the study, the scale was applied at the end of the gestations, height, a Welmy stadiometer (Welmy, Santa Bárbara d’Oeste, between December and February 2015, with the purpose of SP, Brazil) with a capacity for 2,000 mm and sensitivity of identifying food insecurity situations in the households of the 0.5 cm was used. The measurements were taken in duplicity. A pregnant women. It should be observed that this scale was maximum variation of 0.5 cm was accepted for the measure- validated in a study conducted by Demétrio18 in households ment of the length.15 The pregestational body mass index with pregnant women. The variables were categorized in a (BMI) was used as proxy variable of the maternal pregesta- dichotomous manner in the descriptive analysis and in the tional anthropometric nutritional status. This was classified hierarchized model.

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Table 1 Indicators (items) of the short version of the North American Food Security Assessment Scale

Questions Item 1. During the past twelve months, did the food in your house ﬁnishandyouhadnomoneytobuymore? Item 2. During the past twelve months, could you offer varied food to your family, with beans, rice, meat, salad and fruit? Item 3. During the past twelve months, did you or any other member of your household have to decrease the quantity of food or not have a meal for lack of money to buy more food? Item 4. In how many months did this occur? Item 5. During the past twelve months, did you eat less than you would wish to because you had no money to buy more food? Item 6. During the past twelve months, did you feel hungry but did not eat because you had no money to buy more food?

Source: Bickel et al,12 Santos et al.17

The dependent variable was represented by anemia, which which the determinants would act. Model A (block I) estimated was categorized as follows: without anemia (Hb > 11 g/dL) - the total effect of the socioeconomic and environmental deter- no (0), with anemia (Hb < 11 g/dL) - yes. Information on the minants. Model B (block II), included the determinants of the concentration of hemoglobin was obtained by means of blood respective block, and estimated the effect of the socioeconomic collection and analysis performed in a single laboratory that is determinants not mediated by the corresponding block. Models certified by the Brazilian Public Healthcare System (SUS, in the B and C (block III) estimated the effect of the socioeconomic and Portuguese acronym) in the municipality of Santo Antônio de environmental determinants not mediated by the correspond- Jesus, which provides care to pregnant women assisted by the ing factors of the block (III.a) taken singly. Model E (Block III.a) FHU. This laboratory is equipped with appropriate material estimated the effect of the socioeconomic and environmental and equipment for collecting and processing the samples, and determinants not mediated simultaneously by the determi- it has a specialized team responsible for standardizing the nants of block III.a, and the total effects of this block. Model D processing procedures and biosecurity of the blood samples in resulted from the adjustment by Model E. In the hierarchical order to perform the blood count and other prenatal exams. analysis, the variables that remained associated to anemiawere The hemoglobin concentration was obtained by means of a maintained, after control by the variables of confusion of the direct cyanmethemoglobin technique. same level and for those hierarchically superior.17 The gestational age was calculated based on the last The adjustment quality of the models was evaluated using menstruation date available on the record of the pregnant the Akaike information criterion (AIC). This criterion was woman of the first ultrasound performed up until the end of proposed by Akaike,20 and is defined as: AIC ¼ -2ln(L) þ 2p the first gestational quarter. and BIC ¼ -2ln(l) þ pln(n), where l is the likelihood function; n is the number of observations; and p is the number of Statistical Analysis adjusted parameters. In the bivariate and multivariate analyses in a hierarchical The input of the information was performed using the theoretical model, the dependent variable (anemia) was EPIinfo software, version 6.04, and the statistical analyses modeled by means of the application of the logistic regres- were performed using the STATA for Mac (StataCorp, College sion model. This model also enables the estimation of the Station, TX, US) software, version 12.0. odds ratio (OR), with the respective 95% confidence intervals (95%CI), when comparing the exposed group to the group of Ethical Aspects reference of the specific determinant. In this study, a consid- The main project of which this study is a part of was erable increase in the value of the overestimation factor of evaluated and approved by the Ethics Committee in Research the measure of the outcome was identified with the use of OR of one of our institutions under registration number 050/10. in comparison to the PR estimates. In the bivariate analysis, the missing data was inserted Results and attributed the modal value, as proposed by Twisk.19 Intra-block multivariate analyses were applied to select the The maternal socio-environmental, economic, demographic, variables that would compose each one of the blocks in the prenatal care, behavioral and nutritional characterization is hierarchized analysis, adopting the level of significance of 10% presented in ►Table 2. (p 0.10). Later, the hierarchized analysis was performed, A monthly family income between 2 and 4 minimum which consisted of the adjustment of a sequence of models of wages was identified in 52.65% of the women. Most of them logistic regression, including, a step-by-step, and blocks of (77.96%) did not benefit from the Brazilian social welfare possible determinants according to the pre-established con- program called “Bolsa Família”; 80.00% had spouses; 57.55% ceptual model (►Fig. 1).Accordingly,itwaspossibletoobtain were unemployed; most had black skin color (87.76%) and estimates of the OR, with its 95%CI, through the different resided in households with 4 or more people (60.41%). Total models (A, B and C), examining the possible paths through 71.84% of the households with pregnant women were in

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Table 2 Distribution of socio-demographic, environmental, prenatal care, lifestyle and nutritional maternal characteristics according to anemia during gestation; Santo Antônio de Jesus, Bahia. 2014–2015

Variables n% Anemia p (n ¼ 245) No Yes n% n% Block I Family income (monthly income in minimum wages) 0.30 < 2 51 20.82 36 70.59 15 29.41 2 to 4 129 52.65 103 79.84 26 20.16 5 65 26.53 53 81.54 12 18.46 Receiving social welfare (“Bolsa família” program) 0.21 Yes 54 22.04 39 72.22 15 27.78 No 191 77.96 153 80.1 38 19.8 Schooling (years) 0.83 8 or more 94 38.37 73 77.66 21 22.34 Up to 7 151 61.63 119 78.81 32 21.19 Marital status 0.12 With partner 196 80.00 65 84.42 12 15.58 Without partner 49 20.00 127 75.60 41 24.40 Position in the labor market 0.01 Working 104 42.45 89 85.58 15 14.42 Unemployed 141 57.55 103 73.05 38 26.95 Skin color 0.09 Not black 30 12.24 27 90.00 3 10.00 Black 215 87.76 165 76.74 50 23.26 Number of inhabitants in the household 0.02 < 4 148 60.41 123 83.11 25 16.89 4 97 39.59 69 71.13 28 28.87 Block II Food insecurity < 0.0001 No 176 71.84 150 85.23 26 14.77 Yes 69 28.16 42 60.87 27 39.13 Block III Block III.a Planned pregnancy 0.07 Yes 100 40.82 84 84.00 16 16.00 No 145 59.18 108 74.48 37 25.52 Prenatal care < 0.01 Yes 187 76.33 154 82.35 33 17.65 No 58 23.67 38 65.52 20 34.48 Quarter in which the prenatal care began 0.29 I 43 17.55 30 69.77 13 30.23 II 189 77.14 151 79.89 38 20.11 III 13 5.31 11 84.62 2 15.38 (Continued)

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Table 2 (Continued)

Variables n% Anemia p (n ¼ 245) No Yes n% n% Period of gestation (months) 0.38 I Quarter 38 15.51 33 86.84 5 13.16 II Quarter 195 79.59 150 76.92 45 23.08 IIIQuarter 124.909 75.00325.00 Number of prenatal consultations 0.56 < 6 5 2.04 3 60.00 2 40.00 6 to 9 42 17.14 34 80.95 8 19.05 10 198 80.82 155 78.28 43 21.72 Parity 0.04 Primipara 109 44.49 92 84.4 17 15.6 Multipara 136 55.51 100 73.53 36 26.47 Use of medicinal iron supplementation 0.02 Yes 88 35.92 76 86.36 12 13.64 No 157 64.08 116 73.89 41 26.11 Block III.b Received prenatal nutritional guidance 0.13 Yes 112 45.71 83 74.11 29 25.89 No 133 54.29 109 81.95 24 18.05 Pregestational anthropometrical nutritional status 0.23 Low weight 138 56.33 113 81.88 25 18.12 Adequate 22 8.98 14 63.64 8 36.36 Excess weight 85 34.69 65 76.47 20 23.53 Block III.c Alcohol consumption 0.18 No 210 85.71 167 79.52 43 20.48 Yes 35 14.29 25 71.43 10 28.57 Age (years) 0.12 < 18 17 6.94 10 58.82 7 41.18 18 to 30 170 69.39 135 79.41 35 20.59 > 30 58 23.67 47 81.03 11 18.97

Note: Chi-squared test.

situations of food security, and 28.16%, in situations of food Regarding the behavioral, nutritional and maternal char- insecurity; of those, 24.48% were living in situations of food acteristics, we identiﬁed that 85.71% of the women did not insecurity without hunger, and 3.68% were living in situa- consume alcohol, and 54.29% did not receive nutritional tions of food insecurity with hunger. guidance during the prenatal care. Pregestational low weight With reference to the characteristics related to prenatal and excess weight were identiﬁed in 56.33% and 34.69% of care, most of the mothers: had not planned the pregnancy the participants respectively. The age of most of the partic- (59.18%); underwent prenatal care (76.33%); began prenatal ipants (69.39%) ranged from 18 to 30 years, and the average care in the second quarter of gestation (77.14%); were in the age was 25.82 years (SD: 5.94). second quarter of gestation (79.59%); attended 10 or more The prevalence of anemia in the studied population was of prenatal consultations (80.82%); were multiparous (55.51%); 21.8% (95%CI: 16.89–27.7), and the average Hb concentration and reported the use of medicinal supplementation with was 12.06 g/dL (SD: 1.27). In this study, pregnant women ferrous sulfate (64.08%). with levels of Hb < 7.0 g/dL, or, in other words, with severe

Rev Bras Ginecol Obstet Vol. 39 No. 8/2017 Food Insecurity, Prenatal Care and Other Anemia Determinants Demétrio et al. 391 anemia, according to the classification criteria of the WHO,3 (model E). Model D demonstrated that the factors related to were not identified. prenatal care were the greatest mediators of socioeconomic In the bivariate analysis (►Table 2), the results demon- and environmental factors in the determination of anemia in strated that the prevalence of anemia, comparatively, was pregnant women (►Table 3). statistically higher among pregnant women that were unemployed (p ¼ 0.01), lived in households with 4 or more Discussion people (p < 0.01), were multiparas (p ¼ 0.04), did not make use of medicinal iron supplementation (p ¼ 0.02), and were In the present investigation, the prevalence of anemia during in a situation of food insecurity (p < 0.0001). The variables gestation (21.8%), in terms of magnitude, is a moderate public marital status, receiving nutritional guidance during prena- health issue, according to the WHO’s3 criteria. The prevalence tal care, alcohol consumption and age presented p-values of anemia in pregnant women worldwide reduced from 52% to significantly lower than 20%, and were also selected to 41.8%, a reduction of 19.6 percentage points.3 compose the multivariate hierarchized model. The variable In accordance with the list of epidemiological information for receiving social welfare (“Bolsa Família”), although not of the WHO (2008),3 comparatively, the prevalence of ane- statistically significant (p ¼ 0.21), was also selected for the mia in pregnant women identified in the present study is hierarchized multivariate analysis, because it was consid- close to the estimated prevalence for Brazil (29.1%) and other ered a proxy variable of income and of the health promotion countries of the Americas (24.1%), and lower than the actions,21 of which the explanatory importance over the prevalence identified in countries of Africa (57.1%) and outcome at issue is theoretically well-established.2 Southeast Asia (48.2%). In turn, it was similar to the preva- ►Table 3 presents the breakdown of the estimates of the lence identified in other cross-sectional surveys conducted total non-mediated (direct) and mediated effects of the with pregnant women by Rocha et al22 (21.4%) and Fujimori determinants, which were obtained from the adjustment et al5 (20%), and higher than the prevalence found by Miglioli of the three models of regression, according to the previously et al21 (16%) for the state of Pernambuco, and by Abriha defined conceptual model (►Fig. 1). The total effect pre- et al23 (19.7%) for pregnant women from Mokelle, Ethiopia. sented statistical significance for the determinants (models Our prevalence rate was expressively lower than the one A, B and E). Thus, the total effect was statistically significant identified by Ferreira et al2 (50%) for pregnant women from for the determinants of model A: marital status – without Alagoas, and by Khader et al24 (38.6%) for Palestinian preg- spouse (p ¼ 0.09); position in the labor market – unem- nant women, and it was the same as the one found by Murillo ployed (p ¼ 0.03); number of dwellers in the household – 4 et al25 (21.8%) for pregnant women cared for in public and (p ¼ 0.06); and maternal years of schooling – up to 7 private healthcare institutions in Cali, Colombia. (p ¼ 0.37). Model B was statistically significant for food With regards to the epidemiological information on the insecurity (p < 0.0001). In model E, the variables associated prevalence of anemia among pregnant women in Brazil, the to anemia in pregnant women remained statistically signifi- literature review study performed by Côrtes et al26 demon- cant: food insecurity (p < 0.0001); not undergoing prenatal strated that, since the 1970’s, a large portion of the national care (p ¼ 0.01); multiparity (p ¼ 0.04); and lack of use of surveys were conducted in the state of São Paulo, with results medicinal iron supplementation (p ¼ 0.03). The variables for that classify the prevalence of anemia at moderate to severe the labor market position, marital status, maternal schooling epidemiological levels. According to the authors of this study, and age were incorporated and maintained in the final this situation could be even more worrying in socially and model, once these were known as potentially confounding economically less developed states, in which the population in the studied relation. has less access to healthcare services. In a certain manner, Comparing the effects of the associations obtained using this fact corroborates the differences encountered in the the three models, we observed, for example, that the mea- prevalence of anemia for the different regions of Brazil. sure of association of the determinants labor market position Another aspect that has been discussed in the specific and the number of dwellers in the household presented literature that may be related to these differences refers to substantial change after the adjustment by the variable of different cut-off points for the diagnosis of anemia adopted level 2 (model B). Then, comparing the labor market position in this survey.4 In accordance with Bresani et al,4 the choice and the number of dwellers in the household in relation to of hematological parameters (Hb and/or ferritin) and the cut- their respective groups of reference, the total effect was of off points used for the diagnosis of anemia during pregnancy 2.06 and 1.83 respectively (model A). The adjusted effect of could be underestimating the iron deficiency and/or over- the variable of level 2 (model B) was of 1.62 and 1.93 estimating the occurrence of anemia. respectively. Therefore, we observed that the effects of the In this study, the prevalence of anemia was significantly labor market position and the number of dwellers in the higher for pregnant women residing in households with household in the determination of anemia among pregnant more than four people. The investigation conducted with women were mediated by food insecurity. The same was 150 pregnant women in the semi-arid region of Alagoas, observed in the adjustment of model E, in which the socio- Brazil, by Ferreira et al2 also identified this relationship. economic and environmental factors were strongly mediated The number of dwellers in the household was a variable of by prenatal care factors, with an emphasis on marital status the structural level (level 1, block I), in accordance with the (without spouse), which went from 1.95 (model b) to 0.78 hierarchized conceptual model previously defined (►Fig. 1),

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Table 3 Effect of the determinants of anemia in pregnant women according to different models. Santo Antônio de Jesus, Bahia. 2014–2015

Variables Model A Model B Model C Model D Model E þ þ þ þ þ (block I) (blocks I, II) (blocks I, II, III.a) (blocks I, II, III.a) (blocks I, II, III) Level 1–Block I: Socioeconomic and environmental factors Marital status With partner 1 1 1 Without partner 1.88 1.95 0.71 0.86 0.78 (0.89–3.99) (0.90–4.25) (0.22–1.86) (0.34–2.15) (0.29–2.09) Position in the labor market Working 1 1 1 Unemployed 2.06 1.62 1.64 1.73 1.65 (1.04–4.05) (0.80–3.28) (0.79–3.42) (0.83–3.58) (0.77–3.53) Number of residents in the household < 411 1 41.831.93 2.31 2.25 1.97 (0.97–3.43) (1.01–3.70) (1.15–4.64) (1.13–4.48) (0.95–4.09) Schooling (years) 8ormore 1 1 1 Up to 7 1.35 1.40 0.38 0.38 0.36 (0.69–2.63) (0.70–2.80) (0.12–1.14) (0.12–1.16) (0.11–1.15) Level 2–Block II Food insecurity No 1 1 Yes 3.46 3.60 3.74 3.63 (1.78–6.75) (1.78–7.28) (1.86–7.54) (1.77–7.45) Level 3–Block III Block III.a. Prenatal care factors Prenatal care Yes 1 No 5.98 5.15 5.15 (1.74–20.52) (1.52–17.36) (1.43–18.50) Parity Primipara 1 Multipara 1.89 2.27 (0.91–3.94) (1.02–5.05) Use of medicinal iron supplementation Yes 1 No 2.46 2.42 2.45 (1.10–5.48) (1.09–5.35) (1.04–5.76) Block III.b. Nutritional Factors Received nutritional prenatal guidance Yes 1 No 0.64 (0.31–1.33)

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Table 3 (Continued)

Variables Model A Model B Model C Model D Model E (block I)þ (blocks I, II)þ (blocks I, II, III.a)þ (blocks I, II, III.a)þ (blocks I, II, III)þ Block III.c. Lifestyle and maternal factors Alcohol consumption No 1 Yes 1.89 (0.72–4.90) Age (years) < 18 0.64 (0.31–1.33) 18 to 30 1 > 30 0.38 (0.91–1.62) AIC 253.46 242.08 231.21 232.22 234.53

þ Abbreviations: OR (95%CI); 95%CI, 95% conﬁdence interval; AIC, Akaike information criterion; OR, odds ratio. Notes: In model B, the direct effect of the sociodemographic factors is observed (observe the change in OR in relation to model A) due to the mediation of the food insecurity factor. The same is observed in model E, with emphasis to the socioeconomic factors (marital status, with an alteration from 1.95 [model B] to 0.78 [model E], and maternal schooling [from 1.40 to 0.36]). With the adjustment of models C and D in relation to model E, it is observed that the mediation was due to prenatal care factors. The total effect of each factor is underlined (models A, B and E).

which was important in the explication of anemia in preg- surveys conducted by Schlindwein and Kassouf29 revealed that nant women, as it could be observed in the final and adjusted the standard consumption of meat among the Brazilian popu- models. This is an important socio-environmental character- lation is determined by thelevel of income and schooling of the istic in the determination of anemia during pregnancy. This women, and by the composition of the family. Therefore, association was measured considering FI, and is explained, pregnant women without spouses, who are unemployed, in part, by the reduction in the availability of food, in terms have low schooling, and live in households with more than of quality and quantity, to the pregnant women, once the four people and in situations of FI present greater chances of food available in the household is divided by a higher number developing anemia. of people. The situation of FI is an important indicator of the inequal- The effect of the variable “number of dwellers in the ities created by the economic system. Poverty and social household – more than four people” on the prevalence of inequality are the main determinants of FI, since they anemia among pregnant women was even higher in the compromise mainly the access to proper food in terms of presence of factors related to prenatal care. This demonstrates quantity and quality. Therefore, these factors may contribute, the importance of prenatal care, which, under the influence of in a complementary manner, to the diagnosis of FI in house- environmental factors, could contribute to family planning holds with pregnant women. (respecting the right of the women to have children or not) and In the present study, the prevalence rate of FI (28.16%) was to a reduction in the occurrence of anemia during pregnancy. lower than the rates identified by Marano et al30 (37.78%) for In the present study, FI had a direct effect on the genesis of pregnant women in two municipalities in the state of Rio de anemia among pregnant women. We also observed that, Janeiro, Brazil, and by Lôbo31 (59%) for mothers from the city comparatively, the situation of FI represented a chance 2.63 of João Pessoa, Brazil, and expressively higher than the times higher of the pregnant women developing anemia. prevalence found for North-American pregnant women This finding was close to the finding by Park and Eicher- (15.69%) in the study by Park and Eicher-Miller.27 When Miller27 in a study conducted with pregnant women partici- compared with the data on the prevalence of FI produced by pating in the National Health and Nutrition Examination the Brazilian National Survey of Demography and Health of Survey (NHANES), in the United States. They identified a the Woman and Child (PNDS, in the Portuguese acronym),32 chance 3 times higher for the occurrence of anemia, mainly related to the year 2006, the prevalence of FI in this study was due to iron deficiency, among pregnant women in situations lower than the prevalence (38%) identified for women (in the of FI, compared with those in situations of food security. age group between 15 and 49 years of age) and their children According to Fujimori et al,28 in developing countries, (under 5 years of age). In relation to the data estimated by the eating habits do not adequately comply with the necessary 2013 Brazilian National Household Sample Survey (PNAD, in quantity of bioavailable iron that must be consumed due to the the Portuguese acronym),33 the prevalence rate found in the high cost of red meat, which is considered the best source of present study was lower than the estimated value for the heme iron, because it is better absorbed. The results of the Northeast region (38.1%) and for the state of Bahia (37.2%);

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nevertheless, it was higher than the percentage for Brazil as a mother and the fetus, with at least six consultations.36,37 whole (22.6%) and for other regions of the country, in which Clinical procedures that are essential for accompanying the the percentages were below 20%. pregnancy, such as laboratory exams, vaccines, educational It should be mentioned that, during the search for specific activities and family planning,36,37 should also be included. Brazilian literature on the prevalence of FI during pregnancy According to Rasia and Albernaz,37 notwithstanding the and its effects to the health and nutrition of the pregnant advances in relation to the increase in the coverage of women, only the investigations conducted by Marano et al30 prenatal care in Brazil, it is still possible to identify inequal- and Lôbo31 were identified with this approach. ities in the prenatal care offered to the pregnant women. The present study is the first to evaluate the effect of FI on Pregnant women with unfavorable socioeconomic situa- anemia in pregnant women in Brazil as a whole. This reveals tions, low schooling, and who reside in rural areas – factors that the approach of FI during pregnancy is recent and scarce in associated to worse health and nutritional conditions – Brazil, but some of the effects of its importance for the health of continue to be the ones that seek prenatal care the less, women have already been evidencedinthe presentand inother which evidences the social and geographical inequality that investigations;27,30,31 therefore, the results presented here, is reflected in the precarious access to health services such as along with those from other well-conducted studies, should prenatal care, obeying the inverse care law.37 stimulate the development of further research in this direction. Apart from the epidemiological aspects, the influence of In this study, the determinants related to prenatal care other factors related to socio-anthropological impressions and were those exercising greater mediating effect on the socio- expressions toward not performing prenatal care by some economic and environmental factors related to the genesis of pregnant women should be taken into account. For this, it is anemia in pregnant women, with emphasis to marital status necessary to understand the meanings and social representa- without spouse and lower maternal schooling. Such results tions of pregnancy and the realization or not of the prenatal are corroborated by those already found in other studies.28,34 care. In this sense, the review study performed by Silva et al38 If on the one hand these findings evidence that, apart from revealed that the significance of prenatal care involved socio- the biological condition favoring the development of anemia cultural, family and emotional aspects. For some mothers of the during pregnancy,11 it is not only reproduced, but also mentioned study,38 gestation was not considered a happy or influenced, by structural conditions (distal), such as envi- special moment in their lives, and the failure to perform the ronmental conditions (number of dwellers in the household) prenatal care was due to insecurity and fear of the unexpected and socioeconomic (position in the labor market, marital and of punishment from the health professionals, and that made status and maternal schooling as variables of adjustment in these women view prenatal care negatively. The importance of the final hierarchized model), and intermediary (food inse- the caregivers’ approach, integrating the family and considering curity). On the other hand, the relevance of the factors related the necessities of the women as a subject, their difficulties, to prenatal care is emphasized, which was considered, in the expectations and sentiments in relation to the pregnancy.38 present investigation, as hierarchically proximal in the de- In the present study, the higher the parity, the higher the termination of anemia in pregnant women. chance of developing anemia (OR ¼ 2.27). Results obtained Among the prenatal care factors that integrate the concep- from other investigations28,34 demonstrated that the preva- tual model of the present study (►Fig. 1), the non-realization lence of anemia in women increased with subsequent ges- of prenatal care, multiparity and the non-supplementation of tations due to the depletion of iron. It is valid to comment iron demonstrated statistically significant associations with that the occurrence of anemia due to the depletion of the anemia in pregnant women. organic iron reserves can also be linked to a lower interval Results from other studies with different models,7,35 never- between pregnancies and to social and economic conditions, theless, also identified relationships between the non-realiza- which determine the inadequate quality and quantity of food tion of prenatal care and a greater occurrence of anemia during and FI, and to the despoliations caused by intestinal parasit- pregnancy. Ikeanyi and Ibrahim7 and Rezket al35 encountered a osis, which are more frequent among pregnant women living greater chance of developing anemia among pregnant women in households with precarious sanitation.28 who did not perform prenatal care; in their studies, the non- The lack to perform the medicinal supplementation of realization of prenatal care increased, respectively, 130% (OR iron was another factor also related to prenatal care pre- ¼ 2.30) and 25% (OR ¼ 1.25) the chances that the pregnant sented as a risk factor for anemia among the pregnant women would develop anemia. In the study conducted by women in this study; it increased the chances of developing Szarfac et al36 with pregnant women from São Paulo, the anemia to 145% (OR ¼ 2.45) among women who underwent authors observed that prenatal care was associated to a higher the supplementation compared with those who did not. concentration of Hb and lower occurrence of anemia during Results from other studies39,40 corroborate this finding. pregnancy. According to the study performed by Wendt et al39 with The importance of prenatal care for the health of the pregnant women from India, the authors identified chances pregnant woman and the fetus36,37 is scientifically recognized. 37% (OR ¼ 1.37) greater of developing anemia among preg- Thus, the Brazilian Ministry of Health recommends that nant women who did not undergo iron supplementation. In prenatal care should begin at an early stage, offering universal another investigation, conducted by Ononge et al40 with coverage, and performed periodically and integrated with pregnant women from Uganda the chance of developing other curative actions and health promotion actions for the anemia rose to 66% (OR ¼ 1.66). The results of the clinical

Rev Bras Ginecol Obstet Vol. 39 No. 8/2017 Food Insecurity, Prenatal Care and Other Anemia Determinants Demétrio et al. 395 trial by Rivot et al41 involving pregnant Spanish women did From the methodological point of view, it should be not show the effects of iron supplementation in the reduc- considered that even with the statistical adjustment of tion of anemia during pregnancy. In Brazil, a clinical trial42 the models of this study by different confounding factors, performed in the city of Recife, with the aim of evaluating the investigations with cross-sectional designs present some effectiveness of therapeutic regimens using ferrous sulfate in limitations. Among these is the limitation that hinders the pregnant women with anemia, revealed that daily treatment fulfillment of the assumption of temporality, which is was efficient in improving the serum concentrations of essentially important when it is not possible to determine hemoglobin and ferritin. the temporal extension of the variables of exposure on the Even if some degree of dissension is identified in the outcome. Accordingly, the cross-sectional design does not specific literature on the effectiveness of iron supplementa- enable the establishment of a relationship of cause and – tion in pregnant women, well-conducted studies39 42 and effect among the studied events, but identify associations meta-analyses43 have demonstrated significant effects of among these. Nevertheless, a more robust method of anal- iron supplementation in improving the rates of anemia ysis was used, the hierarchical analysis, which is based on a among pregnant women and some impacts on the reduction previously defined conceptual model that enabled a greater of: maternal mortality; the delay in intrauterine growth; low control of the confounding factors and the measurement of birth weight; and low iron reserves of the newborn. the breakdown of the total effect of their non-mediated In this context, it is important to emphasize that, in 2005, components (or direct) in the relationships investigated. the Brazilian Ministry of Health implemented the National Iron Supplementation Programwith the purpose of promoting Conclusions universal supplementation to children aged 6 to 18 months, pregnant women as of the 20th week, and women in the post- The hierarchical analysis used in the present study enabled partum period, in order to control the prevalence of anemia in the identification of the determinants of anemia during preg- these groups.44 nancy, collaborating to the identification of the confounding In the plan for the development of policies for the control factors, and to the interpretation of the results in the light of of anemia in Brazil, emphasis is given to the iron and folic socio-environmental, food safety and prenatal care aspects. acid medicinal supplementation program, and the program In this study, the chance of developing anemia among for the enrichment of wheat and corn flour with iron and pregnant women was significantly higher than in other stud- folic acid, implemented in 2004.5,44 ies, mainly among women in situations of FI, not performing Although the results of the study of national scope by prenatal care, multipara and without iron supplementation. Fujimori et al,5 which evaluated the impact of wheat and corn We hope that these results will contribute to the develop- flour enriched with iron and folic acid in the hemoglobin serum ment of integrated and intersectorial strategies for the control concentrations of pregnant women, demonstrated a significant of anemia in pregnant women, considering, apart from the reduction in the prevalence of anemia from 25% to 20% in the biological determinants, other factors, such as socio-environ- total sample (n ¼ 12,119), the prevalence is still high (in a mental, food safety and prenatal care aspects, which can moderate level) in the Northeast (29%), Midwest (27.8%) and directly or indirectly interfere in the occurrence of anemia. North (25%) regions of Brazil. These rates could be a reflection of the influence of socioeconomic, demographic and environmen- Acknowledgments tal factors that are distributed in a different manner among The authors would like to thank Fundação de Amparo à these regions of the country in relation to the South and Pesquisa do Estado da Bahia (FAPESB) and Conselho Southeast regions, where prevalence rates were lower.5 Nacional de Desenvolvimento Científico e Tecnológico It should be observed that one of the factors related to the (CNPq) for their financial support. They would also like effectiveness of this strategy is the consumption of enriched thank the women who agreed participate in this study. wheat and corn flour, namely by pregnant women.44 Thus, it is Colaborators: F Demétrio conceived the study, partici- possible that FI situations, which are closely associated with pated in the data production, and was responsible for the socioeconomic (family income, the price of flour etc.), envi- preparationandcritical reviewof the manuscript. CAS Teles- ronmental (number of dwellers in the household) and behav- Santos was responsible for the statistical analysis, interpre- ioral aspects, compromise the access to and consumption of tation of the results, and preparation of the manuscript. DB these foods,17 as well as of other adequate foods in terms of dos Santos was responsible for the planning, design, re- quality, quantity and sources of bioavailable iron, contributing, source capture, production of data, research coordination, in this manner, toward the increase in the prevalence of and contributed to the preparation of the manuscript. anemia, especially due to iron deficiency, in pregnant women. The importance of the development of strategies in References nutritional education is also emphasized in the context of prenatal care, with the purpose of promoting healthy eating 1 Vieira BD, Parizzoto APAV. Alterações psicológicas decorrentes do período gravídico. Unoesc Ciênc ACBS 2013;4(01):79–90 practices among the pregnant women, prioritizing the 2 Ferreira HdaS, Moura FA, Cabral Júnior CR. [Prevalence and factors consumption of foods that are sources of iron and of associated with anemia in pregnant women from the semiarid other nutrients related to the synthesis of hemoglobin region of Alagoas, Brazil]. Rev Bras Ginecol Obstet 2008;30(09): (vitamins A, B12, B9, among others). 445–451 Portuguese

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Rev Saude Publica 1987;21(02):73–89 processo reprodutivo e da saúde da criança. Brasília (DF): Min- 12 Bickel G, Nord M, Price C, Hamilton W, Cook J. Guide to measuring istério da Saúde; 2009 household food security revised. Alexandria: USDA; 2000 33 Instituto Brasileiro de Geografia e Estatística. Pesquisa Nacional 13 Instituto Brasileiro de Geografia e Estatística [Internet]. Censo 2010: por Amostra de Domicílios (PNAD): segurança alimentar 2013. Bahia: Santo Antonio de Jesus: infográficos: dados gerais do muni- Rio de Janeiro: IBGE; 2014 cípio. 2010 [cited 2015 Jan 14]. Available from: http://cidades.ibge. 34 Guerra EM, Barretto OCO, Vaz AJ, Silveira MB. The prevalence of gov.br/painel/painel.php?lang¼&codmun¼292870&search¼bahia| anemia in pregnant women in their first visit to health centers of a santo-antonio-de-jesus|infograficos:-dados-gerais-do-municipio metropolitan area, Brazil. Rev Saude Publica 1990;24(05):380–386 14 Genser B, Strina A, Teles CA, Prado MS, Barreto ML. Risk factors for 35 Rezk M, Marawan H, Dawood R, Masood A, Abo-Elnasr M. Pre- childhood diarrhea incidence: dynamic analysis of a longitudinal valence and risk factors of iron-deficiency anaemia among preg- study. Epidemiology 2006;17(06):658–667 nant women in rural districts of Menoufia governorate, Egypt. 15 Lohman TG, Roche AF, Martorell R. Anthropometric standardiza- J Obstet Gynaecol 2015;35(07):663–666 tion reference manual. Champaign: Human Kinetics; 1988 36 Szarfarc SC, de Siqueira AA, Martins IS, Tanaka ACD. Comparative 16 National Academy of Science. Institute of Medicine. Weight gain study of biochemical indicators of iron concentration, in 2 popu- during pregnancy: reexamining the guidelines: report brief. lation of pregnant women, with and without prenatal care. Rev Washington (DC): National Academies Press; 2009 Saude Publica 1982;16(01):1–6 17 Santos CA, Strina A, Amorim LD, et al. Individual and contextual 37 Rasia ICRB, Albernaz E. Atenção pré-natal na cidade de Pelotas, Rio determinants of the duration of diarrhoeal episodes in preschool Grande do Sul, Brasil. Rev Bras Saude Mater Infant 2008;8(04): children: a longitudinal study in an urban setting. Epidemiol 401–410 Infect 2012;140(04):689–696 38 Silva CO, Santos JLG, Pestana AL, Bernardi MC, Erdmann AL. Signifi- 18 Demétrio F. Elas têm fome de quê? (In)segurança alimentar e cados e expectativas de gestantes em relação ao pré-natal na atenção condições de saúde e nutrição de mulheres na fase gestacional básica: revisão integrativa. Saúde Transf Soc. 2013;3(04):98–104 [thesis]. Salvador: Universidade Federal da Bahia; 2015 39 Wendt A, Stephenson R, Young M, et al. Individual and facility- 19 Twisk JWR. Applied longitudinal data analysis for epidemiology: a level determinants of iron and folic acid receipt and adequate practical guide. 2nd ed. Cambridge: Cambridge University Press; 2003 consumption among pregnant women in rural Bihar, India. PLoS 20 Akaike H. Information theory as an extension of the maximum One 2015;10(03):e0120404 likelihood principle. In: Proceedings of the 2nd International 40 Ononge S, Campbell O, Mirembe F. Haemoglobin status and Symposium on Informational Theory; 1973; Budapest, Hungary. predictors of anaemia among pregnant women in Mpigi, Uganda. Budapest: Akadêmia Kiadó; 1973. p. 267–281 BMC Res Notes 2014;7:712 21 Miglioli TC, Brito AM, Lira PIC, Figueroa JN, Batista Filho M. 41 Ribot B, Aranda N, Arija V. Early of late supplementation: similar Mother-child anemia in the State of Pernambuco, Brazil. Cad evolution of the iron status during pregnancy. Nutr Hosp 2012; Saude Publica 2010;26(09):1807–1820 27(01):219–226 22 Rocha DS, Netto MP,Priore SE, Lima NMM, Rosado LEFPL, Franceschini 42 de Souza AI, Batista Filho M, Ferreira LOC, Figueirôa JN. The effec- SCC. Estado nutricional e anemia ferropriva em gestantes: relação tiveness of three regimens using ferrous sulfate to treat anemia in com o peso da criança ao nascer. Rev Nutr 2005;18(04):481–489 pregnant women. Rev Panam Salud Publica 2004;15(05):313–319 23 Abriha A, Yesuf ME, Wassie MM. Prevalence and associated factors 43 Haider BA, Olofin I, Wang M, Spiegelman D, Ezzati M, Fawzi WW; of anemia among pregnant women of Mekelle town: a cross Nutrition Impact Model Study Group (anaemia). Anaemia, pre- sectional study. BMC Res Notes 2014;7:888 natal iron use, and risk of adverse pregnancy outcomes: systema- 24 Khader A, Madi H, Riccardo F, Sabatinelli G. Anaemia among tic review and meta-analysis. BMJ 2013;346:f3443 pregnant Palestinian women in the Occupied Palestinian Terri- 44 Szarfarc SC. Políticas públicas para o controle da anemia ferro- tory. Public Health Nutr 2009;12(12):2416–2420 priva. Rev Bras Hematol Hemoter 2010;32(Suppl 2):2–7

Rev Bras Ginecol Obstet Vol. 39 No. 8/2017 THIEME Original Article 397

Proﬁle of Reproductive Issues Associated with Different Sickle Cell Disease Genotypes Perﬁl reprodutivo associado aos diferentes genótipos da doença falciforme

Flávia Anchielle Carvalho1,2 Ariani Impieri Souza1,2 Ana Laura Carneiro Gomes Ferreira1 Simone da Silva Neto2 Ana Carolina Pessoa de Lima Oliveira2 Maria Luiza Rodrigues Pinheiro Gomes2 Manuela Freire Hazin Costa1,3

1 Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Address for correspondence Ariani Impieri Souza, PhD, Instituto de Recife, PE, Brazil Medicina Integral Prof. Fernando Figueira (IMIP), Rua dos Coelhos, 300 2 Faculdade Pernambucana de Saúde (FPS), Recife, PE, Brazil Boa Vista, 50070-550–Recife, PE, Brazil (e-mail: [email protected]). 3 Universidade Federal de Pernambuco (UFPE), Recife, PE, Brazil

Rev Bras Ginecol Obstet 2017;39:397–402.

Abstract Purpose To describe the reproductive variables associated with different sickle cell disease (SCD) genotypes and the influence of contraceptive methods on acute painful episodes among the women with the homozygous hemoglobin S (HbSS) genotype. Methods A cross-sectional study was conducted between September of 2015 and April of 2016 on 158 women afflicted with SCD admitted to a hematology center in the Northeast of Brazil. The reproduction-associated variables of different SCD genotypes were assessed using the analysis of variance (ANOVA) test to compare means, and the Kruskal-Wallis test to compare medians. The association between the contraceptive method and the acute painful episodes was evaluated by the Chi-square test. Results The mean age of women with SCD was 28.3 years and 86.6% were mixed or of African-American ethnicity. With respect to the genotypes, 134 women (84.8%) had HbSS genotype, 12 women (7.6%) had hemoglobin SC (HbSC) disease genotype, and 12 (7.6%) were identified with hemoglobinopathy S-beta (S-β) thalassemia. The mean age of HbSS diagnosis was lower than that of HbSC disease, the less severe form of SCD (p < 0.001). The mean age of menarche was 14.8 1.8 years for HbSS and 12.7 1.5 years for HbSC (p < 0.001). Among women with HbSS who used progestin-only contraception, 16.6% had more than 4 acute painful episodes per year. There was no statistically significant difference when compared with other contraceptive Keywords methods. ► sickle cell disease Conclusion With respect to reproduction-associated variables, only the age of the ► sickle cell anemia menarche showed delay in HbSS when compared with HbSC. The contraceptive ► menarche method used was not associated with the frequency of acute painful episodes among ► contraception the HbSS women.

received DOI https://doi.org/ Copyright © 2017 by Thieme Revinter January 16, 2017 10.1055/s-0037-1604179. Publicações Ltda, Rio de Janeiro, Brazil accepted ISSN 0100-7203. April 25, 2017 published online July 6, 2017 398 Profile of Reproductive Issues Associated with Different SCD Genotypes Carvalho et al.

Resumo Objetivo Descrever as variáveis reprodutivas em diferentes genótipos da doença falciforme (DF) e a influência dos métodos contraceptivos na frequência das crises álgicas em mulheres com homozigose da hemoglobina S (HbSS). Métodos Estudo de corte transversal realizado entre setembro de 2015 e abril de 2016 com 158 mulheres com DF atendidas em um centro de hematologia no Nordeste do Brasil. As variáveis reprodutivas dos diferentes genótipos da DF foram avaliadas utilizando-se o teste de análise de variância (ANOVA) para comparação de médias e o teste de Kruskal-Wallis para comparação de medianas. A associação entre o método contraceptivo e a frequência das crises álgicas foi avaliada pelo teste Qui-quadrado. Resultados A idade média das mulheres com DF foi de 28,3 anos e 86,6% eram afrodescentes. Em relação aos genótipos, 134 mulheres (84,8%) tinham genótipo HbSS, 12 mulheres (7,6%) tinham genótipo para doença da hemoglobina SC (HbSC) e 12 (7,6%) foram identificadas com beta talassemia (S-β). A idade média do diagnóstico de HbSS foi menor do que a da HbSC, sendo esta a forma menos grave da DF (p < 0,001). A idade média da menarca foi de 14,8 1,8 anos para HbSS e de 12,7 1,5 anos para HbSC (p < 0,001). Entre as mulheres com HbSS que fizeram contracepção com progesterona isolada, 16,6% apresentaram mais de 4 episódios de Palavras-Chave crises álgicas agudas por ano. Não houve diferença estatisticamente significativa ► doença falciforme quando comparado com outros métodos anticoncepcionais. ► anemia falciforme Conclusão Em relação às variáveis reprodutivas, apenas a idade da menarca apre- ► menarca sentou atraso no HbSS em relação ao HbSC. O método anticoncepcional utilizado não ► anticoncepção foi associado à frequência de crises álgicas entre as mulheres com HbSS.

Introduction issues, there are limited data regarding other SCD genotypes.5,7,9 The objective of this study was to describe the Sickle cell disease (SCD) includes any hemoglobinopathy in reproductive variables in different SCD genotypes and the which the sickle mutation is inherited, such as homozygosity influence of the contraceptive method on acute painful for hemoglobin S (HbSS, sickle cell anemia) and heterozygosity episodes among women with the HbSS genotype. for hemoglobin S (HbS) with other hemoglobin anomalies, resulting in: hemoglobin SC disease (HbSC), hemoglobin SD Methods disease, hemoglobinopathy S-α-thalassemia (Sα-thalassemia), hemoglobinopathy S-β-thalassemia (Sβ-thalassemia), From September of 2015 to April of 2016, a cross-sectional study and other less commons SCD genotypes. The disease course was performed on women with SCD. The subjects were between depends in part on the SCD genotype; HbSS tends to result in 14 and 47 years of age and had been treated at a Hematology and the most severe form of the disease, while a more benign Hemotherapy Center in Pernambuco, in the Northeast of Brazil. course may occur with HbSC, although adverse events have The datawere collected by interviewing158 womenwho agreed been observed in all genotypes.1 to participate in the research and signed the Informed Consent Sickle cell disease is associated with hypoxia-induced po- Form. This study is part of a larger project, which was approved lymerization of the abnormal HbS molecule, followed by red by the Research Ethics Board of the institution. blood cell injury and the sickling process. Consequently, a The sociodemographic, reproductive, and clinical data microvascular occlusion (vaso-occlusion) can occur and clini- were collected via interview and examination of medical cally manifest as hemolysis and acute painful episodes.2,3 records, where the SCD genotype was checked. We consid- Recently, the mortality of patients with SCD has decreased ered painful crises to have occurred when the woman due to the better understanding of SCD physiopathology, reported some episode of bone pain. allowing earlier diagnostic and therapeutic interventions, A database was created using the Microsoft Office Excel such as newborn screening, antibiotic prophylaxis with peni- 2007 (Microsoft, USA) software. In the statistical analysis, we cillin, immunization, the use of hydroxyurea, and multidisci- used the mean (standard deviation) when the numerical plinary assistance.4 Consequently, reproductive issues will take variable conformed to a normal distribution, and the median a higher priority in SCD, such as delay of pubertal development, (interquartile range) when it was non-normal distribution. delay of first pregnancy, complications in pregnancy and post- The reproductive variables of the different SCD genotypes – partum, and the choice of contraceptive method.4 8 were assessed by using the analysis of variance (ANOVA) test Although several studies have demonstrated the influ- to compare means, and the Kruskal-Wallis test to compare the ence of the HbSS genotype on some sexual and reproductive medians.

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When the ANOVA results indicated statistical significance, Table 1 Sociodemographic profile of women with sickle cell we performed the Tukey test. The association between the disease. Brazil, 2015–2016 contraceptive method and the acute painful episodes was evaluated by the Chi-square test. The statistical analyses were Variables n ¼ 158 % performed with Stata version 12.1 (StataCorp LLC, College Age (years) (mean ¼ 28.3) Station, USA), and the tests were considered statistically 19 23 14.5 significant when the p-value was less than 0.05. 20–34 93 58.9 Results 35 42 26.6 Location A total of 158 women with SCD were included in this study. Recife 50 31.6 Their ages ranged from14 to 47 years, with a mean of Other cities in the RMA 51 32.3 28.3 years. Out of the total population, 64.0% were from the metropolitan region of Recife, 86.6% had mixed or Countryside 57 36.1 African-American ethnicity, 59.5% had 11 or more years of Ethnicity schooling, 36.7% were retired, and 25.3% had no occupation. Mixed 99 62.6 A total of 54.4% reported the family income to be less than the African-American 38 24.0 ►Table 1 minimum wage (MW) ( ). 1.3 As for the genotypes, 134 women (84.8%) had HbSS, White 17 10.8 12 women (7.6%) had HbSC, and 12 (7.6%) were identified with Sβ-thalassemia. Indigenous 02 1.3 The mean age for SCD diagnosis for all women was No information 02 1.3 fi 6.5 7.4 years. There was a signi cant difference in the Schooling mean age at diagnosis between HbSC (18.9 9.2 years) and 0 to 3 years 07 4.4 the other two groups (p < 0.001). A significant difference in the mean age for menarche was observed between the groups 4 to 7 years 18 11.4 with HbSS (14.8 1.8 years) and HbSC (12.7 1.5 years) 8to10years 39 24.7 (p < 0.001). There was no difference among the groups with 11 years 94 59.5 regard to the mean age of first sexual intercourse (p ¼ 0.119) Occupation and the first pregnancy (p ¼ 0.248). The median number of No Job/Housewife 40 25.3 pregnancies was one for HbSS and two for both HbSC and Sβ-thalassemia (p ¼ 0.510). The median number of living Self-employed/Other 27 17.1 children was one for all SCD genotypes (p ¼ 0.427) (►Table 2). Student 33 20.9 Of the 130 women (82.3%) who reported being sexually Retired 58 36.7 active, 93 used contraceptive methods. The majority used Family Income condoms (34.4%), followed by combined hormonal contraceptives (33.3%), and only 6.5% reported taking progestin- 1MW 86 54.4 only contraceptives. However, 63 of 89 (70.8%) women who 1–2MW 36 22.8 got pregnant did not plan the last pregnancy, in spite of > 2MW 29 18.4 having received counseling on reproduction (►Table 3). No information 7 4.4 In this study, we investigated the effect of the contraceptive methods on the frequency of acute painful episodes only Abbreviations: MW, minimum wage; RMA, Recife metropolitan area. in the HbSS group, since this is the most severe form of SCD. We observed 4 or more acute painful episodes per year in 60.0%of the women using combined hormonal contraceptives, in 50.7% of the women using non-hormonal methods, later than in the other groups. There was a delay in the age of and in 16.6% of those who used progestin-only contracep- menarche in the HbSS group compared with the HbSC group. tion. There was no statistical difference between the proges- The ethnicity data of this study differ from the Brazilian tin-only and the combined hormonal contraception population data, where most of the women with SCD are (p ¼ 0.072), and there was no statistical difference when black.10,11 This difference of ethnicity can be explained comparing the progestin-only and the non-hormonal meth- because the women interviewed in this study self-reported ods (p ¼ 0.118). (►Table 4) to be of mixed ethnicity. Most of the women reported more than 11 years of Discussion schooling. This reflects the findings of another Brazilian study, which showed an increase of schooling level for women over The women in this study were predominantly young, of mixed the years. Advances in therapeutics have improved survival ethnicity, well educated, and of low income families, as would rates of women with SCD and thus, there are increasing be expected in this population. The diagnosis of HbSC occurred numbers of women enjoying a better quality of life.12

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Table 2 Association between sickle cell disease genotypes and reproductive proﬁle. Brazil, 2015/2016

Variables All the genotypes HbSS HbSC disease Sβ-thalassemia (n ¼ 12) p (n ¼ 158) (n ¼ 134) (n ¼ 12) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Age of diagnosis 6.5 (7.4) 5.5 (6.2) 18.9 (9.2)a 5.2 (6.8) < 0.001 Age of menarche 14.5 (1.9) 14.8 (1.8)b 12.7 (1.5)b 13.7 (2.0) < 0.001 Age of ﬁrst intercourse 19.4 (4.2) 19.7 (4.4) 18.3 (2.6) 17.1 (2.2) 0.119 Age of ﬁrst pregnancy 22.0 (4.7) 22.2 (4.7) 22.3 (4.7) 19.1 (3.1) 0.248 Median (IQR) Median (IQR) Median (IQR) Median (IQR) Number of pregnancies 1 (1–2) 1 (1–2) 2 (1–2) 2 (1–2) 0.510 Number of living children 1 (1–2) 1 (1–1.5) 1 (1–1.5) 1 (1–2) 0.427

Abbreviations: HbSS, homozygous hemoglobin S; HbSC, hemoglobin sickle cell; IQR, interquartile range; SD: standard deviation. ANOVA-to compare the means of the HbSS, HbSC and Sβ-thalassemia. Kruskal-Wallis- to compare the medians of HbSS, HbSC and Sβ-thalassemia. aThe difference was in this group (Tukey test). bThe difference occurred only between these two groups (Tukey test).

Table 3 Reproductive variables of women with sickle cell disease. The mean age of menarche for HbSS was 14.8 years. This Brazil, 2015–2016 result is supported by other studies that showed a delay of menarche for this condition.7,15,16 The delay in menarche may Variables n % be associated with a weight deficit and the delay of skeletal n ¼ Sexual activity ( 158) development. It seems reasonable to postulate that the phe- Yes 130 82.3 nomenon of vaso-occlusion may interfere with physiologic 6,9,16 No 28 17.3 mechanisms of growth hormone release in these women. The socioeconomic factors seem to contribute as well to the Pregnancy history (n ¼ 130) delay of the menarche in these women. This hypothesis is Yes 89 68.5 supported by a study of Jamaican girls by Alleyne et al,16 which No 41 31.5 showed that poorer and less educated women experienced Unplanned pregnancy (n ¼ 89) their first menstruation later than those in a better economic Yes 63 70.8 andeducational situation. When comparing the HbSS andHbSC groups, the difference in age of the menarche was statistically No 26 29.2 significant in accordance with the Jamaican data.5 The delay of Contraceptive methods (n ¼ 93) the menarche may occur due to HbSC resulting in fewer vaso- Condom 32 34.4 occlusive events and fewer clinical consequences.5,17 fi Combined hormonal 31 33.3 In this present study, the mean age of rst sexual intercourse and of the first pregnancy showed no difference Surgical methods 19 20.4 (vasectomy and tubal ligation) between the genotypes. A Jamaican study comparing women with HbSS to a control group (women without the disease) Progestin-only 6 6.5 did not find any difference, suggesting that HbSS does not Others 5 5.4 influence fertility.16 The median number of pregnancies of women with HbSS was lower than the median in the other groups; however, The higher educational level in this study was not reflected there was no statistical significance, possibly due to the small by these women’s income. More than half earned a monthly sample size of the other SCD genotypes. Studies relate HbSS family income of minimum wage or less. These data agree with to a smaller number of pregnancies due to factors such as other studies that show less access to paid labor activity among reduction in the frequency of sexual intercourse, fear of the population with SCD, possibly due to the high absenteeism becoming pregnant due to the high incidence of fetal loss caused by the clinical events of the disease.2,13 in pregnancy, and increased risk of morbimortality during The mean age for HbSS diagnosis was around 5.5 years. This pregnancy and during the postpartum period.4,16 is high, considering that the National Neonatal Screening There was no difference in the number of living children Program can diagnose hemoglobinopathy at birth. However, among the SCD genotypes, in contrast to the findings by the program was established in 2001, when the majority of the Serjeant et al.5 According to their data, the women with HbSS women in this study had already been born.14 The mean agefor had a lower number of living children when compared with HbSC diagnosis (18.9 years), which displays milder clinical women with HbSC. This divergence may be due to the small conditions, was later than that of the other groups.5 sample size of women with HbSC in this present study. In

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Table 4 Association between the type of contraceptive method and frequency of acute painful episodes in 108 women with homozygous hemoglobin S (HbSS). Brazil, 2015/2016

Contraceptive method Frequency of acute painful episodes last year Up to 3 episodes/year 4 or more p episodes/year N% n% Progestin-only (n ¼ 6) 5 83.4 1 16.6 0.093 Combined hormonal (n ¼ 35) 10 40.0 15 60.0 0.072 Non-hormonal methods (n ¼ 73) 36 49.3 37 50.7 0.118 Total 51 49.0 53 51.0

Fisher Test.

Brazil, a study showed that most women with HbSS had only Conclusion one living child.15 These women have high morbimortality, with increased risk of prematurity, low birth weight, In the evaluation of reproductive aspects, only the age of the restricted intrauterine growth, and perinatal mortality.18 menarche showed a delay in HbSS women when compared The majority of women who got pregnant reported that with HbSC women. The contraceptive method used was not they did not plan to get pregnant, despite having received associated with the frequency of the acute painful episodes counseling about pregnancy risks. This supports the idea that among the HbSS women. the final decision in using a contraceptive method is complex, and difficult to assess in quantitative studies.19,20 In ’ addition to each woman s individual issues, this decision Conflict of Interests fl may be in uenced by their complex health condition, since The authors declare no conflict of interests. there is no robust evidence regarding the safety of various contraceptive methods in women with SCD.8 Among the users of contraceptive methods, most mentioned the use of condoms or combined hormonal methods. References The frequency of combined hormonal contraceptive use 1 Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ found in this study is greater than the frequency found by 2008;86(06):480–487 Qureshi et al,21 probably because combined hormonal con- 2 Felix AA, Souza HM, Ribeiro SBF. Aspectos epidemiológicos e traception is the most widespread method in Brazil, accord- sociais da doença falciforme. Rev Bras Hematol Hemoter 2010; ing to a population-based survey conducted in 2006.22 32(03):203–208 In the HbSS group, 83.4% of women who used progestin- 3 Brasil. Ministério da Saúde. Instituto Sírio-Libanês de Ensino e only contraception had up to three acute painful episodes in Pesquisa. Protocolo de atenção básica: saúde das mulheres. Brasília (DF): Ministério da Saúde; 2016 the past year, and 40% of the users of the estrogen-proges- 4 Rogers DT, Molokie R. Sickle cell disease in pregnancy. Obstet terone combination had up to three acute painful episodes, Gynecol Clin North Am 2010;37(02):223–237 but we did not find any statistically significant difference. 5 Serjeant GR, Hambleton I, Thame M. Fecundity and pregnancy The effects of progesterone on the clinical parameters of outcome in a cohort with sickle cell-haemoglobin C disease SCD are still unclear. A systematic review examined the followed from birth. BJOG 2005;112(09):1308–1314 safety of hormonal contraceptive methods used among 6 Verissimo MPA. Crescimento e desenvolvimento nas doenças falciformes. Rev Bras Hematol Hemoter 2007;29(03):271–274 women with SCD and found that the progestin-only method 7 Balgir RS. Age at menarche and first conception in sickle cell 8 has been associated with a decrease in painful episodes. hemoglobinopathy. Indian Pediatr 1994;31(07):827–832 Isaacs suggested, in 1967 that the progestin-only contracep- 8 Haddad LB, Curtis KM, Legardy-Williams JK, Cwiak C, Jamieson DJ. tion methods might increase the stability of the membranes Contraception for individuals with sickle cell disease: a systema- of the red blood cells subject to the sickling phenomenon.23 tic review of the literature. Contraception 2012;85(06):527–537 One of the limitations of this present study was the 9 Serjeant GR, Singhal A, Hambleton IR. Sickle cell disease and age at menarche in Jamaican girls: observations from a cohort study. predominance of women with HbSS, and a small number Arch Dis Child 2001;85(05):375–378 β fi of women with HbSC or S -thalassemia. This poses dif cul- 10 Lopes TO, Amorim ACM, Oliveira DL, et al. Prevalência de casos de ties in comparing the SCD genotype groups. Prospective anemia falciforme, no ano de 2014, registrados na Secretaria studies with larger samples could reveal differences that Municipal de Saúde de Paracatu-MG. Rev Med Fac Atenas. 2015; – may not have been observed in this study. Another limitation 9(01):1 5 11 Brasil. Ministério da Sáude. Secretaria de Atenção à Saúde. may be the low frequency of the use of progestin-only Departamento de Atenção Hospitalar e de Urgência. Coordena- contraception, preventing observation of the differences in ção-Geral de Sangue e Hemoderivados. Doença falciforme: aten- the frequency of the acute painful episodes among the ção integral à saúde das mulheres. Brasilía (DF): Ministério da different contraceptive methods. Saúde; 2015

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Evaluation of Cases of Abdominal Wall Endometriosis at Universidade Estadual de Campinas in a period of 10 Years Avaliação dos casos de endometriose de parede abdominal na Universidade Estadual de Campinas em um período de 10 anos

Daniela Angerame Yela1 Lucas Trigo1 Cristina Laguna Benetti-Pinto1

1 Department of Obstetrics and Gynecology, Faculdade de Ciências Address for correspondence Daniela Angerame Yela, PhD, Médicas, Universidade Estadual de Campinas (Unicamp), Campinas, Departmento de Obstetrícia e Ginecologia, Faculdade de Ciências São Paulo, Brazil Médicas, Universidade Estadual de Campinas – Unicamp, Rua Alexander Fleming 101, 13083-970, Campinas, SP, Brazil Rev Bras Ginecol Obstet 2017;39:403–407. (e-mail: [email protected]).

Abstract Purpose To determine the clinical and epidemiological characteristics of abdominal wall endometriosis (AWE), as well as the rate and recurrence factors for the disease. Methods A retrospective study of 52 women with AWE was performed at Universi- dade Estadual de Campinas from 2004 to 2014. Of the 231 surgeries performed for the diagnosis of endometriosis, 52 women were found to have abdominal wall endometriosis (AWE). The frequencies, means and standard deviations of the clinical characteristics of these women were calculated, as well as the recurrence rate of AWE. To determine the risk factors for disease recurrence, Fisher’s exact test was used. Results The mean age of the patients was 30.71 5.91 years. The main clinical manifestations were pain (98%) and sensation of a mass (36.5%). We observed that 94% of these women had undergone at least 1 cesarean section, and 73% had used medication for the postoperative control of endometriosis. The lesion was most commonly located in the cesarean section scar (65%). The recurrence rate of the Keywords disease was of 26.9%. All 14 women who had relapsed had surgical margins compro- ► abdominal wall mised in the previous surgery. There was no correlation between recurrent AWE and a p ¼ p ¼ endometriosis previous cesarean section ( 0.18), previous laparotomy ( 0.11), previous p ¼ p ¼ ► pelvic pain laparoscopy ( 0.12) and postoperative hormone therapy ( 0.51). ► recurrence Conclusion Women with previous cesarean sections with local pain or lumps should ﬁ ► cesarean section scar be investigated for AWE. The recurrence of AWE is high, especially when the rst surgery is not appropriate and leaves compromised surgical margins.

Resumo Objetivos Determinar as características clínicas e epidemiológicas da endometriose de parede, bem como sua taxa de recorrência e os fatores que levam a ela. Métodos Estudo retrospectivo, em que se avaliaram 52 mulheres com endometriose de parede na Universidade Estadual de Campinas no período de 2004 a 2014. Entre as

received DOI https://doi.org/ Copyright © 2017 by Thieme Revinter January 21, 2017 10.1055/s-0037-1603965. Publicações Ltda, Rio de Janeiro, Brazil accepted ISSN 0100-7203. April 3, 2017 published online June 21, 2017 404 Evaluation of Cases of AWE at Unicamp in a period of 10 Years Yela et al.

231 cirurgias para diagnosticar endometriose, foram encontradas 52 mulheres que apresentavam endometriose de parede. Foram calculadas as frequências, a média e o desvio padrão das características clínicas destas mulheres, bem como a taxa de recorrência da endometriose de parede. Para determinar os fatores de risco de recorrência, foi utilizado o teste exato de Fisher. Resultados A idade média das mulheres foi de 30.71 5,91 anos. As principais manifestações clínicas foram dor (98%) e sensação do nódulo (36,5%). Foi observado que 94% dessas mulheres tinham pelo menos uma cesárea, e 73% destas ﬁzeram uso de medicação para controle da endometriose no pós-operatório. A localização mais frequente da lesão foi na cicatriz da cesárea (65%). A taxa de recorrência da doença foi de 26,9%. Todas as 14 mulheres que tiveram recidiva tinham margens cirúrgicas comprometidas na cirurgia prévia. Não houve correlação entre a endometriose de parede recorrente e a cesariana Palavras-chave prévia (p ¼ 0,18), a laparotomia prévia (p ¼ 0,11), a laparoscopia prévia (p ¼ 0,12) e ► endometriose de receber terapia hormonal no pós-operatório (p ¼ 0,51). parede Conclusão Mulheres com antecedente de cesárea anterior com dor local ou nódulo ► dor pélvica devem ser investigadas com relação à endometriose de parede. A recorrência do ► recorrência endometrioma de parede é alta, principalmente quando aprimeiracirurgianãoé ► cicatriz de cesárea adequada, e deixa margens cirúrgicas comprometidas.

Introduction The preferential treatment is surgery, and the diagnosis is confirmed by histopathology. Other therapeutic options are Endometriosis is a disease characterized by the presence of the suppression of menstruation with progestins or a gonado- endometrial tissue with glands and stroma implanted outside tropin-releasing hormone (GnRH) analogue.20 In spite of the the uterine cavity, which responds to ovarian hormone stimu- surgical removal of thelesion, there may be a recurrence rate of lation. It is usually confined to the pelvic organs, commonly 1.5 to 9.1%. To prevent this occurrence, surgical resection with – the ovaries, fallopian tubes, uterosacral ligaments, posterior free margins should be performed.20 23 cul-de-sac, rectovaginal septum and peritoneum.1,2 The dis- Therefore, this study aimed at determining the clinical ease is less commonly (9–15%) located outside the pelvic cavity, and epidemiological characteristics of AWE, as well as the and is termed extrapelvic endometriosis.3 The abdominal wall rate of recurrence of the disease and the factors that lead to it. is the most common site for extrapelvic endometriosis. Other organs may also be affected, such as the liver, bowels, adrenal – Methods glands, lungs, kidneys, and brain.4 11 Cases of endometriosis have been described in the surgi- A retrospective study in which 52 women with AWE were cal scar, cesarean section scar, episiotomy scar after vaginal evaluated at Universidade Estadual de Campinas (Unicamp) delivery, or following procedures where there was contact from January 2004 to December 2014 was performed. The with endometrial tissue, such as hysterotomy performed in clinical characteristics of these women were assessed, as well the first midterm of pregnancy, hysterectomy, ectopic preg- as the rate of recurrence of the disease and the factors that nancy and tubal ligation.2,12,13 In these patients, the rate of lead to it. occurrence of pelvic endometriosis is similar to that of other The medical charts of the women undergoing surgeries women, and is not regarded as a risk factor for the disease.14 described as exploratory laparotomy, exploratory laparoto- The incidence of abdominal wall endometriosis (AWE) is my due to endometriosis, and resection of endometrioma rare. The disorder occurs in 0.03–3.5% of cases, and some were assessed, totaling 917 surgeries. Of the total number of studies have reported a rate of up to 12%.12,15 It is associated surgeries, 231 were selected for the removal of endometri- with a history of obstetric or gynecologic procedures,2,12 osis lesions. Only cases of AWE were included in the study, although some cases occur spontaneously.16 The disease totaling 56 women. mostly affects patients with a history of cesarean section.17 Of the 56 surgeries for excision of AWE, insufficient data in However, endometrioma has also been observed in the the chart or lack of histopathological results that confirmed surgical incision following a conventional hysterectomy or the diagnosis of endometriosis excluded another 4 cases. laparoscopy, appendectomy and inguinal hernia.18 In these Therefore, 52 women remained for data analysis. cases, the lesions, which were frequently evaluated by the The variables analyzed were age, pregnancies, parity, general surgeon for diagnosis, were commonly misdiag- cesarean section, abortion, body mass index (BMI), symp- nosed as hernia, hematoma, granuloma, abscess or lipoma.19 tomatology of the endometrioma (pelvic pain, sensation of a

Rev Bras Ginecol Obstet Vol. 39 No. 8/2017 Evaluation of Cases of AWE at Unicamp in a period of 10 Years Yela et al. 405 mass, bleeding), duration of the symptomatology, associated Table 2 Characteristics of the lesions of women with abdominal diseases, postsurgical treatment with medication that sup- wall endometriosis (n ¼ 52) pressed menstruation (continuous combination estrogen/ progestin-only oral contraceptives or progestin), size and Lesion characteristics Mean SD or n (%) location of the endometrioma. Clinical manifestations The study was approved by the Research Ethics Committee Nodule pain 51 (98) of the institution under number 342430/2013. Mass 19 (36.5) The frequencies, means and standard deviations of the clinical characteristics of the patients were calculated, as Bleeding 7 (13.4) well as the recurrence rates of AWE. In order to determine the Duration of clinical 39.83 34.09 recurrence factors, Fisher’s exact test was used. For the manifestations (months) performance of these procedures, the Statistical Analysis Injury site Systems (SAS, SAS Institute, Inc., Cary, NC, US) software, Cesarean section 34 (65.4) version 9.4, was used. Umbilical 4 (7.7) Results Iliac fossa 14 (26.9) Size of endometrioma 2.52 1.21 The mean age of the women was 30.71 5.91 years. The mean in ultrasound (cm) 2 BMI was 26.48 5.24 kg/m , and the main clinical manifes- Size of endometrioma 3.98 1.72 tations were nodule pain (98%) and the sensation of a mass in surgery (cm) (36.5%). Only one woman had a painless mass (►Tables 1, 2). Abbreviation: SD, standard deviation. The mean duration of the clinical treatment was 39.83 34.09 months. Of the total number of women evaluated, 94% had undergone at least 1 cesarean section, and predominant location of the endometriotic lesion was in 73% had used medication for the control of endometriosis in the scar of the previous cesarean section, and the mean size the postoperative period. The lesion appeared most com- of the lesion was 4cm. The diagnosis was clinical, with the aid monly in the cesarean section scar (65%), and the mean size of ultrasonography. The recurrence rate of AWE was of 26.9%. of the lesion was 2.52 1.21 cm on ultrasound, and After a literature review including 445 cases of AWE, we 3.98 1.72 cm in the intraoperative period (►Table 2). obtained a mean patient age of 31.4 years. The main com- The recurrence rate of the disease was of 26.9%. All 14 plaints were a palpable mass and pain at the site of the lesion. women who had relapsed had surgical margins compro- The majority of women had a previous cesarean section scar mised in the previous surgery. There was no correlation or some other surgical scar. The mean time between the between recurrent AWE and a previous cesarean section surgery and the emergence of symptoms was 3.6 years. The (p ¼ 0.18), previous laparotomy (p ¼ 0.11), previous lapa- recurrence rate was of 4.3%.24 roscopy (p ¼ 0.12) and postoperative hormone therapy (p ¼ 0.51) (►Table 3).

Discussion Table 3 Factors associated with the recurrence of abdominal wall endometriosis (n ¼ 14) Our results showed that the mean age of the women was 31 years. The main complaints were a palpable mass and pain Factors n (%) p RR 95%CI at the site of the lesion. The mean duration of the symptom- Cesarean section atology was 40 months. We observed that 94% of these 0 2 (14.3) 0.18 0.38 0.15–0.97 patients had undergone at least 1 cesarean section. The 112(85.7) Treatment Table 1 Clinical characteristics of women with abdominal wall – endometriosis (n ¼ 52) No 4 (28.6) 0,51 1.55 0.57 4.21 Yes 10 (71.4) Women Mean SD or n (%) Laparotomy Age (years) 30.71 5.92 No 9 (64.2) 0.11 2.22 0.95–5.17 BMI (kg/m2) 26.48 5.24 Yes 5(25.19) Pregnancy Laparoscopy No pregnancy (0) 1 (2) No 11(78.5) 0.12 2.45 1.01–5.92 Pregnancy 151(98) Yes 3(21.5) Cesarean section 49 (94) Abbreviations: 95%CI, 95% conﬁdence interval; RR, relative risk. Abbreviations: BMI, body mass index; SD, standard deviation. Note: Fisher’sexacttest.

Rev Bras Ginecol Obstet Vol. 39 No. 8/2017 406 Evaluation of Cases of AWE at Unicamp in a period of 10 Years Yela et al.

A study evaluating 527 cases of endometriosis in Istanbul study. It should be reinforced that if pelvic endometriosis also obtained similar results. The mean patient age was persists, along with AWE, hormone therapy should be used to 33 years. All patients had a history of at least one pregnancy, control the disease.24 a previous surgical procedure, and 90% of these women had In the present study, the precise relationship between undergone a cesarean section. The predominant symptom- cesarean section and AWE could not be established, despite atology was also a palpable mass and pain. The mean the high rate of cesarean sections in patients with AWE. duration of the symptomatology was 18 months. The main A limitation of the study is its retrospective nature, location of the lesions was in the surgical scar in 84.7% of which makes data collection and complete data acquisition cases, and the mean size of the lesion was 4.6 cm. The more difficult. A prospective study has been suggested, in diagnosis was clinical, with the aid of ultrasonography. The which data can be collected in a correct and detailed recurrence rate was of 9.1%.2 manner. Another study with 227 patients was conducted in China. Although a large part of the data obtained in this project is The mean patient age was 32 years. All women had under- consistent with the literature, the difference in the recurrence gone a previous surgery, childbirth, and 99.6% (226 patients) rate of AWE is notable. Studies have reported an average rate of reported a history of cesarean section. The main imaging 4.3–9.1% of disease relapse. In contrast, our study obtained a modality used for the preoperative diagnosis was ultraso- recurrence rate of 26.9%. The discordant results can be nography. The major complaints were a palpable mass and explained by the fact that in a tertiary hospital we usually pain. The mean duration of the symptomatology was treat more complex and difficult cases. Another possible 28 months. All lesions were in the surgical scar, with recur- explanation is that, during surgery, care to isolate and rence rates of 7.14%.21 exchange surgical fields and material, washing and drying According to the literature, endometriosis affects women the abdominal cavity, attention during hysterorrhaphy, and of reproductive age. It is more common in multiparous closure of the remaining planes may be ineffective in this women aged 25 to 35 years.25 Our results are similar to hospital setting. In the university hospital, residents receive those of other studies. The mean age of our patients was training and knowledge that will last for a lifetime, and the 31 years, and 94% of these women had a history of at least 1 surgeries are not only performed by skilled specialists. cesarean section. This data was also present in some studies Endometriosis of the abdominal wall is not a highly as a risk factor for the development of AWE.20,26,27 Athor- prevalent disease in the population. However, it may lead ough follow-up and detailed investigation of the women of to a great deal of discomfort, and impair the quality of life of reproductive age with pelvic pain is important for better women of reproductive age. Despite contrary results in the disease control and improvement in the patients’ quality of literature, the recurrence rate in our service was elevated. life. Since many cases of AWE are evaluated by physicians More caution and attention is required while operating other than gynecologists, the differential diagnosis should be patients with endometriosis, particularly when a hysterec- kept in mind, when a woman of reproductive age complains tomy has been performed. A prospective study should be of pain or a mass adjacent to a surgical scar, particularly in performed to better evaluate the possible factors related to cases of previous childbirth or hysterotomy. the disease for the improvement of patient care. A study indicated that alcohol consumption and heavy We conclude that women with previous cesarean menstrual bleeding may be risk factors for the development sections with local pain or lumps should be investigated of AWE. In contrast, multiparity may be a protective factor.27 for AWE. The recurrence of AWE is high, especially when the Cesarean section indicated after the onset of contractions first surgery is not appropriate and leaves compromised also seems to offer protection against the disease, compared surgical margins. with elective cesarean section.28 In this study, only 51% of the patients had a history of at least 1 cesarean delivery, a data 20 similar to the case series described by Leite et al, in which Financial Disclosure/Conflicts of Interest 30.3% of cases were of multiparous women. The authors declare no conflicts of interest. There arefewevaluations on how to prevent AWE. However, somesuggestions werefound: dislocation of the uterus outside the pelvic cavity for the performance of hysterotomy, the use of References different suture needles and materials for the uterus and 1 Giudice LC, Kao LC. Endometriosis. Lancet 2004;364(9447):1789–1799 remaining cavity plans, irrigation with high-jet saline, avoiding 2 Bektaş H, Bilsel Y, Sari YS, et al. Abdominal wall endometrioma; a the use of surgical sponges to clean the endometrial cavity in 10-year experience and brief review of the literature. J Surg Res the intraoperative period, thorough cleaning of the abdominal 2010;164(01):e77–e81 cavity after hysterorrhaphy, attention while delivering the 3 Douglas C, Rotimi O. Extragenital endometriosis–a clinicopatho- placenta to avoid spillage of uterine contents into the abdomi- logical review of a Glasgow hospital experience with case illus- – nal cavity, and protection of the surgical margins to prevent trations. J Obstet Gynaecol 2004;24(07):804 808 4 Mascaretti G, Di Berardino C, Mastrocola N, Patacchiola F. Endome- endometrial implants in the surgical incision.2,17,29 triosis: rare localizations in two cases. Clin Exp Obstet Gynecol fi In the literature, there was no signi cant evidence that the 2007;34(02):123–125 clinical course of the patient was better with the use of 5 Liu K, Zhang W, Liu S, Dong B, Liu Y. Hepatic endometriosis: a rare hormones after surgery, which is in agreement with our case and review of the literature. Eur J Med Res 2015;20:48

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6 Lee HJ, Park YM, Jee BC, Kim YB, Suh CS. Various anatomic on the same site: a case report. Am J Obstet Gynecol 2005;193 locations of surgically proven endometriosis: A single-center (3 Pt 1):878–880 experience. Obstet Gynecol Sci 2015;58(01):53–58 19 Rao R, Devalia H, Zaidi A. Post-caesarean incisional hernia or scar 7 Badawy SZ, Shrestha P. Recurrent catamenial pneumothorax endometrioma? Surgeon 2006;4(01):55–56 suggestive of pleural endometriosis. Case Rep Obstet Gynecol 20 Leite GKC, Carvalho LFP, Korkes H, Guazzelli TF, Kenj G, Viana 2014;2014:756040 AdeT. Scar endometrioma following obstetric surgical incisions: 8 Huang H, Li C, Zarogoulidis P, et al. Endometriosis of the lung: retrospective study on 33 cases and review of the literature. Sao report of a case and literature review. Eur J Med Res 2013;18:13 Paulo Med J 2009;127(05):270–277 9 Mostafa HA, Saad JH, Nadeem Z, Alharbi F. Rectus abdominis 21 Ding Y, Zhu J. A retrospective review of abdominal wall endome- endometriosis. A descriptive analysis of 10 cases concerning this triosis in Shanghai, China. Int J Gynaecol Obstet 2013;121(01): rare occurrence. Saudi Med J 2013;34(10):1035–1042 41–44 10 Nezhat C, King LP, Paka C, Odegaard J, Beygui R. Bilateral thoracic 22 Vilarino FL, Bianco B, Martins ACM, Christofolini DM, Barbosa CP. endometriosis affecting the lung and diaphragm. JSLS 2012;16 [Surgical scar endometriosis: a series of 42 patients]. Rev Bras (01):140–142 Ginecol Obstet 2011;33(03):123–127 Portuguese 11 Veeraswamy A, Lewis M, Mann A, Kotikela S, Hajhosseini B, Nezhat 23 Ecker AM, Donnellan NM, Shepherd JP, Lee TT. Abdominal wall C. Extragenital endometriosis. Clin Obstet Gynecol 2010;53(02): endometriosis: 12 years of experience at a large academic institu- 449–466 tion. Am J Obstet Gynecol 2014;211(04):363.e1–363.e5 12 Nominato NS, Prates LFVS, Lauar I, Morais J, Maia L, Geber S. 24 Horton JD, Dezee KJ, Ahnfeldt EP, Wagner M. Abdominal wall Caesarean section greatly increases risk of scar endometriosis. Eur endometriosis: a surgeon’s perspective and review of 445 cases. J Obstet Gynecol Reprod Biol 2010;152(01):83–85 Am J Surg 2008;196(02):207–212 13 Nominato NS, Prates LFVS, Lauar I, Morais J, Maia L, Geber S. [Scar 25 Zhao X, Lang J, Leng J, Liu Z, Sun D, Zhu L. Abdominal wall endometriosis: a retrospective study of 72 patients]. Rev Bras endometriomas. Int J Gynaecol Obstet 2005;90(03):218–222 Ginecol Obstet 2007;29(08):423–427 Portuguese 26 Akbulut S, Sevinc MM, Bakir S, Cakabay B, Sezgin A. Scar 14 Sinha R, Kumar M, Matah M. Abdominal scar endometriosis after endometriosis in the abdominal wall: a predictable condition Caesarean section: a rare entity. Australas Med J 2011;4(01):60–62 for experienced surgeons. Acta Chir Belg 2010;110(03):303–307 15 Chang Y, Tsai EM, Long CY, Chen YH, Kay N. Abdominal wall 27 de Oliveira MA, de Leon ACP, Freire EC, de Oliveira HC. Risk factors endometriomas. J Reprod Med 2009;54(03):155–159 for abdominal scar endometriosis after obstetric hysterotomies: a 16 Papavramidis TS, Sapalidis K, Michalopoulos N, et al. Spontaneous case-control study. Acta Obstet Gynecol Scand 2007;86(01): abdominal wall endometriosis: a case report. Acta Chir Belg 2009; 73–80 109(06):778–781 28 Wicherek L, Klimek M, Skret-Magierlo J, et al. The obstetrical history 17 Wasﬁe T, Gomez E, Seon S, Zado B. Abdominal wall endometrioma in patients with Pfannenstiel scar endometriomas–an analysis of 81 after cesarean section: a preventable complication. Int Surg 2002; patients. Gynecol Obstet Invest 2007;63(02):107–113 87(03):175–177 29 Nissotakis C, Zouros E, Revelos K, Sakorafas GH. Abdominal wall 18 Sirito R, Puppo A, Centurioni MG, Gustavino C. Incisional hernia endometrioma: a case report and review of the literature. AORN J on the 5-mm trocar port site and subsequent wall endometriosis 2010;91(06):730–742, quiz 743–745

Rev Bras Ginecol Obstet Vol. 39 No. 8/2017 THIEME 408 Original Article

Detection of High-Risk Human Papillomavirus in Cervix Sample in an 11.3-year Follow-Up after Vaccination against HPV 16/18 Detecção de papilomavírus humano de alto risco em amostras de colo uterino em 11.3 anos de acompanhamento após vacinação contra HPV 16/18

Cirbia Silva Campos Teixeira1 Julio Cesar Teixeira1 Eliane Regina Zambelli Mesquita Oliveira1 Helymar Costa Machado2 Luiz Carlos Zeferino1

1 Department of Obstetrics and Gynecology, Faculdade de Ciências Address for correspondence Julio Cesar Teixeira, MD, PhD, Faculdade Médicas, Universidade de Campinas (Unicamp), Campinas, SP, Brazil de Ciências Médicas da Universidade de Campinas (UNICAMP), Centro 2 Department of Statistics, Women’sHealthHospital– Centro de de Atenção Integral à Saúde da Mulher (CAISM), Rua Alexandre Atenção Integral à Saúde da Mulher - CAISM), Universidade de Fleming, 101–Cidade Universitária, Campinas, SP, Brazil 13083-881 Campinas (Unicamp), Campinas, SP, Brazil (e-mail: [email protected]; [email protected]).

Rev Bras Ginecol Obstet 2017;39:408–414.

Abstract Purpose the aim of this study was to evaluate the pattern of human papillomavirus (HPV) detection in an 11.3-year post-vaccination period in a cohort of adolescent and young women vaccinated or not against HPV 16/18. Methods a subset of 91 women from a single center participating in a randomized clinical trial (2001–2010, NCT00689741/00120848/00518336) with HPV 16/18 AS04- adjuvanted vaccine was evaluated. All women received three doses of the HPV vaccine (n ¼ 48) or a placebo (n ¼ 43), and cervical samples were collected at 6-month Keywords intervals. Only in this center, one additional evaluation was performed in 2012. Up to ► human 1,492 cervical samples were tested for HPV-DNA and genotyped with polymerase chain papillomavirus reaction (PCR). The vaccine group characteristics were compared by Chi-square or ► cervix uteri Fisher exact or Mann-Whitney test. The high-risk (HR)-HPV 6-month-persistent infec- ► papillomavirus tion rate was calculated. The cumulative infection by HPV group was evaluated by the vaccines Kaplan-Meier method and the log-rank test. ► human Results the cumulative infection with any type of HPV in an 11.3-year period was 67% papillomavirus in the HPV vaccine group and 72% in the placebo group (p ¼ 0.408). The longitudinal vaccine 16 and 18 L1 analysis showed an increase of 4% per year at risk for detection of HR-HPV (non-HPV 16/ VLP 18) over time (p ¼ 0.015), unrelated to vaccination. The cumulative infection with HPV ► HPV DNA tests 16/18 was 4% for the HPV vaccine group and 29% for the placebo group (p ¼ 0.003). ► polymerase chain There were 43 episodes of HR-HPV 6-month persistent infection, unrelated to reaction vaccination.

received DOI https://doi.org/ Copyright © 2017 by Thieme Revinter November 16, 2016 10.1055/s-0037-1604133. Publicações Ltda, Rio de Janeiro, Brazil accepted ISSN 0100-7203. April 28, 2017 Detection of High-Risk HPV in Cervix Sample Follow-Up after Vaccination against HPV Teixeira et al 409

Conclusions this study showed the maintenance of viral detection rate accumulating HR-HPV (non-HPV-16–18) positive tests during a long period post-vaccination, regardless of prior vaccination. This signalizes that the high number of HPV-positive tests may be maintained after vaccination.

Resumo Objetivos avaliar o padrão de detecção do papilomavírus humano (HPV) em um período de 11.3 anos após a vacinação em uma coorte de adolescentes e mulheres jovens vacinadas ou não contra HPV 16/18. Métodos avaliou-se um subgrupo de 91 mulheres de um único centro, participantes de ensaio clínico randomizado (2001–2010, NCT00689741/00120848/00518336) com a vacina contra HPV 16/18 com adjuvante AS04. Todas as mulheres receberam três doses de vacina contra HPV (n ¼ 48) ou placebo (n ¼ 43), e tiveram amostras cervicais coletadas em intervalos de 6 meses. Somente neste centro, uma avaliação adicional foi realizada em 2012. Um total de 1.492 amostras cervicais foram testadas para DNA-HPV e genotipadas com reação em cadeia da polimerase (RCP). As carac- terísticas dos grupos de vacina contra HPVou placebo foram comparadas pelo teste de Qui-quadrado ou teste exato de Fisher ou teste de Mann-Whitney. A infecção persistente por 6 meses pelo HPV de alto risco (AR) foi calculada. A infecção cumulativa Palavras-Chave por grupo foi avaliada pelo método de Kaplan-Meier e pelo teste log-rank. ► papilomavírus Resultados a infecção cumulativa com qualquer tipo de HPV em 11.3 anos foi de 67% humano no grupo vacina contra HPV e de 72% no grupo placebo (p ¼ 0,408). A análise ► colo uterino longitudinal mostrou um aumento de 4% ao ano no risco de detecção de HR-HPV ► vacinas contra (não-HPV 16/18) ao longo do tempo (p ¼ 0,015), não relacionado com a vacinação. A papilomavírus infecção cumulativa com HPV 16/18 foi de 4% para o grupo vacina contra HPV e 29% ► vacina contra para o grupo placebo (p ¼ 0,003). Houve 43 episódios de infecção persistente por 6 papilomavírus meses por HR-HPV, não relacionados com a vacinação. humano16 e 18 VLP L1 Conclusões este estudo mostrou a manutenção da taxa de detecção viral, acumu- ► testes de DNA-HPV lando testes positivos de HR-HPV (não HPV-16–18) durante longo período pós- ► reação em cadeia da vacinação, independentemente da vacinação prévia. Isto sinaliza que a alta positivi- polimerase dade dos testes de HPV pode ser mantida após a vacinação.

Introduction Campinas, Brazil, has participated in clinical trials of vaccines against HPV since 2000. This study presents an evaluation of The etiology of cervical cancer is related to persistent infec- a cohort of women vaccinated against HPV 16/18 or with tion with a high-risk human papillomavirus (HR-HPV).1,2 control vaccine in 2001 and followed-up until 2012, describ- Our knowledge of the relationship between these viral ing the pattern of HR-HPV DNA detection in cervical samples infections and uterine cervical cancer has led to the devel- over time as a preliminary estimate of the future perfor- opment of prophylactic vaccines and their licensing for use in mance of HPV tests. 2006. Since then, the use of these vaccines has progressively expanded in population-based programs around the world, – Methods and some preliminary results are already available.3 6 Pre- sumably, HPV vaccination on a large scale should interfere We analyzed the data from 91 women who participated in a with the diversity of HPV types distributed in nature, even phase IIB, multicenter, clinical trial, with the GlaxoSmithKline those unrelated to the HPV vaccine types.7,8 A long transi- (GSK) HPV 16/18 AS04-adjuvanted vaccine, as a prospective tional period is expected and understanding this process is cohort study. This clinical trial comprised the primary study important to deﬁne strategies for the detection of women at and two follow-up extension studies, between 2001 and 2010 risk and to screen for precursor lesions in the post-vaccina- (NCT 00689741/ 00120848/ 00518336, www.clinicaltrials. – – tion era.7 11 There is evidence that HPV testing may have gov), with their results already published.12 14 In 2001, 98 – better performance in a vaccinated population9 11 and that it women started their participation; they were between 15 and will be more efﬁcient in the future screening of vaccinated 25 years old, reported six or fewer previous sexual partners, women, when compared with cytology.8 Our institution in and were naive for HR-HPV detectable infection according to

Rev Bras Ginecol Obstet Vol. 39 No. 8/2017 410 Detection of High-Risk HPV in Cervix Sample Follow-Up after Vaccination against HPV Teixeira et al

screening performed 90–105 days before vaccination. Ninety- of HPV infection: new sexual partner reported in the preceding one of them received three doses of vaccine, given in a year, previous pregnancy, regular use (continuous use for randomized double-blind manner, on a 6-month schedule 3 months or more each year) of hormonal contraceptives or (0/1/6): 48 women received the HPV vaccine against HPV condoms, and smoking (any amount). Information were

16/18 and 43 received the placebo (Al[OH]3). They were recorded at four tie points (in years 2001, 2005, 2010, and followed-up until 2010 and cervical samples were collected 2012). The analysis was performed using the chi-squared (χ2), at intervals of 180 45 days, except in 2003 χ2 for trend, Fisher’s exact, or Mann–Whitney tests. The In 2012, 78 women for whom contact information was longitudinal analysis to estimate the cumulative risk of available were invited to attend an additional evaluation for HPV-positive test result in 11.3 years after vaccination was the present study, and those who received the placebo in 2001 performed using the Kaplan–Meier method and log-rank (35 subjects) were offered the opportunity to receive the test.18 The HPV types detected were pooled as follows: any licensed vaccine against HPV 16/18. Sixty-seven women ac- HPV, HR-HPV, HR-HPV (non-HPV 16/18) and HPV 16/18. The cepted the invitation and 59 (32 previously vaccinated with HR-HPV 6-month-persistent infection (6MPI) was calculated. the HPV vaccine and 27 with the placebo) agreed to participate For statistical analysis, the SAS 9.2 software (SAS Institute Inc., in the current study and undergo a gynecological evaluation Cary, NC, USA)19 was used and p values < 0.05 were consid- with cervical samples collection. The gaps in data collection ered significant. that occurred in years 2003 and 2011 arose because of the time required for regulatory approval of the research, and in 2003, it Results was aggravated by the wait for the results from the primary multicenter study analysis before we could move forward. In At study entry, the age range distributions were similar addition, in 2011, there was a period spent to define the cross- between the groups and there were no significant differences vaccination feasibility to the placebo recipients because the in terms of the risk factors considered associated with HPV same vaccine had just been licensed and available for vaccina- acquisition between the vaccination groups (►Table 1). The tion in Brazil (year 2010), but only for women up to 25 years- maximum follow-up time was 135 months. old. As most of the women were older than 25s, a new study The cumulative percentages of subjects with HPV infec- had to be designed and submitted for regulatory approval just tion throughout the 11.3-year study period and pooled in any to provide cross-vaccination. HPV type or HR-HPV type were 67% and 60%, respectively, for The cervical samples collected were preserved in Preserv- the HPV vaccine group and 72 and 63%, respectively, for the Cyt (Cytyc Corporation, Boxborough, MA, USA) and tested placebo group (p ¼ 0.408 and p ¼ 0.452, respectively) 15 with SPF10 LiPA25 assay, a polymerase chain reaction (PCR) (►Table 2). The cumulative infection rate in the 11.3-year genotyping tool for the detection of 25 HPV types (15 HR- period by HR-HPV (non-HPV 16/18) was 57–58% for both HPV), performed by a centralized laboratory with careful groups (p ¼ 0.652) (►Fig. 1), with an increasing trend of 4% quality control, between 2001 and 2010. The samples from per year (p ¼ 0.015). the last visit, in 2012, were stored at - 30°C until 2014 and On the last visit (2012, CLART-HPV2 test), four HR-HPV tested with the CLART-HPV2 test (Genomica S.A.U., Madrid, (non-HPV 16/18) infections were detected in each group; in Spain),16 a PCR genotyping tool that detects 35 HPV types, the HPV vaccine group as a first detection (all four), and in the

the same 15 HR-HPV types as SPF10 LiPA25 plus 5 additional placebo group, the other four as repeated detections. The oncogenic high-risk types (HR-HPV 26, 53, 73, 82, and 85), HPV types detected in these eight cases by CLART-HPV2 test

totaling 20 HR-HPV types. The CLART-HPV2 tests were were types that could be detected by SPF10 LiPA25 test too, performed at a molecular diagnostic laboratory in São Paulo, reducing possible interference in results due to different Brazil, with experience in HPV testing, and, as a quality assays applied. control of the stored samples, a set of 20 frozen samples As expected, the cumulative infection by HPV 16/18 was and other 20 ‘fresh’ cervical samples were tested in two 4% for the HPV vaccine group and 29% for the placebo group laboratories, and by three different assays (local innovative (p ¼ 0.003) (►Fig. 2 and ►Table 2). prototype assay, Cobas HPV test [Roche Molecular Systems, We observed 52 episodes of HR-HPV 6MPI in 31 patients Inc., Pleasanton, CA, USA] and CLART-HPV2). The results throughout the 11.3-year period. The cumulative rate of HR- were concordant and storage time until samples analysis HPV 6MPI detections for the 11.3-year period was 31% for the was not considered a concern. HPV vaccine group and 45% for the placebo group (p ¼ 0.189) The studies (three consecutive phases of a multicenter (►Fig. 3). Considering HPV 16/18 6MPI, no event was ob- study in the period of 2001–2010 and the current single- served in the HPV vaccine group, whereas six events were center study) followed the regulatory standards of the recorded in the placebo group. Of these six events, four were National Health Council of Brazil17 and were approved by related to HPV-16 and two events related to HPV18. the local Ethics Committee. All subjects signed an informed consent form before their participation in each study. Discussion

Statistical Analysis This is a unique long-term HPV study done in the post- We compared the groups (HPV vaccine and placebo) in respect vaccination era, and it emphasizes that HR-HPV (non-HPV to age and potential risk factors associated with the acquisition 16/18) continues to occur at the same rate in HPV vaccinated

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Table 1 Distribution of the demographic characteristics checked by time point (years 2001, 2005, 2010 and 2012) and by vaccination group

Parameter Year Number of answer ‘Yes’ ‘Yes’/total Vaccination group HPV vaccine Placebo n%N% New sexual partner in last year 2001 11/88 5/47 10.6 6/41 14.6 2005 20/78 10/42 23.8 10/36 27.8 2010 10/75 3/41 7.3 7/34 20.6 2012 5/59 3/32 9.4 2/27 7.4 Previous pregnancy reported 2001 38/88 19/47 40.4 19/41 46.3 2005 33/78 18/42 42.3 15/36 41.7 2010 14/75 8/41 19.5 6/34 17.6 2012 0/59 0/32 0/27 Hormonal contraceptive 2001 48/88 25 53.2 23 56.1 !regular use 2005 49/78 28 66.7 21 58.3 2010 42/75 23 56.1 19 55.9 2012 35/59 16 50.0 19 70.4 Condom 2001 26/88 9/47 19.1 17/41 41.5 !regular use 2005 10/78 5/42 11.9 5/36 13.9 2010 6/75 4/41 9.8 2/34 5.9 2012 5/59 3/32 9.4 2/27 7.4 Current smoking 2001 26/88 14 29.8 12 29.3 2005 12/78 6 14.3 6 16.7 2010 14/75 9 22.0 5 14.7 2012 10/59 4 12.5 6 22.2

Regular use indicates having used the method for at least 3 consecutive months in the last 12 months. For each parameter and period: all tests by Chi-square or Fisher exact or Mann-Whitney were p > 0.05.

Table 2 Cumulative percentage and number of subjects with HPV infection according to HPV group and vaccine received

Months after dose 1 Cumulative percentage and number of subjects by HPV group Any HPV High risk High risk HPV 16/18 (non-HPV 16/18) HPV Placebo HPV Placebo HPV Placebo HPV Placebo vaccine (n ¼ 43) vaccine (n ¼ 43) vaccine (n ¼ 43) vaccine (n ¼ 43) (n ¼ 48) (n ¼ 48) (n ¼ 48) (n ¼ 48) %Subj.%Subj.%Subj.%Subj.%Subj.%Subj.%Subj.%Subj. 12 31 15 35 15 17 8 21 9 13 6 12 5 4 2 9 4 24 40 19 47 20 25 12 33 14 21 10 23 10 4 2 12 5 60 51 24 64 27 40 19 54 22 38 18 47 19 4 2 20 8 120 5526692947226024452158234 2 2610 135 6730723060266325572558234 2 2911 p 0.408 0.452 0.652 0.003

Abbreviations: HPV, Human Papillomavirus; Subj., subjects. Log-rank test. Multiple HPV detection was considered one event by HPV group.

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Fig. 1 Cumulative percentage of women with high-risk HPV (non-HPV 16/18) infection detected in long-term follow-up by vaccination group.

Fig. 2 Cumulative percentage of women with HPV 16/18 infection detected in long-term follow-up by vaccination group.

Fig. 3 Cumulative percentage of women with high-risk HPV 6-month persistent infection detected in long-term follow-up by vaccination group.

Rev Bras Ginecol Obstet Vol. 39 No. 8/2017 Detection of High-Risk HPV in Cervix Sample Follow-Up after Vaccination against HPV Teixeira et al 413 group versus unvaccinated women. The cumulative infection The CLART-HPV2 test used in the last samples evaluation rate by any HPV type in 11.3 years after vaccination was detected eight cases of HR-HPV (non-HPV 16/18) (four in signiﬁcant and unrelated to the vaccine received (67% in the each vaccine group), the same HPV types already tested by

HPV vaccine group and 72% in the placebo group). The SPF10 LiPA25. The cumulative infection by HR-HPV (non-HPV detection of HR-HPV (non-HPV 16/18) was similar in the 16/18) showed a final convergence demonstrated by the 11.3-year post-vaccination period and was not associated elevation of the curve for the HPV vaccine group (►Fig. 1). with the vaccination received in 2001, and increasing 4% per This final pattern of the curve can be explained by the fact year. As expected, the HPV 16/18 detection rate tended to that all four cases detected in the HPV vaccine group were decrease in the period studied, with a 90% lower risk of new detections, in contrast with the four detections done in detection if previously vaccinated. placebo group, which happened in patients with previously The aim of this study was to assess the long-term pattern positive tests, and thus, had no impact on the curve. No of HPV detection, particularly of HR-HPV (non-HPV 16/18), additional HPV types were detected. Therefore, we believe and our results indicate that the previous vaccination against that the difference between the HPV test assays did not affect HPV 16/18 was not associated with lower detection rates of the longitudinal aggregated data and results. HR-HPV (non-HPV 16/18) in this group of 91 women. Our Our results signalize the possibility of maintaining the results are in line with the published findings from the major performance of HPV tests at standard rates, particularly with study that analyzed data from all centers and showed an high positivity rate and limited specificity. These patterns evident vaccine efficacy related to HPV 16/18 detection and may directly influence the application of the HPV tests in no statistic power to show cross-protection against others large-scale, particularly in younger women and in the vacci- – HR-HPV types.12 14 nated population, as discussed in some researches.11,21,22 The local cohort studied showed an increase of 4% per year The cohort studied here showed the same pattern with high in the chance of a new HR-HPV detection when samples were positivity rate for HPV tests. taken every 6 months. This finding is consistent with previous In conclusion, in addition to the fact that the prophylactic observations in the population cohort studied, that the HPV vaccination provided protection against vaccine-targeted HPV infection remains detectable and with a significant rate of 3 to types for up to 11.3 years, the detection of HR-HPV (non-HPV 7% for women aged 20 to 44 years (and unvaccinated), as 16/18) was maintained for a long period post-vaccinationwith a described by Muñoz et al (2004)20 for the general population. slight annual increase of 4%, even in women previously vacci- The clinical significance of our results can be translated to nated, in a well-controlled study. The women vaccinated may maintenance of HPV-positive test results even in vaccinated remain at the same risk of having an HPV-positive test result in women, with a significant probability to have a positive test their regular screening and a new approach or screening tests result during their regular follow-up. This finding became must be defined to find the women who are really at risk. important once the HPV tests started to be applied for screening. The expectation of improved performance of HPV tests in the future vaccinated population9,10 may not happen. Financial Support Considering HR-HPV, the persistent infection by the same This study was partially funded by FAEPEX (Unicamp) HPV type detected in 6-month interval showed episodes 519292–1016/13. similarly distributed in both groups (data not shown). Six cases of persistent infection were associated with HPV-16 or Acknowledgments -18 and all detected in the placebo group. Additional infor- GlaxoSmithKline provided the data from the Campinas mation about follow-up of these cases: three of these six Center for the HPV 16/18 vaccine studies. cases had cytological abnormalities, one had CIN1 and another had CIN2 diagnostic, and all abnormalities were associated with HPV-16. These findings confirm the previ- – References ously published results for the GSK HPV vaccine trial.12 14 1 Walboomers JM, Jacobs MV, Manos MM, et al. Human papillo- This study had some limitations including the small mavirus is a necessary cause of invasive cervical cancer world- number of cases evaluated and the high frequency (6-month wide. J Pathol 1999;189(01):12–19 intervals) of sample collection. The strengths were the long 2 Kjaer SK, van den Brule AJ, Paull G, et al. Type specific persistence follow-up period and the characteristics of the participants of high risk human papillomavirus (HPV) as indicator of high who initially were naive for HR-HPV previous detectable grade cervical squamous intraepithelial lesions in young women: population based prospective follow up study. BMJ 2002;325 infection, randomly vaccinated, placebo controlled and (7364):572 maintained as double-blind, with a good adherence rate 3 Tabrizi SN, Brotherton JM, Kaldor JM, et al. Fall in human (86%) to the study procedures scheduled up to 2010. papillomavirus prevalence following a national vaccination pro- The additional non-randomized, unblinded visit (2012), gram. J Infect Dis 2012;206(11):1645–1651 performed only at our center, made it possible to increase the 4 Markowitz LE, Hariri S, Lin C, et al. Reduction in human papillo- follow-up time to 11.3 years and reach the number of 1,492 mavirus (HPV) prevalence among young women following HPV vaccine introduction in the United States, National Health and tests evaluated from both groups. It is important to note that Nutrition Examination Surveys, 2003-2010. J Infect Dis 2013; were differences related to HPV test assays used in this study. 208(03):385–393

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5 Kavanagh K, Pollock KG, Potts A, et al. Introduction and sustained 14 Naud PS, Roteli-Martins CM, De Carvalho NS, et al. Sustained efficacy, high coverage of the HPV bivalent vaccine leads to a reduction in immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted prevalence of HPV 16/18 and closely related HPV types. Br J Cancer vaccine: final analysis of a long-term follow-up study up to 9.4 years 2014;110(11):2804–2811 post-vaccination. Hum VaccinImmunother 2014;10(08):2147–2162 6 Mesher D, Panwar K, Thomas SL, Beddows S, Soldan K. Continuing 15 Quint WG, Scholte G, van Doorn LJ, Kleter B, Smits PH, Lindeman J. reductions in HPV 16/18 in a population with high coverage of Comparative analysis of human papillomavirus infections in bivalent HPV vaccination in England: an ongoing cross-sectional cervical scrapes and biopsy specimens by general SPF(10) PCR study. BMJ Open 2016;6(02):e009915 and HPV genotyping. J Pathol 2001;194(01):51–58 7 Stanley M, Lowy DR, Frazer I. Chapter 12: Prophylactic HPV 16 Clart Human Papillomavirus 2 [Internet]. Genotyping of human vaccines: underlying mechanisms. Vaccine 2006;24(Suppl 3): papillomavirus via genomic identification for in vitro diagnosis. S3, 106–113 2013 [cited 2015 Feb 6]. Available from: http://genomica.es/en/ 8 Markowitz LE, Hariri S, Unger ER, Saraiya M, Datta SD, Dunne EF. documents/CLARTHPV2V10Feb2013English.pdf Post-licensure monitoring of HPV vaccine in the United States. 17 Brasil. Ministério da Saúde. Conselho Nacional de Saúde. Co- Vaccine 2010;28(30):4731–4737 missão Nacional de Ética em Pesquisa [Internet]. Resolução N° 9 Stanley M. Human papillomavirus vaccines versus cervical cancer 196/96 versão 2012. 2012 [citado 2015 Fev 6]. Disponível em: screening. Clin Oncol (R Coll Radiol) 2008;20(06):388–394 http://conselho.saude.gov.br/web_comissoes/conep/aquivos/re- 10 Ronco G, Dillner J, Elfström KM, et al; International HPV screening solucoes/23_out_versao_final_196_ENCEP2012.pdf working group. Efficacy of HPV-based screening for prevention of 18 Hand DJ, Crowder MJ. Practical longitudinal data analysis. Lon- invasive cervical cancer: follow-up of four European randomised don: Chapman & Hall; 1996 controlled trials. Lancet 2014;383(9916):524–532 19 SAS Institute. The SAS System for Windows (Statistical Analysis 11 El-Zein M, Richardson L, Franco EL. Cervical cancer screening of System), version 9.2. Cary: SAS Institute Inc; 2002–2008 HPV vaccinated populations: Cytology, molecular testing, both or 20 Muñoz N, Méndez F, Posso H, et al; Instituto Nacional de Cancer- none. J Clin Virol 2016;76(Suppl 1):S62–S68 ologia HPV Study Group. Incidence, duration, and determinants of 12 Harper DM, Franco EL, Wheeler C, et al; GlaxoSmithKline HPV cervical human papillomavirus infection in a cohort of Colombian Vaccine Study Group. Efficacy of a bivalent L1 virus-like particle women with normal cytological results. J Infect Dis 2004;190(12): vaccine in prevention of infection with human papillomavirus 2077–2087 types 16 and 18 in young women: a randomised controlled trial. 21 Arbyn M, Sasieni P, Meijer CJ, Clavel C, Koliopoulos G, Dillner J. Lancet 2004;364(9447):1757–1765 Chapter 9: Clinical applications of HPV testing: a summary of 13 Romanowski B, de Borba PC, Naud PS, et al; GlaxoSmithKline meta-analyses. Vaccine 2006;24(Suppl 3):S3, 78–89 Vaccine HPV-007 Study Group. Sustained efficacy and immuno- 22 Hestbech MS, Lynge E, Kragstrup J, Siersma V, Vazquez-Prada genicity of the human papillomavirus (HPV)-16/18 AS04-adju- Baillet M, Brodersen J. The impact of HPV vaccination on future vanted vaccine: analysis of a randomised placebo-controlled trial cervical screening: a simulation study of two birth cohorts in up to 6.4 years. Lancet 2009;374(9706):1975–1985 Denmark. BMJ Open 2015;5(08):e007921

Rev Bras Ginecol Obstet Vol. 39 No. 8/2017 THIEME Original Article 415

Survey on Aesthetic Vulvovaginal Procedures: What do Portuguese Doctors and Medical Students Think? Inquérito sobre procedimentos estéticos vulvovaginais: qual a opinião dos médicos e estudantes de medicina portugueses?

Pedro Vieira-Baptista1 Joana Lima-Silva1 José Fonseca-Moutinho2 Virgínia Monteiro3 Fernanda Águas4

1 Department of Obstetrics and Gynecology, Centro Hospitalar de São Address for correspondence Pedro Vieira Baptista, MD, João,Porto,Portugal Departmento de Obstetrícia e Ginecologia, Centro Hospitalar de São 2 Faculdade de Ciências da Saúde, Universidade da Beira Interior, João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal Covilhã, Portugal (e-mail: [email protected]). 3 Colposcopy and Laser Unit, Hospital da Luz, Lisboa, Portugal 4 Department of Gynecology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal

Rev Bras Ginecol Obstet 2017;39:415–423.

Abstract Objective To assess the medical doctors and medical students’ opinion regarding the evidence and ethical background of the performance of vulvovaginal aesthetic procedures (VVAPs). Methods Cross-sectional online survey among 664 Portuguese medical doctors and students. Results Most participants considered that there is never or there rarely is a medical reason to perform: vulvar whitening (85.9% [502/584]); hymenoplasty (72.0% [437/607]); mons pubis liposuction (71.6% [426/595]); “G-spot” augmentation (71.0% [409/576]); labia majora augmentation (66.3% [390/588]); labia minora augmentation (58.3% [326/559]); or laser vaginal tightening (52.3% [313/599]). Gynecologists and specialists were more likely to consider that there are no medical reasons to perform VVAPs; the opposite was true for plastic surgeons and students/residents. Hymenoplasty raised ethical doubts in 51.1% (283/554) of the participants. Plastic surgeons and students/residents were less likely to raise ethical objections, while the Keywords opposite was true for gynecologists and specialists. ► nymphoplasty Most considered that VVAPs could contribute to an improvement in self-esteem (92.3% ► hymenoplasty [613/664]); sexual function (78.5% [521/664]); vaginal atrophy (69.9% [464/664]); ► aesthetic surgery quality of life (66.3% [440/664]); and sexual pain (61.4% [408/664]). ► ethics Conclusions While medical doctors and students acknowledge the lack of evidence ﬁ ► vulvar surgery and scienti c support for the performance of VVAPs, most do not raise ethical ► laser objections about them, especially if they are students or plastic surgeons, or if they havehadorhaveconsideredhavingplasticsurgery.

received DOI https://doi.org/ Copyright © 2017 by Thieme Revinter January 4, 2017 10.1055/s-0037-1603967. Publicações Ltda, Rio de Janeiro, Brazil accepted ISSN 0100-7203. April 17, 2017 published online June 23, 2017 416 Survey on Aesthetic Vulvovaginal Procedures Vieira-Baptista et al.

Resumo Objetivos Avaliar a opinião de médicos e estudantes de medicina relativamente à evidência e contexto ético para a realização de procedimentos estéticos vulvovaginais (PEVVs). Métodos Estudo transversal, consistindo de inquérito online a 664 médicos e estudantes de medicina portugueses. Resultados A maioria dos participantes considerou que nunca ou raramente há uma razão médica para a realização de: branqueamento vulvar (85,9% [502/584]); himenoplastia (72,0% [437/607]); lipoaspiração do mons pubis (71,6% [426/595]); aumento do “ponto G” (71,0% [409/576]); aumento dos grandes lábios (66,3% [390/588]); aumento dos pequenos lábios (58,3% [326/559]) ou aperto vaginal com laser (52,3% [313/599]). Ser ginecologista e especialista associou-se a maior probabilidade de considerar não haver razões médicas para a realização de PEVV; o oposto foi verdade para os cirurgiões plásticos e estudantes/internos. A himenoplastia levantou dúvidas em termos éticos em 51,1% (283/554) dos participantes. Cirurgiões plásticos e estudantes/internos relataram menos dúvidas em termos éticos; o oposto foi verdade para os ginecologistas ou especialistas. Palavras Chave A maioria considerou que os PEVVs podem contribuir para uma melhoria na autoestima ► ninfoplastia (92,3% [613/664]); função sexual (78,5% [521/664]); atroﬁa vaginal (69,9% [464/664]); ► himenoplastia qualidade de vida (66,3% [440/664]); e dor sexual (61,4% [408/664]). ► cirurgia estética Conclusões Ainda que os médicos e estudantes de medicina reconheçam a falta de ► ética evidência e bases cientíﬁcas para a realização de PEVVs, a maioria não levanta ► cirurgia vulvar objecções em termos éticos, especialmente se forem estudantes, cirurgiões plásticos, ► laser ou se eles próprios tiverem sido submetidos a cirurgia plástica ou considerem vir a sê-lo.

Introduction although the autonomy principle is the most important, in this setting, the principle of non-maleficence must not be Vulvovaginal aesthetic procedures (VVAPs), also referred to as disregarded. “intimate surgery” or “female cosmetic genital surgery”,area Given the availability of VVAPs, the number of women trending topic in the media that has been poorly addressed in demanding it, and the lack of data, it is critically important to the medical literatureso far. Despitebeing available all over the know the clinicians’ perception, knowledge and personal world, these procedures are a marginal, gray area of medicine: opinion on this topic. This could help in the development of there is no coherent classification of the procedures, and there reasonable and fair guidelines, while providing information is an evident lack of good quality, long-term, randomized, for the public in general. independent studies.1 This lack of evidence has not restricted This study aimed at evaluating the opinions of medical the performance or advertisement of these procedures, which doctors and medical students on the existence of any medical is easier than ever before in this digital era, due to the inability justification or ethical concerns regarding the different avail- of other health professionals and/or medical societies to filter able VVAPs, as well as which factors might affect their opinion. the information available.2 It has been shown that these advertisements are mostly inaccurate, omit risks and compli- Methods cations, and exaggerate the potential benefits.2,3 There is also indirect pressure to perform these procedures, since the A cross sectional study was performed between September 01, pornographic industry and the media in general have created 2015 and February 28, 2016. The study was approved by the a new standard for the ideal “normal” vulva:4 hairless and with Ethical Committee of one of our institutions. The participants the labia minora totally hidden by the labia majora; anything were informed of the objectives of the study, and total con- that is different from this pre-pubertal model is now consid- fidentiality of the data was assured. Consent for participation ered unaesthetic, abnormal and, thus, eligible for correction or was declared prior to the questionnaire. The eligibility criteria perfection by the surgeon’s blade or laser. were: being a medical student at a Portuguese University, or Medical societies are slowly starting to take public positions being a medical doctor working in Portuguese territory. – and publish guidelines,5 8 and more of them are expected to do Due to the unavailability of validated scales, a web-based the same in the near future. In the absence of good scientific (https://docs.google.com/forms/, Mountain View, CA, USA) ques- evidence, it is difficult to assure the fulfillment of all medical tionnaire was specifically designed by the authors, following the ethical principles, which these guidelines must encompass: checklist for reporting results of internet surveys (CHERRIES)

Rev Bras Ginecol Obstet Vol. 39 No. 8/2017 Survey on Aesthetic Vulvovaginal Procedures Vieira-Baptista et al. 417 protocol.9 It consisted of 25 questions, divided into 3 sections. Results The first section was intended to characterize the demographics of the participants (age, district of residence), differentiation Questionnaires from 664 participants were obtained. Thelargest (student, resident or specialist), specialty, type of practice (public group of respondents were specialists (37.0% [246/664], and/or private), and if the participants themselves have had or followed by students (34.2% [227/664]) and residents (28.8% have considered having plastic surgery (yes/no). [191/664]). The age of the sample ranged from 18 to 69 years In the second section, the participants’ opinion about any (32.9 12.15 years old), and most participants were female medical justification for, and ethical objections against, (67.2% [442/664]). VVAPs was addressed. Given that there is currently no About one third had had or had considered having plastic coherent nomenclature for these procedures, they were surgery (29.7% [188/633]), and there were no differences re- explained and clarified whenever necessary. garding the stage of medical differentiation (specialists - 27.9% In this section of the questionnaire, the 3 or 4-point Likert [63/226] versus residents - 30.1% [57/189] versus students - scales were used. The participants were asked to answer 31.2% [68/218]; p ¼ 0.88). However, women were more likely to whether several VVAPs were medically justifiable, with the consider plastic surgery for themselves (34.1% [145/425] versus following answer options: “it is never justifiable,”“it is rarely 20.7% [43/208]). Additionally, plastic surgeons (residents or justifiable,”“it is sometimes justifiable,” or “it is frequently specialists) or students intending to be become plastic surgeons justifiable”). For the purpose of analysis, the first two options were nearly twice as likely to report this than gynecologists were considered as a single answer, and the same was done (50.0% [13/26] versus 26.7% [36/135], p ¼ 0.018]). with the last two. Most specialists work in private practice (exclusively or For the question of whether or not a procedure was ethical, not) (65.9% [162/246]). considering the scientific data available, the answer options The representation by specialties (students were divided included: “clearly against medical ethics,”“doubtful in terms according to the specialty they intend to choose) was: gyne- of medical ethics,” and “no medical ethical objections.” For the cology (25.4%; 155/611); plastic surgery (4.2%; 28/611); other purpose of analysis, the first two options were grouped and surgical specialty (14.2%; 94/611); and other non-surgical compared against “no medical ethical objections.” specialty (50.3%; 334/611). In the third section, the participants were questioned about More than half of the participants considered that there the possible benefits of VVAPs, and general statements and never or there rarely exists a medical reason to perform guidance on this topic were evaluated. A set of statements the following: vulvar whitening (85.9% [502/584]); hymeno- concerning practical issues regarding VVAPs (minimum age of plasty (72.0% [437/607]); liposuction of the mons pubis (71.6% performance, whether or not it should be performed in [426/595]); “G-spot” augmentation (71.0% [409/576]); aug- public hospitals, etc.) was evaluated using a 4-point Likert mentation of the labia majora (66.3% [390/588]); augmenta- scale with the following options: “totally agree,”“partially tion of the labia minora (58.3% [326/559]); and vaginal agree,”“neither agree nor disagree,” and “totally disagree.” tightening with laser (52.3% [313/599]). Laser treatment of Several potential benefits were presented, and the parti- vaginal atrophy and nymphoplasty were the procedures that cipants had to choose whether they agreed or not with the most participants considered as having a medical indication statements (yes/no). (77.2% [467/605] and 74.7% [430/576] respectively) (►Fig. 1). There was an option of “don’ t answer/don’tknow” in the The answers in this topic were independent of the fact second and third sections of the questionnaire, but not on the that the respondents worked in private practice or not, of if first one. they had had or had considered having plastic surgery The online survey was sent to the target population via themselves. Gender did not influence this opinion, except email (collected from the databases of medical societies), and in the case of liposuction of the mons pubis (female - 74.1% posted in the Web sites of medical societies and in specific [303/409] versus male - 66.1% [123/186]; p ¼ 0.046) and social network groups (exclusively for doctors/medical stu- vulvar whitening (female - 89.1% [351/394] versus male - dents). According to the number of sent emails and the number 79.5% [151/190]; p ¼ 0.002). Gynecologists were much more of members on the social network groups, it was estimated likely to consider that there is no medical reason to perform that the questionnaire reached around 4,000 potential parti- these procedures, while the opposite was true for plastic cipants. According to the estimated size of the population of surgeons. The answers of the group of other medical doctors and medical students, a sample of 382 would be specialties, which was considered as a whole, scored in- enough to achieve a confidence level of 95% and a confidence between. The grade of differentiation also had an influence interval of 5% (http://www.surveysystem.com/sscalc.htm, on the outcome, with specialists more likely to consider Sebastopol, CA, USA). there was an absence of medical justification for the proce- The statistical analysis was performed using the Microsoft dures, while students were more likely to consider the Excel 2011 software (Microsoft Corporation, Redmond, WA, opposite (►Table 1). USA) and the Statistical Package for the Social Sciences (SPSS) Only hymenoplasty raised ethical doubts in more than software, version 20.0 (IBM Corp., Armonk, NY, USA). The chi- half of the participants (51.1% [283/554]). A quarter or less squared test was used for the nominal variables, and the raised concerns about reduction of the labia majora (25.2% Student’s t-test for the continuous variables. A p < 0.05 was [138/547]), laser for the treatment of vaginal atrophy (20.7% considered statistically significant. [112/541]), and nymphoplasty (18.5% [95/514]) (►Fig. 2).

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Fig. 1 Participants’ opinion in terms of medical justiﬁcation for the performance of VVAPs.

The gender of the participants and the fact that they had had plastic surgery themselves were less likely to raise worked in private practice did not inﬂuence the opinion ethical concerns; the same was true for the residents, and about the ethical issues associated with these procedures. On even more so for the students (►Table 2). the contrary, specialty had an effect, since being a plastic Only 2.1% (14/664) of the participants considered that surgeon was associated with a lower likelihood of having there is never any beneﬁt from VVAPs. Most participants ethical objections, while being a gynecologist was associated considered that they could contribute to an improvement with the opposite. Those who had considered having or who in: self-esteem (92.3% [613/664]); sexual function (78.5%

Table 1 Percentage of participants who answered that a speciﬁc procedure did not or rarely had a medical indication

Gender Private practice Specialty %(n/N) %(n/N) %(n/N) Female Male p Yes No p ObGyn Plastic Other Other p surgery non-surgical surgical Vaginal laser 23.2% 21.9% 0.709 27.0% 30.0% 0.873 33.8% 4.2% 21.7% 17.6% 0.001 (atrophy) (96/413) (42/192) (38/141) (23/76) (50/148) (1/24) (65/300) (15/85) Nymphoplasty 25.3% 25.3% 0.941 32.6% 31.5% 1.000 30.9% 0.0% 24.5% 26.2% 0.009 (reduction) (47/184) (99/392) (44/135) (23/73) (47/152) (0/26) (68/278) (21/80) Reduction of the 38.8% 35.1% 0.374 52.7% 48,1% 0.508 59.2% 16.7% 31.2% 36.5% < 0.001 labia majora (161/415) (68/194) (78/148) (37/77) (90/152) (4/24) (95/304) (31/85) Clitoral hood 43.1% 37.1% 0.164 53.4% 54.1% 0.924 61.7% 20,0% 35.6% 38.6% < 0.001 surgery (172/399) (72/194) (79/148) (40/74) (92/149) (5/25) (104/292) (32/83) Clitoral surgery 44.1% 45.2% 0.806 59.9% 62.0% 0.765 65.8% 25% 38.1% 41.2% < 0.001 (173/392) (85/182) (88/147) (44/71) (96/146) (6/24) (107/281) (35/85) Vaginal 50.0% 42.9% 0.099 42.3% 48.1% 0.408 55.8% 30.8% 45.2% 44.6% 0.043 rejuvenation (208/416) (84/196) (63/149) (37/77) (86/154) (8/26) (137/303) (37/83) Laser (tightening) 54.6% 47.1% 0.086 54.0% 54.5% 0.934 63.3% 40.0% 48.0% 50.0% 0.012 (224/410) (89/189) (75/139) (42/77) (93/147) (10/25) (144/300) (40/80) Nymphoplasty 59.3% 56.4% 0.514 66.4% 67.6% 0.864 74.7% 56.0% 55.0% 46.2% < 0.001 (augmentation) (224/378) (102/181) (89/134) (48/71) (109/146) (14/25) (149/271) (36/78) Augmentation of 65.7% 67.7% 0.621 70.3% 73.3% 0.642 78.9% 60.9% 62.3% 65.1% 0.005 the labia majora (262/399) (128/189) (102/145) (55/75) (116/147)) (14/23) (182/292) (54/83) “G-spot” 71.8% 69.3% 0.538 84.2% 77.1% 0.215 86.4% 56.0% 69.0% 61.4% < 0.001 augmentation (285/397) (124/179) (112/133) (54/70) (121/140) (14/25) (196/284) (51/83) Liposuction 74.1% 66.1% 0.046 75.0% 77.9% 0.629 83.8% 56.0% 71.1% 72.3% 0.001 (303/409) (123/186) (105/140) (60/77) (119/142) (14/25) (212/298) (52/84) Hymenoplasty 73.9% 68.0% 0.131 73.6% 83.3% 0.100 75.8% 57.7% 74.3% 70.4% 0.238 (303/410) (134/197) (109/148) (65/78) (113/149) (15/26) (225/303) (57/81) Whitening 89.1% 79.5% 0.002 83.9% 92.0% 0.095 91.0% 76.0% 86.9% 79.3% 0.036 (351/394) (151/190) (120/143) (69/75) (132/145) (19/25) (252/290) (65/82)

(continues)

Rev Bras Ginecol Obstet Vol. 39 No. 8/2017 Survey on Aesthetic Vulvovaginal Procedures Vieira-Baptista et al. 419

Table 1 Percentage of participants who answered that a speciﬁc procedure did not or rarely had a medical indication (continuation)

Considering/had Differentiation plastic surgery %(n/N) %(n/N) Yes No p Student Resident Specialist p Vaginal laser 24.6% 22.8% 0.635 15.8% 24.6% 28.1% 0.008 (atrophy) (43/175) (91/400) (33/209) (44/179) (61/217) Nymphoplasty 27.7% 26.6% 0.674 15.7% 28.1% 32.2% < 0.001 (reduction) (46/166) (99/381) (31/197) (48/171) (67/208) Reduction of the 38,2% 37.9% 0.940 23.8% 36.3% 51.1% < 0.001 labia majora (68/178) (153/404) (48/202) (66/182) (115/225) Clitoral hood surgery 39.3% 43.1% 0.398 27.8% 40.1% 53.6% < 0.001 (68/173) (169/392) (54/194) (71/177) (119/222) Clitoral surgery 39.1% 47.6% 0.061 27.7% 42.7% 60.6% < 0.001 (68/174) (180/378) (53/191) (73/171) (132/218) Vaginal rejuvenation 46.3% 49.4% 0.497 45.1% 55.0% 44.2% 0.065 (82/177) (200/405) (93/206) (99/180) (100/226) Laser (tightening) 51.4% 54.0% 0.568 45.6% 57.6% 54.2% 0.050 (89/173) (214/396) (94/206) (102/177) (117/216) Nymphoplasty 61.3% 58.9% 0.608 45.0% 63.0% 66.8% < 0.001 (augmentation) (98/160) (219/372) (85/189) (104/165) (137/205) Augmentation of 66.1% 68.3% 0.607 56.8% 70.5% 71.4% 0.003 the labia majora (113/171) (267/391) (109/192) (124/176) (157/220) “G-spot” augmentation 66.5% 72.6% 0.143 60.8% 70.1% 81.8% < 0.001 (115/173) (278/383) (121/199) (122/174) (166/203) Liposuction 69.5% 73.0% 0.381 62.9% 76.1% 76.0% 0.003 (123/177) (290/397) (127/202) (134/176) (165/217) Hymenoplasty 74.2% 72.3% 0.646 64.9% 73.7% 77.0% 0.017 (132/178) (290/401) (131/202) (132/179) (174/226) Whitening 84.9% 88.3% 0.267 81.8% 89.7% 86.7% 0.088 (146/172) (339 (157/192) (156/174) (189/218)

Abbreviation: ObGyn, Gynaecologists/Obstetricians. Note: Includes only specialists.

[521/664]); vaginal atrophy (69.9% [464/664]); quality of life possible benefits of these procedures, and the differences (66.3% [440/664]); and sexual pain (61.4% [408/664]). There were statistically significant regarding the improvements in: were no differences when the stratification for gender was sexual function (92.9% [26/28] versus 65.2% [101/155]; performed (data not shown). Plastic surgeons, when com- p ¼ 0.003); quality of life (85.7% [24/28] versus 52.3% pared with gynecologists, were more likely to consider the [81/155]; p ¼ 0.001]); sexual pain (78.6% [22/28] versus

Fig. 2 Participants’ opinion in terms of ethical objections for the performance of VVAPs.

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Table 2 Percentage of participants who considered that there may be ethical issues concerning the performance of speciﬁc vulvovaginal aesthetic procedures

Gender Private practice Specialty %(n/N) %(n/N) %(n/N)

Female Male p Yes No P ObGyn Plastic Other Other p surgery non-surgical surgical

Nymphoplasty 16.9% 21.6% 0.193 20.6% 22.7% 0.742 21.3% 8.7% 17.1% 19.2% 0.468 (reduction) (58/343) (37/171) (13/63) (30/132) (30/141) (2/21) (41/240) (15/78)

Vaginal laser 19.9% 22.3% 0.530 26.6% 23.1% 0.589 29.6% 8.3% 17.0% 22.0% 0.011 (atrophy) (73/366) (39/175) (37/139) (15/65) (40/135) (2/24) (45/265) (18/82)

Reduction of the 25.0% 25.7% 0.862 33.8% 29.9% 0.569 41.3% 12.5% 19.1% 25.0% < 0.001 labia majora (91/364) (47/183) (48/142) (20/67) (59/143) (3/24) (51/267) (20/80)

Clitoral hood surgery 33.5% 29.0% 0.283 43.3% 39.7% 0.632 48.2% 17.4% 26.8% 28.9% < 0.001 (119/355) (53/183) (61/141) (25/63) (66/137) (4/23) (70/261) (24/83)

Laser (tightening) 33.9% 30.7% 0.458 40.3% 38.7% 0.833 49.3% 12.5% 27.6% 31.3% < 0.001 (121/357) (54/176) (56/139) (24/62) (66/134) (3/24) (71/257) (26/83))

Vaginal rejuvenation 34.0% 31.3% 0.504 38.0% 31.2% 0.348 44.9% 16.7% 28.6% 32.9% 0.003 (123/362) (56/180) (54/142) (20/64) (62/138) (4/24) (74/259) (28/85)

Liposuction 34.5% 32.6% 0.666 43.8% 44.8% 0.901 54.3% 16.7% 29.6% 24.1% < 0.001 (123/357) (56/172) (57/130) (30/67) (69/127) (4/24) (77/260) (20/83)

Clitoral surgery 35.0% 32.6% 0.587 45.3% 41.9% 0.655 51.5% 13.6% 29.5% 28.4% < 0.001 (122/349) (58/178) (63/139) (26/62) (70/136) (3/22) (75/254) (23/81)

Nymphoplasty 35.1% 37.8% 0.550 50.4% 46.0% 0.570 54.7% 18.2% 28.7% 36.7% < 0.001 (augmentation) (119/339) (65/172) (66/131) (29/63) (76/139) (4/22) (69/240) (29/79)

Augmentation of 37.1% 36.0% 0.800 47.5% 50.0% 0.739 56.5% 17.4% 29.3% 37.0% < 0.001 the labia majora (132/356) (64/178) (66/139) (32/64) (78/138) (4/23) (76/259) (30/81)

Whitening 43.5% 41.7% 0.685 52.9% 55.4% 0.740 57.8% 26.1% 39.4% 41.0% 0.001 (154/354) (75/180) (73/138) (36/65) (78/135) (6/23) (102/259) (34/83)

“G-spot” 45.4% 42.0% 0.460 59.2% 52.3% 0.357 68.0% 30.4% 36.9% 42.9% < 0.001 augmentation (164/361) (71/169) (77/130) (34/65) (87/128) (7/23) (96/260) (36/84)

Hymenoplasty 53.7% 45.9% 0.087 58.5% 62.7% 0.560 65.0% 37.5% 48.5% 48.1% 0.004 (198/369) (85/185) (83/142) (42/67) (91/140) (9/24) (132/272) (39/81)

Considering/had plastic surgery Differentiation %(n/N) %(n/N)

Yes No p Student Resident Specialist p

Nymphoplasty (reduction) 16.4% 20.5% 0.289 15.1% 17.7% 22.1% 0.223 (25/152) (69/336) (26/172) (26/147) (43/195)

Vaginal laser (atrophy) 15.2% 23.0% 0.042 16.5% 19.4% 25.5% 0.082 (25/164) (81/352) (30/182) (30/155) (52/204)

Reduction of the labia majora 19.1% 28.1% 0.029 19.6% 22.0% 32.5% 0.007 (31/162) (101/359) (35/179) (35/179) (68/209)

Clitoral hood surgery 25.8% 34.4% 0.051 24.6% 27.1% 42.2% < 0.001 (42/121) (120/329) (44/179) (42/155) (86/204)

Laser (tightening) 27.3% 35.7% 0.061 24.7% 33.3% 39.8% 0.007 (44/161) (124/347) (45/182) (50/150) (80/201)

Vaginal rejuvenation 26.7% 35.8% 0.042 29.2% 33.8% 35.9% 0.359 (43/161) (127/355) (54/185) (51/151) (74/206)

Liposuction 25.3% 37.1% 0.008 27.5% 28.0% 44.2% 0.001 (41/162) (130/350) (50/182) (42/150) (87/197)

Clitoral surgery 25.8% 37.7% 0.009 25.7% 30.5% 44.3% < 0.001 (41/159) (129/342) (45/175) (46/151) (89/201)

Nymphoplasty (augmentation) 30.9% 39.0% 0.087 27.1% 29.3% 49.0% < 0.001 (46/149) (131/336) (46/170) (43/147) (95/194)

Augmentation of the labia majora 28.9% 40.7% 0.011 29.9% 29.2% 48.3% < 0.001 (46/159) (142/349) (53/177) (45/154) (98/203)

Whitening 33.5% 47.6% 0.003 34.5% 38.3% 53.7% < 0.001 (54/161) (166/349) (61/177) (59/154) (109/203)

“G-spot” augmentation 35.2% 47.7% 0.007 34.1% 40.5% 56.9% < 0.001 (58/165) (166/348) (62/182) (62/153) (111/195)

Hymenoplasty 47.9% 52,9% 0.284 42.7% 49.4% 59.8% 0.003 (81/169) (190/359) (79/185) (79/160) (125/209)

Abbreviation: ObGyn, Gynaecologists/Obstetricians.

Rev Bras Ginecol Obstet Vol. 39 No. 8/2017 Survey on Aesthetic Vulvovaginal Procedures Vieira-Baptista et al. 421

Fig. 3 Percentage of participants who considered that aesthetic procedures can have a positive impact in several questions (total includes all participants).

36.8% [57/155], p ¼ 0.000); and urinary incontinence (42.9% medical justification or ethical concerns about the perfor- [12/28] versus 23.2%, p ¼ 0.030) (►Fig. 3). mance of VVAPs. The secondary outcomes included the Most participants disagreed that VVAPs fit into the World determining factors that influenced their answers, and which Health Organization’s (WHO) definition of female genital potential impacts the participants considered these proce- mutilation (51.4% [341/664]). The majority agreed, at least dures can have. partially, that: these procedures should not be performed in For most VVAPs, more than half of the participants con- patients under the age of 18 years old (582/664 [87.6%]); they sidered that there is never or there rarely is any medical should be considered in the same way as surgery at any other justification to perform the procedures. Despite this common anatomical site (568/664 [85.5%]); all women should be opinion, the percentage of participants who considered VVAPs evaluated by a psychiatrist/sexologist prior to surgery to be unethical was much lower, and most even considered (552/664 [83.1%]); if performed, these surgeries should that VVAPs could have a positive impact in terms of self- take place in public hospitals (381/664 [57.3%]); advertising esteem, sexual function, vaginal atrophy, quality of life, and them should be forbidden (339/664 [51.0%]) (►Fig. 4). sexual pain. Vulvar whitening was considered the procedure with the Discussion least scientific background supporting its performance. It is frequently performed along with anal whitening,1,10 and is not The primary objective of this study was to evaluate the opinion exempt from complications. It was followed by hymenoplasty, of medical students and doctors on the existence of any liposuction of the mons pubis, “G-spot” augmentation,

Fig. 4 Participants’ agreement with several questions concerning VVAPs.

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augmentation of the labia majora, augmentation of the labia complications, outcomes, etc.). It is generally assumed minora, and the use of laser for vaginal tightening. The existence that the risk associated with most procedures is low (non- of the “G-spot” itself is debatable, and all procedures aiming at maleficence principle), and that they can have some benefits its augmentation, despite being offered by some providers, are (beneficence principle). However, the few studies in this area considered useless and unethical – just like laser vaginal do not support the idea that the risk is low enough to – tightening.5,11,12 Hymenoplasty was suggested by Reziciner overcome the non-maleficence principle.10,23 25 It must be as a way to prevent recurrent post-coital cystitis,13 but without kept in mind that the beneficence principle is secondary to any scientific support to recommend it. Although there is never the autonomy one, but the perceptions of the benefits may any medical indication to perform it, it has been life-saving for not be real, and there are no long-term satisfaction studies.22 some Muslim girls, and this highlights how important relative Almost all participants stated that the performance of ethical issues can be in different communities.14 Liposuction VVAPs can have advantages. Systematically, gynecologists can be considered after significant weight loss.15 Augmentation considered VVAPs less likely to have benefits than plastic of the labia majora and minora is often offered as an aesthetic surgeons. It is relevant to state that 61% of all participants procedurefor aging women – especially with the use of fillers or (79% of plastic surgeons and 37% of gynecologists) consid- autologous fat; despite the absence of studies, it can be con- ered that some of these procedures can treat sexual pain. We sidered in very special cases (marked loss of weight, neoplasia, highlight the dangers of the performance of VVAPs without a hidradenitis suppurative, antiretroviral use).15,16 previous evaluation by a gynecologist to exclude vulvar and/ On the contrary, only a quarter or less of the respondents or pelvic floor diseases. It is not uncommon to encounter in considered that there is no scientific evidence for the use of the clinical practice women with vulvodynia attributing laser for thetreatmentof vaginal atrophyand for nymphoplasty. their symptoms to the size of their labia minora. Failure to Despite the wide commercialization and use of laser for the recognize lichen sclerosus can lead to unexpected results, as treatment of vaginal atrophy,17 there have been no randomized, the disease tends to manifest in the scars (isomorphism). case control studies published. The long-term effects and safety More than 80% of the participants agreed that VVAPs should have not been demonstrated so far. Nymphoplasty is probably not be performed in patients under the age of 18 years old. Full the most performed VVAP, and the one with most published genital growth and development is not achieved before that papers. However, there is still no definition of labial hypertro- age, so VVAPs should never be performed in adolescents – phy,18 20 no studies comparing surgery and non-intervention, (patients with genital malformations are special cases that as well as no data about the long-term satisfaction or late should be evaluated by adolescent gynecology experts).6,7,26 complications (scar retraction in menopause, for example). The claim that VVAPs are not different from procedures in Despite the heterogeneity of the sample, there was a good other anatomical regions was also accepted by the majority of correlation between the opinion of the participants and the participants. Therefore, the ethical concern threshold must be evidence or lack thereof in the literature. However, some raised to the same level as other procedures (breast augmen- factors influenced the opinion of the participants, namely tation, rhinoplasty, etc.). However, the vulva is a part of the the specialty and the degree of differentiation, as plastic body that is not directly exposed; therefore, many women do surgeons and students were more likely to consider that not know the normal range of anatomical variation. In reality, there were medical indications for the procedures. On the most women seeking surgery are anatomically normal.27 other hand, gynecologists were more likely to raise doubts The need for previous evaluation by a sexologist/psychia- about medical indications. Gender, not having a private trist was acknowledged by nearly 75% of the participants. Body practice, and having had or considering having plastic sur- dysmorphic disorder is quite rare in the population in general, gery did not play a significant role in the opinions. The but is very common in women seeking plastic surgery.28 These general overview changed when they were questioned if patients are likely to be dissatisfied with their surgical out- the performance of such procedures was unethical or not: come and go on to have repeated procedures.29 more than half of the subjects only raised ethical issues about In Portugal, most VVAPs are performed in private settings, hymenoplasty. Concerning the medical justification, despite without insurance coverage. This clearly does not fit thejustice minor variations in the order, the results were fairly similar principle, as not everyone can have access to undergo these to those obtained previously. Unlike what was found in the procedures. More than half of the respondents considered that previous question, the participants who had had or had these procedures should be performed in public hospitals, considered having plastic surgery (nearly one third of where there is a finer triage of the patients and thorough them) were less likely to raise ethical questions about the psychiatric and gynecologic evaluations are performed. procedures. While personal beliefs did not seem to affect the Only 41% of participants agreed with the statement that opinion in terms of the medical reason for the procedures, advertising puts pressure in women;22 however some med- they had an effect when the ethics question was asked. This ical societies have already recommended against it.8 shows the importance and relativity of one of the four ethical The WHO has defined female genital mutilation as “all principles, the principle of autonomy:21,22 the participants procedures involving partial or total removal of the external state that there is no medical reason for the performance of female genitalia, or other injury tothefemale genital organs for the procedures, but respect one’s right to undergo them. non-medical reasons”.30 Given that there is no medical reason However, the autonomy principle implies informed consent, to perform most of the discussed procedures, they can be and it cannot exist in the absence of scientific data (about included in this definition31–with serious legal implications in

Rev Bras Ginecol Obstet Vol. 39 No. 8/2017 Survey on Aesthetic Vulvovaginal Procedures Vieira-Baptista et al. 423 most countries. Although only one third of the respondents Available from: https://sogc.org/wp-content/uploads/2013/09/ agreed with this statement, this highlights the need for clear December2013-CPG300-ENG-Online_final.pdf definitions and guidelines for the procedures, for the protec- 9 Eysenbach G. Improving the quality of Web surveys: the Checklist for Reporting Results of Internet E-Surveys (CHERRIES). J Med tion of both the patients and doctors involved in them. Internet Res 2004;6(03):e34 The weak points of the present study include the fact that 10 Cihantimur B, Herold C. Genital beautification: a concept that there may have been several biases in the participants’ enrol- offers more than reduction of the labia minora. Aesthetic Plast ment: those interested in the subject and the younger ones Surg 2013;37(06):1128–1133 (who are more likely to use the internet) may have been more 11 Puppo V, Gruenwald I. Does the G-spot exist? A review of the prone to answer – as shown by the fact that the distribution of current literature. Int Urogynecol J Pelvic Floor Dysfunct 2012; 23(12):1665–1669 the answers was balanced between the different grades of 12 Kilchevsky A,VardiY,LowensteinL,GruenwaldI. Is thefemaleG-spot differentiation, despite the fact that medical doctors comprise truly a distinct anatomic entity? J Sex Med 2012;9(03):719–726 the largest group. The lack of validated scores to evaluate one’s 13 Reziciner S. [Prevention of recurrent post-coital cystitis using opinion/attitudes toward these procedures can make it more hymenoplasty]. Ann Urol (Paris) 1988;22(06):446–451 French difficult for future comparisons. 14 Ahmadi A. Ethical issues in hymenoplasty: views from Tehran’s physicians. J Med Ethics 2014;40(06):429–430 Medical doctors and medical students acknowledge thelack 15 Alter GJ. Management of the mons pubis and labia majora in the fi of scienti c support for the performance of VVAPs. However, massive weight loss patient. Aesthet Surg J 2009;29(05):432–442 most of them do not raise ethical objections for their perfor- 16 Lapalorcia LM, Podda S, Campiglio G, Cordellini M. Labia majora mance, especially if they are less specialized, are plastic labioplasty in HIV-related vaginal lipodystrophy: technique descrip- surgeons, or have themselves had or considered having plastic tionand literature review. Aesthetic Plast Surg 2013;37(04):711–714 fi surgery. This, in part, may be due to an assumed potential 17 Sokol ER, Karram MM. An assessment of the safety and ef cacy of a fractional CO2 laser system for the treatment of vulvovaginal benefit, despite the inexistence of reliable clinical data. atrophy. Menopause 2016;23(10):1102–1107 18 Goodman MP. Female genital cosmetic and plastic surgery: a review. J Sex Med 2011;8(06):1813–1825 Acknowledgments 19 Ostrzenski A. Selecting aesthetic gynecologic procedures for The authors would like to thank to Sociedade Portuguesa plastic surgeons: a review of target methodology. Aesthetic Plast – de Ginecologia (Portuguese Society of Gynecology), and Surg 2013;37(02):256 265 20 Radman HM. Hypertrophy of the labia minora. Obstet Gynecol Mr. Peter Greenhouse, FRCOG, from Bristol, UK, for his 1976;48(1, Suppl)78S–79S assistance with the text. The authors have received no 21 Gillon R. Medical ethics: four principles plus attention to scope. funding for the preparation or writing of this paper. BMJ 1994;309(6948):184–188 22 Goldstein AT, Jutrzonka SL. Ethical considerations of female genital plastic/cosmetic surgery. In: Goodman MP, editor. Female genital plastic and cosmetic surgery. Hoboken: John Wiley & References Sons; 2016. p. 39–44 “ ” 1 Vieira-Baptista P, Lima-Silva J, Beires J. Intimate surgery :whatis 23 Alter GJ. Aesthetic labia minora and clitoral hood reduction using done and under which scientif basis? Acta Obstet Ginecol Port. extended central wedge resection. Plast Reconstr Surg 2008; 2015;9(05):393–399 122(06):1780–1789 2 Liao LM, Taghinejadi N, Creighton SM. An analysis of the content 24 Rouzier R, Louis-Sylvestre C, Paniel BJ, Haddad B. Hypertrophy of and clinical implications of online advertisements for female labia minora: experience with 163 reductions. Am J Obstet genital cosmetic surgery. BMJ Open 2012;2(06):e001908 Gynecol 2000;182(1 Pt 1):35–40 “ ”– 3 Vieira-Baptista P. Cirurgia íntima tempo de impor limites. Acta 25 Goodman MP, Placik OJ, Benson RH III, et al. A large multicenter Obstet Ginecol Port. 2014;8(03):223–225 outcome study of female genital plastic surgery. J Sex Med 2010; 4 Sharp G, Tiggemann M, Mattiske J. Factors that influence the 7(4 Pt 1):1565–1577 decision to undergo labiaplasty: media, relationships, and psy- 26 Lloyd J, Crouch NS, Minto CL, Liao LM, Creighton SM. Female genital chological well-being. Aesthet Surg J 2016;36(04):469–478 appearance: “normality” unfolds. BJOG 2005;112(05):643–646 5 Committee on Gynecologic Practice, American College of Obste- 27 McDougall LJ. Towards a clean slit: how medicine and notions of tricians and Gynecologists. ACOG Committee Opinion No. 378: normality are shaping female genital aesthetics. Cult Health Sex Vaginal “rejuvenation” and cosmetic vaginal procedures. Obstet 2013;15(07):774–787 – Gynecol 2007;110(03):737 738 28 Tadisina KK, Chopra K, Singh DP. Body dysmorphic disorder in 6 Female genital cosmetic surgery: a resource for general practi- plastic surgery. Eplasty 2013;13:ic48 tioners and other health professionals. Melbourne: The Royal 29 Likes WM, Sideri M, Haefner H, Cunningham P, Albani F. Aesthetic Australian College of General Practitioners; 2015 practice of labial reduction. J Low Genit Tract Dis 2008;12(03): 7 British Society for Paediatric & Adolescent Gynaecology [Inter- 210–216 net]. Position Statement: labial reduction surgery (Labiaplasty) 30 World Health Organization [Internet]. Eliminating female genital on adolescents. 2013 [cited 2016 Dec 10]. Available from: http:// mutilation: an interagency statement: UNAIDS, UNDP, UNECA, www.britspag.org/sites/default/files/downloads/Labiaplasty% UNESCO, UNFPA, UNHCHR, UNHCR, UNICEF, UNIFEM, WHO. Gene- 20%20final%20Position%20Statement.pdf vaWHO2008 [cited 2014 Aug 29]. Available from: http://apps.who. 8 Society of Obstetricians and Gynaecologists of Canada. Female int/iris/bitstream/10665/43839/1/9789241596442_eng.pdf genital cosmetic surgery: SOGC Policy Statement, 300. J Obstet 31 Conroy RM. Female genital mutilation: whose problem, whose Gynaecol Can [Internet]. 2013 [cited 2016 Feb 12];35(12):e1-e5. solution? BMJ 2006;333(7559):106–107

Rev Bras Ginecol Obstet Vol. 39 No. 8/2017 THIEME 424 Review Article

Physical Activity during Pregnancy: Recommendations and Assessment Tools Atividade física durante a gestação: recomendações e ferramentas de avaliação

Cibele Santini de Oliveira1 Thiago dos Santos Imakawa2 Elaine Christine Dantas Moisés1

1 Department of Gynecology and Obstetrics, Faculty of Medicine of Address for correspondence Elaine Christine Dantas Moisés, Ribeir Ribeirão ao Preto, Universidade de São Paulo, Ribeirão Preto, MD, PhD, Departamento de Ginecologia e Obstetrícia do Hospital das SP, Brazil Clínicas - 8° andar, Faculdade de Medicina de Ribeirão Preto, 2 Faculty of Medicine of Ribeirão Preto, Universidade de São Paulo, Universidade de São Paulo, Av Bandeirantes 3900 - Campus da USP, Ribeirão Preto, SP, Brazil 14049-900 - Ribeirão Preto, SP, Brazil (e-mail: [email protected]). Rev Bras Ginecol Obstet 2017;39:424–432.

Abstract The literature that supports and recommends the practice of exercise during pregnancy is extensive.However, although a more complete research on ways to evaluate the physical activity performed by pregnant women has been perfomed, it is found that there is no gold standard and that the articles in the area are inconclusive. Thus, the objective of the present article is to review relevant aspects, such as, technique and applicability of the different Keywords methods for the assessment of physical activity during pregnancy to provide more reliable ► physical exercise and safe information for health professionals to encourage their pregnant patients to questionnaire engage in the practice of physical activity. This review concluded that all tools for the ► physical activity analysis of physical activity have limitations. Thus, it is necessary to establish the objectives ► evaluation of evaluation in an appropriate manner, as well as to determine their viability and cost- ► pregnancy effectiveness for the population under study.

Resumo A literatura que apoia e recomenda a prática do exercício durante a gravidez é extensa. Apesar disso, embora tenha sido feita uma pesquisa mais completa sobre as formas de avaliar a atividade física realizada por mulheres grávidas, verifica-se que não há padrão ouro, e que os artigos na área são inconclusivos. Assim, o objetivo do presente artigo é revisar aspectos relevantes, como a técnica e a aplicabilidade dos diferentes métodos Palavras-chave de avaliação da atividade física durante a gestação, a fim de fornecer aos profissionais ► questionário de de saúde informações mais confiáveis e seguras para encorajar as pacientes grávidas à exercício físico prática de atividade física. Esta revisão concluiu que todas as ferramentas para a análise ► atividade física da atividade física têm limitações. Assim, é necessário estabelecer os objetivos da ► avaliação avaliação de forma adequada, bem como determinar a sua viabilidade e custo- ► gravidez efetividade para a população em estudo.

received DOI https://doi.org/ Copyright © 2017 by Thieme Revinter December 4, 2016 10.1055/s-0037-1604180. Publicações Ltda, Rio de Janeiro, Brazil accepted ISSN 0100-7203. May 4, 2017 Physical Activity during Pregnancy: Recommendations and Assessment Tools Oliveira et al. 425

Introduction tages are improved pulmonary function with an increase in peak flow, reduction of the anaerobic threshold and, improved 10 The benefits of physical exercise during pregnancy for both oxygen uptake (O2); reduced risk of developing gestational mother and fetus have been reported in the literature.1,2 diabetes due to the increase in insulin affinity for its cell However, a reduction of physical activity is frequently ob- receptor with a consequent decrease in insulin resistance;11 served during this period in the life of a woman, motivated by a lower risk of developing gestational hypertension and pre- both popular beliefs in the contraindication of its practice eclampsia;1,12 a lower weight gain and a reduced risk of and by the interference of factors such as age, ethnicity, obesity;13 improved muscle conditioning due to both strength schooling and socioeconomic level.3,4 gain and improved flexibility;2 increased sensation of well- This review will describe the main tools available to assess being; reduction of anxiety; improved self-esteem; reduced the level of physical activity for pregnant women and thus, it risk of depression;13 improved quality of sleep, greater dispo- can contribute to greater confidence of health professionals sition throughout the day, increased motivation to exercise; in recommending the practice of physical activity to their improvement of physical discomfort that may occur during patients. pregnancy; prevention and reduction of low back pain; reduction of edema in the extremities.2 In addition, there are reports Background Considerations of an equilibrated increase in fetal growth,14 a reduced dura- Some concepts need to be established for an appropriate tion of labor, a lower necessity of cesarean delivery, a lower understanding of the physiological and pathophysiological incidence of obstetrical complications,15 a lower risk of pre- basis of the use of parameters for the assessment of physical term delivery,3 and a lower risk of neonatal complications.13 activity during pregnancy, as indicated below. Risks and Contraindications • Physical activity can be defined as any body movement As postulated by the American College of Gynecology and produced by the contraction of skeletal muscles.5 Obstetrics, the National Institute for Health and Care Excel- • Physical exercise is defined as physical activity consisting lence and the Canadian Society of Gynecology and Obstetrics, of the execution of planned, structured and repetitive the risks of practicing moderate physical activity during body movements with the objective of improving physical pregnancy are minimal, involving neither maternal injuries, fitness.5 nor fetal growth or development. In addition, exercise does • Sport can be defined as “an institutionalized competitive not interfere with lactation when practiced during the activity involving vigorous physical effort or the use of puerperal period.8,16 Thus, sedentary pregnant women relatively complex motor skills.”6 with no gestational complications should be encouraged to Types practice physical activity to maintain a healthy life.16 Several types of physical exercises can be practiced by Starting from the second trimester of pregnancy, some pregnant women, although, in general, they are divided precautions should be taken during the practice of physical into three major categories: aerobic exercises aiming at activity. It is recommended to avoid the supine position gaining strength and involving more expressive cardiovas- during the exercises, since it may cause difficulties in venous cular adaptations, resistance exercises mainly performed to return with a consequent decrease of cardiac output and an obtain muscle hypertrophy and strength, and stretching increased risk of orthostatic hypotension.8 exercises that cause an increased muscle fiber size, thus The situations that can determine the discontinuation of improving flexibility.2 Within aerobic exercises, bicycle physical activity are vaginal bleeding, resting dyspnea, diz- ergometer pedaling, swimming, dancing, using an arm ziness, headache, precordial pain, calf swelling, and muscle ergometer, walking, and climbing stairs are the modalities weakness affecting equilibrium.8 more commonly practiced during pregnancy. Regarding Contraindications considered to be relative are: severe resistance exercises, resistance can be offered with weights, anemia, maternal cardiac arrhythmia that is not monitored, elastic tapes, springs, or manual resistance.7 heart disease with hemodynamic repercussions, asthma, restrictive lung disease, decompensated type 1 diabetes, morbid Benefits obesity, severe malnutrition (BMI below 12 kg/m2), an In general, regular exercise has been shown to improve extremely sedentary lifestyle, intrauterine growth restriction, conditioning, to reduce the muscle skeletal complaints ha- orthopedic limitation, severe smoking, and uncontrolled bitually related to pregnancy, to provide well-being, to hypothyroidism, nephropathy, unconscious hypoglycemia, improve body image, and to reduce maternal weight gain. and neuropathic dysautonomia.8,17,18 In addition, regular physical activity during pregnancy im- There are also obstetric situations that are considered proves or maintains physical conditioning, helps control absolute contraindication of physical exercise such as: isth- weight gain and provides psychological well-being.8 mocervical incompetence, cerclage, multiple gestation preg- Depending on its type, frequency and intensity, the practice nancy with risk of preterm delivery, persistent bleeding in of physical exercise during pregnancy can also improve the second and third trimesters, placenta previa before cardiovascular function by reducing heart rate and blood 26 weeks of gestational age, preterm labor during the current pressure, even with increased volume and cardiac output pregnancy, premature chorioamniorhexis and, hypertensive both during rest and during exercise itself.9 Additional advan- syndromes of pregnancy.8,18

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Recommendations about the Practice of Physical conceptional, gestational and puerperal periods, permitting Activity during Pregnancy data collection in large samples by means of this tool. Most women benefit from the practice of physical activity, For these reasons, most of the studies designed to identify with few risks when practicing it during the various phases of the predictors of participation in physical activities during life. During a gravidic cycle of habitual risk, that is, not pregnancy are based on self-reported assessment. Since associated with clinical or obstetrical complications, women these studies are used to elaborate interventions that can should be stimulated to pratice aerobic and muscle strength- be planned to increase physical activity during or before ening exercises. A complete clinical evaluation is necessary pregnancy, it is fundamental that the conclusions reached be for the recommendation of a program of physical exercises valid and reliable.23 and its implementation to guarantee that the patient does The disadvantages of questionnaires are that they involve not present any contraindications.8 subjective measures of low reliability since they may over- Current recommendations regarding the practice of physi- estimate the levels of physical activity compared with objec- cal activity are based on the norms of the American College of tive measures such as those obtained with an accelerometer Sports Medicine, which state that physical activity should be or pedometer.24,25 performed for at least 30 minutes daily at moderate intensity, The adoption of the system elaborated by Sternfeld and preferably 5 times a week or for a total of 150 minutes per Goldman-Rosas (2012),26 consisting of the 10 questions week, avoiding more than 2 consecutive days without physical listed below, can be of help in the choice of the instrument activity.17,19,20 It is also indicated the combination of aerobic for the assessment of physical activity that best satisfies the physical activity with resistance physical activity, at least objectives of the examiner: what is the primary objective of twice a week, with the execution of at least five exercises the study or program?; what is the design of the study?; what involving large muscle groups in each session.20 are the hypotheses of the study?; what is the physical activity During a pregnancy considered to be of habitual risk, the or sedentary behavior to be measured?; which domains of activities listed here are considered to be safe for initiation or physical activity need to be measured?; which parameters of continuation, with the need of adaptation in some modalities physical activity or sedentary behavior need to be assessed?; due to the physiological changes occurring during this period should nonspecific physical activities be assessed or can they and to the fetal necessities: walking, swimming, stationary be categorized?; what is the summary measure desired of bike, aerobic activities of low impact, modified yoga and physical activity or sedentary behavior?; which is the target pilates (avoiding positions that result in decreased venous public?; what are the important logistic constraints? return and hypotension), racquet sports (avoiding very To assess physical activity among pregnant women it is rapid movements that might affect equilibrium, thus in- necessary to use a questionnaire validated for this phase of a creasing the risk of falls), running and resistance training woman’s life, since the instruments elaborated for non- for women who were already practicing these activities pregnant women or for men may be less sensitive to differ- before they became pregnant and who are under medical ences in the levels of activity among pregnant women. These monitoring.8 questionnaires may include activities that cannot be adapted On the other hand, the following activities should be to the gravidic period or may omit low intensity activities, at avoided during the gestational period: contact sports such times inappropriately classifying pregnant women as seden- as ice hockey, boxing, soccer and basketball, activities involv- tary rather than active.27 ing a high risk of falls such as water skiing, surfing, cycling, Since women spend more time on occupational activity horse riding, diving and sky diving, hot yoga or hot pilates.8 and household and family care tasks and, less time on leisure Among the main fundamentals of physical activity during or conditioning activities, to dimension the physical activity pregnancy, it is important to point out that:21 women who did of women in an objective manner it is necessary to use an not exercise routinely before pregnancy should start with no assessing instrument that contains such activities.28 more than 15 minutes of continuous exercise 3 times a week, • Physical Activity Readiness Medical Examination gradually increasing the daily sessions to 30 minutes; women (PARMed-X) who did exercise routinely before pregnancy can maintain their exercise routine without the occurrence of adverse This instrument is part of a program for pregnant women effects; recreational exercises such as swimming or fast walk- developed by the Canadian Society for Exercise Physiology ing and exercises for the conditioning of muscle strength are and validated by using peak oxygen consumption.29 safe and beneficial; the objective of recreational exercise is to This tool classifies recreational physical activity into differ- keep in shape and not to increase physical fitness. ent levels according to its intensity, frequency and duration (►Table 1). Individuals who practice physical activity at a Methods for the Assessment of Physical Activity frequency of less than once or twice a week and for a period of time of less than 20 minutes have a zero index of physical Indirect Methods: Self-report Instruments activity and therefore, are considered to be unfit. Those who With their good acceptability and practicality, questionnaires practice physical activity once to twice a week for 20 minutes, are one of the subjective forms of assessments most frequently or more than twice a week for less than 20 minutes have a used in epidemiological studies.22 This concept is applicable to physical activity index of one and are considered to be active. the analysis of the impact of physical activity on the pre- Finally, individuals who perform physical activity more than

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Table 1 Classiﬁcation into recreational physical activity levels Table 2 Types of activity and number of questions per item of according to the physical activity readiness medical examination the pregnancy physical activity questionnaire (PPAQ) (PARMed-X)29 Type of activity Number of questions Levels of Physical Frequency Time Household chores/care 12 recreational activity (times/week) (minutes) physical activity index Occupational activities 5 Unﬁt0< 1-2 < 20 Exercise/sports 9 Active 1 1 - 2 ¼ 20 Transportation/displacement 3 1 > 2 < 20 Inactivity/sedentarism 4 Fit 2 > 2 > 20

twice a week for more than 20 minutes are considered to be fit There are smaller versions of this questionnaire with a and have a physical activity index of two. smaller number of questions taking into consideration the Advantage - it permits the classification of recreational reality of the population to which it is administered.32 physical activity, which serves as a parameter for the rec- Advantages - it takes into account small activities that are ommended prescription of physical activity. important for EE but that are usually neglected;30 it was Disadvantages - difficult validation, since the cost of the translated and validated for various countries;30,33,34 this measurement of oxygen consumption (VO2) limits its prac- questionnaire has been found to be reliable for the measure- tice in small centers and in places without the appropriate ment of physical activity in pregnant women with different structure; limited applicability to populations with a low intensities of obesity and can be used as a tool to detail index of recreational activity and, there are few reports about physical activity.35 this instrument in the literature, requiring the need of more Disadvantages - the questionnaire is imprecise regarding studies for the analysis of its applicability. self-reported physical activity, a fact that may generate inflated estimates of its validity.27 • Pregnancy Physical Activity Questionnaire (PPAQ) • Kaiser Physical Activity Survey (KPAS) In view of the need for an instrument that could be applied to pregnant women, in 2004, Chasan-Taber et al30 elaborated This is a questionnaire based on the Baecke et al36 physical and validated for the English language a short, easily under- activity research and was specifically projected for the stood and self-administered questionnaire denoted Pregnancy assessment of physical activity in women. Physical Activity Questionnaire (PPAQ), which intended to This instrument evaluates the multiple domains of physi- assess the level of physical activity specifically in pregnant cal activity (domestic activity/caregiver, occupational, active women. The PPAQ was first elaborated to become an instru- life and sports/exercises) and, although similar to the PPAQ in ment of worldwide applicability that would determine the structure, its objective is to measure the types of physical practice of physical activity in populations of pregnant activity performed by women and not their EE or their level women.30 This instrument is an adaptation to the population of physical activity. The KPAS provides an encompassing of pregnant women of the International Physical Activity assessment of each activity domain, and can be more useful Questionnaire developed by the World Health Organization.31 for studies in which physical activity is the primary out- The activities selected for the PPAQ permit the establish- come.27 The questions of the KPAS are grouped into four ment of the relationship between type of physical activity blocks, as can be seen in ►Table 4.27 and energy expenditure (EE) for each participant. This Activity indices are calculated for each activity domain by approach prioritizes the ability of the questionnaire to adding the specific categorical responses and dividing their classify the subjects into activity quartiles in a correct sum by the number of items, with mean values ranging from manner, in addition to eliminating the need for unnecessar- one to five. ily long instruments.27 The PPAQ proposes the measurement of the level of physical activity during the participation of a subject in 33 activities (►Table 2). Table 3 fi As response options, the PPAQ proposes a time scale in Classi cation into groups according to exercise intensity relation to the daily situations questioned: none, less than and its correspondence to metabolic equivalents (METs) 30 minutes per day, 30 minutes to 1 hour per day, 1 to 2 hours Classification Correspondence to METs per day, 2 to 3 hours per day, 3 hours or more per day. < According to the recording of type of physical activity, Sedentary 1.5 intensity, duration, frequency and, consequently, metabolic Mild 1.5 to < 3.0 fi equivalent (MET) rate, each woman is classi ed in terms of Moderate 3.0 - 6.0 practice of physical activity into one of four categories during Vigorous > 6.0 the last trimester (►Table 3).30

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Table 4 List of speciﬁc activities assessed by the Kaiser Physical Activity Survey27

Block Type of activity Number of items 1) Household chores/ family care House cleaning, shopping, gardening, care of elderly persons and 11 children, construction work. 2) Occupational activities working activities in the sitting and standing positions, walking 11 while carrying weights, efforts that cause transpiration. 3) Life habits Watching television, riding a bicycle or walking to go to work or to 4 school. 4) Participation in The frequency and duration of up to three sports or exercises 15 sports and exercises performed periodically are included.

Advantages - the KPAS investigates a larger number of regarding the steps taken, the distance covered, the time activities than the PPAQ.27 spent in the activity, and an estimate of EE.42,45 Disadvantages - the data do not reflect expenditure in This device provides the rate of steps/day as a standard MET, impairing their comparison to other questionnaires;27 measure for the assessment of physical activity, facilitating few studies are available about the use of this questionnaire its direct comparison in different studies.25,46 Thus, it is for pregnant women.37 being used as a measuring tool by athletes in physical – conditioning training programs.47 49 The pedometer has Objective Measures also been included as a component of broader health pro- Several movement sensors have been developed to measure in motion programs, which also associates other strategies such a more objective manner the physical activity performed as activities based on the characteristics of the population, during a determined period of time.38 The applicability of these physical exams for health control and healthier dietary tools at assistance centers is impaired by the fact that they need proposals.42 The use of this device in these programs is training to be used, and proximity of the patient for data based on the fact that the visual response of cumulative collection, with a higher cost compared with questionnaires.24 step count is immediate, leading to an increased perception Other measures of objective assessment are calorimetry, on the part of an individual of how his behavior affects his physiological markers, and direct observation and monitor- physical activity. It is indicated as a self-monitoring mecha- ing of heart rate parameters.24 These devices can be used as nism as part of a goal setting process, in addition to instruments for the validation of the reports of the subjects providing minute-to-minute information and thus helping investigated.24,39 to fulfill the objectives of physical activity.45 Each direct measure has its own limitation and there is no Advantages - characteristics of motivation end encour- “gold standard” for the determination of physical activi- agement of physical activity since it shows the number of ty.24,40 The choice of the tool to be used depends on a series steps taken by a person;46,50,51 in adults, it is possible to of factors such as the specific element of physical activity correlate the increase of 2000 steps/day with the reduction that is interested in measuring, the necessary precision of the of body mass index (BMI) and blood pressure.41 measurement, the target population of interest, and the cost Disadvantages - inability to provide estimates of moder- and logistic of the measurements.39 ate to vigorous physical activity;25 presence of a substantial error in predicting EE in MET;46 the prescription of physical • Pedometer/Step counter activity to young people is compromised since the device This is a small device of low cost that can be used attached does not provide information about the intensity of physical to the clothes of the person on the hip or at any other activity;45 impossibility to record activities that do not convenient site to count each step of the individual along involve walking;45 inability to measure non-ambulatory the day.41,42 The first commercial versions of the device were activities, posture or EE and dependence on specific algo- based on gear-driven mechanical technology and were pro- rithms for the determination of number of steps and, preci- duced to measure the distance covered, although with low sion is compromised in slow walking (less than 2 rpm).52 precision.43 Pedometers with microelectromechanical sys- • Accelerometer tems, whose data are processed by an algorithm, are available today. The device has a horizontal pendulum with a The accelerometer is a device to be attached to the hip, spring lever that moves up and down with vertical accel- calves or wrists that permits to monitor the frequency, erations to measure the total number of steps. When the arm intensity and duration of the episodes of physical activity of the lever is shifted above a given threshold it determines by means of direct measurements of body accelerations and an electric contact with a sensor that records the step.39,44 decelerations.53,54 Some types of accelerometers present Pedometers first became available as self-monitoring sensitivity of movement detection on different planes, tools for the promotion of a life style directed at the practice although most of them are uniaxial, that is, they are sensitive of physical activity. Pedometers provide a valuable response to movement only on the vertical axis. Even accelerometers

Rev Bras Ginecol Obstet Vol. 39 No. 8/2017 Physical Activity during Pregnancy: Recommendations and Assessment Tools Oliveira et al. 429 that are sensitive to acceleration on the anteroposterior and/ instantaneous HR variability.34 Heart rate monitoring is an or lateral plane (biaxial or triaxial) have sensors that are effective objective method used to monitor the intensity, more sensitive to movement on the vertical plane, thus being duration and frequency of daily activities using a physiological fundamentally uniaxial.55,56 parameter that detects the cardiovascular adaptation to exer- They have a microelectromechanical system that can cise and estimates energy expenditure.34,63 record gravitational accelerations, which can be calibrated Advantages - the device can measure non-ambulatory and converted to measurements of oxygen consumption.39 activities.34 Laboratory investigations have established a linear relation- Disadvantages - Heart rate is a poor predictor of EE in the ship between the measurements recorded by the accelerom- low-intensity range of physical activity and the technique eter and the O2 volume consumed (VO2). This permits to requires calibration of thefrequency meter for each individual; relate these data to EE during locomotion and to develop since data processing is laborious and time consuming, long equations for the prediction of MET level and, consequently periods of use cause electrode wear and may also cause skin to determine the classification of the intensity of physical irritation; since HR can be altered by other stimuli in addition activity into mild, moderate, strong or vigorous.38,43 to physical activity, the device needs to be calibrated for The most diffuse accelerometer is the Actigraph, followed persons who are taking certain medications;64 loss of contact by the Tracmor.55 After the first version of the Actigraph, and external noise (usually starting at 60 Hz) may cause more than 15 different regression equations were developed electrical interference with the analysis of the results. These to estimate EE.38,54,57 In general, the regression equations problems can be reduced by appropriate fixation of the sensor developed to record if a person is standing still or is moving to the skin of the user, by the positioning of the transducer may slightly overestimate the EE of locomotion and of light close to the system of data acquisition and by the use of an exercise while greatly underestimating the EE of activities of electrolyte gel;65 ocurrence of biases in the recordings moderate intensity. In contrast, regression equations devel- obtained due to changes in HR not related to exercise;34 not oped by using daily life activities of moderate intensity usable for the validation of questionnaires.31 provide more precise estimates of EE for this type of activity, • Calorimetry although they may considerably overestimate the EE of sedentary persons and of light activities and underestimate Energy expenditure can be measured in a precise manner in that of vigorous activities.58 humans by direct or indirect calorimetry. Since all energy Advantages - axial and triaxial monitors can record physical reactions that occur in the organism require oxygen and since activity for long periods of time;59 an excellent method for the oxygen consumption (VO2) is proportional to EE, the indirect measurement of daily life activity of pregnant women, such as calorimetry method is based on respiratory exchange.52 household chores and child care, also avoiding the problem of In indirect calorimetry, the participant wears a mask and counting twice chores that are performed simultaneously.60 carries the equipment necessary for the analysis of expired air Disadvantages - there is no standard measurement, impair- to measure VO2 during physical activity, performed in an ing the comparison of different studies; the algorithms used environment with controlled humidity, luminosity and tem- are very specific; low sensitivity for physical activities of light perature. The program that analyzes inspired oxygen and intensity or sedentary, inability to differentiate between exhaled carbonic gas is calibrated according to maufacturer’s activities and to measure non-ambulatory activities such as instructions.58 One disadvantage of this technique is that bicycle ridingor weight lifting;59 technique artifacts mayoccur wearing the equipment will probably impact the performance in pregnant women due to variation in the positioning of the of the physical activity (Hawthorne effect). In addition, this is a device according to abdominal size and stomach position in complicated and expensive method.66 In turn, direct calorim- each phase of pregnancy;27 the cut-off points needed to etry is based on the fact that all metabolic processes occurring calibrate the data of the accelerometer according to specific in the organism produce and store heat, with the quantity of categories of intensity (light, moderate, strong, and vigorous) heat lost being proportional to EE.58 In the rooms where have not been calculated for pregnant women.23 calorimetry is performed, it is possible to obtain precise EE measures, since the subjects are confined to a small space with • Frequency meter controlled temperature, humidity and luminosity throughout This is a light device that can be used to estimate the the measuring time.67 Even under these conditions, the rela- physical activity’s EE (PAEE) on the basis of the linear tionship between body temperature and EE may be altered by relationship between heart rate (HR) and EE.61 The validity the level of physical conditioning. In these situations, the and reliability of the frequency meter have not been well monitoring of body temperature is not adequate as the single determined.62,63 measurement of EE, but may be useful as part of an integrated The frequency meter is a device consisting of a transducer monitoring system.66 associated with a data acquisition system placed on the The gold standard for the “outdoor” measurement of EE is abdominal or wrist region. The sensor system captures, digi- the “double-labeled water” method, which is based on the tizes and stores the HR signal on a full timebasis, and calculates principles of indirect calorimetry. The process involves the the mean for each pre-programmed time range (usually 5 to intake of a dose of stable 2H2OandH218O isotopes immedi- 15 seconds). Some monitors can store the interbeat interval ately followed by the measurement of the elimination of (IIB series) for several hours, permitting the calculation of these isotopes in urine. The difference in isotope elimination

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rate is proportional to the metabolically produced CO2 higher cost, since they can detect and record the real magni-

(VCO2), a result which is then used to calculate total VO2 tude of acceleration, permitting the determination of the and EE.68 This approach yields the mean EE occurring over a quality or intensity of movement.38 Their high cost is their measuring period of 7 to 14 days.66 Although this method has most relevant disadvantage.25 The main advantages of these already been used for different populations of pregnant devices are their small size that permits a person to be women,59 it does not provide information about the patterns monitored for long periods of time without interfering with of activity and cannot be used to differentiate the intensity, normal movements, as well as their capacity to store data in a duration and frequency of the activities evaluated. The high continuous manner. This permits analysis of the information cost of the isotope, together with the need for mass spec- regarding the patterns of activity over several days or weeks.38 trometry to analyze the urine, causes this method to be too A study conducted on 81 patients who performed selected costly for use in clinical practice. Thus, the method is more tasks from six general categories (gardening, housework, job, often used for validation in epidemiological studies.66 family care, conditioning, and recreation) tested the validity Advantages - precise measurement methods.69 of four movement sensors for measuring EE during physical Disadvantages- it is not useful for epidemiological studies activities of moderate intensity in field and laboratory since it inhibits the normal physical activity of the person environments. Energy expenditure was measured during and is too expensive to be applied to large populations.69 each activity using a portable system, as well as three accelerometers and an electronic pedometer. The authors Combination of Analytical Methods concluded that the movement sensors tend to overestimate With good acceptability and practicality, questionnaires EE during a walk. On the other hand, they may underestimate represent one of the subjective forms of assessment of many other activities due to their inability to detect arm physical activity most extensively used in epidemiological movements or types of exercise in an outdoor environment, studies.22 However, their reliability is low since they can representing limitations of these instruments.58 overestimate the levels of physical activity compared with Different methods for the assessment of physical activity objective measurements such as those obtained with an have advantages and limitations. However, in view of the fact accelerometer or pedometer.24,25 that they provide complementary information, their joint A strategy for the reduction of errors during the use of use provides an appropriate assessment of the time, level and self-answered physical activity questionnaires is to follow a intensity of activity.72 conceptual structure consisting of six steps:70 determination of the need to measure physical activity; selection of an Conclusion instrument; data collection; data analysis; development of a scoring system; interpretation of the data. All tools for the analysis of physical activity have limitations. The literature is controversial regarding the possibility to Thus, it is necessary to establish the objectives of evaluation in validate questionnaires using objective tools such as an accel- an appropriate manner, as well as to determine their viability erometer of pedometer. In 2004, Chasan-Taber et al30 devel- and cost-effectiveness for the population under study oped a specific questionnaire for pregnant women and, when attempting to validate it with the use of an accelerometer, they detected a low to moderate correlation between tools. A study conducted on 48 pregnant women with gesta- Declaration of Conflicting Interests tional ages ranging from 26 to 28 weeks, to compare subjec- The authors declare that they have no conflicts of interest tive and direct measurements, observed that the pedometer that are directly relevant to the content of this article. provides a reliable estimate of physical activity during pregnancy, whereas the International Physical Activity Ques- 71 tionnaire is less precise. References In a study conducted on 59 women with a BMI of more 1 Gavard JA, Artal R. Effect of exercise on pregnancy outcome. 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Differential Diagnosis between Bartholin Cyst and Vulvar Leiomyoma: Case Report Diagnóstico diferencial entre cisto de Bartholin e leiomioma vulvar: relato de caso

Kelly Alessandra da Silva Tavares1 Thomas Moscovitz1 Marcos Tcherniakovsky1 LucianodeMeloPompei1 César Eduardo Fernandes1

1 Department of Gynecology and Obstetrics, Faculdade de Medicina Address for correspondence Kelly Alessandra da Silva Tavares, MD, do ABC, Santo André, São Paulo, Brazil Rua dos Democratas, 277, apartamento 41, 04305-000, SãoPaulo, Brazil (e-mail: [email protected]). Rev Bras Ginecol Obstet 2017;39:433–435.

Abstract Genital leiomyomas are rare tumors that can often be misdiagnosed as Bartholin cyst. Keywords We report a case of a 32-year-old patient who had a cystic nodulation in the left labium ► vulvar neoplasms majus that was suggestive of Bartholin cyst. A resection surgery was performed, and ► Bartholin gland the deﬁnitive histopathology diagnosis was vulvar leiomyoma. The macroscopic ► leiomyoma features of cystic lesions difﬁcult the differential diagnosis between leiomyoma and ► histology Bartholin cyst; therefore, a histopathologic examination is often recommended. ► case report

Resumo Os leiomiomas genitais são tumores raros, e frequentemente são diagnosticados como Palavras-Chave cisto de Bartholin. Relatamos o caso de uma paciente de 32 anos em que ocorreu ► neoplasias vulvares nodulação cística no grande lábio esquerdo sugestiva de cisto de Bartholin. Uma ► glândula de Bartholin cirurgia de ressecção foi realizada, e o diagnóstico histopatológico deﬁnitivo foi ► leiomioma leiomioma vulvar. As características macroscópicas das lesões císticas diﬁcultam o ► histologia diagnóstico diferencial entre o leiomioma e o cisto de Bartholin, de modo que o exame ► relato de caso histopatológico é frequentemente recomendado.

Introduction Some features that support the diagnosis of Bartholin cyst are everted labia minora and cystic consistency of the swelling. Uterine leiomyomas are benign monoclonal tumors, and the However, finding inverted labia minora and firm consistency most frequent site for their occurrence is the muscle cells of of the swelling suggests vulvar leiomyoma. A histopathologic the myometrium. However, they develop in any site where examination is often recommended for the final diagnosis.7 smooth muscle cells are present,1 such as the vulva, the vagina, the ovaries, the urinary bladder, the urethra, the Case Report round ligaments, the uterosacral ligaments, the inguinal canal and the retroperitoneum.2,3 Patient Information Genital leiomyomas are rare tumors.4 Less than 160 cases of A 32-year-old white woman presented to the gynecological vulvar leiomyoma have been reported in the literature, and outpatient service at our institution complaining of vaginal – this condition can often be misdiagnosed as Bartholin cyst.4 6 pain and a vulvar nodulation that had developed six months

received DOI https://doi.org/ Copyright © 2017 by Thieme Revinter October 29, 2016 10.1055/s-0037-1604178. Publicações Ltda, Rio de Janeiro, Brazil accepted ISSN 0100-7203. May 5, 2017 434 Differential Diagnosis between Bartholin Cyst and Vulvar Leiomyoma Tavares et al.

before. She stated feeling no abdominal pain and having no When the patient was first evaluated, the main hypothesis fever and urinary and intestinal disorders. She reported tubal was a Bartholin cyst. Most vulvar leiomyomas are usually – ligation and prolonged menstrual bleeding. misdiagnosed as Bartholin cyst or abscess initially.4 6,10,11 After the surgery, a specimen was sent for a histopathologic Physical Examination examination that confirmed the vulvar leiomyoma diagnosis. Her general physical and systemic examinations were unre- Degenerative alterations are very common; some authors markable. Upon local examination, a 5 Â 5 cm cystic lesion in have reported myxoid degeneration in some cases of vulvar the lower part of left labium majus was observed. It was leiomyoma.12,13 However, no degenerative alteration was clinically diagnosed as Bartholin cyst. observed in our case. These lesions need to be surgically excised, and the prog- Diagnostic Assessment nosis isgood if theyare completely removed.14 Closelong-term Baseline investigations were performed with a transvaginal follow-up is required because of the high risk of recurrence,8 ultrasound that evidenced multiple intramural uterine but no recurrence was observed after one year of follow-up in leiomyomas, with the largest measuring 28 mm. The uter- this patient. Excision of the tumor with some of the surround- ine volume was 239 cc. The vulvar region was not assessed ing normal tissue is the treatment of choice. It decreases the with ultrasound because the first hypothesis was Bartholin rate of recurrence and increases the five-year survival rate.8 cyst. In conclusion, vulvar leiomyomas are very rare. The macroscopic features of cystic lesions difficult the differential diag- Interventions nosis between leiomyoma and Bartholincyst. A histopathologic Nine months after the initial consultation, the patient came examination is often recommended for the final diagnosis. back for surgery, and we observed a growth in the tumor fi during this period; we found a broelastic mass of 10 cm. Informed Consent The tissue appeared to be a leiomyoma, which made us Consent was taken for the procedure and publication. question the initial hypothesis of Bartholin cyst. A specimen was sent for a histopathologic examination. Conflicts of Interest The authors of this manuscript have no conflicts of inter- Follow-Up and Outcomes est to disclose. The patient had an uneventful postoperative recovery, and was fi discharged on the rst postoperative day. A gross examination Contribution to Authorship of the excised tumor of the left labium majus showed: a piece KASTwas responsible for the conception and design of the fi with irregular surface, mousey and rm tissue, measuring study, the acquisition of data, and the draft of the article; Â Â 8 6 3 cm. Microscopy revealed a mature tumor of mes- TM and MT critically revised the article for important enchymal nature characterized by proliferation of spindle cells intellectual content; LMP critically revised the article for similar to smooth muscle cells. There were no indications of important intellectual content, and gave the final fi malignancy. The nal diagnosis was leiomyoma. approval for the version that was submitted; CEF gave The patient was called for follow-up after two weeks and the final approval for the version that was submitted. was asymptomatic; one year later, no recurrence was observed. Note Discussion This research received no specific grants from any public, private or non-profit funding agencies. Uterine leiomyomas are very common benign tumors; however, their occurrence in the vulva is rare. Less than 160 cases 4–6 of vulvar leiomyoma have been reported in the literature. References The mean age when these tumors tend to occur varies from 1 Weston G, Healy DL. Uterine fibroids. In: Shaw RW, Luesley D, 13 to 71 years, and they usually occur as solitary lesions, with Monga A, editors. Gynaecology. 4th ed. Edinburgh: Elsevier an average tumor size of 0.5 to 15 cm.8 Corroborating with the Science; 2011. p. 473–85 cases described in theliterature, we report a 8-cm single vulvar 2 Hillard P. Benign diseases of the female reproductive tract. In: ’ lesion in a 32-year-old woman who complained of pain in the Berek J, Adashi E, Hillard P, editors. Novak s gynecology. 12th ed. Baltimore: Williams & Wilkins; 1996. p. 331–97. vulvar region 6 months prior to the consultation. Nevertheless, 3 Kunhardt Urquiza E, de la Cruz SI, Fernández Martínez RL, vulvar leiomyomas are usually asymptomatic, but sometimes Hernández Zúñiga VE. Myomatosis of rare localization. Ginecol can cause swelling and local discomfort. Obstet Mex 1997;65(12):541–544 Ultrasound is the most reliable and widely used diagnos- 4 Fasih N, Prasad Shanbhogue AK, Macdonald DB, et al. Leiomyomas tic tool for uterine and extra uterine leiomyomas, and beyond the uterus: unusual locations, rare manifestations. Radio- – magnetic resonance imaging is sparingly used in cases that graphics 2008;28(07):1931 1948 5 Reyad MM, Gazvani MR, Khine MM. A rare case of primary are difficult to diagnose.4 The simultaneous development of leiomyoma of the vulva. J Obstet Gynaecol 2006;26(01):73–74 9 vulvar and uterine leiomyomas is very common. In our case 6 Zhao T, Liu X, Lu Y. Myxoid epithelial leiomyoma of the vulva: a report, a transvaginal ultrasound evidenced an increase in case report and literature review. Case Rep Obstet Gynecol 2015; uterine volume associated with the leiomyoma. 2015:894830

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Cotyledonoid Dissecting Leiomyoma with Symplastic Features: Case Report Leiomioma dissecante cotiledonoide com aspectos simplásticos: relato de caso

Fatma Cavide Sonmez1 Zeynep Tosuner1 Ayse Filiz Gökmen Karasu2 Dilek Sema Arıcı1 Ramazan Dansuk2

1 Department of Pathology, School of Medicine, Bezmialem Vakif Address for correspondence Ayse Filiz Gokmen Karasu, MD, University, Istanbul, Turkey Department of Gynecology and Obstetrics, Bezmialem Vakif 2 Department of Gynecology and Obstetrics, School of Medicine, University, Faculty of Medicine, Istanbul, Turkey Bezmialem Vakif University, Istanbul, Turkey (e-mail: [email protected]).

Rev Bras Ginecol Obstet 2017;39:436–440.

Abstract Purpose Cotyledonoid dissecting leiomyoma is a leiomyoma variant exhibiting unusual growth patterns. We aimed to demonstrate this, as well as to point out another feature that has not been previously reported. Case Report A congested, multinodular myomectomy specimen was resected. Histologically, smooth muscle fascicles with marked vascularity and extensive hydropic degeneration were detected. A total of 2 mitoses per 10 high power ﬁelds were

counted, and the Ki-67 index was of 2–3%. We encountered atypical bizarre cells that have not been previously reported. Coagulative necrosis was not present. The patient was alive and well 36 months after surgery, with no evidence of recurrence. Keywords Conclusions Albeit the gross aggressive appearance, cotyledonoid dissecting leio- ► benign myomas are benign in nature. To this day, atypical cells have not been reported in this ► cotyledonoid type of tumor. Despite the presence of symplastic features, cotyledonoid dissecting ► leiomyoma leiomyomas are clinically benign entities. Surgeons and pathologists should be ► symplastic acquainted with this variant.

Resumo Introdução O leiomioma dissecante na forma cotiledonoide é uma variante de leiomioma com padrões raros de crescimento. Além de demonstrá-los, vamos apontar outro aspecto anteriormente não relatado. Relato de Caso Uma amostra congestionada, multinodular de miomectomia foi excisada. Histologicamente, detectaram-se fascículos de músculos lisos com marcada vascularidade e extensa degeneração hidrópica. Contaram-se 2 mitoses por 10 campos

de alta potência, e o índice Ki-67 foi de 2–3%. Encontramos células atípicas, bizarras, que não haviam sido relatadas anteriormente. Não foi observada necrose coagulativa. A paciente encontrava-se saudável e sem evidências de recorrência 36 meses após a cirurgia.

received DOI https://doi.org/ Copyright © 2017 by Thieme Revinter December 5, 2016 10.1055/s-0037-1604057. Publicações Ltda, Rio de Janeiro, Brazil accepted ISSN 0100-7203. March 27, 2017 Cotyledonoid Dissecting Leiomyoma with Symplastic Features Sonmez et al. 437

Palavras-chave Conclusão De aparência bruta e grosseira, os leiomiomas dissecantes na forma ► benigno cotiledonoide têm natureza benigna. Até hoje, células atípicas não haviam sido ► cotiledonoide relatadas nesse tipo de tumor. Apesar dos aspectos simplásticos, os leiomiomas ► leiomioma dissecantes na forma cotiledonoide são entidades clínicas benignas. Cirurgiões e ► simplástico patologistas devem estar familiarizados com essa variante.

– Introduction growth patterns.1 4 Dissecting leiomyomas exhibit an unusual growth pattern, with apparent broad tongues infiltrat- Cotyledonoid dissecting leiomyomas are a rare variant of ing between myometrial muscle bundles. Cotyledonoid leiomyomas with a disparate gross appearance. They gener- dissecting leiomyoma, or ‘Sternberg tumor,’ was first de- ally arise from the myometrium and extend to the broad scribed in 1996 by Roth et al.2 Menolascino-Bratta et al5 ligaments. This particular type of tumor typically incorpo- coined the term ‘angionodular dissecting leiomyoma’. These rates various characteristics, including dissecting growth tumors have been described in women from the third to the and perinodular hydropic degeneration.1,2 Mitoses, coagu- early sixth decade of life.1 The common clinical findings are lative necrosis and atypical cells have not been reported in pelvic masses and abnormal uterine bleeding.3,6 These tu- this variant. We report a case of a cotyledonoid dissecting mors can be large with an average dimension of 15 cm (range leiomyoma in a 38-year-old woman who presented with 4–41 cm). Three potential types have been described. The abdominal pain and underwent myomectomy. first type is the cotyledonoid dissecting leiomyoma (Stern- berg tumor), which comprises an exophytic mass of multi- Case Presentation nodular tissue resembling the placenta, and is often protruding from the lateral surface of the uterine corn in A 38-year-old multigravid woman presented with abdominal continuation with the myometrium. The second type is the pain. An ultrasonography examination showed an irregularly intramural dissecting tumor, which is confined to the uterus. contoured, subserous myoma with 95 mm x 93 mm dimen- These two types are histologically similar. The last type is sions arising from the uterine fundus. A cervicovaginal smear pure cotyledonoid leiomyoma, which is not associated with displaying normal cytology and endometrial sample dem- either a parent intramural mass or intramural dissection.7 onstrating proliferative endometrium was obtained prior to Cotyledonoid dissecting leiomyoma is characterized by the operation. A congested, multinodular mass was surgical- disorganized smooth muscle fascicles with extensive hy- ly resected by myomectomy, and the uterus was salvaged. dropic degeneration and marked vascularity.1 Histological Macroscopically, the mass was reddish brown colored and features suggestive of malignancy, such as cytological atypia, 135 mm x 105 mm x 90 mm in dimensions with a multi- necrosis and increased mitotic activity, are absent.8 nodular appearance (►Fig. 1). Closely packed, variable-sized nodules were resembling cotyledons. The cut surface was gray-white and congested in some areas. Microscopically, the tumor showed smooth muscle fascicles and micronodules (►Fig. 2A). Dilated and congested vessels were prominent at the peripheral areas of the nodules. Cellularity varied because of extensive hydropic degeneration (►Fig. 2B). Mono- nuclear and multinuclear atypical, bizarre cells were detected (►Fig. 2C). Coagulative necrosis was not observed. There were 2 mitoses per 10 high power fields, and the immunohistochemical Ki-67 index of was 2–3% (►Fig. 2D). Intravascular involvement was not encountered. The result of our macroscopic and microscopic examinations was ‘cotyledonoid leiomyoma with the presence of symplastic (atypical) features’. The patient was followed up with regular postoperative visits in the gynecology outpatient clinic, and was alive and well 36 months after surgery, with no evidence of recurrence.

Discussion

Smooth muscle tumors are the most common neoplasms of Fig. 1 Gross appearance of the lesion reminiscence of placental the female genital tract, and they can demonstrate different cotyledons.

Rev Bras Ginecol Obstet Vol. 39 No. 8/2017 438 Cotyledonoid Dissecting Leiomyoma with Symplastic Features Sonmez et al.

Fig. 2 (A) There are smooth muscle fascicles and nodules separated by vascularized and hydropic tissue (H&E stain, x 20). (B) Perinodular extensive hydropic degeneration is present (H&E stain, x 40). (C) There are mono and multinucleated atypical cells (H&E stain, x400). (D)The

immunohistochemical Ki-67 index is of 2–3%.

The microscopic ﬁndings of our case were similar except myoma with perinodular hydropic changes does not have for the atypical cells. Edema and congestion were prominent a gross appearance like placenta.4 Inﬁltrative growth pat-

in some areas. Tumor cell necrosis, increased mitotic activity, tern and high Ki-67 index are important to differentiate

and high immunohistochemical Ki-67 index were not myxoid leiomyosarcoma from cotyledonoid dissecting leio- detected, but a few mononuclear and multinuclear atypical, myoma.4 In our case, edematous areas resembled myxoid

bizarre cells were observed, which makes our case unique. As leiomyosarcoma, but were not infiltrative, and the Ki-67 an isolated finding, cytologic atypia, even when severe, is an index was of 2–3%. unreliable criterion for the diagnosis of clinically malignant Atypical cells are not features of cotyledonoid dissecting uterine smooth muscle tumor, as it may be observed in leiomyomas. Both atypical (symplastic) and dissecting leio- clinically benign neoplasms such as our case. These changes myomas are benign. Despite the macroscopic and micro- have been noted in leiomyomas excised from women taking scopic aggressive appearance, no example of malignant progestin; however, there was no history of progestin use in behavior or recurrence has been reported in a dissecting our patient. A leiomyoma that exhibits moderate to severe leiomyoma.3 So, it is important that surgeons and patholo- cytologic atypia is designated as an atypical leiomyoma. By gists are aware of this rare, unusual entity to prevent definition, mitotic figures cannot be present in numbers in misdiagnosis and overtreatment. excess of 10/10 high power fields. In atypical leiomyomas and tumor cells, necrosis must be absent.1 Intravenous leiomyomatosis, leiomyoma with perinodu- Conflicts of Interest lar hydropic degeneration, and myxoid leiomyosarcoma The authors report no conflicts of interest. The authors enter into the differential diagnosis.3 The tumor grows alone are responsible for the content and writing of the within the lumina in intravenous leiomyomatosis. Leio- paper.

Rev Bras Ginecol Obstet Vol. 39 No. 8/2017 Cotyledonoid Dissecting Leiomyoma with Symplastic Features Sonmez et al. 439

Acknowledgments 4 Weissferdt A, Maheshwari MB, Downey GP, Rollason TP, Ganesan The authors would like to thank Nurya Tatianya Buyuk R. Cotyledonoid dissecting leiomyoma of the uterus: a case Aleksanyan for the translation of the abstract. report. Diagn Pathol 2007;2:18 5 Menolascino-Bratta F, García de Barriola V, Naranjo de Gómez M, García Tamayo J, Suarez JA, Hernández Chacón AV. Cotyledonoid dissecting leiomyoma (Sternberg tumor): an unusual form of References leiomyoma. Pathol Res Pract 1999;195(06):435–438, discussion 1 Ersöz S, Turgutalp H, Mungan S, Güvendı G, Güven S. Cotyledonoid 439 leiomyoma of uterus: a case report. Turk Patoloji Derg 2011;27 6 Smith CC, Gold MA, Wile G, Fadare O. Cotyledonoid dissecting (03):257–260 leiomyoma of the uterus: a review of clinical, pathological, and 2 Roth LM, Reed RJ, Sternberg WH. Cotyledonoid dissecting leio- radiological features. Int J Surg Pathol 2012;20(04):330–341 myoma of the uterus. The Sternberg tumor. Am J Surg Pathol 7 Fox H, Wells M. Haines & Taylor Obstetrical and Gynaecological 1996;20(12):1455–1461 Pathology. 5th ed. London: Churchill Livingstone; 2003 3 Kim MJ, Park YK, Cho JH. Cotyledonoid dissecting leiomyoma of 8 Nucci MR, Oliva E. Gynecological Pathology: A Volume in the the uterus: a case report and review of the literature. J Korean Series Foundations in Diagnostic Pathology. London: Churchill Med Sci 2002;17(06):840–844 Livingston; 2009

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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.manuscript- central.com/rbgo-scielo There is no fee for submission and review articles.

Dê o próximo passo e lute por esta paciente. Há muito a ser feito por ela.

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