nº 3 - Febrasgo

Transcrição

nº 3 - Febrasgo

ISSN 0100-7203
Na endometriose
Revista Brasileira de Ginecologia e Obstetrícia
Tratamento simples e eficaz
Março
2013
Indicado especificamente para
o tratamento da endometriose
Março 2013
Reduz lesões
1
nº 3
2,4
volume 35
Reduz de forma eficaz a dor
Indicado para uso
a longo prazo
Adequada tolerabilidade
3
e segurança
2
CONTRAINDICAÇÕES: DISTURBIOS CARDIOVASCULARES, DIABETES MELLITUS COM ENVOLVIMENTO VASCULAR.
INTERAÇÕES MEDICAMENTOSAS: ANTICONVULSIVANTES, ANTIFÚNGICOS AZÓLICOS, ANTIDEPRESSIVOS.
número 3 p. 93 - 142
ALLURENE® (DIENOGESTE) RG MS-1.7056.0088
INDICAÇÃO: TRATAMENTO DA ENDOMETRIOSE. CONTRA-INDICAÇÕES: DISTÚRBIO TROMBOEMBÓLICO VENOSO EM ATIVIDADE, PRESENÇA OU HISTÓRICO DE DOENÇA CARDIOVASCULAR E ARTERIAL, DIABETES MELITUS COM ENVOLVIMENTO VASCULAR, PRESENÇA OU HISTÓRICO DE
DOENÇA HEPÁTICA GRAVE ENQUANTO OS VALORES DA FUNÇÃO HEPÁTICA NÃO RETORNAREM AO NORMAL, PRESENÇA OU HISTÓRICO DE TUMOR HEPÁTICO (BENIGNO OU MALIGNO), SUSPEITA OU DIAGNÓSTICO DE NEOPLASIAS DEPENDENTES DE HORMÔNIOS SEXUAIS, SANGRAMENTO
VAGINAL NÃO DIAGNOSTICADO, HIPERSENSIBILIDADE À SUBSTÂNCIA ATIVA OU A QUALQUER UM DOS COMPONENTES DA FORMULAÇÃO. ADVERTÊNCIAS E PRECAUÇÕES: ANTES DE INICIAR O TRATAMENTO COM ALLURENE®, DEVE-SE EXCLUIR A POSSIBILIDADE DE GRAVIDEZ. DURANTE O TRATAMENTO COM ALLURENE® A OVULAÇÃO É INIBIDA NA MAIORIA DAS PACIENTES. ENTRETANTO, ALLURENE® NÃO É UM CONTRACEPTIVO E CASO SEJA NECESSÁRIO PREVENIR A GRAVIDEZ, AS PACIENTES DEVEM SER ORIENTADAS A UTILIZAR MÉTODOS CONTRACEPTIVOS
NÃO HORMONAIS (POR EXEMPLO, MÉTODO DE BARREIRA). COM BASE NOS DADOS DISPONÍVEIS, O CICLO MENSTRUAL RETORNA AO NORMAL DENTRO DE 2 MESES APÓS O TÉRMINO DO TRATAMENTO COM ALLURENE®. EM MULHERES COM HISTÓRICO DE GRAVIDEZ EXTRAUTERINA
OU DE ALTERAÇÃO DA FUNÇÃO DAS TROMPAS, O USO DE ALLURENE® DEVE SER DECIDIDO APENAS APÓS CUIDADOSA AVALIAÇÃO DA RELAÇÃO RISCO/BENEFÍCIO. COMO ALLURENE® É UM MEDICAMENTO QUE CONTÉM SOMENTE PROGESTÓGENO, DEVEM SER CONSIDERADAS AS
PRECAUÇÕES E ADVERTÊNCIAS DE TODOS OS MEDICAMENTOS QUE CONTEM SOMENTE PROGESTÓGENO, EMBORA NEM TODAS ESTEJAM BASEADAS EM ACHADOS DOS ESTUDOS CLÍNICOS REALIZADOS COM ALLURENE®. CASO QUALQUER UMA DAS CONDIÇÕES/FATORES DE RISCO
DESCRITAS A SEGUIR ESTEJA PRESENTE OU SE AGRAVE, DEVE-SE REALIZAR UMA ANÁLISE INDIVIDUAL DA RELAÇÃO RISCO/BENEFÍCIO ANTES DE INICIAR OU CONTINUAR O USO DE ALLURENE®: DISTÚRBIOS CIRCULATÓRIOS; TUMORES; ALTERAÇÕES NO PADRÃO DE SANGRAMENTO;
HISTÓRICO DE DEPRESSÃO; DESENVOLVIMENTO DE HIPERTENSÃO CLINICAMENTE SIGNIFICATIVA DIABETES MELITUS (SOBRETUDO HISTÓRICO DE DIABETES MELITUS GESTACIONAL); E OCORRÊNCIA FOLÍCULOS OVARIANOS PERSISTENTES (CISTOS OVARIANOS FUNCIONAIS). RECORRÊNCIA
DE ICTERÍCIA COLESTÁTICA E/OU PRURIDO OCORRIDO ANTERIORMENTE DURANTE UMA GRAVIDEZ OU DURANTE O USO ANTERIOR DE ESTEROIDES SEXUAIS REQUER A DESCONTINUAÇÃO DE ALLURENE®. MULHERES COM TENDÊNCIA A MELASMA/CLOASMA DEVEM EVITAR EXPOSIÇÃO
AO SOL OU RADIAÇÃO ULTRAVIOLETA DURANTE O TRATAMENTO COM ALLURENE®. RECOMENDA-SE ACOMPANHAMENTO REGULAR, COM ATENÇÃO ESPECIAL À PRESSÃO ARTERIAL, MAMAS, ABDOME E ÓRGÃOS PÉLVICOS, INCLUINDO CITOLOGIA CERVICAL. ALLURENE® NÃO DEVE SER
ADMINISTRADO A MULHERES GRÁVIDAS UMA VEZ QUE NÃO HÁ NECESSIDADE DE TRATAR A ENDOMETRIOSE DURANTE A GRAVIDEZ - CATEGORIA B – “ESTE MEDICAMENTO NÃO DEVE SER UTILIZADO POR MULHERES GRÁVIDAS SEM ORIENTAÇÃO MÉDICA OU DO CIRURGIÃO-DENTISTA”. A
ADMINISTRAÇÃO DE ALLURENE® DURANTE A LACTAÇÃO NÃO É RECOMENDADA. INTERAÇÕES MEDICAMENTOSAS: INDUTORES OU INIBIDORES ENZIMÁTICOS INDIVIDUAIS (CITOCROMO P450); SUBSTÂNCIAS COM PROPRIEDADES DE INDUÇÃO ENZIMÁTICA (FENITOÍNA, BARBITÚRICOS,
PRIMIDONA, CARBAMAZEPINA, RIFAMPICINA E POSSIVELMENTE TAMBÉM OXCARBAZEPINA, TOPIRAMATO, FELBAMATO, GRISEOFULVINA, NEVIRAPINA E ERVA-DE-SÃO JOÃO); SUBSTÂNCIAS COM PROPRIEDADES DE INIBIÇÃO ENZIMÁTICA (ANTIFÚNGICOS AZÓLICOS, CIMETIDINA, VERAPAMIL, MACROLÍDEOS, DILTIAZEM, INIBIDORES DA PROTEASE, ANTI-DEPRESSIVOS E SUCO DE TORONJA). COM BASE EM ESTUDOS DE INIBIÇÃO IN VITRO, É IMPROVÁVEL QUE HAJA INTERAÇÃO CLINICAMENTE RELEVANTE ENTRE ALLURENE® E O METABOLISMO DE OUTROS MEDICAMENTOS
MEDIADO PELA ENZIMA DO CITOCROMO P450. O USO DE PROGESTÓGENOS PODE INFLUENCIAR OS RESULTADOS DE CERTOS EXAMES LABORATORIAIS, INCLUINDO PARÂMETROS BIOQUÍMICOS DO FÍGADO, TIREÓIDE, FUNÇÃO RENAL E ADRENAL, NÍVEIS PLASMÁTICOS DE PROTEÍNAS
(CARREADORAS), POR EXEMPLO, FRAÇÕES LIPOPROTEICAS/LIPÍDICAS, PARÂMETROS DO METABOLISMO DE CARBOIDRATADOS E PARÂMETROS DA COAGULAÇÃO E FIBRINÓLISE. DE MODO GERAL, AS ALTERAÇÕES PERMANECEM DENTRO DA FAIXA LABORATORIAL NORMAL. POSOLOGIA:
UM COMPRIMIDO POR DIA SEM INTERVALO DE PAUSA, TOMADO, PREFERENCIALMENTE, NO MESMO HORÁRIO TODOS OS DIAS, COM UM POUCO DE LÍQUIDO, SE NECESSÁRIO, INDEPENDENTEMENTE DE SANGRAMENTO VAGINAL. AO TÉRMINO DE UMA CARTELA, A PRÓXIMA DEVE SER
INICIADA, SEM INTERRUPÇÃO. A INGESTÃO DOS COMPRIMIDOS PODE SER INICIADA EM QUALQUER DIA DO CICLO MENSTRUAL. REAÇÕES ADVERSAS: FREQUENTES: CEFALEIA, DESCONFORTO NAS MAMAS, HUMOR DEPRIMIDO, ACNE, NÁUSEA, AUMENTO DE PESO, DOR ABDOMINAL,
CISTO OVARIANO, CONDIÇÕES ASTÊNICAS, FLATULÊNCIA, FOGACHOS, DISTÚRBIOS DO SONO, IRRITABILIDADE, SANGRAMENTO UTERINO/VAGINAL INCLUINDO GOTEJAMENTO, NERVOSISMO, PERDA DE LIBIDO, ALOPECIA, DOR NAS COSTAS, DISTENSÃO ABDOMINAL, VÔMITO, ENXAQUECA, HUMOR ALTERADO. POUCO FREQÜENTES: RESSECAMENTO VULVOVAGINAL, DESEQUILÍBRIO DO SISTEMA NERVOSO AUTÔNOMO, CANDIDÍASE VAGINAL, PELE SECA, ANSIEDADE, DEPRESSÃO, DISTÚRBIO DA ATENÇÃO, CONSTIPAÇÃO, DESCONFORTO ABDOMINAL, INFLAMAÇÃO
GASTRINTESTINAL, HIPERIDROSE, PRURIDO, DIARRÉIA, INFECÇÃO DO TRATO URINÁRIO, CORRIMENTO GENITAL, DOR PÉLVICA, EDEMA, ANEMIA, DIMINUIÇÃO DE PESO, AUMENTO DE APETITE, OLHO SECO, ZUMBIDO, DISTÚRBIOS INESPECÍFICOS DO SISTEMA CIRCULATÓRIO, PALPITAÇÕES,
HIPOTENSÃO, DISPNÉIA, HUMOR ALTERADO, GENGIVITE, HIRSUTISMO, ONICÓLISE, CASPA, DERMATITE, CRESCIMENTO ANORMAL DE PÊLOS, REAÇÃO DE FOTOSSENSIBILIDADE, DISTÚRBIO DE PIGMENTAÇÃO, DOR NOS OSSOS, ESPASMOS MUSCULARES, DOR NA EXTREMIDADE, PESO NAS
EXTREMIDADES, VULVOVAGINITE ATRÓFICA, MASSA MAMÁRIA, DOENÇA FIBROCÍSTICA DA MAMA, ENDURECIMENTO DA MAMA. VENDA SOB PRESCRIÇÃO MÉDICA. SAC 0800 7021241. VE0211-CCDS4. REFERÊNCIAS: 1. KÖHLER G, FAUSTMANN TA, GERLINGER C, SEITZ C, MUECK
AO. A DOSE-RANGING STUDY TO DETERMINE THE EFFICACY AND SAFETY OF 1, 2, AND 4MG OF DIENOGEST DAILY FOR ENDOMETRIOSIS. INT J GYNAECOL OBSTET 2010; 108: 21 -25. 2. KÖHLER G, GORETZLEHNER G, BRACHMANN K. LIPID METABOLISM DURING TREATMENT OF ENDOMETRIOSIS WITH THE PROGESTIN DIENOGEST. ACTA OBSTET GYNECOL SCAND 1989; 68. 3. PETRAGLIA F, ET AL. REDUCED PELVIC PAIN IN WOMEN WITH ENDOMETRIOSIS: EFICACY OF LONG-TERM DIENOGEST TREATMENT. ARCH GYNECOL OBSTET (2012) 285:167 -173 . 4. STROWITZKI
T, FAUSTMANN T,GERLINGER C, SEITZ C. DIENOGESTE IN THE TREATMENT OF ENDOMETRIOSIS- ASSOCIATED PELVIC PAIN: A 12-WEEK, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY. EUR J OBST GYNECOL REPROD BIOL 2010.
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L.BR.WH.2012-07-30.0837
volume 35
Publicação mensal
ISSN 0100-7203
Órgão Oficial de Divulgação Científica da Federação Brasileira das
Associações de Ginecologia e Obstetrícia
Rev Bras Ginecol Obstet v. 35, n. 3, p. 93-142, março 2013
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Publicação mensal
ISSN 0100-7203
Rev Bras Ginecol Obstet v. 35, n. 3, p. 93-142, março 2013
Sumário
Editorial
93
Climatério e sexualidade
Climacteric and sexuality
Aarão Mendes Pinto Neto
Ana Lúcia Ribeiro Valadares
Lúcia Costa-Paiva
Artigos originais
97
Fernando Nalesso Aguiar
Henrique Nogueira Mendes
Carlos E. Bacchi
Filomena Marino Carvalho
103
Luiz Francisco Baccaro
Ilka de Fátima Boin
Lúcia Costa-Paiva
Aarão Mendes Pinto-Neto
111
Alina Coutinho Rodrigues Feitosa
Luciana Nunes Sampaio
Ana Graciele Lessa Batista
Carla Borges Pinheiro
117
Edward Araujo Júnior
Rogério Caixeta Moraes de Freitas
Zsuzsanna Ilona Katalin de Jármy Di Bella
Sandra Maria Alexandre
Mary Uchiyama Nakamura
Luciano Marcondes Machado Nardozza
Antonio Fernandes Moron
Comparison of nuclear grade and immunohistochemical features
in situ and invasive components of ductal carcinoma of breast
Comparação do grau nuclear e perfil imunoistoquímico nos componentes in situ e invasivo de
carcinoma mamário
Quality of life and menopausal symptoms in women with
liver transplants
Qualidade de vida e sintomas da menopausa em mulheres transplantadas hepáticas
Frequency of fear of needles and impact of a multidisciplinary
educational approach towards pregnant women with diabetes
Frequência de medo de agulhas e impacto de uma abordagem educacional multidisciplinar em
gestantes com diabetes
Assessment of pelvic floor by three-dimensional-ultrasound
in primiparous women according to delivery mode: initial
experience from a single reference service in Brazil
Avaliação do assoalho pélvico por meio da ultrassonografia tridimensional de mulheres primíparas
de acordo com o tipo de parto: experiência inicial de um centro de referência do Brasil
123
Sthela Maria Murad-Regadas
Leonardo Robson Pinheiro Sobreira Bezerra
Claudio Regis Sampaio Silveira
Jacyara de Jesus Rosa Pereira
Graziela Olivia da Silva Fernandes
José Ananias Vasconcelos Neto
Iris Daiana Dealcanfreitas
130
Alberto Moreno Zaconeta
Indara Ferreira Braz de Queiroz
Angélica Amorim Amato
Lucília Domingues Casulari da Motta
Luiz Augusto Casulari
Anatomical and functional characteristics of the pelvic floor in
nulliparous women submitted to three-dimensional endovaginal
ultrasonography: Case control study and evaluation of
interobserver agreement
Características anatômicas e funcionais do assoalho pélvico em nulíparas avaliadas por
ultrassonografia tridimensional endovaginal: Estudo caso-controle e avaliação da confiabilidade
interobservador
Depression with postpartum onset: a prospective cohort study
in women undergoing elective cesarean section in Brasilia, Brazil
Depressão com início após o parto: estudo de corte prospectivo em mulheres submetidas à cesárea
eletiva em Brasília, Brasil
Artigo de revisão
136
Gustavo Salata Romão
Paula Andréa de Albuquerque Salles Navarro
Uso clínico do hormônio antimülleriano em ginecologia
Clinical use for anti-mullerian hormone in gynecology
Resumos de tese
141
Autora: Cristianne Serafim da Silva Feuser
Orientador: Prof. Dr. Sebastião Freitas de Medeiros
141
Autora: Carolina Barbara Nogueira de Oliveira
Orientadora: Profa. Dra. Luciana de Barros Duarte
Co-orientadora: Priscila Falagan-Lotsch
Avaliação da função gonadotrópica hipofisária na síndrome dos
ovários policísticos, após a introdução dos critérios de Roterdã
Assessment of gonadotropic pituitary function in polycystic ovary syndrome after the Rotterdam criteria
Avaliação de polimorfismos nos genes EGF e EGFR e a
susceptibilidade à pré-eclâmpsia severa
Assessment of polymorphisms in EGF and EGFR genes and susceptibility to severe preeclampsia
Agenda
142
Agenda
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Conflito de interesses: devem ser mencionadas as situações que podem
influenciar de forma inadequada o desenvolvimento ou as conclusões do
trabalho. Entre essas situações, menciona-se a participação societária
nas empresas produtoras das drogas ou dos equipamentos citados
ou utilizados no trabalho, assim como em concorrentes da mesma.
São também consideradas fontes de conflito os auxílios recebidos, as
relações de subordinação no trabalho, as consultorias etc.
3.
No texto, deve ser mencionada a submissão e a aprovação do estudo por um Comitê de Ética em Pesquisa reconhecido pelo Comitê
Nacional de Ética em Pesquisa (CONEP).
4.
Artigo que trate de pesquisa clínica com seres humanos deve incluir
a declaração, na seção Métodos, de que os sujeitos do estudo
assinaram o termo de consentimento livre e informado. Os autores
relação aos casos já publicados. O texto das seções Introdução e
Discussão deve ser baseado em revisão bibliográfica atualizada. O
número de referências pode ser igual ao dos trabalhos completos.
3.
Técnicas e Equipamentos, para apresentação de inovações em diagnóstico, técnicas cirúrgicas e tratamentos, desde que não sejam, clara ou
veladamente, propaganda de drogas ou outros produtos. Valem para essa
categoria todas as normas aplicadas para trabalhos completos.
4.
Artigos de Revisão, incluindo avaliação crítica e sistematizada da literatura,
meta-análises ou revisões sistemáticas. A seleção dos temas e o convite
aos autores têm como base planejamento estabelecido pela editoria.
Contribuições espontâneas podem ser aceitas. Nesse caso, devem ser
enviados inicialmente um resumo ou roteiro do texto, a lista de autores e
v
devem informar, também, que a pesquisa foi conduzida de acordo
com a Declaração de Helsinque revisada em 2008.
5. No caso de trabalhos envolvendo experimentação animal, os
autores devem indicar na seção Métodos que foram seguidas as
normas contidas no CIOMS (Council for International Organization
of Medical Sciences) Ethical Code for Animal Experimentation (WHO
Chronicle 1985; 39(2):51-6) e os preceitos do Colégio Brasileiro
de Experimentação Animal - COBEA (www.cobea.org.br).
6. Todos os ensaios controlados aleatórios (randomized controlled
trials) e clínicos (clinical trials) submetidos à publicação devem ter
o registro em uma base de dados de ensaios clínicos. Essa é uma
orientação da Plataforma Internacional para Registros de Ensaios
Clínicos (ICTRP) da Organização Mundial da Saúde (OMS), e
do International Committee of Medical Journal Editors (ICMJE). As
instruções para o registro estão disponíveis no endereço eletrônico
do ICMJE (http://www.icmje.org/clin_trialup.htm) e o registro pode
ser feito na base de dados de ensaios clínicos da National Library
of Medicine, disponível em http://clinicaltrials.gov/ct/gui.
Preparo dos manuscritos
As normas que seguem foram baseadas no formato proposto pelo ICMJE
e publicado no artigo “Uniform Requirements for Manuscripts Submitted to
Biomedical Journals”, atualizado em Outubro de 2008 e disponível no
endereço eletrônico: http://www.icmje.org/.
Apresentação do texto
1.
Os trabalhos devem ser digitados em espaço 2 em todas as seções, da
página de rosto às referências bibliográficas, tabelas e legendas. Cada
página deve conter aproximadamente 25 linhas em uma coluna. Usar
preferencialmente o processador de texto Microsoft Word® e a fonte Times
New Roman 12. Não dar destaque a trechos do texto: não sublinhar ou
usar negrito. Numerar todas as páginas, iniciando pela de rosto.
Não usar maiúsculas nos nomes próprios (a não ser a primeira letra)
no texto ou nas referências bibliográficas. Não utilizar pontos nas
siglas (DPP em vez de D.P.P.). Quando usar siglas ou abreviaturas,
descrevê-las por extenso na primeira vez que mencionadas no texto.
Iniciar cada seção em uma nova página: página de rosto; resumo e
palavras ou expressões-chave; abstract e keywords; texto; agradecimentos; referências; tabelas individuais e legendas das figuras.
7.
O número de autores de trabalhos completos e relatos de casos é limitado a sete. Trabalhos de autoria coletiva (institucionais) devem ter os
responsáveis especificados. Trabalhos e estudos multicêntricos podem
ter número de autores compatível com o número de centros (cada situação será avaliada pela editoria e pelos revisores). Os investigadores
responsáveis pelos protocolos aplicados devem ser especificados. Todos
os autores devem ter conhecimento do texto enviado para a revista.
2.
8.
O conceito de coautoria é baseado na contribuição de cada um, para
a concepção e planejamento do trabalho, análise e interpretação
dos dados, para a redação ou revisão crítica do texto. A inclusão
de nomes cuja contribuição não se enquadre nos critérios citados ou
que tenham fornecido apenas suporte material não é justificável.
Página de rosto
9. Os autores serão informados, por correspondência eletrônica, do
recebimento dos trabalhos. Os trabalhos que estiverem de acordo
com as Instruções aos Autores e se enquadram na política editorial
da revista serão enviados para análise por revisores indicados pelo
editor. Os originais em desacordo com os objetivos da revista ou
com essas instruções são devolvidos aos autores para as adaptações
necessárias antes da avaliação pelo Conselho Editorial ou recusados
sem análise por revisores.
10. Junto dos arquivos originais, deve ser enviada uma carta de encaminhamento, na qual deve ficar explícita a concordância com as
normas editoriais, com o processo de revisão e com a transferência
de copyright para a revista.
11. Para manuscritos originais, não ultrapassar 25 páginas de texto
digitado ou aproximadamente 30.000 caracteres. Limitar o número
de tabelas e figuras ao necessário para apresentação dos resultados
que são discutidos (como norma geral, limitar a cinco). Para manuscritos do tipo Relato de Caso, não ultrapassar 15 páginas de texto
ou 18.000 caracteres (ver “Preparo do manuscrito”, “Resultados”).
12. O trabalho deve ser enviado pelo sistema de submissão online no portal
SciELO. O endereço eletrônico de todos os autores deve ser fornecido.
Desta forma, os coautores receberão informação sobre a submissão do
vi
trabalho e, assim, não será necessária a assinatura de todos na carta
de encaminhamento. O endereço eletrônico para correspondência com
a revista é [email protected]. O arquivo correspondente ao trabalho
deve ser único e deve conter texto, referências, tabelas e figuras.
Apresentar o título do trabalho em português e em inglês; nomes
completos dos autores sem abreviaturas; endereços eletrônicos válidos de
todos os autores (opcional, em substituição à carta de encaminhamento);
nome da instituição onde o trabalho foi desenvolvido; afiliação institucional
dos autores; informações sobre auxílios recebidos sob forma de bolsas de
estudos, financiamento, fornecimento de drogas, reagentes ou equipamentos. Obrigatoriamente deve ser fornecido o endereço da instituição onde o
trabalho foi desenvolvido, o qual é publicado na página inicial do trabalho.
Devem ser indicados nome, endereço, telefone/fax e e-mail do autor para
o qual a correspondência deve ser enviada. Essas informações pessoais
são empregadas apenas para correspondência com a revista e somente
são publicadas se houver pedido do(s) autor(es).
Resumo
O resumo do trabalho deve aparecer na segunda página. Para trabalhos completos, redigir um resumo estruturado, que deve ser dividido em
seções identificadas: objetivo, métodos, resultados e conclusões. Deve ter
aproximadamente 300 palavras. O resumo deve conter as informações
relevantes, permitindo que o leitor tenha uma ideia geral do trabalho. Deve
incluir descrição resumida de todos os métodos empregados e da análise
estatística efetuada. Expor os resultados numéricos mais relevantes, e não
apenas indicação de significância estatística. As conclusões devem ser
baseadas nos resultados do trabalho e não da literatura. Evitar o uso de
abreviações e símbolos. Não citar referências bibliográficas no resumo.
Abaixo do texto do resumo indicar o número de registro e/ou identificação para os ensaios controlados aleatórios e ensaios clínicos (ver item
5 das “Informações Gerais”).
Na mesma página do resumo, citar pelo menos três palavras ou
expressões-chave que serão empregadas para compor o índice anual da
revista. Devem ser baseadas nos Descritores em Ciências da Saúde (DeCS)
publicado pela Bireme, que é uma tradução do Medical Subject Headings
(MeSH) da National Library of Medicine e está disponível no endereço
eletrônico: http://decs.bvs.br.
O abstract deve ser versão fiel do texto do resumo estruturado (purpose,
methods, results e conclusions). Deve ser também acompanhado da versão
para o inglês das palavras ou expressões-chave (keywords). O resumo e o
abstract dos Relatos de Casos e dos Artigos de Revisão e de Atualização
não devem ser estruturados e são limitados a 150 palavras.
Introdução
Repetir, na primeira página da introdução, o título completo em português
e inglês. Nessa seção, mostre a situação atual dos conhecimentos sobre o
tópico em estudo, divergências e lacunas que possam eventualmente justificar o desenvolvimento do trabalho, mas sem revisão extensa da literatura.
Para Relatos de Casos, apresentar um resumo dos casos já publicados,
epidemiologia da condição relatada e uma justificativa para a apresentação
como caso isolado. Expor claramente os objetivos do trabalho.
Métodos
Iniciar essa seção indicando o planejamento do trabalho: se prospectivo
ou retrospectivo; ensaio clínico ou experimental; se a distribuição dos casos
foi aleatória ou não etc. Descrever os critérios para seleção das pacientes
ou Grupo Experimental, inclusive dos Controles. Identificar os equipamentos
e reagentes empregados (fabricante, cidade e país). Se a metodologia
aplicada já tiver sido empregada, indicar as referências, além da descrição
resumida do método. Descrever também os métodos estatísticos empregados
e as comparações para as quais cada teste foi empregado.
Os trabalhos que apresentam como objetivo a avaliação da eficácia
ou a tolerabilidade de tratamentos ou drogas devem, necessariamente,
incluir Grupo Controle adequado. Para informações adicionais sobre o
desenho de trabalhos desse tipo, consultar ICH Harmonized Tripartite
Guideline - Choice of Control Group and Related Issues in Clinical Trials
(http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/e10_e.html). Ver também
itens 4 e 5 das “Informações Gerais”.
Resultados
Apresentar os resultados em sequência lógica, no texto, nas tabelas
e nas figuras. Expor os resultados relevantes para o objetivo do trabalho
e que são discutidos. Não repetir no texto dessa seção todos os dados
das tabelas e figuras, mas descrever e enfatizar os mais importantes, sem
interpretação dos mesmos (ver também “Tabelas”). Nos Relatos de Casos,
as seções “Métodos” e “Resultados” são substituídas pela “Descrição do
caso”, mantendo-se as demais.
Discussão
Devem ser realçadas as informações novas e originais obtidas na
investigação. Não repetir dados e informações já mencionados nas seções
“Introdução” e “Resultados”. Evitar citação de tabelas e figuras. Ressaltar
a adequação dos métodos empregados na investigação. Comparar e
relacionar suas observações com as de outros autores, comentando e explicando as diferenças. Explicar as implicações dos achados, suas limitações
e fazer as recomendações decorrentes. Para Relatos de Casos, basear a
discussão em ampla e atualizada revisão da literatura. As informações
sobre os casos já publicados podem ser tabuladas e exibidas nessa seção
para comparações.
Agradecimentos
Dirigidos a pessoas que tenham colaborado intelectualmente, mas
cuja contribuição não justifica coautoria, ou para aquelas que tenham
provido apoio material.
Referências
Todos os autores e trabalhos citados no texto devem constar dessa
seção e vice-versa. Numerar as referências bibliográficas por ordem de
entrada no trabalho e usar esses números para as citações no texto. Evitar
número excessivo de referências, selecionando as mais relevantes para
cada afirmação e dando preferência para os trabalhos mais recentes.
Não empregar citações de difícil acesso, como resumos de trabalhos
apresentados em congressos, teses ou publicações de circulação restrita
(não indexados). Não empregar referências do tipo “observações não
publicadas” e “comunicação pessoal”. Artigos aceitos para publicação
podem ser citados acompanhados da expressão: “aceito e aguardando
publicação” ou “in press”, indicando-se periódico, volume e ano. Trabalhos
aceitos por periódicos que estejam disponíveis online, mas sem indicação
de fascículos e páginas, devem ser citados como “ahead of print”.
Outras publicações dos autores (autocitação) devem ser empregadas
apenas se houver necessidade clara e forem relacionadas ao tema. Nesse
caso, incluir entre as referências bibliográficas apenas trabalhos originais
publicados em periódicos regulares (não citar capítulos ou revisões).
O número de referências bibliográficas deve ser aproximadamente
35. Os autores são responsáveis pela exatidão dos dados constantes das
referências bibliográficas.
Para todas as referências, citar os autores até o sexto. Se houver
mais de seis autores, citar os seis primeiros, seguidos da expressão et al.,
conforme os seguintes modelos:
Formato impresso
• Artigos em revistas
- Ceccarelli F, Barberi S, Pontesilli A, Zancla S, Ranieri E. Ovarian
carcinoma presenting with axillary lymph node metastasis: a case
report. Eur J Gynaecol Oncol. 2011;32(2):237-9.
- Jiang Y, Brassard P, Severini A, Goleski V, Santos M, Leamon A, et al.
Type-specific prevalence of Human Papillomavirus infection among
women in the Northwest Territories, Canada. J Infect Public Health.
2011;4(5-6):219-27.
• Artigos com título em inglês e texto em português ou outra língua
Utilizar o titulo em inglês, entre colchetes e no final da referência,
indicar a língua na qual o artigo foi publicado.
- Prado DS, Santos DL. [Contraception in users of the public and private
sectors of health]. Rev Bras Ginecol Obstet. 2011;33(7)143-9.
Portuguese.
- Taketani Y, Mizuno M. [Application of anti-progesterone agents for
contraception]. Rinsho Fujinka Sanka. 1988;42(11):997-1000.
Japanese.
• Livro
- Baggish MS, Karram MM. Atlas of pelvic anatomy and gynecologic
surgery. 2nd ed. Philadelphia: WB Saunders; 2006.
vii
• Capítulos de livro
- Picciano MF. Pregnancy and lactation. In: Ziegler EE, Filer LJ, editors.
Present knowledge in nutrition. Washington (DC): ILSI Press; 1996.
p. 384-95.
Formato eletrônico
Apenas para informações estatísticas oficiais e citação de referências de periódicos não impressos. Para estatísticas oficiais, indicar
a entidade responsável, o endereço eletrônico, o nome do arquivo
ou entrada. Incluir o número de tela, data e hora do acesso. Termos
como “serial”, “periódico”, “homepage” e “monography”, por
exemplo, não são mais utilizados. Todos os documentos devem ser
indicados apenas como [Internet]. Para documentos eletrônicos com o
identificador DOI (Digital Object Identifier), este deve ser mencionado
no final da referência, além das informações que seguem:
- Brasil. Ministério da Saúde. DATASUS [Internet]. Informações de
Saúde. Estatísticas vitais. Mortalidade e nascidos vivos: nascidos
vivos desde 1994. Brasília (DF): Ministério da Saúde; 2008. [citado
2007 Fev 7]. Disponível em: <http://tabnet.datasus.gov.br/cgi/
deftohtm.exe?sinasc/cnv/nvuf.def>
Legendas
Digitar as legendas usando espaço duplo, acompanhando as respectivas figuras (gráficos, fotografias e ilustrações). Cada legenda deve ser
numerada em algarismos arábicos, correspondendo a cada figura, e na
ordem em que foram citadas no trabalho.
Abreviaturas e siglas
Devem ser precedidas do nome completo quando citadas pela primeira
vez no texto. Nas legendas das tabelas e figuras, devem ser acompanhadas
de seu nome por extenso. As abreviaturas e as siglas não devem ser usadas
no título dos artigos e nem no resumo.
Empregar o seguinte endereço para correspondências não previstas nas
instruções:
Jurandyr Moreira de Andrade
Editor
Revista Brasileira de Ginecologia e Obstetrícia – Editoria – Avenida
Bandeirantes, 3.900, 8º andar – Campus Universitário – CEP 14049-900 –
Ribeirão Preto (SP) – Fone: (16) 3602-2803 – Fax: (16) 3633-0946 –
E-mail: [email protected].
• Monografia na Internet ou livro eletrônico
- Foley KM, Gelband H, editors. Improving palliative care for cancer [Internet]. Washington: National Academy Press; 2001 [cited 2002 Jul 9].
Available from: http://www.nap.edu/books/0309074029/html/.
Tabelas
Apresentar as tabelas em páginas separadas, com espaço duplo e
preferencialmente fonte Arial 8. A numeração deve ser sequencial, em
algarismos arábicos, na ordem em que foram citadas no texto. Todas as
tabelas devem ter título e todas as colunas da tabela devem ser identificadas
com um cabeçalho. A legenda deve conter informações que permitam ao
leitor entender o conteúdo das tabelas e figuras, mesmo sem a leitura do
texto do trabalho. As linhas horizontais devem ser simples e limitadas a
duas no topo e uma no final da tabela. Não empregar linhas verticais.
Não usar funções de criação de tabelas, comandos de justificação, tabulações decimais ou centralizadas. Utilizar comandos de tabulação (tab)
e não o espaçador para separar as colunas e, para nova linha, a tecla
enter. No rodapé da tabela, deve constar legenda para abreviaturas e
testes estatísticos utilizados.
Figuras (gráficos, fotografias e ilustrações)
As figuras devem ser apresentadas em páginas separadas e numeradas
sequencialmente, em algarismos arábicos, conforme a ordem de aparecimento
no texto. Todas as figuras devem ter qualidade gráfica adequada e apresentar
título e legenda. Para evitar problemas que comprometam o padrão da revista,
o processo de digitalização de imagens (scan) deve obedecer aos seguintes
parâmetros: para gráficos ou esquemas, usar 300 dpi/bitmap para traço;
para ilustrações e fotos (preto e branco), usar 300 dpi/RGB ou grayscale. Em
todos os casos, os arquivos devem ter extensão .tif e/ou .jpg. Também são
aceitos arquivos com extensão .xls (Excel), .eps, .psd para ilustrações em curva
(gráficos, desenhos e esquemas). São aceitas, no máximo, cinco figuras. Se as
figuras já tiverem sido publicadas, devem vir acompanhadas de autorização
por escrito do autor/editor e constando a fonte na legenda da ilustração.
viii
Itens para a conferência para a submissão do manuscrito
Antes de enviar o manuscrito, conferir se as Instruções aos Autores foram
seguidas e verificar o atendimento dos itens listados a seguir:
1.
carta de encaminhamento assinada por todos os autores (escaneada
e anexada como documento suplementar ou enviada pelo correio)
ou informação dos endereços eletrônicos válidos de todos os autores
na página de rosto;
2. citação da aprovação do projeto do trabalho por Comissão de
Ética em Pesquisa, assinatura do termo de consentimento livre e
informado (na seção “Métodos”) e informação sobre o atendimento
das exigências para pesquisa em animais;
3.
número ou código do registro do estudo, se necessário, na página
de rosto (item 5 das “Informações Gerais”);
4.
conflito de interesses: informar se há ou não. Se houver, explicar sem
omissão de informações relevantes;
5.
página de rosto com todas as informações solicitadas;
6.
resumo e abstract estruturados e compatíveis com o texto do trabalho;
7. três ou mais palavras-chave relacionadas ao texto e respectivas
keywords baseadas no Decs;
8.
verificar se todas as tabelas e figuras estão corretamente citadas no
texto e numeradas, e se as legendas permitem o entendimento das
mesmas;
9. referências bibliográficas: numeradas na ordem de aparecimento e
corretamente digitadas. Verificar se todos os trabalhos citados estão
na lista de referências e se todos os listados estão citados no texto.
Aarão Mendes Pinto Neto1
Ana Lúcia Ribeiro Valadares2
Lúcia Costa-Paiva3
Climacteric and sexuality
Editorial
A função sexual feminina é multifacetada, é o resultado de uma complexa interação
entre fatores fisiológicos, psicológicos e sociais. Esse complexo cruzamento de domínios
sociais, psicológicos e biológicos pode ser entendido como a interação de pelo menos quatro
fenômenos: desejo, crenças, valores e motivação. O primeiro é devido parcialmente a mecanismos biológicos, neuroendócrinos que estimulam o interesse sexual espontâneo, endógeno.
Crenças e valores são consequências de experiências sociais que promovem as expectativas
e a idealização da atividade sexual, que, por sua vez, participam no disparo de fenômenos
fisiológicos, ligados ao interesse sexual. Por seu lado, a motivação depende tanto de fatores
emocionais, quanto interpessoais1.
A compreensão da função sexual feminina desenvolveu-se significativamente a partir
das investigações de Masters e Johnson, em 1966, dentro dos modelos tradicionais, lineares, biologicamente determinados da resposta sexual humana. Sua abordagem dividia a
resposta sexual em quatro fases distintas: excitação, platô, orgasmo e resolução2. Cerca de
uma década mais tarde, Kaplan3 incorporou o desejo no seu modelo. A maior compreensão
da função sexual feminina levou à proposição de representações não lineares, que enfatizam
a importância de fatores não biológicos, tendo Basson4,5 apontado para a importância da
associação entre intimidade emocional e satisfação no relacionamento e a função sexual.
Ela sugeriu que as mulheres têm muitas razões para se envolverem nas atividades sexuais
que não sejam o desejo sexual, como os modelos tradicionais sugerem. O desejo espontâneo e interesse aparecem mais frequentemente no início de um relacionamento, ou após
uma longa separação de um parceiro, por exemplo, e não é frequente em relacionamentos
de longa duração. Nesse último caso, sugere Basson4,5, a maior proximidade emocional e
intimidade podem predispor as mulheres a se envolverem na atividade sexual. A partir de
um ponto de neutralidade sexual, ocorre a excitação e o desejo sexual é ativado. A excitação, portanto, pode preceder o desejo e acioná-lo, permitindo que a relação sexual ocorra
de forma prazerosa. No entanto, para cada mulher, individualmente, haverá uma definição
específica do que é uma função sexual normal, com base na sua cultura, na sua história de
vida, nas suas experiências sexuais anteriores e na sua própria estrutura biológica. Neste
sentido, a função sexual de uma mulher deve ser vista como os outros aspectos individuais
Correspondência
Aarão Mendes Pinto Neto
Departamento de Tocoginecologia da Faculdade
de Ciências Médicas da UNICAMP
Rua Alexander Fleming, 101 – Cidade Universitária
“Zeferino Vaz” – Barão Geraldo
CEP: 13083-881
Campinas (SP), Brasil
Recebido
21/09/2012
Aceito com modificações
01/10/2012
Trabalho realizado no Departamento de Tocoginecologia, Faculdade da Ciências Médicas, Universidade Estadual de Campinas –
UNICAMP – Campinas (SP), Brasil.
1
Departamento de Tocoginecologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas – UNICAMP –
Campinas (SP), Brasil.
2
Programa de Pós-Doutorado do Departamento de Tocoginecologia, Faculdade de Ciências Médicas, Universidade Estadual de
Campinas – UNICAMP – Campinas (SP), Brasil.
3
Departamento de Tocoginecologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas – UNICAMP –
Campinas (SP), Brasil.
Pinto Neto AM , Valadares ALR, Costa-Paiva L
de sua forma de ser6. Os problemas sexuais devem ser avaliados com sensibilidade no que diz respeito a diferenças
individuais na atividade e interesse sexual7.
Com o aumento da expectativa de vida, os estudos sobre sexualidade e suas diversas formas de expressão têm se
tornado relevantes, uma vez que a função sexual influencia a qualidade de vida dentro do processo de envelhecimento8.
A disfunção sexual de curta duração pode provocar frustração e angústia. Quando crônica, pode levar à ansiedade e
depressão, prejudicando relacionamentos, ou criando problemas em diferentes áreas da vida da mulher9,10. As queixas
sexuais são prevalentes durante toda a vida reprodutiva, mas durante o climatério as mulheres podem ficar mais vulneráveis à disfunção sexual feminina (DSF) devido à interação de vários fatores10. Durante a transição menopausal e
menopausa, além dos fatores físicos, psicológicos, sociais e relativos ao parceiro sexual, que influenciam a função sexual
aparecem alterações hormonais que provocam diferentes efeitos nos órgãos genitais e no sistema nervoso central. Esse
fato é compreensível, uma vez que os hormônios podem influenciar direta ou indiretamente a função sexual feminina11.
Os estrogênios são particularmente importantes na manutenção do tecido genital saudável, e a atrofia vulvovaginal,
causada pela deficiência de estrogênio na pós-menopausa, leva ao afinamento do epitélio vaginal, perda de elasticidade,
aumento do pH vaginal, redução da lubrificação e alterações na sensação genital, ressecamento vaginal e dispareunia,
sintomas muito comuns nessa fase12. A atrofia vaginal tem impacto significativo sobre o funcionamento sexual e pode
afetar todos os domínios da função sexual, incluindo o desejo sexual13. Além disso, durante a peri- ou pós-menopausa,
os efeitos sistêmicos da deficiência estrogênica, tais como sintomas vasomotores, insônia, alterações do humor e sentimentos negativos que são frequentes podem piorar a função sexual nas mulheres14,15, o que foi evidenciado utilizando-se
o questionário Short Personal Experiences Questionnaire (SPEQ), adaptado no Brasil16.
Embora não haja compreensão precisa do seu papel na sexualidade feminina, os andrógenos, produzidos na glândula
adrenal e ovários, parecem ter importância no desejo e na excitação sexual17. O nível de andrógenos circulantes declina
gradualmente com a idade, devido a uma redução da produção adrenal: os níveis de andrógenos circulantes em uma
mulher de 40 anos correspondem à metade do que é encontrado aos 2018.
A redução da produção hormonal, que afeta os receptores em vários sistemas do corpo, provoca, portanto, consequências na função sexual que variam de efeitos na função cognitiva à resposta genital local. Quando há diminuição
abrupta da produção desses hormônios, como na menopausa cirúrgica ou quimioterapia, o efeito adverso sobre a função
sexual, especialmente no desejo sexual é ainda mais significativo19.
O desejo sexual hipoativo (DSH) foi o problema sexual mais prevalente identificado em estudo populacional em mulheres brasileiras de meia-idade, seguido pela disfunção da excitação e orgasmo. O estudo identificou o
DSH em aproximadamente 60% dessas mulheres20. Estudos conduzidos em outros contextos divulgaram resultados
similares, indicando o DSH como a alteração sexual feminina mais comum no Egito (66,4%)21, Índia (73,2%)22 e
Turquia (60,6%)23. Existem evidências de que fatores psicossociais, incluindo a qualidade do relacionamento interpessoal, suporte social, bem-estar emocional, doenças crônicas e depressão influenciam a função sexual24, assim como
a ausência de parceiro ou parceiro com problemas de saúde25. No entanto, entre todos os fatores que afetam o desejo
sexual feminino, o envelhecimento parece ser o mais significativo26. Além disso, as doenças crônicas, que aparecem com
o envelhecimento e os tratamentos relacionados, podem afetar direta ou indiretamente a função sexual feminina, pela
diminuição dos níveis dos esteroides sexuais, inervação e perfusão sanguínea dos órgãos genitais femininos27. Para as
mulheres de meia-idade, sentir-se bem/excelente foi fator protetor para a ocorrência de disfunção sexual e associou-se
à melhoria da função sexual em diversos domínios da função sexual20. Essa melhor autopercepção pode estar associada
a ter propósito de vida, o que foi evidenciado em estudo que verificou a associação entre maior satisfação sexual e um
sentido maior de propósito de vida28.
Em relação ao parceiro sexual, estudos indicam associação entre grau de intimidade emocional com o parceiro e
satisfação sexual. No entanto, a maior duração do relacionamento teve efeitos adversos na sexualidade em estudo realizado com mulheres brasileiras de meia-idade29. Algumas possíveis explicações incluem a habituação, rotina, papéis
de gênero, assim como polarização de interesses, e outros problemas como conflitos e dificuldades de comunicação30.
Nesse mesmo estudo, a sexualidade foi influenciada positivamente pela presença de relações sexuais com penetração29,
que foi confirmado também em outros estudos31. No entanto, constatou-se que no decorrer do envelhecimento, a atividade sexual parece mudar e consiste predominantemente de beijos, abraços e toque sexual, como foi documentado
em pesquisas com casais com 65 anos ou mais32. Além da mudança na forma de expressão da sexualidade, estudos
mostram também uma diminuição da frequência da atividade sexual com o envelhecimento, mas a satisfação sexual
permanece para a maioria das que continuam sexualmente ativas33. A presença de atividade sexual, nesse processo de
envelhecimento, apesar de menos frequente, pode tornar-se cada vez mais importante, não somente como ato sexual
físico, mas como preservação de relacionamento íntimo que ajuda diminuir os sentimentos de solidão e isolamento,
94
Rev Bras Ginecol Obstet. 2013; 35(3):93-6
uma vez que, no processo de envelhecimento, existe um estreitamento na rede de relacionamentos sociais e o papel
social dos indivíduos se restringe. Além disso, a atividade sexual pode ser uma força básica para conectar as pessoas
com o significado de suas próprias vidas34. Como a sexualidade envolve a percepção e controle do corpo e como a vida
é movimento, é importante adequar este movimento do corpo no decorrer do climatério e envelhecimento, assumir
limitações impostas pelas mudanças corporais, cientes de que elas são parte da evolução natural dos indivíduos e ferramentas usadas para o amadurecimento e crescimento dos seres humanos35.
Todos esses dados confirmam a complexidade da resposta sexual e a importância do entendimento dos fatores que podem influenciar os diversos domínios da função sexual no climatério, assim como a compreensão das mudanças que
ocorrem no decorrer do processo de envelhecimento para um melhor atendimento dessas mulheres pelo ginecologista.
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96
Fernando Nalesso Aguiar1
Henrique Nogueira Mendes2
Carlos E. Bacchi3
Filomena Marino Carvalho4
Comparison of nuclear grade and
immunohistochemical features in situ and invasive
components of ductal carcinoma of breast
Comparação do grau nuclear e perfil imunoistoquímico nos
componentes in situ e invasivo de carcinoma mamário
Artigo Original
Abstract
Keywords
PURPOSE: To compare the prognostic and predictive features between in situ and invasive components of ductal breast
carcinomas. METHODS: We selected 146 consecutive breast samples with ductal carcinoma in situ (DCIS) associated
with adjacent invasive breast carcinoma (IBC). We evaluated nuclear grade and immunohistochemical expression
of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin
5/6 (CK5/6), and epidermal growth factor receptor (EGFR) in both components, in situ and invasive, and the Ki-67
percentage of cells in the invasive part. The DCIS and IBC were classified in molecular surrogate types determined
by the immunohistochemical profile as luminal (RE/PR-positive/ HER2-negative), triple-positive (RE/RP/HER2-positive),
HER2-enriched (ER/PR-negative/HER2-positive), and triple-negative (RE/RP/HER2-negative). Discrimination between
luminal A and luminal B was not performed due to statistical purposes. Correlations between the categories in the two
groups were made using the Spearman correlation method. RESULTS: There was a significant correlation between
nuclear grade (p<0.0001), expression of RE/RP (p<0.0001), overexpression of HER2 (p<0.0001), expression of
EGFR (p<0.0001), and molecular profile (p<0.0001) between components in situ and IBC. CK 5/6 showed different
distribution in DCIS and IBC, presenting a significant association with the triple-negative phenotype in IBC, but a negative
association among DCIS. CONCLUSIONS: Our results suggest that classical prognostic and predictive features of IBC
are already determined in the preinvasive stage of the disease. However the role of CK5/6 in invasive carcinoma
may be different from the precursor lesions.
Breast neoplasms/chemistry
Carcinoma, ductal, breast/chemistry
Immunoenzyme techniques
Receptors, estrogen/analysis
Receptor, erbB-2/analysis
keratin-5/analysis
keratin-6/analysis
Ki-67 antigen/analysis
Tumor makers, biological
Palavras-chave
Neoplasias da mama/química
Carcinoma ductal de mama/química
Técnicas imunoenzimáticas
Receptores estrogênicos/análise
Receptor, erbB-2/análise
Queratina-5/análise
Queratina-6/análise
Antígeno Ki-67/análise
Marcadores biológicos de tumor
Correspondence
Filomena Marino Carvalho
Faculdade de Medicina da Universidade de São Paulo,
Departamento de Patologia Avenida Doutor Arnaldo, 455, sala 1149
Zip code: 02146-903
São Paulo (SP), Brazil
Received
01/11/2013
Accepted with modifications
02/01/2013
Resumo
OBJETIVO: Comparar características prognósticas e preditivas entre os componentes in situ e invasivo de carcinomas
ductais da mama. MÉTODOS: Selecionamos 146 amostras mamárias consecutivas com carcinoma ductal in situ (CDIS)
associado com carcinoma invasivo (CI) adjacente. Avaliamos grau nuclear e a expressão imunoistoquímica de receptor
de estrogênio (RE), receptor de progesterona (RP), receptor do fator de crescimento epidérmico humano 2 (HER2),
citoqueratina 5/6 (CK5/6) e o receptor do fator de crescimento epidérmico (EGFR) em ambos componentes, in situ
e invasor, e a porcentagem de células marcadas pelo Ki-67 no componente invasivo. CDIS e CI foram classificados
nos tipos moleculares, determinados pelo perfil imunoistoquímico, como luminal (RE/RP-positivo/HER2-negativo), triplopositivo (RE/RP/HER2-positivo), HER2-puro (RE/RP-negativo/HER2-positivo) e triplo-negativo (RE/RP/HER2-negativo).
A discriminação entre luminal A e Luminal B não foi feita por motivos estatísticos. Correlações entre as categorias dos
dois grupos foram feitas pelo método de correlação de Spearman. RESULTADOS: Houve significante associação entre
grau nuclear (p<0,0001), expressão de RE/RP) (p<0,0001), superexpressão de HER2 (p<0,0001), expressão de
EGFR (p<0,0001) e perfil molecular (p<0,0001) entre os componentes in situ e invasivo. CK5/6 mostrou distribuição
distinta em CDIS e CI, apresentando significante associação com o fenótipo triplo-negativo em CI, mas uma associação
negativa ente os CDIS. CONCLUSÕES: Nossos resultados sugerem que as características prognósticas e preditivas
clássicas dos CI estão já determinadas no estágio pré-invasivo da doença. Entretanto, o papel da CK5/6 no carcinoma
invasivo pode ser diferente daquele das lesões precursoras.
Study carried out at the Pathology Department, Faculdade de Medicina, Univerisdade de São Paulo – USP – São Paulo (SP), Brazil.
Instituto do Câncer do Estado de São Paulo – ICESP – São Paulo (SP), Brazil; Department of Pathology, Faculdade de Medicina,
Universidade de São Paulo – USP – São Paulo (SP), Brazil.
2
Faculdade de Medicina, Universidade de São Paulo – USP – São Paulo (SP), Brazil.
3
Consultancy in Pathology – Botucatu (SP), Brazil.
4
Department of Pathology, Faculdade de Medicina, Universidade de São Paulo – USP – São Paulo (SP), Brazil.
1
Aguiar FN, Mendes HN, Bacchi CE, Carvalho FM
Introduction
Ductal carcinomas in situ (DCIS) are immediate precursors of most breast cancer, but they are heterogeneous
regarding morphology and invasiveness risk1. The prevalence of DCIS has been rising in the last decades, probably
due to better screening programs and now accounts for
approximately 20‒25% of all breast cancer diagnoses2.
The formerly accepted linear multi-step process of breast
carcinogenesis, from hyperplasia, atypical hyperplasia, and
carcinoma in situ, to invasive and metastatic carcinoma,
changed to a more complex process involving a series of
stochastic genetic events that lead to distinct and divergent pathways towards invasive carcinoma3-7. Although
the progression of DCIS to invasive breast carcinoma
(IBC) is believed to be an important aspect feature of
tumor aggressiveness, identification of biomarkers and
molecular profiles of IBC and DCIS is yet far to be fully
elucidated6,8,9. Previous studies indicate that DCIS may
be classified in a similar manner to invasive breast cancer10-13. The understanding of the transition between
the preinvasive and invasive stages in breast carcinomas
is the key to more efficient strategies for early diagnosis
and treatment, as well as it expands the knowledge about
the complex mechanisms of carcinogenesis. In this study
our aim was to compare the prognostic and predictive
pathological features between the in situ and invasive
components of ductal breast carcinoma.
Methods
This study was approved by the Department of
Pathology Scientific Committee of the Faculdade de
Medicina da Universidade de São Paulo and by the Ethical
Committee for Research Projects of the Hospital das
Clínicas da Faculdade de Medicina da Universidade de São
Paulo (CAPPesq, process 2011/14741-7). As the study
was retrospective, informed patient consent was waived
and any form of patient identification was abolished.
We selected breast samples from patients with confirmed diagnosis of IBC after an initial sample represented
by DCIS only. Cases were obtained from the files of the
Division of Surgical Pathology of Faculdade de Medicina
da Universidade de São Paulo in the period from 2000 to
2009. All tissues had been fixed in 10% buffered formaldehyde and embedded in paraffin. The slides were rigorously
reviewed and classified by the same pathologist with expertise in breast pathology (FNA). For cases with discordant
interpretation in relation to original report, a consensus was
determined by simultaneous examination under a dual-head
microscope (FNA and FMC). We included only carcinomas
of non-special type according criteria of the histological
classification of tumors of World Health Organization,
98
201214. Carcinomas of special types and cases with insufficient material to immunohistochemistry evaluation, signs
of tissue autolysis and from pregnant patients were excluded
from the study. We obtained 146 breast samples that met
the criteria of inclusion. The age of the patients ranged
from 29 to 87 years (median=59 years). Nuclear grades 1
(G1) and 2 (G2) were grouped as low-grade category, while
nuclear grade 3 (G3) was defined as high-grade category
(Figure 1). Immunohistochemistry was performed on
3 µm-thick histological sections containing in situ and invasive neoplasia. The source and dilutions of the antibodies
and epitope retrieval methods used are listed in Table 1.
Novolink® was used as the dectection system (Leica,
Bannockburn, IL, USA). Nuclear positivity was considered specific for estrogen receptor (ER) (Figure 1B and
1E), progesterone receptor (PR) and Ki-67; membranous
positivity for human epidermal growth factor receptor 2
(HER2) (Figure 2) and epidermal growth factor receptor
(EGFR), and cytoplasmic, for cytokeratin 5/6 (CK5/6)
(Figure 1). Lesions with at least 10% of cells stained were
considered positive for ER and PR. For CK5/6 expression
we considered any positivity above 1% of epithelial cells.
For HER2 and EGFR we only considered samples positive
if they scored 3+ according to American Society of Clinical
Oncology (ASCO) and College of American Pathologists
(CAP) recommendations15.
An approximation of breast cancer molecular subtypes
was used according to the following immunohistochemical surrogate criteria modified from St. Gallen consensus16: Luminal A (ER/PR-positive and Ki-67<14%),
Luminal B (ER/PR-positive, HER2-negative and Ki67≥14%), triple-positive (ER/PR/HER2 positive), HER2enriched (ER/PR-negative and HER2-positive), and
triple-negative (ER/PR/HER2-negative) (TN). For DCIS
we considered luminal A as being the lesions with at least
50% of ER and/or PR positive neoplastic cells, and HER2
negative; Luminal B as being the lesions with less than
Table 1. Source, dilutions of the antibodies and epitope retrieval methods used
Antigen
Clone
Dilution
Antigen retrieval
Manufacturer
ThermoScientific
Dako
ER
SP1
1:500
PC, 9 min with citric acid
pH 6.0
PR
PgR636
1:1000
pH 6.0
SP3
1:100
pH 6.0
MIB1
1:600
pH 6.0
Dako
D5/16B4
1:100
MO, 3.3 min with citric acid
ph 6.0
Dako
31G7
1:200
0.1% Pronase, 15 min
Zymed
HER2
Ki-67
CK 5/6
EGFR
ThermoScientific
ER: estrogen receptor; PR: progesterone receptor; HER2: human epidermal growth
factor receptor 2; CK: cytokeratin 5/6; EGFR: epidermal growth factor receptor; PC:
pressure cooker; MO: microwave oven.
Comparison of nuclear grade and immunohistochemical features in situ and invasive components of ductal carcinoma of breast
50% of ER and/or RP positive cells, and HER2 negative;
Triple-positive as being ER and/or PR positive associated
with HER2 positivity; HER2-enriched as being ER and/
or PR negative and HER2 positive, and TN as being
negative for ER, PR and HER2. The subgroups luminal
A and B were grouped as luminal category, as only three
cases expressed less than 50% of hormonal receptors.
Associations between CK5/6 with the TN phenotype
were determined by chi-square test and Odds Ratio with 95%
confidence interval was calculated for the DCIS and IBC.
Correlations between the categories of DCIS and IBC were
made using the Spearman correlation method. Statistical
analyses were performed using MedCalc for Windows (version 11.5.0.0; MedCalc Software, Mariakerke, Belgium),
and a p-value less than 0.05 was considered significant.
A
B
C
D
E
F
Figure 1. Upper row shows a low grade DCIS (A), ER-positive (B) and
CK 5/6-positve (C). The second row presents a high grade DCIS (D),
ER-positive (E) and CK5/6-positive (F).
A
B
Results
The distribution of the variables among in situ and
invasive components of our cases of breast carcinoma is
summarized in Table 2. Three cases of IBC G3 were associated with DCIS G2. All DCIS cases revealing G3 were
associated with G3 in the invasive component as well.
Two ER-negative DCIS cases showed invasive component
ER-positive. Only one case of DCIS HER2-positive was
associated with IBC HER2-negative. This was a 46 years-old
patient with a luminal B tumor presenting with ERnegative, PR-positive and 30% cell proliferation index
by Ki-67 immunostaining. Fifteen DCIS cases expressed
CK5/6, but only 5/15 expressed this cytokeratin in the
invasive component. On the other hand, of the 14 IBC
with expression of CK5/6, 7 expressed it also in the DCIS.
The expression of CK5/6 was associated with the
triple-negative phenotype in IBC (OR=7.8; 95%CI
2.4–25.3; p=0.0006). Oppositely, the expression of
CK5/6 was negatively associated with TN phenotype
among DCIS (OR=0.2; 95%CI 2.4–25.3; p=0.02).
Only 2 cases out of 16 DCIS-EGFR-positive were
negative for this marker in the IBC. Among the 100
cases of DCIS without expression of EGFR, only 5 had
an invasive component positive for this growth factor.
All TN DCIS were associated with TN IBC. Only one
TN breast cancer had a luminal DCIS component characterized by G3 and presence of ER/PR in 10% of the
tumor cells. The basal-like profile defined by ER/PR/
HER2 negative and CK5/6 and/or EGFR positive was
identified in 10 cases of DCIS, all of them with the same
profile in the invasive component. There were 2 cases
of IBC TN basal-like with an unknown status of the
DCIS component, and 3 cases with a TN non-basal DCIS.
Six cases of TN DCIS with non-basal-like phenotype
were associated with 3 basal-like and 3 non-basal-like
phenotypes in the invasive components.
Figure 2. HER2 score 3+ in DCIS (A) and invasive carcinoma (B), both
components nuclear grade 3.
Table 2. Comparison of pathological and immunohistochemical features in situ and invasive
components of 146 ductal carcinomas
Carcinoma
in situ
Invasive
carcinoma
G1 or G2 (low grade)
95
92
G3 (high grade)
51
54
Positive
104
106
40
Variables
Nuclear grade
ER/PR
HER2
CK 5/6
EGFR
Immunohistochemical
profile
Triple-negative
Negative
42
Positive (score 3)
27
26
Negative (score 0 or 1)
119
120
Positive
15
14
132
Negative
118
Non-available
13
0
Positive
16
22
Negative
100
107
Non-available
30
17
Luminal (A+B)
98
98
Triple-positive
6
8
HER2-enriched
21
18
Triple-negative
21
22
Basal-like profile
10
15
Non-basal-like profile
6
7
Non-available
5
0
ER: estrogen receptor; PR: progesterone receptor; HER2: human epidermal growth
factor receptor 2; CK: cytokeratin 5/6; EGFR: epidermal growth factor receptor.
99
Table 3. Correlation between pathological and immunohistochemical features of ductal
carcinoma in situ and adjacent invasive carcinoma (n=146)
Variables
Nuclear grade
Low (G1 or G2)
ER/PR
HER2
EGFR
High (3)
Positive
Negative
Positive
Negative
Positive
Negative
p-value
Rho*
95%CI for
Rho
<0.0001
0.96
0.94–0.97
<0.0001
0.93
0.91–0.95
<0.0001
0.91
0.88–0.94
<0.0001
0.76
0.68–0.83
<0.0001
0.96
0.95–0.97
Luminal (A+B)
Molecular
profile
Triple-positive
HER2
Triple-negative
*Spearman correlation method; ER: estrogen receptor; PR: progesterone receptor;
HER2: human epidermal growth factor receptor 2; CK: cytokeratin 5/6; EGFR:
epidermal growth factor receptor.
There was a significant correlation between nuclear
grade (p<0.0001), expression of ER/PR (p<0.0001),
overexpression of HER2 (p<0.0001) and molecular profile
(p<0.0001) between components in situ and invasive. The
value of the correlation coefficient ranged from 0.918
(HER2) to 0.967 (molecular profile) (Table 3).
Discussion
In this study we observed similar distribution of
the nuclear grade and immunohistochemical variables in
DCIS and the correspondent invasive component. This
observation suggests that these classical prognostic and
predictive factors may be predetermined in the preinvasive
stage of the disease.
The management of breast cancer is largely based
on some clinical and pathological parameters, including
age of patient, size of tumor, nodal status, histologic
and nuclear grade, and immunohistochemical evaluation of ER, PR, HER2, and Ki-67, either as individual
information, or as panel of markers to approximate the
molecular subtyping classification16. DCIS are genuine
precursors of breast cancer, but the mechanisms involved
in this transition are mostly unknown. DCIS is a very
heterogeneous disease with variable risk of invasion as
well of recurrence, not to mention that one half of all
recurrences occur as invasive cancer17,18.
According to our results the phenotype of IBC
is very similar to the in situ component, suggesting
that the classical prognostic and predictive factors
are determined previously to the invasive capacity of
the precursors. Similar results have been presented in
100
the literature10,11,19,20. Ottesen found similar morphology, immunohistochemistry, and DNA ploidy both
in DCIS and the invasive component19. Park et al.20
compared HER2 status between in situ and invasive
component of 270 breast carcinomas and found a high
concordance of 98.5 and 99.3%, respectively by FISH
and immunohistochemistry. Steinman et al.21 studied ER,
PR, HER2, EGFR and several cytokeratins, including
CK5/6, in 96 cases of DCIS with co-existing invasive
carcinoma and they found a high rate of concordance
ranging from 92.3% for ER to 100% for HER2 and
EGFR. Our findings support the evidence that molecular
changes implicated in the progression from in situ status
to invasive one occur before morphological manifestation of invasiveness. Interestingly, among these classical
parameters, nuclear grade is one of the most powerful
prognostic and predictive factors and it is associated with
distinct genetic changes22-25. According to some studies,
it is possible that even molecular changes described in
DCIS, although could be related to grade, are not determinant of invasion. Moelans et al.26 compared copy
numbers changes in 21 breast cancer related genes and
the methylation status of 25 breast cancer-related genes27
between laser-microdissected ductal carcinoma in situ
(DCIS) and adjacent invasive ductal cancer (IDC) lesions.
These authors did not observe significant differences
between DCIS and adjacent IBC, suggesting that DCIS
is genetically as advanced as its invasive counterpart. In
an elegant study, Muggerud et al.12 analyzed gene expressions patterns of 31 pure DCIS, 36 pure invasive cancers
and 42 cases of DCIS with invasive cancer. The authors
found a DCIS signature associated to gene expression
characteristics more similar to advanced tumors. This set
of genes was independent of grade, ER-status, and HER2status, and it was suggestive of several processes related
to the re-organization of the microenvironment12. In our
opinion one of the most promising way to investigate
the tendency of breast carcinoma to invade the stroma
is to try to understand the factors related to interaction
of the tumor cells with the microenvironment.
Although nuclear grade is considered the most important parameter to classify DCIS together with tumor
size and margins status, it becomes evident that it is not
a good predictor of invasive potential. Holmes et al.28
studied 141 patients who underwent conservative surgery with clear margins for DCIS. They observed 60
recurrences occurred with a median follow-up of 191
months. After multivariate analysis, HER2 score 3+ was
associated with reduced time to recurrence. However, no
pathological or immunohistochemical characteristic was
predictive of recurrence. The comprehensive systematic
review conducted by Lari and Kuerer29 to identify the
Comparison of nuclear grade and immunohistochemical features in situ and invasive components of ductal carcinoma of breast
role of biological markers in DCIS, including steroid
receptors, proliferation markers, cell cycle regulation
and apoptotic markers, angiogenesis-related proteins,
epidermal growth factor receptor family receptors, extracellular matrix-related proteins, and COX-2, failed
to find any useful marker.
After the molecular classification of breast into
intrinsic subtypes luminal A, Luminal B, HER2 and basallike30 and the demonstration of immunohistochemical
surrogates31, several groups dedicated to investigate the
role of the same profiles in DCIS10,13,32. Our results show
a similar distribution of the molecular subtypes between
in situ and invasive carcinomas. The more controversial
subtype is the basal-like. According Nielsen et al.31,
the better determination of the basal-like subgroup
is based on TN phenotype associated to expression of
CK5/6 and/or EGFR. We studied a substantial number
of TN DCIS (21 cases), all of them were associated with
TN in the invasive component. However, our results
indicate that the significance of basal cytokeratin 5/6 in
DCIS may be different of that in invasive carcinomas.
In fact, CK5/6 was negatively associated with the TN
phenotype and more prevalent in the other subtypes.
Further studies are needed to clarify the role of this
cytokeratin in DCIS.
Acknowledgement
This study was supported by grants from FAPESP (São
Paulo Research Founding), process number 2011/14741-7.
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Luiz Francisco Baccaro1
Ilka de Fátima Boin2
Lúcia Costa-Paiva1
Aarão Mendes Pinto-Neto1
Quality of life and menopausal symptoms in
women with liver transplants
Qualidade de vida e sintomas da menopausa em mulheres
transplantadas hepáticas
Artigo Original
Abstract
Keywords
Hot flashes
Liver transplantation
Menopause
Quality of life
Palavras-chave
Fogachos
Transplante de fígado
Menopausa
Qualidade de vida
PURPOSE: To assess quality of life and climacteric symptoms in women with and without liver transplants. METHODS: This
was a cross-sectional study of 52 women undergoing follow-up at a university hospital in southeastern Brazil from
February 4th, 2009 to January 5th, 2011. Twenty-four of these women were 35 years old or older and had undergone
liver transplantation at least one year before study entry. The remaining 28 women had no liver disease and were
matched by age and menstrual patterns to the patients with transplants. The abbreviated version of the World Health
Organization (WHOQOL-BREF) questionnaire was used to assess quality of life. Menopausal symptoms were assessed
using the Menopause Rating Scale (MRS). Statistical analysis was carried out by Student’s t -test, Mann-Whitney test and
analysis of variance. Correlations between MRS and the WHOQOL-BREF were established by correlation coefficients.
RESULTS: The mean age of the women included in the study was 52.2 (±10.4) years and the mean time since
transplantation was 6.1 (±3.3) years. Women with liver transplants had better quality of life scores in the environment
domain (p=0.01). No difference was noted between the two groups in any domain of the MRS. For women in the
comparison group, there was a strongly negative correlation between somatic symptoms in the MRS and the physical
domain of the WHOQOL-BREF (p<0.01; r=-0.8). In contrast, there was only a moderate association for women with
liver transplants (p<0.01; r=-0.5). CONCLUSIONS: Women with liver transplants had better quality of life scores in
the domain related to environment and did not exhibit more intense climacteric symptoms than did those with no liver
disease. Climacteric symptoms negatively influenced quality of life in liver transplant recipients, although less intensely
than in women without a history of liver disease.
Resumo
OBJETIVO: Avaliar a qualidade de vida e os sintomas do climatério em mulheres com e sem transplante de fígado.
MÉTODOS: Estudo de corte transversal com 52 mulheres em acompanhamento ambulatorial em um hospital universitário
na região sudeste do Brasil no período de 04/02/09 a 05/01/11. Dessas mulheres, 24 tinham 35 anos ou mais e
haviam sido submetidas a transplante de fígado a pelo menos um ano antes do início do estudo. As outras 28 mulheres
não tinham doença hepática e suas idades e padrões menstruais eram similares ao das transplantadas hepáticas. Para
avaliação da qualidade de vida foi usada a versão abreviada do questionário da Organização Mundial da Saúde
(WHOQOL-bref). Os sintomas da menopausa foram avaliados através do Menopause Rating Scale (MRS). A análise
estatística foi realizada através dos testes t de Student, Mann-Whitney e ANOVA. As correlações entre o MRS e o
WHOQOL-bref foram realizadas através de coeficientes de correlação. RESULTADOS: A idade média das mulheres
incluídas no estudo foi de 52,2 (±10,4) anos e o tempo médio desde a realização do transplante foi de 6,1 (±3,3)
anos. As mulheres transplantadas hepáticas tiveram melhores escores de qualidade de vida no domínio relacionado
ao meio ambiente (p=0,01). Não houve diferença entre os dois grupos em nenhum domínio do MRS. As mulheres no
grupo de comparação tiveram uma correlação fortemente negativa entre os sintomas somáticos do MRS e o domínio
físico do WHOQOL-bref (p<0,01; r=-0,8), diferentemente das mulheres com transplante de fígado que tiveram uma
Correspondence
Departament of Tocogynecology, UNICAMP
Avenida Alexander Fleming, 101
Cidade Universitária Zeferino Vaz
Zip code: 13083-881
Campinas (SP), Brazil
Received
09/20/2012
12/12/2012
Study carried out at Departament of Tocogynecology, Hospital da Mulher Professor José Aristodemo Pinotti, Centro de Atenção
Integral à Saúde da Mulher, Universidade Estadual de Campinas – UNICAMP – Campinas (SP), Brazil.
1
Departament of Tocogynecology, Faculdade de Ciências Médicas, Universidade Estadual de Campinas – UNICAMP – Campinas,SP, Brazil.
2
Departament of Surgery, Faculdade de Ciências Médicas, Universidade Estadual de Campinas – UNICAMP – Campinas, SP, Brazil.
Conflict of interest: none
Baccaro LF, Boin IF, Paiva, LC, Pinto-Neto AM
correlação apenas moderada (p<0,01; r=-0,5). CONCLUSÕES: As mulheres com transplante de fígado tiveram melhores escores de qualidade de vida
no domínio relacionado ao meio ambiente e não tiveram sintomas climatéricos mais intensos. Os sintomas do climatério influenciaram negativamente a
qualidade de vida nas transplantadas hepáticas, porém com menor intensidade do que nas mulheres sem antecedentes de doença hepática.
Introduction
Liver transplantation aims to prolong the survival of patients with end-stage liver disease. Five- and
ten-year survival rates are around 70 and 60%, respectively1. Increasing survival has led to a greater concern
with quality of life after transplantation2. Previous studies
have shown that patients undergoing liver transplantation
have alterations in quality of life, with increased fatigue,
physical problems and a higher prevalence of depression and anxiety after transplantation than before it3–6.
However, despite resulting in some negative changes, liver
transplantation leads to an overall improved quality of life
for patients and their caregivers and companions7,8. This
improvement often becomes apparent three to five years
after transplantation, by which time patients typically
achieve a new level of psychosocial stability9.
Women account for approximately one-third of
patients undergoing liver transplantation. The major
causes of liver failure indicating liver transplantation
in these women are primary biliary cirrhosis and cirrhosis secondary to post-viral hepatitis and autoimmune hepatitis10. In Brazil, alcohol abuse and chronic
hepatitis C are also important indications for liver
transplantation11. The liver is an essential organ to sex
hormone metabolism. It conjugates estrogens to form
glucuronides and sulfates. About one-fifth of these
products are excreted in bile, while most of the remainder is excreted in urine. Furthermore, liver converts
the estrogens estradiol and estrone into estriol, which
is a less potent estrogen12. Women with severe liver
disease have alterations in liver function which may
compromise the metabolism of sex hormones and sex
hormone-binding globulin (SHBG), leading to clinical repercussions. Studies on hypogonadism in liver
transplant recipients have largely assessed only men.
The few studies that have evaluated women undergoing transplantation have determined that the main
gynecologic repercussions are abnormalities in the
menstrual cycle. Following transplantation, 80 to 90%
of women recover menstrual function13-15.
Climacteric is defined as a group of physiological
events manifested as a decline in ovarian function, both
before and after the last menstrual period16. It is a universal phenomenon and includes other aspects, such as
the end of a woman’s childbearing years and the so-called
“empty-nest syndrome” when children leave home17.
104
The manner in which each woman reacts to this period
in her life varies greatly according to cultural/psychosocial/biological factors and social relationships18. There
is currently no consensus on the impact of menopausal
status on quality of life. Some studies have demonstrated
that menopause has a negative influence on quality of
life scores19,20, whereas others have not shown this18. In
addition, several studies have shown that menopausal
transition-associated symptoms such as hot flashes and
those caused by genital atrophy have a greater negative
influence on quality of life than do cultural and psychosocial factors21–23.
In the near future, an increasing number of women
with liver transplants will experience menopausal transitions. However, there are few studies evaluating menopausal transitions in this particular female subgroup. We
postulated that variations in serum concentrations of sex
hormones and long-term use of immunosuppressive agents
would result in worse quality of life and more intense
climacteric symptoms in women with liver transplants
than in those without them. We therefore conducted
a study in women with and without a history of liver
transplantation attending outpatient clinics of a university hospital in southeastern Brazil. The aims of this
study were to assess the influence of liver transplants and
climacteric symptoms on quality of life in these subjects.
Methods
This cross-sectional study included women who
had undergone liver transplantation and were attending the Liver Transplant Outpatient Unit of the
Clinics Hospital at the State University of Campinas
(UNICAMP) School of Medicine and women with no
history of liver disease undergoing follow-up at the
Menopause Outpatient Clinic of the Professor Dr.
José Aristodemo Pinotti Women’s Hospital (CAISM/
UNICAMP) from 4th February 2009 to 5th January 2011.
All women aged 35 years or older who had received a
liver transplant at least one year prior to the study were
included. For each liver transplant recipient, a woman of
similar age (within three years) and menstrual pattern
was selected for comparison. Women were considered
postmenopausal if they had been amenorrheic for at least
12 months. Women who had menstrual irregularity
without an identified anatomic cause were classified as
perimenopausal. Women who had regular menstrual
Quality of life and menopausal symptoms in women with liver transplants
cycles were considered premenopausal24. Women with
debilitating clinical conditions that precluded them
from participating in the study, those with a history
of bilateral oophorectomy, and those who had taken
hormones for treatment of menopausal symptoms or
as contraception in the three months before the study
were excluded. Thirty-three (33) women with liver
transplants who met the inclusion criteria were identified. Of these, five could not be contacted by telephone
and four declined to participate in the study. Therefore,
the final number of participating transplant recipients
was 24. The comparison group consisted of 28 women
without a history of liver disease who were matched
by age (within 3 years) and menstrual pattern with the
transplant recipients. Therefore, the final number of
women in the study was 52.
Interviews with the participants were conducted in the
Menopause Outpatient Clinic of CAISM at UNICAMP. The
same researcher interviewed all participants and obtained
data on age, skin color, level of school education, marital
status, date of transplantation, time since transplantation,
disease causing liver failure, type of current immunosuppressive medication, presence of arterial hypertension
or diabetes mellitus, smoking habits, date of menarche,
date of last menstruation, menstrual pattern and if the
woman was sexually active. Weight (kg), height (m) and
arterial pressure (mmHg) were also measured. Women
then responded to questionnaires that assessed menopausal
symptoms and quality of life. All women signed free and
informed written consents before their interviews. The
study was approved by the Research Ethics Committee
of UNICAMP under number 721/2008 and financed by
FAPESP under number 2008/09726-6.
Menopause rating scale
Menopausal symptoms were assessed using a scale
that has been formally validated according to the requirements for quality of life instruments and translated into
Portuguese, namely the Menopause Rating Scale (MRS)25.
This questionnaire consists of 11 questions covering 3
dimensions of symptoms: psychological, somatic and urogenital. For each item, women could choose between five
categories, namely no symptoms, less severe, moderate,
severe and very severe symptoms. The total MRS score
can vary from 0 (no symptoms) to 44 (maximum symptomatology). MRS scoring can also be analyzed in relation
to the 3 domains of psychological symptoms (depression,
irritability, anxiety, physical and mental fatigue, accounting
for 0–16 points); somatic (sweating/hot flashes, cardiac
symptoms, sleep disturbances, and muscular and joint
problems, accounting for 0–16 points); and urogenital
symptoms (sexual issues, bladder disorders,; and vaginal
dryness, accounting for 0–12 points)25.
Quality of life assessment
For assessment of quality of life, the abbreviated
version of the World Health Organization (WHOQOLBREF) questionnaire was used. This questionnaire is a
generic instrument used to assess quality of life that had
already been validated and translated into Portuguese26.
It contains 26 questions in four domains: physical, psychological, social relationships, and environment. There
are an additional two questions about quality of life and
general health. Higher scores indicate a better quality
of life. The questionnaire was administered directly to
subjects by the researcher in face-to-face interviews26.
Statistical analysis
Sample characteristics were compared between the
transplantation group and non-transplantation group by
χ2 or Fisher’s exact tests. Neither the WHOQOL-BREF
(physical, psychological and social) nor the MRS domains
(psychological, somatic and urogenital) had normal
distributions. Data transformation was used (quadratic,
cubic and square root) to apply parametric tests. For the
quality of life and health domains, data normalization was
not possible. Comparisons were made between transplant
recipients and non-transplant patients according to menopausal status by Student’s t-test or the Mann-Whitney
test. For each group studied, the quality of life domains
(normal data) were assessed after eliminating the effect
of control variables by analysis of variance. Correlations
between WHOQOL-BREF domains and MRS domains
were established by Pearson’s (normal data) or Spearman’s
(non-normal data) correlation coefficients. A classification
proposed by Santos in 2007 was used to classify linear
correlations27. The level of significance was set at 5%
and SAS version 9.2 was the software used for analysis.
Results
Relevant clinical and sociodemographic data on the
women studied are shown in Table 1. Their mean age
was 52.2±10.4 years (median 49.02, range 35.0–72.2).
Mean patient age at liver transplantation was 46.0±12.3
years (median 43.4, range 25.7–63.9). The mean time
since transplantation was 6.1±3.3 years (median 5.8,
range 1–12.5). The mean body mass index (BMI) was
27.6±4.8 (median 26.7, range 18.8–40.9). Of the 52
women studied, 14 (26.9%) were premenopausal, 13
(25%) perimenopausal, and 25 (48.1%) postmenopausal.
There were no significant differences between the groups
of women regarding age, level of education, marital status,
menopausal status, presence of diabetes mellitus, age at
menarche, BMI, sexual activity, number of births (deliveries), estradiol concentrations, and smoking habits. There
was a significant difference in terms of skin color; 83.3% of
105
women in the liver transplant group were white, whereas
only 53.6% were white in the comparison group (p=0.02).
Fewer women with liver transplants had chronic arterial
hypertension than in the comparison group (p=0.04).
However, at the time of the interviews there were no
significant differences between the groups in systolic or
diastolic arterial blood pressures. As expected, there was a
difference in the use of immunosuppressive drugs, because
none of the women in the comparison group were taking
this type of medication (p<0.01) (Table 1).
Domain scores for the WHOQOL-BREF are shown
in Table 2. Comparing the group of women with liver
transplants and those without a history of liver disease,
statistically significant differences were observed in the
domain related to environment, with values of 65.6
(±12.7) for liver transplant recipients and 57.5 (±14.7)
for women without a history of liver disease, both by
bivariate analysis (p=0.03) and multivariate analysis
adjusted for age, color, school education, marital status,
sexual activity and comorbid conditions such as chronic
arterial hypertension, diabetes mellitus and smoking
(p=0.01) (Table 2).
A comparison between women according to history
of liver transplantation can be seen in Table 3, which
shows WHOQOL-BREF scores for premenopausal and
peri/postmenopausal women. In the liver transplant
group, no difference between peri/postmenopausal and
premenopausal women in quality of life was observed. In
the comparison group, there was a significant difference
in the physical domain, with values of 80.1 (±9.6) for
premenopausal and 64.1 (±19.3) for peri/postmenopausal
women (p=0.04). Again, in the comparison group, for the
question on general health, values of 85.7 (±13.4) for
premenopausal and 60.7 (±29.1) for peri/postmenopausal
women (p=0.04) were found (Table 3).
For statistical analysis of MRS scores, different
approaches were used. First, total scores and domain
scores from the questionnaires were compared according
to history of liver transplantation. No significant difference was noted in any domain of the questionnaire.
Second, MRS scores were compared in premenopausal
women only; again, no significant difference was noted
in any domain. Finally, peri/postmenopausal women
alone were compared; again, no significant difference
was observed (Table 4).
To assess the influence of menopausal symptoms
on quality of life scores both in the liver transplant and
comparison groups, correlation coefficients were applied
between domain scores for the MRS and WHOQOLBREF. In the transplantation group, there were moderately negative correlations (i.e. higher MRS scores
corresponding to worse quality of life) between psychological symptoms on the MRS and the physical domain
106
of the WHOQOL-BREF (p<0.01, r=-0.6), between
somatic symptoms of the MRS and the physical (p<0.01,
r= 0.5) and general health (p<0.01, r=-0.6) domains of
the WHOQOL-BREF, and between the total MRS score
and the physical (p<0.01, r=-0.6) and general health
(p<0.01, r=-0.5) domains of the WHOQOL-BREF. There
were weakly negative correlations between psychological
Table 1. Clinical and sociodemographic data according to liver transplantation status (n=52)
Liver
transplantation
Control
n
(%)
n
(%)
≤49 years
12
(50.0)
14
(50.0)
>49 years
12
(50.0)
14
(50.0)
20
(83.3)
15
(53.6)
4
(16.7)
13
(46.4)
0–7 years
8
(33.3)
16
(57.1)
8–12 years
13
(54.2)
12
(42.9)
>12 years
3
(12.5)
0
(0.0)
With partner
14
(58.3)
22
(78.6)
Without partner
10
(41.7)
6
(21.4)
4
(16.7)
12
(42.9)
5
(20.8)
2
(7.1)
7
(29.2)
7
(25.0)
Age
1.0
Color
White
Non-white
0.02
Schooling
0.06*
Relationship status
0.1
Hypertension
Yes
0.04
Diabetes mellitus
Yes
0.2*
Menopausal status
Premenopausal
Perimenopausal
0.4
4
(16.7)
9
(32.1)
13
(54.2)
12
(42.9)
≤13 years
13
(54.2)
17
(60.7)
>13 years
11
(45.8)
11
(39.3)
16
(66.7)
19
(67.9)
≤27
12
(50.0)
15
(53.6)
>27
12
(50.0)
13
(46.4)
16
(66.7)
28
(100.0)
8
(33.3)
0
(0.0)
3
(12.5)
3
(10.7)
1
9
(37.5)
5
(17.9)
≥2
12
(50.0)
20
(71.4)
<44.5 pg/mL
14
(58.3)
17
(63.0)
≥44.5 pg/mL
10
(41.7)
10
(37.0)
1
(4.2)
4
(14.3)
Menopausal
Menarche
0.6
Sexually active
Yes
0.9
BMI
0.7
Immunosuppression
No corticosteroids
With corticosteroids
<0.01
Parity
0
0.2*
Serum estradiol concentration
0.7
Smoking
Yes
p-value
0.3*
Unasterisked p-values, χ2 test; *Fisher´s exact test; BMI: Body Mass Index.
Table 2. Scores for the World Health Organization quality of life questionnaire – abbreviated version (liver transplant recipients and con trols) (n=52)
Liver transplant recipients (n=24)
Control (n=28)
Domain
Mean
SD
Mean
SD
p-valuea
p-valueb
Physical
66.2
15.0
68.1
18.6
0.6
0.44
Psychological
66.5
17.1
67.4
16.6
0.8
0.84
Social relationships
64.2
28.5
59.5
24.1
0.2
0.27
Environment
65.6
12.7
57.5
14.7
0.03
0.01
Overall QOL
79.2
17.6
72.3
14.2
0.1*
**
General health
76.0
20.2
67.0
28.1
0.3*
**
Student’s t-test. Analysis of variance with adjustment for age, race, education, marital status, sexual activity, comorbidities. *Mann-Whitney test. **Not assessed. QOL: quality of life.
a
b
Table 3. Scores for the World Health Organization quality of life questionnaire – abbreviated version according to history of liver transplantation (premenopausal versus peri/postmenopausal) (n=52)
Domain
(Liver transplantation)
Premenopausal (n=7)
Peri/postmenopausal (n=17)
p-value
Mean
SD
Mean
SD
Physical
72.5
13.9
63.7
15.1
0.1
Psychological
72.0
16.8
64.2
17.1
0.2
72.6
20.3
60.8
31.2
0.4
Environment
67.0
12.5
65.1
13.1
0.7
Overall QOL
89.3
13.4
75.0
17.7
0.08*
General health
85.7
19.7
72.1
19.5
0.1*
Domain
Premenopausal (n=7)
Peri/postmenopausal (n=21)
p-value
(Control)
Mean
SD
Mean
SD
Physical
80.1
9.6
64.1
19.3
0.04
Psychological
76.8
7.9
64.3
17.7
0.1
64.3
13.4
57.9
26.8
0.8
Environment
62.5
4.0
55.8
16.6
0.3
Overall QOL
75.0
0.0
71.4
16.4
0.6*
General health
85.7
13.4
60.7
29.1
0.04*
QOL: quality of life; WHOQOL-BREF: World Health Organization quality of life questionnaire – abbreviated version.
Unasterisked p-values, Student’s t-test; *Mann-Whitney test.
Table 4. Scores for the Menopause Rating Scale (liver transplantation versus controls) (n=52)
Total group
Liver transplantation (n=24)
Control (n=28)
p-value
Mean
SD
Mean
SD
Psychological
5.1
3.6
4.9
3.6
0.6
Somatic
3.5
2.8
4.2
3.5
0.8
Urogenital
2.0
1.9
2.0
2.2
0.9
Total score
10.7
6.0
11.1
7.8
0.8
Premenopausal
Control (n=7)
p-value
Mean
SD
Mean
SD
Psychological
4.6
2.6
2.3
2.1
0.1
Somatic
1.9
1.6
1.3
1.3
0.4
Urogenital
1.9
2.0
0.3
0.8
0.07
Total score
8.3
4.7
3.9
3.0
0.06
Peri/postmenopausal
Control (n=21)
p-value
Mean
SD
Mean
SD
Psychological
5.4
4.0
5.8
3.6
0.8
Somatic
4.2
2.9
5.2
3.5
0.5
Urogenital
2.1
1.9
2.5
2.3
0.7
Total score
11.7
6.4
13.5
7.4
0.4
p-values: Student’s t-test; SD: standard deviation.
107
symptoms of the MRS and the psychological (p=0.04,
r=-0.4) and environmental (p=0.01, r=-0.4) domains of
and the psychological domain (p=0.03, r=-0.4) of the
WHOQOL-BREF. In the comparison group, there was a
strongly negative correlation between somatic symptoms
on the MRS and the physical domain of the WHOQOLBREF (p<0.01; r=-0.8). There were moderately negative
correlations between psychological symptoms of the
MRS and the physical domain of the WHOQOL-BREF
(p<0.01; r=-0.5), between somatic symptoms of the
MRS and general health (p<0.01; r =-0.5) domain of
and the physical (p<0.01, r=-0.7) and general health
(p<0.01, r=-0.5) domains of the WHOQOL-BREF. There
were weakly negative correlations between psychological
symptoms of the MRS and the environmental (p=0.03,
r=-0.4) and general health (p=0.01, r=-0.4) domains of
the WHOQOL-BREF, between somatic symptoms of the
MRS and the environmental domain (p=0.01, r=-0.4) of
and psychological (p=0.01, r=-0.4) and environmental
(p=0.01, r=-0.4) domains of the WHOQOL-BREF.
Discussion
The aim of this study was to obtain an accurate understanding of how liver transplantation influences quality of
life and menopausal symptoms in women. Furthermore,
we correlated menopausal symptoms with quality of life
scores to measure the effect of these symptoms on quality
of life in liver transplant recipients.
Women with a history of liver transplantation had
better quality of life scores in the domain related to
environment than did women with no history of liver
disease, even after adjusting for the remaining variables
such as age, color, school education, marital status,
sexual activity, chronic arterial hypertension, diabetes
mellitus and smoking. This result is in agreement with
previously reported data. Telles-Correia et al. reported
that one month after liver transplantation, patients with
end-stage liver disease have significant improvements
in quality of life in the physical and mental domains28.
There is significant improvement in quality of life in
the physical domain28 six months after transplantation,
and after three to five years there is an even greater
improvement in quality of life because by this stage
transplant recipients have achieved greater psychosocial stability9. In our study, it is noteworthy that liver
transplant recipients not only had good quality of life
but indeed superior values than did women with no
history of liver transplantation. We believe that several
factors may have contributed to this finding.
108
First, in this study the mean time since transplantation
was approximately six years. As previously reported, the
more time has elapsed since transplantation, the higher
the quality of life scores are. Furthermore, women with a
history of liver transplantation receive multidisciplinary
follow-up care. It is likely that women feel strongly supported by this type of management and that it therefore has
a beneficial effect on quality of life scores. Another factor
that may explain this finding is that transplant recipients
have already experienced periods of severely debilitated
health. After going through the stressful experience of
organ transplantation, recipients cherish their subsequent
stability in health and tend to complain less about various
aspects of their lives. Some authors suggest that surviving
a potentially lethal disease may change internal values and
moral concepts, altering the manner in which survivors
cope with anxiety, depression and fatigue29-31.
Various studies have explored the influence of menopausal status and climacteric symptoms on quality of
life. Some authors have found no difference in overall
quality of life between premenopausal and postmenopausal women18,32-34, although some note that vasomotor
symptoms have a negative effect on it18. In 2009, a study
entitled “Study of Women’s Health across the Nation”
found that, after final adjustment for all variables, the only
independent relationship between menopausal status and
quality of life indicators was with physical limitations. The
same study showed that impaired quality of life during
menopausal transition is most strongly related to symptoms such as vasomotor symptoms, urinary incontinence,
sleep disturbances, and those caused by genital atrophy
and morbid conditions associated with aging, such as
rheumatoid arthritis, depression and stress23.
In 2012, a study entitled “Do Stage Transitions Result
in Detectable Effects?” showed that the transition from
premenopausal to postmenopausal status is associated
with impaired quality of life, irrespective of the symptoms
experienced17. In this study, negative impacts were more
intense in the physical, pain and general health domains,
as well as in energy levels and fatigue. One important
finding of this study was that impaired quality of life did
not impose limitations on daily living. It was suggested
that, despite feeling worse, women did not let menopause
interfere in their lives. Symptoms such as hot flashes and
vaginal dryness in particular resulted in deterioration in
quality of life, negatively interfering with social activities
with friends and family17. In the present study, we analyzed
the influence of menopausal status on quality of life scores
in the liver transplant comparison groups separately. Being
peri/postmenopausal did not influence quality of life in
the liver transplant group. However, in the comparison
group, peri/postmenopausal women had worse quality
of life scores in the physical and general health domains.
Liver transplant recipients did not have more intense
climacteric symptoms than women in the comparison group.
We found no significant differences between the groups in
total or domain scores from either questionnaire, regardless of menopausal status. There is still no published data
about menopausal symptoms in liver transplant recipients.
Previous studies have reported only that the main gynecologic symptom of premenopausal women with end-stage
liver disease is secondary amenorrhea. After transplantation,
most women resume having regular menstrual cycles13-15.
Our results are in agreement with these data: we did not
find more severe menopausal symptoms in liver transplant
recipients than in comparison patients without liver disease. We therefore believe that when liver transplantation
is successful, hormone metabolism reverts to normal and
transplants have no influence on menopausal symptoms.
To test the hypothesis that menopausal symptoms
have a greater influence on quality of life scores in liver
transplant recipients than in comparison patients without
liver disease, we measured correlation coefficients between
various domains of the MRS and WHOQOL-BREF.
We used both sets of coefficients to assess correlations
between findings for women in the post transplantation and comparison groups and found that menopausal
symptoms negatively influenced quality of life in both
groups. Climacteric symptoms had greater influences on
the physical and general health domains than they did
on the environmental and psychological domains. For
women in the comparison group, there was a strongly
negative correlation between somatic symptoms in the
MRS and the physical domain of the WHOQOL-BREF.
In contrast, there was only a moderate association for
women with liver transplants. We believe that the same
explanation accounts for the higher quality of life scores
and the smaller influence of somatic menopausal symptoms on quality of life in women with liver transplants.
A limitation of this study was the small number
of cases and the fact that they were in two subgroups,
which made it difficult to perform analyses and reach
definitive conclusions. However, we did include all eligible liver transplant patients attending our institution
and available for study during the study period. Because
this is the first study on quality of life and menopause
symptoms in liver transplant recipients, we believe that,
despite the limitation of few participants, our findings
broaden knowledge about the needs of women undergoing
liver transplantation, particularly during the climacteric
years. Further studies are needed to enable the reaching
of definitive conclusions.
Women with liver transplants had better quality of
life scores in the environment domain and did not report
more intense climacteric symptoms than did comparison
patients without liver disease. Climacteric symptoms
negatively influence quality of life in liver transplant
recipients, although less intensely than in women without
a history of liver disease.
Acknowledgments
To Fundação de Amparo à Pesquisa do Estado de São
Paulo (FAPESP), number 2008/09726-6.
And Sirlei Siani for the statistical analysis.
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Alina Coutinho Rodrigues Feitosa1
Luciana Nunes Sampaio2
Ana Graciele Lessa Batista3
Carla Borges Pinheiro3
Frequency of fear of needles and impact
of a multidisciplinary educational approach
towards pregnant women with diabetes
Frequência de medo de agulhas e impacto de uma abordagem
educacional multidisciplinar em gestantes com diabetes
Artigo Original
Abstract
Keywords
Gestational diabetes/psychology
Insulin/administration & dosage
Health education
Fear
Injections, intravenous/psychology
Palavras-chave
Diabetes gestacional/psicologia
Insulina/administração & dosagem
Educação em saúde
Medo
Injeções intravenosas/psicologia
PURPOSE: To evaluate the frequency of fear of needles and the impact of a multidisciplinary educational program in
women with pre-gestational and gestational diabetes taking insulin during pregnancy. METHODS: The short Diabetes
Fear of Injecting and Self-testing Questionnaire (D-FISQ), composed by two subscales that access fear of self injection
(FSI) and fear of self testing (FST), was administered twice during pregnancy to 65 pregnant women with pre-gestational
and gestational diabetes: at the first endocrine consult and within the last two weeks of pregnancy or postpartum.
An organized multidisciplinary program provided diabetes education during pregnancy. Statistical analysis was
carried out by Wilcoxon and McNemar tests and Spearman correlation. A p<0.05 was considered to be significant.
RESULTS: Data from the short D-FISQ questionnaire shows that 43.1% of pregnant women were afraid of needles in
the first evaluation. There was a significant reduction in scores for FSI and FST subscales between the first and second
assessments (first FSI 38.5% compared with second 12.7%, p=0.001; first FST 27.7% compared with second FST
14.3%, p=0.012). CONCLUSIONS: The fear of needles is common in pregnant women on insulin therapy and an
organized multidisciplinary educational diabetes program applied during pregnancy reduces scores of such fear.
Resumo
OBJETIVO: Avaliar a frequência do medo de agulhas e o impacto de um programa educacional multidisciplinar em
mulheres com diabetes pré-gestacional e gestacional em uso de insulinas durante a gravidez. MÉTODOS: O questionário
Diabetes Fear of Injecting and Self-testing Questionnaire (D-FISQ) resumido, composto por duas subescalas que acessam
o medo de injeções (FSI) e o medo da automonitoração (FST), foi administrado duas vezes durante a gestação de
65 mulheres com diabetes pré-gestacional e gestacional: na primeira consulta endocrinológica e dentro das últimas
duas semanas de gestação ou pós-parto. Durante a gravidez, as gestantes foram submetidas a um programa
multidisciplinar sistematizado para prover educação em diabetes. A análise estatística foi realizada por meio dos
testes de Wilcoxon e McNemar e a correlação de Spearman. Valor p<0,05 foi considerado como significativo.
RESULTADOS: A aplicação do questionário D-FISQ resumido indicou que 43,1% das gestantes apresentavam medo
de agulhas na primeira avaliação. Houve significativa redução nos escores das subescalas FSI e FST entre a primeira
e segunda avaliação (primeiro FSI 38,5% comparado com o segundo 12,7%, p=0,001; primeiro FST 27,7%
comparado com segundo FST 14,3%, p=0,012). CONCLUSÃO: O medo de agulhas é frequente em gestantes em
uso de terapia com insulina, e um organizado programa multidisciplinar educacional em diabetes aplicado durante
a gestação reduz os escores do medo.
Correspondence
Alina Coutinho Rodrigues Feitosa
Coordenação de Ensino e Pesquisa da Maternidade Prof. José Maria de
Magalhães Netto
Rua Marques de Maricá, s/n – Pau Miúdo
Zip code: 41500-300
Salvador (BA), Brazil
Received
07/11/2012
01/21/2013
Study carried out at department of Obstetrics and Gynecology, Maternidade de Referência Professor José Maria de Magalhães Netto
and Departament of Internal Medicine, Hospital Santa Izabel – Salvador (BA), Brazil.
1
Ambulatory of Endocrinopathies in the Departament of Obstetrics, Maternidade de Referência Professor José Maria de Magalhães Netto –
Salvador (BA), Brazil.
2
Obstetrics and Gynecology, Maternidade de Referência Professor José Maria de Magalhães Netto – Salvador (BA), Brazil.
3
Ambulatory of Endocrinopathies in Pregnancy, Maternidade de Referência Professor José Maria de Magalhães Netto – Salvador (BA), Brazil.
Feitosa ACR, Sampaio LN, Batista AGL, Pinheiro CB
Introduction
Although insulin treatment is the mainstay of diabetes
management in type 1 and type 2 diabetes with secondary pancreatic insufficiency or uncontrolled glycemia,
poor adherence to insulin injections occurs due to factors
such as fear of insulin or fear of needles1. Patient barriers
to accept insulin initiation/treatment also include fear of
hypoglycemia, weight gain and reluctance to adapt the
inflexible timing of scheduled insulin doses2. Patients
often consider insulin as the last treatment option, as a
form of punishment or failure of self control3, but fear of
needles and its association with pain remains as one of the
most important factors. This fear has a negative impact
on the treatment of patients with diabetes1.
In women with pre-gestational diabetes (PGD) and
gestational diabetes (GD), insulin therapy is the treatment of choice for blood glucose control and prevention
of poor fetal outcomes4-8. Insulin therapy is essential for
pregnant women who have been on insulin prior to pregnancy, and is the next step to achieve glycemic control
in women with gestational diabetes and type 2 diabetes
who did not obtain optimal glycemic control after one or
two weeks of healthy lifestyle changes9. Even when oral
hypoglycemic agents are used as an alternative therapy
for glycemic control in women with gestational diabetes,
supplemental insulin is required to achieve target levels
of glucose in 20.9–46.3% of those using metformin10,11
and 4% of those on glyburide12.
Extreme fear of self-injecting insulin (injection phobia)
is likely to compromise glycemic control as well as to cause
psychological distress1,13. Likewise, fear of self monitoring
of blood glucose (SMBG) or finger prick can be a source of
distress and may seriously stop self-management. Evidence
suggests that fear of blood and injury is associated with
less frequent self-testing8,14 and poor glycemic control14.
In pregnancy, when glycemic control must be more strict9,
intensive basal-bolus insulin regimen with at least three
daily injections of insulin and frequent self-monitoring
(three to eight times a day) are, in general, the methods
used to achieve optimal blood glucose levels9. The fear
of needles can hamper the intensive insulin therapy and
affect adherence and glycemic control of women with
PGD diabetes, and especially those with GD.
The Diabetes Fear of Injecting and Self testing
Questionnaire (D-FISQ) has been validated in children
and adults with diabetes15,16. The D-FISQ is a 30-item
self-report questionnaire consisting of two subscales
that measure fear of self-injecting insulin (FSI) and fear
of self-testing (FST), the latter measuring fear of blood
glucose testing13. The short version of the D-FISQ has
been proved useful for research with insulin-treated
diabetes patients17.
112
For pregnant women who started on insulin therapy in the antenatal care, learning and acquiring skills as
to insulin injections and self-monitoring should be fast
because strict control must be achieved in the shortest time possible. These characteristics increase difficulties
and certainly worsen adherence. Our objectives were to
evaluate the frequency of fear of needles among diabetic
pregnant women population and the influence of the type
of diabetes in pregnancy (gestational or pre-gestational)
and the fear of needles in order to determine the impact
of an educational diabetes program during pregnancy as
to such fear.
Methods
The present report is a prospective cohort of pregnant women aged 18–45 years with both pre-gestational
(PGD) and gestational diabetes (GD). They were eligible
to participate if they were on insulin by injection and if
they had antenatal and endocrine appointments in the
institution. Potential subjects were approached by study
personnel in regularly scheduled clinic visits, and consent was obtained. A total of 65 patients with diabetes
mellitus volunteered to participate and 63 completed
follow-up. Gestational diabetes mellitus was defined according to theAmerican Diabetes Association criteria by
2-h 75-g OGTT as at least two values higher than a fasting glucose of 95 mg per deciliter (5.3 mmol per liter), a
1-h glucose of 180 mg per deciliter (10 mmol per liter), or
a 2-h glucose of 155 mg per deciliter (8.6 mmol per liter)18.
This study was carried out at Maternidade Professor
José Maria de Magalhães Netto, a tertiary referral public
academic institution. This maternity is a reference for
high risk pregnancy in the state of Bahia and the patients
were recruited from the Ambulatory of Endocrinopathies
in Pregnancy, a multidisciplinary outpatient clinic of the
maternity. All health care professionals of the multidisciplinary team have access to the ambulatory medical record.
The study was approved by the institutional review board.
Participants and procedures
Insulin therapy was only continued if previously used
by women with both gestational and pre-existing diabetes,
and was started among those who had not achieved glycemic control after one to two weeks of lifestyle changes.
The goals of the treatment were the achievement of a
fasting blood glucose concentration of 63 to 90 mg per
deciliter (mmol per liter), preprandial blood glucose concentration of 65 to 99 mg per deciliter (mmol per liter)
and a 2-hour postprandial blood glucose concentration
of less than 126 mg per deciliter. Insulin regimens were
based on predicted total daily insulin requirements according to current weight and stage of pregnancy. We
Frequency of fear of needles and impact of a multidisciplinary educational approach towards pregnant women with diabetes
used human NPH and regular insulin as a basal-bolus
scheme given in two to four injections a day. Basal insulin
(NPH) was given 30 minutes before breakfast, lunch and
at bedtime, and was adjusted by 2 to 10 U at a time to
achieve, respectively, pre-lunch, pre-dinner and fasting
capillary blood glucose target. Pre-meal regular insulin
was given in a fixed dose, mixed with NPH in the same
syringe, 30 minutes before the meal, and was adjusted by
2 to 10 U at a time to achieve postprandial blood glucose
target. Insulin doses were adjusted weekly or biweekly
by an endocrinologist. Insulin was injected in the arms,
legs, buttocks and abdomen, when comfortable. All patients were counseled to rotate the placement of insulin
injections and to do intensive self monitoring of capillary
blood glucose with at least three finger pricks per day.
Multidisciplinary educational approach
Antenatal care was provided by a multidisciplinary
team composed by endocrinologists, obstetricians, nurse
educators, dietitians and social workers. Endocrine and
nurse consultation took place every two weeks, and appointments with dietitians and obstetrician happened
every month. At the first endocrine consultation, the
endocrinologist provided 20 to 30 minutes of individualized counseling using principles of adult education.
Patients were taught about the importance of glycemic
control during pregnancy, the impact of hyperglycemia in
the fetus and mother and how to control hyperglycemia
using insulin, dietary plan and healthy life style.
Explanations about blood glucose targets and ideal
weight gain during pregnancy were given for each patient. We calculated the basal-bolus insulin scheme using pre-pregnant body weight and advised patients to
do self-monitoring of blood glucose levels three times
a day, during suggesting symptoms of hypoglycemia,
and eight times a day (including bed time and at 3 am)
once a week. Patients should record capillary blood
glucose measures in a standardized diary. Patients were
instructed to recognize symptoms of hypoglycemia and
were trained to promptly respond to early autonomic or
neuroglycopenic symptoms. Educational printed material
about healthy food choices, artificial sweeteners, insulin
use and hypoglycemia was provided to each pregnant
woman. They were instructed to carry a diabetes orientation card and 15 g of oral glucose in order to recover
from a hypoglycemia episode.
In subsequent visits, endocrinologists asked about
insulin use, place of insulin injections, SMBG, symptoms
or signs of hypoglycemia and adherence to dietary recommendations. We checked the acquired skills in adapting
the timing and content of meals to fixed doses of insulin.
Patients were questioned about ideal glycemic targets and
weight gain and their results were compared with ideal
blood glucose levels and weight gain. Each patient had to
circle registered capillary blood glucose out of the target
and they were taught to identify the reasons for it and
how to provide corrections in a problem-solving manner.
When a hypoglycemic episode occurred, the patient was
led to identify the reason(s) that best explained it in order
to prevent a new episode.
In the first nutritional consultation, a registered dietitian (RD) evaluate the caloric intake based on a 24-hour
food recall, gave individualized dietary advice and a written
dietary plan with meals. The written dietary plan consisted
of three main meals and two or three snacks per day. The RD
considered pre-pregnancy body weight and weight gain
during the current pregnancy to elaborate a dietary plan.
Subsequent monthly visits until delivery reviewed adherence
to written dietary plan, food preparation, food choices and
monitor weight gain.
In the first nurse consultation, a registered nurse
(RN) gave advice about the importance of strict glycemic
control and risk of hypoglycemia in pregnant women
with diabetes. Patients were instructed and trained on
how to do SMBG and insulin injections. They were
also instructed on how to record capillary blood glucose
measurements in a standardized diary. In subsequent biweekly visits, the RN reviewed the SMBG diary and the
acquired skills, asked about doubts and cleared missing
or misunderstood information. The patient were guided
as to signs and symptoms of hypoglycemia, risk factors
and the need to carry the diabetes orientation card and
absorbable carbohydrates at all times. They were instructed
to share advice on hypoglycemia with family members
for prompt treatment of severe hypoglycemic episodes.
All acquired knowledge was reinforced every visit.
Data collection procedure and measures
The short version of the D-FISQ questionnaire was
administered to each subject by a trained interviewer.
The short D-FISQ is a 15-item self-report questionnaire consisting of two subscales that measure fear of
self-injecting (6-item subscale) and fear of self-testing
(9-item subscale), the latter measuring fear of blood
glucose testing13,17. The items were scored on a 4-point
Likert scale, ranging from zero (almost never) to three
(almost always). The short D-FISQ was administered to
each pregnant woman as follows: for women with pregestational diabetes already on insulin, it was applied in
the first endocrine appointment. For women with GD and
PGD who started on insulin therapy during pregnancy,
the questionnaire was administered two weeks after the
onset of insulin therapy.
A total score was obtained for each questionnaire
by summing the item scores. A score ≥6 was considered
positive for fear of needle, as it has previously shown to be
113
consistent with needle fear in an adult population15. These
questionnaires were administered for 65 pregnant women.
Additionally, investigators reapplied the questionnaire
for each subject in the final pregnancy period (in the last two
weeks) or in the early postpartum period (the first two weeks).
Data analyses
Statistical analyses were performed using SPSS 13.0
for Windows. Values are expressed as mean±standard
deviation for normally distributed data or as median and
interquartile range for skewed data. Spearman correlation
coefficients were calculated to determine associations
between different variables. The Wilcoxon test was used
to compare paired continuous variables (FSI and FST in
the first and second assessments) and the McNemar test
served to compare paired dichotomous variables (FSI or
FST ≥6 in the first and second assessments). Differences
were considered significant when p<0.05.
Results
A total of 65 pregnant women were included. The
median and interquartile range age of the subjects was
33 (interquartil interval: 27.5–37.5 years). Forty patients
(61.5%) had diabetes prior to pregnancy: 9 had type 1
and 31 had type 2 diabetes. Gestational age at the first
administration of the questionnaire was 26.9±7.6 weeks
gestation. Sixty three patients completed follow-up. The
median follow-up period was 9.7±6.9 weeks gestation,
and the administration of the questionnaire for the second
time was in median 36.7±2.0 weeks gestation. In four
Table 1. Subscale scores of fear of self-Injection and fear of self-testing compatible with
fear of needles (score ≥6)
First assessment (n=65)
FSI
Second assessment (n=63)
FST
FSI
FST
n
%
n
%
n
%
n
%
Total
25
38.5
18
27.7
8*
12.7
9†
14.3
PGD (n=40)
16
40.0
13
32.5
6
15.4
6
15.4
GD (n=25)
7
28.0
7
28.0
2
8.3
3
12.5
PGD: pre-gestational diabetes mellitus; GD: gestational diabetes mellitus; FSI: fear
of self-injection; FST: fear of self-testing; McNemar test: *p=0.001 for differences
between first and second FSI assessment; †p=0.012 for differences between first and
second FST assessment.
patients, the questionnaire was applied at postpartum.
The participation rate was >95% of those who agreed
to participate.
The short D-FISQ indicated that 43.1% of pregnant
women had significant FSI or FST in the first evaluation
(≥6 points). The comparison between frequency of fear
of needles in PGD and GD did not reveal differences.
There was a significant reduction in FSI and FST scores
between the first and second assessments. Comparison
of FSI and FST subscale scores are shown in Table 1.
No fear at all on both subscales was present in 18.5%
(12/65) in the first assessment, and in 42.9% (27/63) in
the second assessment.
Descriptive statistics and distributions of the scores
are demonstrated in Table 2. There was no correlation
between FSI and FST scores with doses of insulin and
maternal age (data not shown).
Discussion
Injection phobia is a severe and limiting fear of needles classified as an anxiety disorder in the Diagnostic and
Statistical Manual of Mental Disorders IV (DSM-IV-TR).
The estimated prevalence of blood and injection phobia in
pregnancy is 7.2%19, and women with this anxiety disorder present increased risk for adverse obstetric outcomes,
premature delivery and higher neonatal morbidity20. Fear
is a different emotion, not as severe as phobia, but it may
hamper therapy in patients that are on insulin therapy.
Fear of needles during pregnancy is a relatively unexplored
subject in literature and, to our knowledge, this is the
first study that assesses fear of needles among women
with diabetes during pregnancy. Considering that the
maintenance of a tight control of blood glucose during
pregnancy is essential to reduce complications of diabetes
in the offspring, the detection of pregnant women who
are afraid of injections is extremelly important.
The fear of needles is often neglected21, but this
study has shown that the short D-FISQ can help identify pregnant women with diabetes who may have FSI
with or without FST by means of a rapid and practical
tool, which can be part of a prenatal appointment.
The frequency of such fear in this study was higher
Table 2. Fear of self-injection and fear of self-testing scores in first and second assessments
First assessment (n=65)
FSI
FST
Second assessment (n=63)
Total score
FSI
FST
Total score
Mean±SD
Median (IQ)
Mean±SD
Median (IQ)
Mean±SD
Median (IQ)
Mean±SD
Median (IQ)
Mean±SD
Median (IQ)
Mean±SD
Median (IQ)
Total
5.2±6.1*
3.0 (0–8.5)
5.3±7.5†
0 (0–8.5)
10.5±12.3‡
5.0 (1.0–18.0)
2.2±4.3*
0 (0–3.0)
2.5±5.0†
0 (0–2.0)
4.8±8.8‡
1 (0–5.0)
PGD
5.9±6.4*
3.5 (0–9.0)
5.9±8.2†
2.0 (2.0–10.7)
11.8±12.7‡
6.5 (2.0–20.5)
2.6±4.9*
0 (0–4.0)
2.5±4.8†
0 (0–2.0)
5.1±9.4‡
1 (0–5.0)
GD
4.2±5.6*
2.0 (0–6.0)
4.3±6.4†
1.0 (0–5.5)
8.5±11.4 ‡
4.0 (0.5–12.5)
1.7±3.2*
0 (0–2.0)
2.7±5.3†
0.5 (0–2.0)
4.3±8.0‡
1 (0–5.0)
PGD: pre-gestational diabetes mellitus; GD: gestational diabetes mellitus; FSI: fear of self-injection; FST: fear of self-testing; IQ: interquartil interval; SD: standard deviation; Wilcoxon
test: *p<0.001 for differences between first and second FSI assessment; †p<0.001 for differences between first and second FST assessment; ‡p<0.001 for differences between
total scores in first and second assessments.
114
Frequency of fear of needles and impact of a multidisciplinary educational approach towards pregnant women with diabetes
(43.1%) than among adults15. This finding may reveal a specific characteristic of the analyzed sample
or represent the fear of needles and superimposed fear
of effects of diabetes during pregnancy. We expected
that the PGD patients had were less afraid of needles
than those with GD, because of the previous experience with the disease and the treatment. The similar
frequency may have been caused by the limited sample
size to demonstrate differences, but the results that
we found demonstrate the need to investigate fear in
both groups with similar motivation. The initiation of
insulin therapy during pregnancy and the optimization
of treatment in previous users of insulin aim to lead
to a rapid glycemic control. However, the need for
fast control and maintenance of strict goals9 require
complex insulin regimen, which probably hamper the
treatment. Multiple daily doses, high doses, and rapid
dose adjustments make adherence to insulin therapy
difficult and increase the risk of hypoglycemia. These
factors require more injections and finger pricks per
day, and can justify the development or intensification
of fear of needles in both PGD and GD patients.
The reapplication of the questionnaire after the multidisciplinary approach revealed a significant reduction
in scores concerning fear of needles. This finding suggests that an organized education program helps reduce
fears, and probably improves adherence to therapy, and
also strict blood glycemic control. Some might say that
the reduction in scores concerning the fear of needles
could be a result of simply getting used to self-injecting
rather than the education program itself, but it does not
explain the reductions in scores of pregnant women with
PGD, already accustomed to the self-injection.
There are some limitations to our study. We did
not assess the impact of the educational program on
glycemic control or on weight at birth. Fear of injection is associated with poor glycemic control, clinical
complications, poor general well-being and health status
in non-pregnant patients with diabetes1. Therefore, we
hypothesized that the same association could be present in both PGD and GD patients. Larger population
samples would probably be needed to assess whether or
not there are differences.
We conclude that the identification of pregnant
women who are afraid of injections through the short
D-FISQ questionnaire is practical and can be incorporated into the antenatal care of women with diabetes.
The application of a multidisciplinary educational program
can reduce the scores of fear of injections. We recommend
systematic evaluation concerning the fear of needles in
pregnant women with diabetes and insulin therapy use
to identify those with high scores, thus giving space to
the establishment of special attention that promotes
significant improvement as to fear.
Acknowledgments
To Gilson Feitosa, professor of the Bahiana Medical
School and Public Health, for the consultation on this
project, and the collaborators of the maternity hospital.
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Edward Araujo Júnior1
Rogério Caixeta Moraes de Freitas2
Zsuzsanna Ilona Katalin de Jármy Di Bella2
Sandra Maria Alexandre3
Mary Uchiyama Nakamura3
Luciano Marcondes Machado Nardozza1
Antonio Fernandes Moron4
Artigo Original
Assessment of pelvic floor by threedimensional-ultrasound in primiparous women
according to delivery mode: initial experience
from a single reference service in Brazil
Avaliação do assoalho pélvico por meio da ultrassonografia tridimensional de
mulheres primíparas de acordo com o tipo de parto: experiência inicial de um
centro de referência do Brasil
Abstract
Keywords
PURPOSE: To evaluate changes to the pelvic floor of primiparous women with different delivery modes, using three-dimensional
ultrasound. METHODS: A prospective cross-sectional study on 35 primiparae divided into groups according to the delivery
mode: elective cesarean delivery (n=10), vaginal delivery (n=16), and forceps delivery (n=9). Three-dimensional ultrasound
on the pelvic floor was performed on the second postpartum day with the patient in a resting position. A convex volumetric
transducer (RAB4-8L) was used, in contact with the large labia, with the patient in the gynecological position.
Biometric measurements of the urogenital hiatus were taken in the axial plane on images in the rendering mode, in
order to assess the area, anteroposterior and transverse diameters, average thickness, and avulsion of the levator
ani muscle. Differences between groups were evaluated by determining the mean differences and their respective
95% confidence intervals. The proportions of levator ani muscle avulsion were compared between elective cesarean
section and vaginal birth using Fisher’s exact test. RESULTS: The mean areas of the urogenital hiatus in the cases
of vaginal and forceps deliveries were 17.0 and 20.1 cm2, respectively, versus 12.4 cm2 in the Control Group
(elective cesarean). Avulsion of the levator ani muscle was observed in women who underwent vaginal delivery (3/25),
however there was no statistically significant difference between cesarean section and vaginal delivery groups (p=0.5).
CONCLUSION: Transperineal three-dimensional ultrasound was useful for assessing the pelvic floor of primiparous
women, by allowing pelvic morphological changes to be differentiated according to the delivery mode.
Pelvic floor/ultrasonography
Parity
Natural childbirth
Cesarean section
Imaging, three-dimensional
Palavras-chave
Diafragma da pelve/ultrassonografia
Paridade
Parto normal
Cesárea
Imagem tridimensional
Resumo
OBJETIVO: Avaliar as mudanças no assoalho pélvico de mulheres primíparas em diversos tipos de partos por meio da
ultrassonografia tridimensional. MÉTODOS: Estudo de corte transversal prospectivo com 35 primigestas, divididas em
grupos com relação ao tipo de parto: cesariana eletiva (n=10), parto vaginal (n=16) e fórceps (n=9). A ultrassonografia
tridimensional do assoalho pélvico foi realizada no segundo dia pós-parto com a paciente em repouso. Utilizou-se
transdutor convexo volumétrico (RAB4-8L) em contato com os grandes lábios vaginais, estando a paciente em posição
ginecológica. Medidas biométricas do hiato urogenital foram tomadas no plano axial da imagem renderizada para
avaliar a área, os diâmetros anteroposterior e transverso, a espessura média e a avulsão do músculo elevador do
ânus. Diferenças entre os grupos foram avaliadas pela determinação da média das diferenças com seus respectivos
intervalos de confiança de 95%. As proporções de avulsão do músculo elevador do ânus foram comparadas entre a
cesárea eletiva e o parto vaginal pelo teste exato de Fisher. RESULTADOS: As áreas médias do hiato urogenital dos
partos vaginais e fórceps foram 17,0 e 20,1 cm2, respectivamente, contra 12,4 cm2 do Grupo Controle (cesárea eletiva).
Avulsão do músculo elevador do ânus foi observado em mulheres submetidas ao parto vaginal (3/25); no entanto, não houve
diferença significativa entre os grupos cesárea e parto vaginal (p=0,5). CONCLUSÃO: A ultrassonografia tridimensional por
via perineal foi útil na avaliação do assoalho pélvico de mulheres primíparas, diferenciando alterações pélvicas de acordo
com o tipo de parto.
Correspondence
Edward Araujo Júnior
Rua Napoleão de Barros, 875 – Vila Clementino
Zip code: 04024-002
São Paulo (SP), Brazil
Received
01/07/2013
01/28/2013
Study carried out at the Department of Obstetrics, Universidade Federal de São Paulo – UNIFESP – São Paulo (SP), Brazil.
Fetal Medicine Discipline, Department of Obstetrics, Universidade Federal de São Paulo – UNIFESP – São Paulo (SP), Brazil.
2
Department of Gynecology, Universidade Federal de São Paulo – UNIFESP – São Paulo (SP), Brazil.
3
Physiological and Experimental Obstetrics Discipline, Department of Obstetrics, Universidade Federal de São Paulo – UNIFESP – São
Paulo (SP), Brazil.
4
Department of Obstetrics, Universidade Federal de São Paulo – UNIFESP – São Paulo (SP), Brazil.
1
Araujo Júnior E , Freitas RCM, Bella ZIKJD, Alexandre SM, Nakamura MU, Nardozza LMM, Moron AF
Introduction
Over recent years, because of greater stimulation
aimed at increasing the vaginal delivery rates in many
countries, discussion about its potential negative
effects on the pelvic floor is becoming more widely
disseminated. On the other hand, performing cesarean
section without any formal indication may contribute
towards increased maternal and neonatal morbidity and
mortality, even though this is associated with lower need
for corrective surgery for prolapse or incontinence, and it
protects against prolapse symptoms1.
With regard to some pelvic floor alterations, it is
unclear whether pregnancy or delivery is the real predisposing factor1. Nevertheless, epidemiological evidence
for an association between vaginal delivery, prolapse, and
urinary incontinence exists currently. It remains unclear
whether pelvic floor lesions due to vaginal delivery are
caused by strain or avulsion, and whether the changes
observed are primary (directly resulting from delivery)
or are medium and long-term consequences of damage to
the levator ani muscle2. Several mechanisms may coexist
in the same woman. The risk factors are operative vaginal
delivery, prolonged second stage, and possibly high-birth
weight. However, the extent of the trauma clearly varies
from one woman to another2.
Three-dimensional (3D) ultrasonography provides
images similar to those obtained using magnetic resonance imaging (MRI). It has the capacity for image
postprocessing and improved standardization of the
evaluation and measurement planes3, along with proven
reproducibility of its measurements4. Several studies using 3D ultrasonography in order to evaluate predictions
related to pelvic floor lesions during or after delivery have
recently been published5-12. However, only two of them
evaluated the influence of the delivery mode on predictions of pelvic floor lacerations during the immediate
postpartum period8,11.
Due to the importance of evaluating the integrity of
the pelvic floor during the postpartum period, as a means
of predicting the future risk of disorders such as genital
prolapses, we have presented here our initial experience
at our service, concerning postpartum evaluation of the
pelvic floor by means of transperineal 3D ultrasonography, with comparisons between different delivery modes.
Methods
This was a cross-sectional study conducted on 37
primiparous women who gave birth at the São Paulo
Hospital, Federal University of São Paulo (UNIFESP),
between October 2010 and January 2011. The study was
approved by the Research Ethics Committee of UNIFESP,
118
and the patients who volunteered to participate signed
an informed consent form. The participants were divided
into three groups, according to delivery type: elective
cesarean, vaginal delivery (with or without episiotomy),
or forceps delivery. To meet the inclusion criteria, the
patients had to be 18 years of age or older, primiparous,
and with a single pregnancy and live birth. The exclusion
criteria were the following: newborns with structural
abnormalities or chromosome disorders; prematurity
(under 37 weeks); nonselective cesarean section during
labor; time period of more than 48 hours between the
ultrasound examination and the birth; pain symptoms that
imposed limits on the ultrasound scan; and low-quality
ultrasound images that prevented adequate evaluation
of the parameters.
The maternal parameters t analyzed were: mother’s
age, body mass index (BMI), delivery mode, and gestational age at delivery. The fetal parameters evaluated
included gender, birth weight, and head circumference.
The biometric variables of the pelvic floor that were
taken into consideration were area and anteroposterior
and transverse diameters of the urogenital hiatus; average thickness of the levator ani muscle, and echographic
signs of levator avulsion. The hiatal area was measured
on the plane of minimum hiatal dimensions, which was
referenced as midsagittal, comprising the area between the
posterior region of the pubic symphysis and the anterior
and posterior borders of the muscles and of the levator
ani, including only the anorectal muscle. This transverse
section in the axial plane enables measurements of the
hiatal dimension, such as area (Figure 1A) and transverse
and anteroposterior diameters (Figure 1B), as described by
Dietz et al.13. The mean thickness of the levator ani muscle
was defined in the axial plane as the mean of the levator ani
thicknesses measured bilaterally (Figure 1B). The echographic sign of levator avulsion was stipulated as a
loss of continuity between the muscle and the pelvic
sidewall, as obtained in the axial plane (Figures 1C
and D) and shows a schematic image of the anatomical
structures of the female pelvic floor.
All the biometric parameters were obtained on
the second postpartum day (from 24 to 48 hours after
birth) by a single ultrasound technician (RCMF) with
two years of experience of 3D-ultrasound in obstetrics.
Volume measurements were taken with the patient
at rest in the gynecological position, by means of the
transperineal route, using a 4 to 8 MHz transabdominal volumetric transducer attached to a Voluson 730
Expert machine (General Electric Medical Systems,
Zipf, Austria). The transducer was covered with a sterile
latex condom and placed in the vaginal introitus, without
applying much pressure and by opening the labia minora.
It was oriented in the midsagittal plane, thus allowing,
Assessment of pelvic floor by three-dimensional-ultrasound in primiparous women according to delivery mode: initial experience from a single reference service in Brazil
from right to left, a view of the pubic symphysis, bladder neck, urethra, vaginal length, and distal portion of
the rectum with the anorectal junction and the proximal
part of the anal canal.
The opening angle was standardized to 70º in the sagittal plane and 75º in the axial one. After automatic scanning
(four seconds), the image was displayed on the screen in the
multiplanar (axial, sagittal, and coronal planes) and rendering
modes. The sagittal plane was selected as the reference as
to obtain measurements of the chosen parameters. The
green line (region of interest, ROI) was placed in the upper
portion of the sagittal plane, in order that all the pelvic
floor structures became visible in the rendering image.
Three volumes were acquired for each patient and stored
in the memory of the machine. Subsequently, the volume
with the highest definition image quality was selected
for off-line analysis, which was then transferred to a
personal computer, and the parameters were analyzed
by the same examiner (RCMF) using version 9.0 of the
4D View software (General Electric Medical Systems,
Zipf, Austria). At the time of parameters’ analysis, the
examiner did not have any access to postnatal data.
pubic symphysis
A
B
urethra
genital hiatus
levator ani m.
levator ani m.
canal anal
C
D
levator ani m. avulsion
Figure 1. Axial plane of the female pelvic floor on the second
postpartum day in rendering mode. (A) measurement of the hiatal
area; (B) anteroposterior diameter (measurement 1), transverse diameter (measurement 2), mean thickness of the bilateral levator ani
muscles (measurements 3 and 4); (C) avulsion of the unilateral levator
ani muscle (red circle and blue arrow); (D) avulsion of the bilateral levator ani muscles (red circles and blue arrows).
The sample size calculation was based on data
published by Falkert et al. 6. Considering that the
estimated hiatal area is 16.2±3.2 cm 2 for women
undergoing cesarean section, and 22.2±4.7 cm 2 for
those undergoing vaginal birth, evaluations on a
total of nine subjects per group would be required
in order to have a statistical power of 90% and to
identify this difference.
Data were written down using a specific protocol, transferred to an Excel 2003 spreadsheet (Microsoft, Redmond, WA,
USA), and analyzed using version 13.0 for Windows of the
Statistical Package for the Social Sciences – SPSS (SPSS Inc.,
Chicago, IL, USA). The quantitative variables were subjected
to the Kolmogorov-Smirnov’s test to check for normal
distribution. Differences between groups were evaluated by
determining the mean differences and their respective 95%
confidence intervals (95%CI). The proportions of levator ani
muscle avulsion were compared between elective cesarean
section and vaginal birth by means of Fisher’s exact test.
The significance level was set at 5% (p<0.05).
Results
Thirty-seven primiparous patients with a single pregnancy underwent pelvic floor evaluation by means of 3D
ultrasound on the second postpartum day. Two of them
were excluded from the study: one due to significant pain
in the episiotomy scar at the time of volume measurement,
and the other because of preterm labor (<37 weeks). The
remaining 35 patients were allocated to three groups
according to the delivery mode, as follows: elective
cesarean delivery (n=10), vaginal delivery (n=16) and
forceps delivery (n=9). Episiotomy was performed
in only three women. The quantitative variables
tested for normal distribution using KolmogorovSmirnov’s test did not depart from normality (p>0.05).
Considering the total sample, the maternal age was
24.5±6.3 years-old (mean±standard deviation – SD),
BMI was 27.3±4.5 kg/m², gestational age at delivery was
38.9±1.3 weeks, head circumference was 34.6±1.0 cm,
and birth weight was 3.251±418 g.
When comparing the ultrasound measurements
on the pelvic floor among the groups (Table 1), it was
observed that women who underwent elective cesarean
section had a smaller hiatal area and anteroposterior diameter than those that underwent either non-forceps or
forceps-assisted vaginal delivery.
Avulsion of the levator ani muscle was observed only in
women who underwent vaginal delivery: 3/25 women (one
case in the non-forceps group and two in the forceps group).
However, no significant differences between elective cesarean
section and vaginal delivery were observed (p=0.54).
119
Table 1. Pelvic floor measurements from three-dimensional ultrasonography
Elective C-section
Vaginal
n=10
Non-forceps (n=16)
Forceps (n=9)
Mean
SD
Mean
SD
Mean
SD
Hiatal area (cm²)
12.4
1.6
17.0
2.1
20.1
3.2
Hiatal anteroposterior diameter (cm)
5.0
0.4
6.2
0.4
6.5
0.9
Hiatal transverse diameter (cm)
4.0
0.3
4.2
0.5
4.6
0.5
Levator ani thickness (mm)
7.5
0.8
8.4
10
8.3
0.8
Pairwise comparison
Hiatal area (cm²)
Hiatal anteroposterior diameter (cm)
Hiatal transverse diameter (cm)
Levator ani thickness (mm)
MD
95%CI
Significance
Elective C-section versus vaginal (non-forceps)
-4.6
-7.0– -2.2
*
Elective C-section versus vaginal (forceps)
-7.7
-10.4– -5.0
*
Vaginal (non-forceps) versus vaginal (forceps)
-3.1
-5.6– -0.6
*
-1.1
-1.7– -0.5
*
-1.5
-2.2– -0.8
*
-0.4
-1.0–0.2
–
-0.2
-0.7–0.3
–
-0.6
-1.2– -0.1
*
-0.4
-0.9–0.1
–
-0.9
-1.8–0.0
–
-0.8
-1.8–0.2
–
0.1
-0.8–1.0
–
MD: mean difference; 95%CI: 95% confidence interval; *statistically significant difference in the comparison; – no statistically significant difference in the comparison.
Discussion
The preliminary data from this study indicate that
there are significant differences in the changes to the
pelvic floor corresponding to the delivery mode. The
results show that women who had a vaginal or a forceps
delivery presented greater biometric parameters than
those who had an elective cesarean section. Similar data
have been reported in several other published papers, in
which it is stated that the hiatal area is directly influenced
by age, parity, and pelvic organ prolapse14. DeLancey et al.15
reported that alterations to the muscles are most likely
caused by vaginal delivery and are more evident in both
forceps- and vacuum-assisted deliveries16. Their data are
compatible with our findings, as demonstrated by a larger
hiatal area in the forceps delivery group and a higher
maternal mean age.
In turn, macrotrauma may be responsible for more
pronounced changes to the pelvic floor structure. It can
be observed that levator ani muscle avulsion alters the
anatomical V shape of the posterior pelvic floor structure
to an H one, thus further increasing the dimensions of
the pelvic hiatal area17. Data from our study showed that
such increase in pelvic hiatal area occurred primarily in
the forceps delivery group, in which the muscle avulsion
rate was higher. Our results indicated that there was an
increase of up to 37% for vaginal delivery and 62% for
120
forceps one, compared with the Control Group at rest.
From correlating our results with those reported in the
literature, it was observed that the increase in urogenital
hiatus area in the literature ranged from 13 to 37% for
vaginal delivery and from 28 to 39% for forceps, with
the patients at rest. However, it was unclear whether the
Control Groups comprised elective cesarean section cases.
We believe that the significant difference between our results
and those in the literature for the forceps group is partly
due to the small number of cases in this group and to the
avulsion and maternal age rates, which pushed our results
up higher. Developing this study will help us to come up
with more concrete answers in the future and thus better
compare our data from a miscegenated population with
those published in the worldwide literature.
There was a 12% avulsion rate among patients
postvaginal and forceps deliveries taken together, corresponding to 22.2% for the forceps delivery group
alone and 6.2% for the non-forceps vaginal deliveries.
These data are consistent with those in the literature, which
show an avulsion rate of 10 to 30% for vaginal deliveries18.
It should be emphasized that the incidence of avulsion
has been reported to be up to 63.3% for rotational forceps
deliveries6, and 47% for surgical deliveries among patients
over 30 years of age19. Other studies have indicated that
forceps use correlates with a three to fourfold greater
risk of macrotrauma of the pelvic structures (levator ani
muscle avulsion)5,18,20.
Assessment of pelvic floor by three-dimensional-ultrasound in primiparous women according to delivery mode: initial experience from a single reference service in Brazil
Furthermore, other risk factors such as the
occiput posterior position during the second stage
of labor, prolonged expulsion period and episiotomy
may contribute towards avulsion. However, the
role of such factors is still rather unclear and not
as well-established as that of forceps delivery 17.
Shek and Dietz 17 attempted to determine antenatal
predictive factors that could signal an increased risk
of pelvic floor avulsion, but they did not find any
factors. Curiously, these authors found that patients
with a BMI less than 30 kg/m2 had a greater chance
of avulsion, and they hypothesized that nutritional
status was related to this protective biomechanical
effect of the pelvic muscles. However, their finding
is still considered inconclusive 17,21. Despite the small
number of cases included in this study, 66% of the
patients with levator ani muscle avulsion had a BMI
less than 30 kg/m2, which coincide with the already
presented data. Our results are the opposite of what
was found when studying urinary incontinence
mechanisms related to maternal overweight, i.e.,
that there is a direct relationship between weight and
the chance that the patient will be incontinent. The
latter finding seems obvious, since there is a different
pathophysiological mechanism for this situation22.
The present study shows that there was no difference among groups concerning the mean thickness of
the levator ani muscle. These results may be explained
by the fact that there had not been enough time to
recover from the immediate and temporary deliveryrelated trauma. Some authors had stated that the
postpartum period is not the most appropriate time
for evaluating avulsions or average muscle thickness23.
Based on what was reported, we would suggest that
forceps and vaginal deliveries are important risk factors for morphological alterations to the pelvic floor.
However, many other factors such as prolonged expulsion period, avulsion of the perineal muscles, fetal
weight, maternal BMI, hormone variations, variations
in interpersonal relations, fetal position, surgical team
behavior, and so on, should not be overlooked.
Only two articles in the literature carried out
assessments on the pelvic floor by means of 3D ultrasound during the postpartum period, according
to different delivery modes8,11. The first of these was
conducted by Cassadó Garriga et al.8 and assessed
164 women: 20 nulliparae, 20 primigravidae, and
124 postpartum women (62 at one month and 62 at
nine-month postpartum). They observed that levator
ani avulsion was diagnosed in 59.5% of the forceps
deliveries. Nevertheless, there were no significant
differences in postnatal hiatal dimensions between
normal vaginal deliveries at nine postpartum months,
while the levator hiatal area was significantly greater
after forceps delivery. In another recent study, Albrich
et al.11 evaluated 157 women’s after vaginal deliveries (70), forceps (11) and cesarean sections (76). They
observed that 27 (38.5%) and 5 (45.4%) presented
laceration of the levator ani muscle, respectively. In
comparison with those studies, the incidence of laceration of the levator ani muscle after forceps delivery
among our patients was smaller, probably due to the
small sample.
In summary, we have presented the initial experience of our group from using 3D ultrasonography
for pelvic floor evaluations among primiparae during
the immediate postpartum period, according to the
delivery mode. These initial results prove that there
is a need for routine evaluation of the pelvic floor by
means of 3D ultrasonography, among puerperae who
underwent either spontaneous or operative vaginal
delivery. Because of the low sensitivity of the clinical
assessment, 3D ultrasonography may contribute towards identifying lacerations of the levator ani muscle
that might otherwise have gone unnoticed, and thus
may contribute towards diminishing the future risk
of genital dystopia. Studies with larger samples are
needed in order to prove this assertion.
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G. Impact of mode of delivery on levator morphology: a prospective
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Three-dimensional ultrasound of the pelvic floor 18-24 months
after the first delivery: is there a correlation to delivery mode and
persisting pelvic floor disorders? Ultrasound Obstet Gynecol. 2012
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and levator hiatus by three-dimensional pelvic floor ultrasound.
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Sthela Maria Murad-Regadas1
Leonardo Robson Pinheiro Sobreira Bezerra2
Claudio Regis Sampaio Silveira3
Jacyara deJesus Rosa Pereira1
Graziela Olivia da Silva Fernandes1
José Ananias Vasconcelos Neto4
Iris Daiana Dealcanfreitas1
Anatomical and functional characteristics
of the pelvic floor in nulliparous women
submitted to three-dimensional endovaginal
ultrasonography: Case control study and
evaluation of interobserver agreement
Características anatômicas e funcionais do assoalho pélvico em
nulíparas avaliadas por ultrassonografia tridimensional endovaginal:
Estudo caso-controle e avaliação da confiabilidade interobservador
Artigo Original
Abstract
Keywords
PURPOSE: To determine anatomical and functional pelvic floor measurements performed with three-dimensional (3-D)
endovaginal ultrasonography in asymptomatic nulliparous women without dysfunctions detected in previous dynamic 3-D
anorectal ultrasonography (echo defecography) and to demonstrate the interobserver reliability of these measurements.
METHODS: Asymptomatic nulliparous volunteers were submitted to echo defecography to identify dynamic dysfunctions,
including anatomical (rectocele, intussusceptions, entero/sigmoidocele and perineal descent) and functional changes (nonrelaxation or paradoxical contraction of the puborectalis muscle) in the posterior compartment and assessed with regard
to the biometric index of levator hiatus, pubovisceral muscle thickness, urethral length, anorectal angle, anorectal junction
position and bladder neck position with the 3-D endovaginal ultrasonography. All measurements were compared at rest
and during the Valsalva maneuver, and perineal and bladder neck descent was determined. The level of interobserver
agreement was evaluated for all measurements. RESULTS: A total of 34 volunteers were assessed by echo defecography
and by 3-D endovaginal ultrasonography. Out of these, 20 subjects met the inclusion criteria. The 14 excluded subjects were found to have posterior dynamic dysfunctions. During the Valsalva maneuver, the hiatal area was significantly
larger, the urethra was significantly shorter and the anorectal angle was greater. Measurements at rest and during the
Valsalva maneuver differed significantly with regard to anorectal junction and bladder neck position. The mean values for
normal perineal descent and bladder neck descent were 0.6 cm and 0.5 cm above the symphysis pubis, respectively.
The intraclass correlation coefficient ranged from 0.62–0.93. CONCLUSIONS: Functional biometric indexes, normal
perineal descent and bladder neck descent values were determined for young asymptomatic nulliparous women with
the 3-D endovaginal ultrasonography. The method was found to be reliable to measure pelvic floor structures at rest and
during Valsalva, and might therefore be suitable for identifying dysfunctions in symptomatic patients.
Pelvic floor/anatomy & physiology
Cervix uteri/ultrasonography
Reproducibility of results
Observer variations
Palavras-chave
Diafragma pélvico/anatomia & fisiologia
Colo do útero/ultrassonografia
Reprodutibilidade dos testes Variações dependentes do observador
Resumo
OBJETIVO: Avaliar as medidas anatômicas e funcionais do assoalho pélvico utilizando a ultrassonografia
tridimensional transvaginal em nulíparas assintomáticas sem disfunções do compartimento posterior evidenciado
pela ecodefecografia. Demonstrar o grau de concordância entre observadores do método utilizado para medir
as estruturas anatômicas. MÉTODOS: Voluntárias nulíparas assintomáticas foram submetidas à ecodefecografia
Correspondence
Sthela Maria Murad-Regadas
Centro de Coloproctologia – Hospital São Carlos
Avenida Pontes Vieira, 2.551, 2nd floor – Dionísio Torres
Zip code: 60130-240
Fortaleza (CE), Brazil
Received
11/13/2012
02/25/2013
Study carried out at the Coloproctology Service, Hospital das Clínicas, Universidade Federal do Ceará – UFC – Fortaleza (CE), Brazil.
Anorectal Physiology and Pelvic Floor Unit, Hospital das Clínicas, Universidade Federal do Ceará – UFC – Fortaleza (CE), Brazil.
2
Department of Urogynecology, Hospital Cesar Calls – Fortaleza (CE), Brazil.
3
Department of Radiology, Hospital São Carlos – Fortaleza (CE), Brazil.
4
Department of Urogynecology, Hospital Geral de Fortaleza – Fortaleza (CE), Brazil.
1
Murad-Regadas SM, Bezerra LRPS, Silveira CRS, Pereira JJR, Fernandes GOS, Vasconcelos Neto JA , Dealcanfreitas ID
para identificar alterações dinâmicas no compartimento posterior, incluindo aquelas anatômicas (retocele, intussuscepção, entero/sigmoidocele e
descenso perineal) e funcionais (ausência de relaxamento ou contração paradoxal do puborretal) e avaliadas com ultrassonografia tridimensional
transvaginal para determinar índices biométricos do hiato dos elevadores do ânus, espessura do músculo pubovisceral, comprimento da uretra,
ângulo anorretal, posição da junção anorretal e posição do colo vesical. Todas as medidas foram comparadas em repouso e durante Valsalva;
e determinado descenso perineal e do colo da bexiga. A variabilidade interobservador foi avaliada utilizando o coeficiente de correlação
intraclasse. RESULTADOS: Foram avaliadas 34 voluntárias com a ecodefecografia e a ultrassonografia tridimensional transvaginal. Dessas, 20
foram incluídas no estudo. As 14 excluídas apresentavam alterações dinâmicas no compartimento posterior. Durante a manobra de Valsalva, a área
hiatal foi significativamente maior. A uretra foi significantemente mais curta e o ângulo anorretal foi maior. Medidas em repouso e durante a
Valsalva diferiram significativamente em relação à posição da junção anorretal e do colo vesical. A média de valor do descenso perineal e do
descenso da bexiga foram de 0,6 cm e 0,5 cm acima da sínfise púbica, respectivamente. O coeficiente de correlação intraclasse variou entre
0,62–0,93. CONCLUSÕES: Foram determinados valores normais para os índices biométricos funcionais, descida perineal e colo vesical em
nulíparas assintomáticas utilizando-se a ultrassonografia transvaginal tridimensional. É um método seguro para mensurar a anatomia do assoalho
pélvico durante o repouso e a manobra de Valsalva, e pode ser adequado para a identificação de disfunções em pacientes sintomáticos.
Introduction
Recent advances in imaging technologies have
opened new possibilities of investigation, such as the
successful use of magnetic resonance and an array of
ultrasound modalities in the evaluation of the anatomical and functional characteristics of the pelvic
floor1-16. Some authors have described the pelvic floor
anatomy of asymptomatic females and determined
normal values for anatomic measurements 7,13,16.
However, previous studies have reported voiding
disorders (rectocele, intussusception and paradoxical
contraction) in asymptomatic patients evaluated at
random17-19. In addition, gender and age-related differences in the anal canal anatomy have been reported
in some series 14,20,21, and Regadas et al. 22 described
variations in the anal canal anatomy of patients with
rectocele.
It is therefore important to identify potential
dynamic dysfunctions of the pelvic floor of subjects
without symptoms to evaluate normal anatomy and
establish regular ranges. Posterior pelvic floor dysfunctions may be associated with both anatomical (rectocele,
intussusceptions, entero-sigmoidocele and perineal
descent) and functional changes (non-relaxation or
paradoxical contraction of the puborectalis muscle).
A number of different imaging methods (defecography, dynamic ultrasonography and dynamic magnetic
resonance imaging) may be used to evaluate such
dysfunctions2,6,11,15,23. The purpose of this study was
to evaluate anatomical and functional pelvic floor
measurements performed with 3-D endovaginal ultrasonography in asymptomatic nulliparous women
without dysfunctions detected on previous dynamic
3-D anorectal ultrasonography (echo defecography)
and to demonstrate the interobserver agreement of
these measurements.
124
Methods
Subjects
Consecutive asymptomatic nulliparous volunteers (aged
up to 50 years) were recruited among the employees of two
academic hospitals in Fortaleza (Clinical Hospital of the
Federal University of Ceará and São Carlos Hospital) and
were enrolled in the study between July 2009 and July 2011.
The clinical protocol was approved by the Research Ethics
Committee of the Walter Cantídio University Hospital,
and all subjects gave their written informed consent.
Subjects were evaluated clinically and assigned fecal incontinence24 and constipation25 scores. They were
submitted to 3-D dynamic anorectal ultrasonography
(echo defecography) to identify anatomical (rectocele,
rectal intussusceptions, entero/sigmoidocele and perineal descent) and functional changes (non-relaxation or
paradoxical contraction of the puborectalis muscle) in the
posterior compartment. The study population included
only females reporting to be fully continent, with Wexner
constipation scores under 4 and no anatomical or functional
changes detected at the echo defecography. The subjects
were prospectively submitted to anatomical and functional
measurements with 3-D endovaginal ultrasonography.
Subjects with obstructed defecation symptoms,
fecal incontinence or urgency, sphincter damage at the
3-D ultrasonography, symptoms of stress, urge urinary
incontinence, obesity and diabetic or neurological disorders were excluded, as well as subjects with a history of
colorectal, anorectal or gynecological surgery.
Assessments and variables
All subjects were previously instructed on how to
perform the Valsalva maneuver. Subjects were examined
in the dorsal lithotomy position with a 3-D ultrasound
endoprobe (Pro-Focus 2052; 9-16 MHz; focal distance
Anatomical and functional characteristics of the pelvic floor in nulliparous women submitted to three-dimensional endovaginal ultrasonography: Case control study and evaluation of interobserver agreement
2.8–6.2 cm, BK Medical®, Herlev, Denmark). The endoprobe was introduced above the bladder neck. Images
up to 6 cm long were captured along the proximal-distal
axis for up to 55 seconds by 2 crystals (axial and longitudinal) rotating on the extremity of a stationary transducer.
The examination involved a series of transaxial microsections up to 0.20 mm thick producing a high-resolution
digital volumetric image. Images acquired at rest and
during the Valsalva maneuver were displayed as 3-D cube
images and recorded and analyzed in multiple planes.
The examination was performed by a single colorectal
surgeon with experience in 3-D anorectal ultrasonography
(S.M.M.R.). Finally, all images (complete 3-D cubes) were
numbered randomly, being reassessed and measured independently by two blinded colorectal surgeons (S.M.M.R.
and G.O.S.F.). In their routine clinical practice with 3-D
endovaginal ultrasonography, the investigators use the
same anatomic landmarks and measurements.
The study parameters included: 1) biometric indexes
of the levator hiatus (LH), including the anteroposterior
and the latero-lateral diameter (Figure 1) and area16; 2)
pubovisceral muscle (PVM) thickness in the left (3 o’clock)
and right (9 o’clock) positions; 3) urethral length, measured from the bladder neck to the external urethral
orifice; 4) anorectal angle, measured at the intersection
of the longitudinal axis of the anal canal and a line drawn
along the posterior border of the rectal wall (Figure 2);
5) anorectal junction (ARJ) position, measured from the
anorectal junction to the lowest margin of the symphysis
pubis (SP) (Figure 3). The displacement of the ARJ position between rest and Valsalva indicates perineal descent
and; 6) bladder neck (BN) position, measured from the
bladder neck to the lowest margin of the SP (Figure 4).
The displacement of the BN position between rest and
Valsalva indicates bladder neck descent.
All measurements were registered and compared at
rest and during the Valsalva maneuver. Normal values
were determined for perineal and bladder neck descent.
The level of interobserver agreement was evaluated for
all measurements of all study subjects.
Echo defecography was performed with a 3-D ultrasound device (Pro-Focus, endoprobe model 2052, B-K
Medical®, Herlev, Denmark) placed in the rectum, as
previously described. This procedure had been previously
validated and standardized by Murad-Regadas et al.15
and Regadas et al.14,26. Following rectal enema, the
subjects were given the instructions for the examination
and were evaluated in the left lateral position. Images
were acquired by four automatic scans and analyzed in
the axial, sagittal and, if necessary, the oblique plane.
Scans 1, 3 and 4 used a slice width of 0.25 mm and
lasted 55 seconds each. Scan 2 lasted 30 seconds and
used a slice width of 0.35 mm.
SP: symphysis pubis; U: urethra; PVM: pubovisceral muscle; AC: anal canal; LH-AP:
anteroposterior; LH-LL: latero-lateral.
Figure 1. 3-D endovaginal ultrasound with 2052 endoprobe. Measurements of levator hiatus dimensions, including the anteroposterior and
latero-lateral diameter in axial plane.
Anterior
Posterior
B: bladder; U: urethra; AC: anal canal; R: rectal wall.
Figure 2. 3-D endovaginal ultrasound with 2052 endoprobe. Measurements of anorectal angle in mid-saggital plane, measured at the intersection of the longitudinal axis of the anal canal and a line drawn
along the posterior border of the rectal wall.
125
For scan 1 (at rest): the transducer was positioned
proximally to the PR (anorectal junction) to verify the
anatomical integrity of anal sphincters. For scan 2,
the transducer was positioned proximally to the PR.
The scan started with the patient at rest (3 seconds),
followed by maximum strain with the transducer in
a fixed position. When PR became visible distally,
the scan was stopped. Perineal descent was quantified
by measuring the distance between the position of
the proximal border of the PR at rest and the point
to which it had been displaced by maximum strain
(PR descent). For Scan 3, the transducer was positioned
6 cm from the anal verge. The patient was requested
to rest for the first 15 seconds, to strain at most for
20 seconds, then relax again, with the transducer following the movement. The purpose of the scan was to
evaluate the movement of the PR and the external anal
sphincter during strain, identifying normal relaxation,
non-relaxation and paradoxical contraction. Scan 4:
after the injection of 120–180 mL of ultrasound gel
into the rectal ampulla, the transducer was positioned
7 cm from the anal verge. The scanning sequence was
the same as in scan 3. The purpose of the scan was to
visualize and quantify all anatomical structures and
functional changes associated with voiding (rectocele,
intussusception, sigmoidocele/enterocele).
Statistical analysis
A
B
U: urethra; B: bladder; AC: anal canal; R: rectum; a: at rest; b: Valsalva maneuver;
ARJ: anorectal junction.
Figure 3. 3-D endovaginal ultrasound with 2052 endoprobe. Measurements
of anorectal junction position in mid-saggital plane. Distance from the anorectal junction to the lowest margin of the symphysis pubis (SP)=Line 1.
The data were analyzed with SPSS for Windows
(version 14.0). Differences between the measurements
registered at rest and during the Valsalva maneuver were
assessed with the Student’s t test. The level of statistical
significance was set at p<0.05. The level of interobserver
agreement was evaluated with the intraclass correlation
coefficient (ICC), with a 95% confidence interval. ICC
values greater than 0.70 are acceptable in research, but
for clinical purposes the coefficient should be 0.90 or
higher, and at least 0.95 when used to subsidize important decisions27.
Results
Subject characteristics
A total of 34 volunteers were assessed by echo
defecography and by 3-D endovaginal ultrasonography at rest and during the Valsalva maneuver.
Of these, 20 subjects met the inclusion criteria.
The 14 excluded subjects were found to have grade
I or II rectocele (n=4; 12%) or non-relaxation/
paradoxical contraction of the puborectalis (n=10;
27%). Mean age was 30.3±7.4 years (ranging from
18–44). Mean body mass index was 25.5 kg/m 2
(ranging from 18.8 to 28.6).
3-D dynamic endovaginal ultrasonography
measurements
U: urethra; B: bladder; AC: anal canal; R: rectum; a: at rest; b: Valsalva maneuver;
BN: bladder neck.
Figure 4. 3-D endovaginal ultrasound with 2052 endoprobe. Measurements of bladder neck position in mid-saggital plane. Distance from the
bladder neck to the lowest margin of the symphysis pubis (SP)=Line 1.
126
During the Valsalva maneuver, biometric indexes
of LH, including the anteroposterior and latero-lateral
diameters, increased (though not significantly) whereas the hiatal area was significantly larger. PVM thickness
in the right and left position was similar at rest and during Valsalva (Table 1).
The urethra was significantly shorter and the anorectal
angle was greater during Valsalva. Measurements at rest
and during Valsalva differed significantly with regard
to the ARJ position (2.1 versus 1.4 cm above the SP)
(p=0.01) and the BN position (2.9 versus 2.3 cm above
the SP) (p=0.0004) (Table 1). Mean values for normal
perineal descent and bladder neck descent were 0.6 cm
(range: 0.0–1.6) and 0.5 cm (range: 0.0–1.4) above the
SP, respectively. In 2 subjects, the ARJ position was 0.1
and 0.4 cm below the SP, respectively.
Interobserver variability
As shown in Table 2, the ICC (average measures)
for evaluations performed by the two blinded examiners
ranged from 0.62 to 0.93 in the sample of 20 participants
(including measurements at rest and during Valsalva).
Thus, for almost all measurements the level of interobserver agreement was acceptable for research purposes. The
agreement between LH measurements (anteroposterior
diameter), at rest and during Valsalva, was acceptable
for clinical purposes.
Table 1. Anatomic and functional measurements of the pelvic floor on 3-D endovaginal
ultrasonography at rest and during the Valsalva maneuver in nulliparous women without
posterior pelvic floor dysfunctions
At rest
Valsalva
Maneuver
Mean (±SEM)
Mean (±SEM)
Levator hiatus AP (cm)
4.8 (0.08)
5.01 (0.11)
0.15
Left to right (cm)
3.6 (0.09)
3.9 (0.1)
0.08
Area (cm2)
13.4 (0.2)
14.8 (0.4)
0.01
PVM thickness (cm)
0.65 (0.01)
0.64 (0.01)
0.7
Urethra length (cm)
2.6 (0.09)
2.1 (0.1)
0.001
Anorectal angle
0.01
Parameter
p-value
133.3 (2.3)
143.7 (2.7)
Anorectal junction position (cm)
1.9 (0.1)
1.3 (0.2)
0.01
Bladder neck position (cm)
2.7 (0.08)
2.1 (0.19)
0.0007
AP: anteroposterior; PVM: pubovisceral muscle; SEM: standard error.
Table 2. Intraclass correlation coefficients for anatomic and functional measurements
of the pelvic floor on 3-D endovaginal ultrasonography at rest and during the Valsalva
maneuver in nulliparous women
ICC
Parameter
At rest
ICC
95%CI
Valsalva
Maneuver
95%CI
Levator hiatus AP (cm)
0.93
0.83–0.97
0.93
0.79–0.97
Left to right (cm)
0.64
0.47–0.86
0.63
0.41–0.84
Area (cm2)
0.84
0.59–0.94
0.86
0.68–0.94
PVM thickness (cm)
0.63
0.26–0.84
0.62
0.29–0.86
Urethra length (cm)
0.82
0.54–0.93
0.85
0.61–0.94
Anorectal angle
0.74
0.35–0.91
0.78
0.42–0.92
Anorectal junction position
0.72
0.57–0.90
0.81
0.67–0.96
Bladder neck position
0.88
0.67–0.95
0.81
0.47–0.93
AP: anteroposterior; PVM: pubovisceral muscle; ICC: intraclass correlation coefficients;
SEM: standard error.
Discussion
This study provides anatomical and functional measurements of the pelvic floor at rest and during Valsalva for
a sample of asymptomatic nulliparous women submitted to
automatic 3-D endovaginal ultrasonography. In addition,
normal range and cut-off values of physiological perineal
descent and bladder neck descent were established. This
was made possible by recruiting asymptomatic, nulliparous
volunteers without symptoms of incontinence or obstructed
defecation and without anatomic and functional posterior
dysfunctions at echo defecography.
We excluded 12% of the initial sample of volunteers due
to anatomic changes (rectocele) and 27% due to functional
changes (non-relaxation/paradoxical contraction of the PR) in
order to rule out any effect of such dysfunctions on the pelvic
floor anatomy, even in asymptomatic subjects. Regadas et al.22
clearly demonstrated the presence of anatomical changes in
the anal canal of patients with rectocele. Large rectocele is a
common cause of obstructed defecation due to anatomical
changes, but smaller forms have been observed in up to 80%
of asymptomatic subjects17.
Nevertheless, the definition of rectocele and the factors of prevalence are still controversial. For gynecologists,
rectocele is a prolapse of the posterior vaginal wall associated
with a rectovaginal septum defect28, whereas for colorectal
surgeons, rectocele is a hernia of the anterior wall into the
vagina detectable during functional defecation maneuvers6,11,15,17,26. Different imaging modalities, such as dynamic
ultrasonography and magnetic resonance imaging, have been
used to evaluate posterior pelvic floor dysfunctions, with good
correlation2,6,11,15,23,26,28.
Paradoxical contraction of the PR (or non-relaxation)
is not uncommonly found in asymptomatic subjects and
should be recognized at examination. In a study on pregnant
nulliparous women, Orno and Dietz29 demonstrated that the
Valsalva maneuver is frequently accompanied by pelvic floor
muscle contraction due to levator coactivation and associated
with significant differences in pelvic floor measurements when
comparing the first and the optimal Valsalva maneuvers. In
their study, levator coactivation was found to be associated
with significantly reduced bladder neck descent and lower
hiatal diameter and area measurements. The authors suggested that subjects be instructed and trained as to how to
perform the functional maneuver prior to dynamic scanning.
The expressions “non-relaxation”, “paradoxical contraction
of the puborectalis muscle” and “levator coactivation” refer
to the same dysfunction.
All subjects were previously evaluated with echo defecography to assess the posterior compartment for possible
dysfunctions. The echo defecography technique and the
parameters used in the present study have been previously
described by Murad-Regadas et al.15. Using a 360° transducer,
127
automatic scanning and high frequencies for high-resolution
images, the authors validated the technique in a prospective
multicenter study by demonstrating agreement between
echo defecography and conventional defecography26. The
advantage of echo defecography lies in the possibility of visualizing all anatomical structures of the pelvic floor, changes
during strain and evacuation disorders, without exposing the
patient to radiation.
Our findings for biometric indexes of the levator hiatus
and PVM thickness at rest match the results published by
Santoro et al.16 based on nulliparous patients submitted to 3-D
endovaginal ultrasonography. They are also similar to those
published by Shobeiri et al.13 in a study determining normal
ranges for anatomical measurements of the pelvic floor in
nulliparous subjects using 3-D endovaginal ultrasonography,
although measurements were only taken at rest. Using 3-D
endovaginal ultrasound, images acquired automatically
with a 16-Mhz transducer are merged into a 3-D cube and
recorded in real time for subsequent analysis. The cube image can be freely manipulated in all planes and allows the
visualization of anatomical structures simultaneously after
image processing.
The biometric indexes of the LH increased and the hiatal
area was significantly larger during the Valsalva maneuver,
while PVM thickness in the right and left positions remained
unchanged. In addition, BN and ARJ positions differed significantly in relation to the lower margin of the SP between
rest and Valsalva. To our knowledge, this is the first study
using dynamic 3-D endovaginal ultrasonography to evaluate the position of the anorectal junction and the bladder
neck at rest and during Valsalva, determining the difference
between these measurements and establishing cut-off values
for normal perineal descent and normal bladder neck descent
in nulliparous subjects. Dietz et al.7 studied the position of
the bladder neck during Valsalva with transperineal ultrasonography. Despite differences in technique, their results
match the findings of this study. Shobeiri et al.13 evaluated
the muscles comprising the minimal levator hiatus, determined the minimal levator hiatus area and the anorectal
angle, and described a new measurement called levator plate
descent angle at rest, establishing normal ranges to enable
the identification of abnormalities. Likewise, the results of
a study by Beer-Gabel et al.6 using dynamic transperineal
ultrasonography to determine the anorectal position at rest
and during maximal strain in female patients with obstructed
defecation are comparable to measurements obtained with
defecography; however, the authors did not establish normal
perineal descent values for the technique. Some authors used
dynamic ultrasonography to measure the anorectal angle at
rest16 and during squeezing.12 In our study, the anorectal
angle was significantly larger during Valsalva than at rest
in women without dysfunctions, matching the results of
Beer-Gabel et al.6 for normal relaxation and anismus in their
comparison of dynamic transperineal ultrasonography and
defecography.
In the present study, the level of interobserver agreement
for measurements taken at rest and during Valsalva was within
the acceptable range for research purposes, as established
elsewhere7,30. Technological advances and new high-resolution
modalities of ultrasonography have brought innovation
to research on pelvic floor anatomy and made it possible to
standardize techniques and identify landmarks. Several studies have shown that these techniques are reproducible7,12,30.
3-D endovaginal ultrasonography allows to visualize
the morphology and function of the pelvic floor in multiple
planes and at high resolution, and constitutes an alternative
imaging modality for pelvic floor dysfunctions. Although our
sample was relatively small, the present series has significant
implications on anatomical and functional measurements of
the pelvic floor in selected asymptomatic women submitted
to 3-D endovaginal ultrasonography, following evaluation
by echo defecography. Further studies on other patient series
are required to demonstrate the relation between biometric
indexes in patients with multiple dysfunctions such as perineal
descent and ∕or significant rectocele.
In conclusion, functional biometric indexes, normal
perineal descent and bladder neck descent values were determined for young asymptomatic nulliparous women using
3-D endovaginal ultrasonography. The method was found to
be reliable for measuring pelvic floor structures at rest and
during Valsalva, and might therefore be a suitable method
for identifying dysfunctions in symptomatic patients.
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129
Alberto Moreno Zaconeta1
Indara Ferreira Braz de Queiroz2
Angélica Amorim Amato3
Lucília Domingues Casulari da Motta1
Luiz Augusto Casulari4
Depression with postpartum onset: a
prospective cohort study in women undergoing
elective cesarean section in Brasilia, Brazil
Depressão com início após o parto: estudo de corte prospectivo em
mulheres submetidas à cesárea eletiva em Brasília, Brasil
Artigo Original
Abstract
Keywords
PURPOSE: It was to determine the prevalence of depressive symptoms in a sample of puerperal women from Brasília,
Brazil, distinguishing cases with onset after delivery from those already present during pregnancy. METHODS: A prospective
cohort study with convenience sampling of patients submitted to elective cesarean section at two private hospitals. As an
instrument for assessing depressive symptoms, the Edinburgh Postnatal Depression Scale with cutoff ≥13 was applied
shortly before delivery and four to eight weeks after childbirth. RESULTS: Among the 107 women who completed the study,
11 (10.3%) had significant depressive symptoms during pregnancy and 12 (11.2%) during the postpartum period. Among
the 12 patients with postpartum symptoms, 6 had symptoms during pregnancy, so that 5.6% of the sample had postpartum
onset of depression. The higher overall frequency of depression was significantly among single women than among married
women (p=0.04), a fact mainly due to a higher frequency of single women experiencing persistent depressive symptoms
both before and after delivery (p=0.002). The risk of depression was not influenced by age, parity or educational level.
CONCLUSION: Women with depression identified during the postpartum period comprise a heterogeneous group, in
which symptoms may have started before pregnancy, during pregnancy or after childbirth. In this sample, half of the
postpartum depression cases already presented symptoms during late pregnancy. Since depression can arise before and
after childbirth, it may have different etiologies and, therefore, a different response to treatment, a possibility that should
be considered by clinicians and researchers.
Depression, postpartum
Puerperal disorders
Postnatal care
Perinatal care
Pregnancy complications
Palavras-chave
Depressão pós-parto
Transtornos puerperais
Cuidado pós-Natal
Assistência perinatal
Complicações na gravidez
Resumo
OBJETIVO: Foi determinar a prevalência de sintomas depressivos em uma amostra de puérperas da cidade de Brasília, Brasil,
discriminando os casos com surgimento após o parto daqueles já presentes durante a gestação. MÉTODOS: Estudo de corte
prospectivo. Amostragem por conveniência de pacientes que seriam submetidas à cesariana eletiva em dois hospitais privados.
Como instrumento para avaliar os sintomas depressivos, foi utilizada a Escala de Depressão Pós-natal de Edimburgo,
com ponto de corte ≥13, aplicada momentos antes do parto e quatro a oito semanas após o nascimento da criança.
RESULTADOS: Das 107 mulheres que completaram o estudo, 11 (10,3%) apresentaram sintomas depressivos significativos
na gestação e 12 (11,2%) no período pós-parto. Das 12 pacientes com sintomas no pós-parto, 6 já tinham os sintomas
durante a gestação, de modo que 5,6% da amostra teve depressão com início após o parto. A frequência global de
depressão foi significativamente maior entre as mulheres solteiras em comparação com mulheres casadas (p=0,04)
por causa principalmente da maior frequência de mulheres solteiras apresentando sintomas depressivos persistentes,
antes e depois do parto (p=0,002). O risco de depressão não foi influenciado pela idade, paridade e escolaridade.
CONCLUSÃO: As mulheres com depressão reconhecida no período pós-parto compõem um grupo heterogêneo, no qual
o quadro pode ter tido início antes da gestação, durante a gestação ou após o parto. Na amostra estudada, metade
dos casos de depressão reconhecida após o parto já apresentava os sintomas no final da gestação. Uma vez que a
depressão que surge antes e após o parto pode ter etiologia diferente e, portanto, apresentar resposta ao tratamento
diferente, os clínicos e pesquisadores devem estar atentos a essa possibilidade.
Correspondence
Alberto Moreno Zaconeta
Área de Ginecologia e Obstetrícia do Hospital Universitário de Brasília
SGAN, Avenida L2 Norte, quadra 605
Zip code: 70840-901
Brasília (DF), Brazil
Received
02/10/2012
01/21/2013
Study carried out at Universidade de Brasília – UnB – Brasília (DF), Brazil.
Faculdade de Medicina, Universidade de Brasília – UnB – Brasília (DF), Brazil.
2
Hospital Universitário de Brasília – Brasília (DF), Brazil.
3
Department of Pharmaceutical Sciences, Faculdade de Medicina, Universidade de Brasília – UnB – Brasília (DF), Brazil.
4
Post-Graduation Programs in Health Sciences and Medical Science, Faculdade de Medicina, Universidade de Brasília – UnB –
Brasília (DF), Brazil.
1
Depression with postpartum onset: a prospective cohort study in women undergoing elective cesarean section in Brasilia, Brazil
Introduction
Depression affects one in every eight women in the
postpartum period1 and may have adverse consequences
for mother, infant and their family. The possibility that
the disorder with onset after childbirth has unique features
was first suggested in the sixties. In a pioneering study
by Pitt el al.2, three hundred women were evaluated at
the seventh month of pregnancy and again in the second
month postpartum. Among women whose disorder arose
after delivery, the symptoms were different from those of
classic depression, and the condition was so-called “atypical postpartum depression”2. In the following decade, the
expression “postpartum depression” appeared in scientific
publications, but with an important conceptual change.
Rather than only referring to the condition that emerged
after delivery, the term was used to describe any case of
depression diagnosed in the postpartum period, regardless of when depressive symptoms actually appeared.
As a consequence, the term “postpartum depression” lost
its specificity and its exact meaning became confusing3.
The consequences of this change might be relevant
to clinical practice since there are some peculiarities in
depression with onset after delivery, such as the high probability of concomitant anxiety and obsessive-compulsive
symptoms, lower incidence of suicide, delayed response to
treatment and the need for pharmacological treatment4.
In addition, the distinction of depression that arises after
delivery from that which precedes it is important for the
investigation of its etiology, pathophysiology and triggering factors. If depression with onset after childbirth
is a specific entity, then analyzing these patients together
with patients with antenatal depression would potentially
lead to confusing results. This could be the case when
evaluating the influence of hormonal changes in the occurrence of postnatal depression (PND). There is evidence
that some women may be more sensitive to postpartum
hormonal changes. In these women, the abrupt decline
in the serum level of hormones that follows placental
expulsion is associated with mood changes and depressive
symptoms5-7. The hormones probably involved in these
changes are estrogen5, progesterone5, corticotropin releasing hormone (CRH)6,8-10, and cortisol6,9. In our opinion,
if the drop in the serum levels of placental hormones is
considered to play a role in triggering postpartum depression, then the inclusion of women who were already
depressed during pregnancy — and therefore before the
drop in placental hormones — under this denomination
would mean that distinct disorders would receive the
same denomination.
In a recent review of Brazilian studies4 addressing
postpartum depression, there was a wide variation in its
prevalence, ranging from 7.211 to 43%12. Only one of
these studies distinguished between depressive symptoms
with onset before or after delivery12. Since in all other
studies women were evaluated only in the postpartum
period13-22, the proportion of women whose depressive
symptoms in fact began in the postpartum period remains
largely unknown.
The aim of this study was to determine the prevalence of depressive symptoms in a sample of puerperal
women of Brasília – Brazil, distinguishing women whose
symptoms were already present during pregnancy from
those whose symptoms begun after delivery.
Methods
This was a prospective cohort study carries out
January and April 2011 in two large private hospitals, located in central Brasília, Distrito Federal,
whose users consisted mainly of Supplementary Health
System users (health insurance plans). The study was
approved by the Catholic University of Brasilia Ethics
Committee and all women who agreed to participate
signed the informed consent form.
A convenience sample was composed of women
submitted to elective cesarean section that were enrolled
in a study to evaluate the correlation between hormonal
concentrations in cerebrospinal fluid and the occurrence
of postpartum depression, which is nearing completion.
Women with singleton pregnancies terminated between
37 and 42 weeks by elective caesarean section that agreed
to participate in the study were included. Exclusion criteria were labor pains, hypertensive disorders, diabetes,
premature rupture of membranes, antidepressants use
in the previous six months, glucocorticoid use during
pregnancy and the diagnosis of fetal malformations or
other disorders.
Depressive symptoms were assessed by the Edinburgh
Postnatal Depression Scale (EPDS)23, which is a validated
tool for use both during pregnancy and in the postpartum
period24. The EPDS is a self-report questionnaire with
ten items to which the patient assigns a score ranging
from zero (no symptom) to three (severe symptoms), so
that a final score from 0 to 30 points may be obtained.
The cutoff score of 12 or greater is commonly used as
an indication of the risk of depression, although higher
or lower cutoffs may be used according to the desired
level of specificity. We used a Portuguese version of the
EPDS, which has been previously validated to Brazilian
puerperal women13, and the cutoff score of 13 or higher
was considered indicative of depression. Women were
assessed at two time points: at the hospital, shortly
before delivery, and again at home, four to eight weeks
postpartum. At the hospital, the women completed the
EPDS in the anteroom of the obstetric center, shortly
131
Zaconeta AM, Queiroz IFB, Amato AA, Motta LDC, Casulari LA
before cesarean section without any help from others. They
were instructed about the importance of describing their
feelings in the previous seven days and not only on the
day they were completing the questionnaire. Four to eight
weeks later, the EPDS was left in their homes and collected after confirmation that they had been completed.
The assistant obstetrician of all patients with significant
postpartum depressive symptoms was notified and referral
to specialized treatment was recommended.
Data recording and analysis were performed using
Excel for Mac software version 2011, and for statistical calculations we used SPSS software, version 19. Categorical
variables were described using frequency analysis, and
percentages and quantitative variables were reported as
averages and standard deviations. Fisher’s exact test, χ2
and Student’s t-tests were used to compare women with or
without depressive symptoms, and statistical significance
of differences were considered if p<0.05.
5 (4.7%) of them showed depressive symptoms only before
delivery, 6 (5.6%) experienced these symptoms before and
after childbirth and in 6 (5.6%) depressive symptoms
emerged after delivery.
The prevalence of depression and the influence of
demographic variables were examined in the following
patient subgroups: without depressive symptoms; with
depression at some point before or after delivery; with depression only before delivery; with persistent depression
before and after childbirth and with postpartum depression only (Table 2).
There was no difference in the mean age of women
without depressive symptoms from those who showed these
symptoms at any of the two time points in which they
were assessed, before and after delivery. Most women
Table 1. Characteristics of the participants (n=107)
Parameter
n
%
Age (years)
Results
A total of 113 women were considered eligible, but 2
refused to participate. Among the 111 women who completed the EPDS prior to delivery, 4 patients did not complete
the EPDS in the postpartum period and were excluded from the
study (three of them moved to another city and one wished to
drop out). The characteristics of the final sample, consisting of
107 women, are shown in Table 1.
Depressive symptoms were observed in 17 (15.8%)
of the 107 women evaluated. Eleven women (10.3%)
had depressive symptoms during pregnancy, but five of
them no longer showed these symptoms after childbirth.
In contrast, 12 women (11.2%) had postpartum depressive symptoms. Six of the latter group had experienced
these symptoms during pregnancy and the other six
developed depressive symptoms only after childbirth.
Thus, among all the 107 women included in the study,
<25
9
8.4
25 to 35
73
68.2
>35
25
23.3
Educational status
Elementary school
2
1.8
High school
23
21.4
College
57
53.2
Graduate
25
23.3
Single
14
13.1
Married/Stable relationship
93
86.9
0
60
56
1 or more
47
44
Marital status
Parity (previous)
Gestational age at the moment of delivery (weeks)
37–38
8
7.5
38–40
90
84.1
>40
9
8.4
Table 2. Depression prevalence and characteristics of the sample
Variables
Total sample
n=107
Prevalence of depression – %
None depression symptoms
n=90
Only before childbirth
n=5
Before and after childbirth
n=6
Only after childbirth
n=6
15.8
–
15.8
4.7
5.6
5.6
Age (years; mean±SD)
31.6±5.1
31,6±5,3
31.6±5.3
32.2±4.1
31.8±3.4
31.3±5.1
Educational level – n (%)
Less than college
College or post-graduation
25±23.3
82±76.7
22 (88)
68 (82.9)
3 (12)
14 (17.1)
0
5 (6.1)
2 (8)
4 (4.9)
1 (4)
5 (6.1)
Parity – n (%)
Nulliparous
1 or more
60 (56)
47 (44)
53 (88.3)
37 (78.7)
7 (11.6)
10 (21.2)
2 (3.3)
3 (6.3)
2 (3.3)
4 (8.5)
3 (5)
3 (6.3)
93 (86.9)
14 (13.1)
81 (87.1)
9 (64.3)
12 (12.9)
5 (35.7)*
4 (4.3)
1 (7.1)
2 (2.1)
4 (28.6)†
6 (6.4)
0
Marital status – n (%)
Married
Single
*p=0.04 versus married; †p=0.002 versus married.
132
Depression symptoms
At some point
n=17
(76.7%) had high educational levels, as shown in Table 1,
and there was no association between this parameter and
the occurrence of depressive symptoms, either before or
after delivery, or at both time points (Table 2).
A predominance of nulliparous women (56%) was
seen in this study (Table 1), and there was no difference
between those who were nulliparous or had one or more
children with respect to the presence of depressive symptoms at any time, only before delivery, before and after
delivery, and only after delivery, as indicated in Table 2.
Most women included in this study were married (86.9%),
as shown in Table 1. Overall, it was observed that depressive symptoms were significantly more frequent in
single women (p=0.04), and this difference was due to the
higher frequency of single women in the group of patients
who experienced these symptoms both before and after
childbirth (p=0.002) (Table 2). Marital status did not
influence depression rate in women with symptoms only
before delivery (p=0.43). Similarly, although all women
with depression symptoms arising after childbirth were
married, there was no significant difference between these
and single women (p=0.5) (Table 2).
Discussion
The concept of postpartum depression has significantly changed over the last decades3. It may be
currently considered an imprecise term used to refer
to any case of depression initially recognized after
childbirth, irrespective to the precise onset of depressive symptoms.
In this study, the prevalence of depression with onset
within four to eight weeks postpartum was 5.6%. It is
noteworthy that studies carried out in different populations and using the EPDS and the same cutoff score used
in our study and which similarly assessed the occurrence
of depressive symptoms both before and after delivery have
found similar results25,26. In a large study carried out in
Australia, among 11,136 women who screened negative
for depression during pregnancy, 584 (5.2%) had EPDS
score of 13 or greater 6 weeks after delivery25. Similarly,
when all pregnant women who lived in the city of Avon,
England, were prospectively evaluated, Heron et al.26 found
that 7,233 women were free of depressive symptoms at the
32nd week of pregnancy, but in a second assessment, 8 weeks
after childbirth, 380 (4.6%) had depressive symptoms
indicated by EPDS score of 13 or greater.
To our knowledge, there are two Brazilian studies
that assessed depressive symptoms both before and after
childbirth by using the EPDS. The first one comprised
a small sample of 29 pregnant women evaluated in
the third trimester of pregnancy, and found that the
prevalence of positive screening, also defined by EPDS
score of 13 or greater, was 38%12. Twenty-one of these
patients remained in the study after delivery and were
monthly assessed by the EPDS for six months. The
cumulative depression rate after this period was 43%,
but, when only cases with onset of depressive symptoms
after delivery were considered, this rate dropped to
33%. The high prevalence of depression found in this
study might be explained by the fact that the sample
consisted exclusively of low-income women12.
In the second study, which was recently published27, the prevalence of depression was assessed
early in the third trimester of pregnancy and four
to six weeks after delivery in 600 Brazilian women.
The depression rate during pregnancy was 24%, and
the rate after delivery was 11%. However, in this
study, women with depressive symptoms in the third
trimester of pregnancy whose symptoms persisted
in the postpartum were included in the calculation of
the rate of postpartum depression. Interestingly, the
authors emphasize that depression during pregnancy
had high sensitivity (75%) and specificity (81%) for
predicting the occurrence of postpartum depression27.
One may ask whether some of these women had in fact
persistent depressive symptoms, but were diagnosed
with antenatal depression during pregnancy and postpartum depression after delivery. Accordingly, antenatal depression would not be a predictor of postpartum
depression, but the same symptoms being recognized
at two different time points. Since the prevalence of
depression in the postpartum period found in this
study comprising a large sample of women was similar
to the one found in our study (11%), we believe that
a post-hoc analysis of their results, with the exclusion
of women who already experienced depressive symptoms during pregnancy, would add significantly to
the knowledge of the prevalence of depression with
postpartum onset in Brazil.
Other studies that used the EPDS to assess depression in Brazilian puerperal women did not include an
evaluation during pregnancy and used cutoff scores
equal to or greater than 1115,16,19,22 or 1213,20. In these
studies, the frequency of postpartum depression was
higher than the one found in this study: 1313, 2116,20;
24.322, 3715 and 39%19. When the cutoff score used
decreases, an increase in the frequency of results indicating depression by this scale is indeed expected4.
Other Brazilian studies have used different instruments to assess depressive symptoms, such as the
Beck depression inventory14, Hamilton depression
scale17, Postpartum Depression Screening Scale18, and
the Structured Clinical Interview for DSM-IV Axis I
Disorders21. The results from these studies indicated
a consistently higher rate of depressive symptoms in
133
Zaconeta AM, Queiroz IFB, Amato AA, Motta LDC, Casulari LA
the postpartum period, ranging from 7.2 21 to 19%17.
However, in these studies, women with depressive
symptoms before delivery were not excluded from the
calculation of postpartum depression rates, and this
could explain, at least in part, the higher frequency
of postpartum depression as compared to our results.
In the present study, it was found that depression
with onset after childbirth accounted for half the cases
of depression seen in the postpartum period. This
finding is similar to that described by Gotlib et al.28,
which drew attention to potentially misleading results
of studies that did not distinguish between cases of
depression arising after childbirth from those which
they considered “simply a continuation of antenatal
depression”29. Antenatal depression is associated
with a number of socio-demographic factors, such as
younger age, lower educational level and high number
of children, which do not affect the occurrence of postpartum depression28. Accordingly, we could not find
an association of age, educational level and number of
children with postpartum depression. In another study
that followed more than eight thousand women and
used the EPDS with the same cutoff score as in this
study, the prevalence of depression in the postpartum
period was 9%. Among these cases, also half (4.6%
of the sample) in fact appeared after childbirth26. In
addition, this study showed that antenatal anxiety is
frequent and may overlap with depression symptoms,
increasing the possibility of postpartum depression26.
The assumption that single women are more anxious
would explain why single women had higher percentage of depression before and after deliver compared
to married women. Josefsson et al.29 followed a group
of 1,500 Swedish women and found a prevalence of
postpartum depressive symptoms of 12.7%, defined
by EPDS score of 11 or greater. Again, about half
of these women already had these symptoms by the
end of pregnancy29. In a similar study involving 1,584
women evaluated by using the EPDS and a cutoff score
of 12 or greater, the depression rate was 7.7% during
pregnancy and 6.8% in the postpartum period30. In
this study, 75% of patients with depression in the
postpartum symptoms already had symptoms during
pregnancy.
A study that assessed depressive symptoms using the Revised Clinical Interview Schedule found a
prevalence of depression in the postpartum of 19.6%31.
Although another diagnostic instrument was used, it
was seen that in half of the cases (9.4%) depressive
symptoms actually arose after delivery32, which is
consistent with our findings. In a longitudinal study
that followed more than one thousand women, depressive symptoms were found in 1.7% of women in the
134
eighth month of pregnancy and in 3.2% in the first
month after childbirth31. When analyzing the group
of 13 patients whose symptoms started after delivery,
it was found that 4 of them (31%) had a history of
depression outside the pregnancy-puerperal cycle and
were in fact experiencing a recurrence of the condition. This possibility, largely not considered in other
studies, makes the heterogeneity of women diagnosed
with postpartum depression even more evident.
The fact that some women may have depressive
symptoms during pregnancy and persisting after delivery and others symptoms arising specifically after
childbirth supports the hypothesis that depressive
symptoms arising at these different time points may
have different etiologies29. Since disorders with different
etiologies may have distinct therapeutic responses, we
suggest that the term postpartum depression should
be used exclusively to define the specific group of
women who develop depression when challenged by
biological and social changes that follow childbirth.
When the exact onset of depressive symptoms cannot be defined, the term perinatal depression seems
more adequate33.
The present study has some limitations. The small
number of patients included and the fact that they
were recruited from private hospitals may have favored
the selection of a group with higher social and educational levels, which precludes generalization of the
results. Another limitation was the use of the EPDS,
which is a screening instrument and not a diagnostic
tool. Despite the widespread use of the EPDS due to
its simplicity, the gold standard for the diagnosis of
depression is the structured interview4. Finally, the
time point in which depressive symptoms were assessed
during pregnancy, immediately before birth, may
not have been the most appropriate. Despite the fact
that the EPDS guides women about the importance
of reporting their symptoms in the previous seven
days and not only on the day of the response to the
questionnaire, it is possible that the responses may
have been influenced by the hospital environment
and the fact that the EPDS was completed shortly
before the cesarean section. A post-hoc analysis of a
recently published Brazilian study27 could confirm
or refute the findings described here.
In conclusion, women with depression recognized
in the postpartum period compose a heterogeneous
group, in which the disorder may have arisen before
pregnancy, during pregnancy or after childbirth. Once
depression that arises before or after childbirth may
have different etiologies and, therefore, different responses to treatment, researchers and clinicians should
be aware of this possibility.
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135
Gustavo Salata Romão1
Paula Andréa de Albuquerque Salles Navarro2
Uso clínico do hormônio
antimülleriano em ginecologia
Clinical use for anti-mullerian hormone in gynecology
Artigo de Revisão
Resumo
Palavras-chave
Hormônio antimülleriano
Fertilização in vitro
Gônadas/lesões
Amenorreia
Ovário/fisiologia
Keywords
Anti-mullerian hormone
In vitro fertilization
Gonads/injuries
Amenorrhea
Ovary/physiology
O hormônio antimülleriano (AMH) é uma glicoproteína produzida pelas células granulosas de folículos ovarianos
primários, pré-antrais e pequenos folículos antrais e ultimamente sua aplicabilidade clínica tem sido demonstrada através
de diversos estudos. A predição da resposta à estimulação ovariana para fertilização in vitro corresponde a sua mais
frequente utilização na prática clínica, sendo rotineiramente realizada em muitos serviços para identificar subgrupos
de mulheres suscetíveis a má resposta ou a Síndrome da Hiperestimulação Ovariana. Existem perspectivas de que
o AMH possa ser aplicável na individualização do risco de injúria gonadal iatrogênica em mulheres portadoras de
neoplasia que serão submetidas a quimioterapia. Também é provável que as dosagens de AMH sejam incluídas
nos protocolos de investigação de amenorreias e oligomenorreias, uma vez que seus níveis encontram-se elevados
em pacientes portadoras da Síndrome dos Ovários Policísticos, reduzidos em casos de falência ovariana prematura
e normais em outras condições como a hiperprolactinemia e o hipogonadismo hipogonadotrófico. É possível que
futuramente o AMH venha a ser utilizado na predição da idade de menopausa e do prognóstico reprodutivo da
mulher, fornecendo bases sólidas ao aconselhamento conceptivo e contraceptivo.
Abstract
Anti-mullerian hormone (AMH) is a glycoprotein produced by granulosa cells of primary, pre-antral and small antral
ovarian follicles and its clinical applicability has been recently demonstrated by several studies. Prediction of the
response to ovarian stimulation for in vitro fertilization corresponds to the most frequent utilization of AMH in clinical
practice, being routinely assessed in many services to identify subgroups of women susceptible to a poor response or
to Ovarian Hyperstimulation Syndrome. There are great perspectives that AMH may be applicable to the individual
determination of risk for iatrogenic gonadal injury in women with neoplasms who will be submitted to chemotherapy. It is
also probable that AMH assessment will be included in protocols for the investigation of amenorrhea and oligomenorrhea,
since AMH levels are increased in Polycystic Ovary Syndrome, reduced in premature ovarian failure and normal in
other conditions such as hyperprolactinemia and hypogonadotropic hypogonadism. It is possible that AMH will be
utilized in the future for the prediction of age at menopause and of reproductive prognosis, providing solid bases for
pre-conceptive and contraceptive counseling.
Correspondência
Gustavo Salata Romão
Curso de Medicina da Universidade de Ribeirão Preto
Avenida Costábile Romano, 2201
CEP: 14096-000
Ribeirão Preto (SP), Brasil
Recebido em
21/11/2012
Aceito com modificações
22/01/2013
Trabalho realizado no Curso de Medicina, Universidade de Ribeirão Preto – UNAERP; Departamento de Ginecologia e Obstetrícia,
Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo – USP – Ribeirão Preto (SP), Brasil.
1
Curso de Medicina, Universidade de Ribeirão Preto – UNAERP – Ribeirão Preto (SP), Brasil.
2
Departamento de Ginecologia e Obstetrícia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo – USP – Ribeirão
Preto (SP), Brasil.
A identificação de marcadores apropriados para estimar
a reserva ovariana permaneceu uma questão controversa
durante muitos anos1, até que recentemente a dosagem
sérica do hormônio antimülleriano (AMH) foi reconhecida
pelas evidências como um método de maior acurácia em
relação aos outros tradicionalmente utilizados2.
O hormônio AMH consiste em uma glicoproteína
de 140 kDa3 identificada pela primeira vez em 1940,
quando foi comprovada sua secreção das células de Sertoli
em fetos do sexo masculino e sua principal atividade, na
promoção da regressão dos ductos de Muller. A produção
de AMH pelas células granulosas folículos primários,
folículos pré-antrais e pequenos folículos antrais (com
até 7 mm de diâmetro) foi relatada pela primeira vez em
19814, mas as investigações sobre o seu papel biológico
e utilidade clínica somente se concretizaram na virada
do século, a partir do desenvolvimento de kits comerciais
para dosagens desse marcador.
Atualmente as dosagens de AMH estão inseridas na
rotina de diversos serviços para diferentes utilidades clínicas.
Avaliação da reserva ovariana funcional em
reprodução assistida
Esta corresponde à indicação mais bem estabelecida para
dosagens séricas de AMH em mulheres, sendo em muitos
serviços realizada rotineiramente antes da fertilização in vitro
(FIV). O termo “reserva ovariana funcional”, recentemente
empregado em reprodução assistida, faz referência ao número
médio de folículos recrutáveis sob estímulo de Hormônio
Folículo Estimulante (FSH) exógeno para crescerem até o
estágio pré-ovulatório, disponibilizando oócitos captáveis
para os procedimentos de fertilização, ao passo que a “reserva
ovariana verdadeira” corresponde ao patrimônio estimado
de folículos remanescentes em um dado momento da vida
reprodutiva da mulher2.
Um grande número de estudos confirmou a superioridade do AMH obtido no segundo ou terceiro dia
de estimulação ovariana controlada em relação à idade
feminina, níveis de FSH, estradiol e inibina B na predição
do número de oócitos captados para FIV5,6.
Como o AMH se correlaciona fortemente ao número
de oócitos obtidos após a estimulação ovariana controlada,
as medidas basais de AMH permitem a individualização
dos protocolos de estímulo e das expectativas de resultado
para os casais inférteis7. Mulheres com níveis elevados de
AMH no período de pré-estimulação ovariana são propensas a uma resposta excessiva às gonadotrofinas exógenas e
deve-se proceder a readequação das doses administradas
para prevenir a síndrome da hiperestimulação ovariana
(SHO)2. Por outro lado, mulheres com níveis reduzidos
de AMH são propensas a má resposta a estimulação e
consequentemente piores resultados na FIV, devendo
ser apropriadamente aconselhadas, e nestes casos deve-se
oferecer outras alternativas de tratamento como a doação
de oócitos2.
Embora o AMH esteja relacionado primariamente à
quantidade e não à qualidade dos oócitos, este marcador
também se associa positivamente às taxas de nascidos vivos
após a FIV, independentemente da idade materna8. Isto se
deve a sua relação específica com a produção de oócitos, e
para cada idade, ou seja, quanto mais elevados os níveis
de AMH, mais favorável é a expectativa em relação ao
número de oócitos captados e de embriões disponíveis a
serem selecionados para a transferência2.
O custo-efetividade do uso rotineiro de AMH nos
protocolos de FIV foi recentemente avaliado e os resultados
sugerem uma economia substancial9. Parte dessa economia
atribui-se à identificação de mulheres propensas à SHO,
que podem ser induzidas com doses mais brandas de gonadotrofinas exógenas, com redução significativa nos custos
da internação e tratamento hospitalar2. Outro aspecto a se
considerar é a possibilidade de exclusão de mulheres com
níveis extremamente baixos de AMH dos programas de
FIV, reconhecendo que essas pacientes apresentam chances
quase nulas de sucesso e aquelas com níveis indetectáveis
de AMH que não apresentam nenhuma chance de gravidez
com seus próprios oócitos2.
Diferentemente das dosagens basais, alguns achados
recentes sugerem que as dosagens de AMH obtidas mais
tardiamente no ciclo de estimulação (no sétimo dia) não
apresentam a mesma utilidade na predição do padrão de
resposta, não sendo recomendado seu uso nessa condição10.
Avaliação da reserva ovariana verdadeira
em idade específica
A maior parcela do AMH produzido na mulher
adulta tem origem nas células granulosas dos pequenos
folículos em crescimento e suas concentrações séricas
apresentam apenas pequenas flutuações ao longo do
ciclo menstrual11, o que reflete o contínuo crescimento
não cíclico dos folículos pré-antrais e pequenos folículos
antrais independentes de FSH. Além disto, os níveis
séricos de AMH apresentam grande reprodutibilidade
interciclo e, como conseqüência, uma única amostra
sanguínea é suficiente para uma avaliação realística da
reserva ovariana, o que não ocorre em relação às detecções do FSH e inibina B12. Também se verificou que os
níveis séricos de AMH apresentam menor variação intra
e interciclo em relação à contagem de folículos antrais
(AFC) sendo, portanto, um marcador mais robusto da
reserva ovariana verdadeira6.
Foi demonstrada oscilação dos níveis de AMH ao longo
da infância, adolescência e vida adulta13. Coortes realizadas
com a população adulta demonstraram claramente um
137
Romão GS, Navarro PAAS
declínio das concentrações de AMH relacionados à idade,
atingindo níveis indetectáveis por ocasião da menopausa14.
Mais recentemente, concentrações de AMH em populações
de crianças e adultos jovens foram descritas e a compilação desses dados permitiu a elaboração de um padrão
descritivo dos níveis desse marcador desde o nascimento
até a menopausa2. De acordo com esse perfil, haveria uma
elevação transitória de AMH no período neonatal, que
é similar à minipuberdade descrita nos recém nascidos
de sexo masculino, com subsequente aumento durante
a infância e puberdade, atingindo um pico antes dos 20
anos. A partir de então inicia-se um declínio gradual até
os 30 anos2.
Para mulheres adultas femininas foram estabelecidos
normogramas de valores de AMH a partir dos resultados
obtidos pelas grandes coortes de mulheres15,16. Ainda não
se dispõe de estudos longitudinais a longo prazo, mas as
coortes cruzadas sugerem que esses valores correspondam
aos dados populacionais2.
Avaliação e predição de lesão gonadal
iatrogênica
A possibilidade de interpretar os valores de AMH
para uma idade específica permitiu o desenvolvimento
de novas aplicações para este marcador. Isso inclui a avaliação do impacto da terapia gonadotóxica (radioterapia,
quimioterapia ou cirurgia) sobre a reserva ovariana17.
Verificou-se que os níveis de AMH declinam rapidamente com o início da quimioterapia18. A análise das
dosagens em mulheres portadoras de linfomas permitiu
a demonstração da toxicidade associada ao uso de agentes
alquilantes, havendo pouca ou nenhuma recuperação dos
níveis de AMH após a quimioterapia. Por outro lado,
mulheres que receberam tratamento com agentes não
alquilantes apresentaram uma boa recuperação dos níveis
de AMH após a quimioterapia, atingindo concentrações
próximas aos níveis pré-tratamento18,19. As dosagens séricas
de AMH também mostraram grande utilidade em meninas
pré-púberes submetidas à quimioterapia, verificando-se o
declínio dos níveis durante a quimioterapia e uma recuperação dependente da toxicidade do regime utilizado20, ao
passo que a monitorização da quimiotoxicidade por meio
de outros hormônios do eixo reprodutivo não apresentou
acurácia satisfatória para esta finalidade2.
Em estudos de acompanhamento pós-tratamento para
câncer verificou-se redução dos níveis de AMH após a
radioterapia, tanto na infância quanto na vida adulta19,21.
A capacidade de recuperação do sistema reprodutor
após a perda abrupta de folículos foi sugerida em face à
redução discreta ou imperceptível da fecundidade após
a ooforectomia unilateral22. Achados equivalentes foram
reportados após a cirurgia para endometriose ovariana,
138
com declínio dos níveis de AMH imediatamente após
a cirurgia e recuperação destes a partir de então17.
Se esses resultados forem transpostos para a condição
de pós-quimioterapia, devem ser indicativos de que
somente a perda substancial da reserva ovariana terá
impacto clínico na fecundidade2.
Outra linha de investigação tem procurado verificar
se níveis elevados de AMH no período de pré-tratamento
seriam indicativos de maior probabilidade de recuperação
da função ovariana após a quimioterapia em relação às
mulheres da mesma faixa etária com níveis inferiores
de AMH no mesmo período. Alguns estudos demonstraram que mulheres portadoras de câncer de mama
que mantiveram os ciclos menstruais até um ano após
a quimioterapia apresentavam níveis mais elevados de
AMH no período pré-tratamento23,24. Outros achados,
entretanto, não confirmam esses dados25. Uma recente
análise da função menstrual e ovariana cinco anos após
a quimioterapia para câncer de mama demonstrou que
os níveis de AMH na fase de pré- tratamento foram
preditivos da continuidade dos ciclos menstruais e de
evidências bioquímicas de atividade ovariana no período pós-tratamento26. A idade também foi preditiva da
capacidade de recuperação da função ovariana após a
quimioterapia. Entretanto, em uma análise estritamente
multivariada somente o AMH permaneceu como preditor,
a idade não mais apresentando impacto2. Se confirmados, estes achados poderão representar grande valia na
tomada de decisões, utilizando métodos mais invasivos
de preservação de fertilidade em mulheres com baixas
concentrações de AMH na fase de pré tratamento e
iniciando imediatamente a quimioterapia naquelas que
apresentem níveis elevados de AMH em fase de prétratamento2. Entretanto, deve-se reconhecer que estes
resultados ainda são preliminares, sendo necessário a sua
confirmação por estudos prospectivos de grande porte
antes da sua recomendação na prática clínica2.
Diagnóstico diferencial das oligomenorreias
e amenorreias
Embora se utilize das dosagens de gonadotrofinas e
estradiol para subclassificar as oligo e amenorreias, uma
simples dosagem de AMH poderia corresponder à primeira
linha de investigação2.
Em mulheres com oligo ou amenorreia atribuída à
síndrome dos ovários policísticos (SOP), os níveis de AMH
estão frequentemente elevados devido a sua produção
aumentada pela grande quantidade de folículos antrais27.
Por outro lado, entre as mulheres com falência ovariana
prematura os níveis de AMH estão reduzidos e na amenorreia associada a hiperprolactinemia ou hipogonadismo
hipogonadotrófico os níveis de AMH estão normais2.
Os níveis de AMH também se encontram elevados em
mulheres com tumores das células da granulosa, e apresenta utilidade como marcador tumoral2.
Mulheres com hiperprolactinemia ou hipogonadismo
hipogonadotrófico apresentarão baixas concentrações de
FSH sendo esperada uma redução na produção de AMH
a partir do pool de folículos em crescimento. Contudo, o
grau de supressão gonadotrófica parece ser insuficiente para
impactar a produção de AMH nessas mulheres. De forma
similar a produção de AMH parece não ser alterada pelo
uso de pílulas anticoncepcionais combinadas28, embora
já tenha sido relatado uma elevação de seus níveis após
descontinuação do uso desse contraceptivo29.
Parece que a supressão completa e prolongada da secreção de gonadotrofinas (com o uso de análogos de GnRH)
pode estar associada à redução dos níveis de AMH, tal qual
foi observado em mulheres que utilizaram goserelina em
período prolongado para tratamento do câncer de mama30.
Por meio da confirmação desses dados, verificou-se a redução
dos níveis de AMH durante a gravidez31.
As dosagens de AMH não fazem parte dos atuais critérios diagnósticos da síndrome dos ovários policísticos, mas
tais critérios estão sujeitos a revisão, sendo provável que
o AMH seja incluído nos novos protocolos32. Certamente
a elevação pronunciada dos níveis de AMH em contraste
com os frequentes achados de normalidade dos outros
hormônios reprodutivos na SOP aumenta a possibilidade
de sua utilização como critério diagnóstico da síndrome2.
Predição do futuro reprodutivo
O declínio dos níveis de AMH nos últimos anos
da vida reprodutiva é um achado consolidado, tanto em
estudos prospectivos quanto nos transversais, aumentando assim a possibilidade de predição da menopausa
e do prognóstico reprodutivo da mulher2. Em análise de
amostras seriadas do sangue de 50 mulheres acompanhadas prospectivamente desde os 42 anos, constatou-se
que os níveis de AMH declinam até níveis indetectáveis
nos últimos cinco anos que precedem a menopausa33.
Os níveis de inibina B declinam de maneira similar,
tornando-se indetectáveis nos últimos quatro anos antes
da menopausa2. Entretanto, somente os níveis de AMH
foram significativamente relacionados com a idade e com
o tempo até a menopausa, ao passo que para a Inibina B
esta relação não foi significativa2.
Um grande estudo que incluiu 257 mulheres ovulatórias entre 21 e 46 anos evidenciou que os níveis séricos
de AMH são preditores de longo prazo da idade da menopausa34. Níveis de AMH baixos para a idade específica
relacionaram-se à antecipação da menopausa, enquanto
níveis elevados foram preditores de menopausa mais tardia.
Porém, somente 11% das mulheres desse estudo alcançaram
a menopausa durante o período de acompanhamento e,
portanto, estudos com maiores e amostras de mais longa
duração serão necessários para confirmar esses dados34.
Deve ser reconhecido que a idade da menopausa é
fortemente determinada por fatores genéticos e embora
um grande número de fatores ambientais tenha sido
identificado, seu impacto combinado é modesto35. Seria
interessante verificar se o AMH seria melhor preditor da
idade da menopausa em relação à idade de menopausa
materna2. A possibilidade de predição biológica do futuro reprodutivo da mulher a partir de uma determinada
idade disponibiliza bases sólidas para o aconselhamento
conceptivo e contraceptivo.
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21. Lutchman Singh K, Muttukrishna S, Stein RC, McGarrigle HH, Patel
A, Parikh B, et al. Predictors of ovarian reserve in young women
with breast cancer. Br J Cancer. 2007;96(12):1808-16.
34. Broer SL, Eijkemans MJ, Scheffer GJ, van Rooij IA, de Vet A, Themmen
AP, et al. Anti-mullerian hormone predicts menopause: a long-term
follow-up study in normoovulatory women. J Clin Endocrinol Metab.
2011;96(8):2532-9.
22. Gosden RG, Telfer E, Faddy MJ, Brook DJ. Ovarian cyclicity and
follicular recruitment in unilaterally ovariectomized mice. J Reprod
Fertil. 1989;87(1):257-64.
35. Kok HS, van Asselt KM, van der Schouw YT, Peeters PH, Wijmenga
C. Genetic studies to identify genes underlying menopausal age.
Hum Reprod Update. 2005;11(5):483-93.
Autora: Cristianne Serafim da Silva Feuser
Orientador: Prof. Dr. Sebastião Freitas de Medeiros
Resumo de Tese
Palavras-chave
Síndrome dos ovários policísticos
GnRH
LH
Função Hipofisária
Keywords
Polycystic ovary syndrome Gonadotropin-releasing hormone Luteinizing hormone Pituitary function
Autora: Carolina Barbara Nogueira de Oliveira
Orientadora: Profa. Dra. Luciana de Barros Duarte
Co-orientadora: Priscila Falagan-Lotsch
Avaliação da função gonadotrópica hipofisária
na síndrome dos ovários policísticos, após a
introdução dos critérios de Roterdã
Assessment of gonadotropic pituitary function in polycystic ovary
syndrome after the Rotterdam criteria
Dissertação apresentada ao Departamento de Endocrinologia Ginecológica e Reprodução Humana Programa Ciências da Saúde
da Faculdade de Medicina Universidade Federal de Mato Grosso, em 5 de julho de 2012.
OBJETIVO: avaliar a função gonadotrópica em pacientes com síndrome dos ovários policísticos (SOP), após a introdução dos critérios
de Roterdã.
MÉTODOS: coorte incluindo 42 pacientes com SOP e 15 controles normais. FSH, LH, E2, P4, 17-OHP4, DHEAS, androstenediona, T,
SHBG, T4 livre, índice de androgênios livres (IAL), cortisol, TSH, PRL, e insulina foram mensurados. A resposta hipofisária após a injeção
de GnRH foi avaliada pelo incremento do LH e FSH aos 60 min bem como pela área sob a curva.
RESULTADOS: os níveis basais de LH, PRL, DHEAS, T, A, IAL, e 17OHP4 foram maiores no grupo SOP (p<0,05), mas os níveis de
SHBG foram menores (p<0,05). Houve correlação negativa entre o IMC e LH basal nas pacientes com SOP. Nos controles, não houve
influência do IMC nos níveis basais de LH e FSH. Correlação negativa entre os níveis basais de insulina e de LH foi observada no grupo
SOP. A área sob a curva do LH após a injeção de GnRH foi superior nas pacientes com SOP do que nos controles (p<0,05). Correlações
positivas entre LH basal e P4 com ASC-LH foram encontradas apenas em pacientes com SOP. Não foi encontrada associação entre E2
ou andrógenos e ASC-LH em ambos os grupos (p>0,05). Não houve correlação entre a insulina e ASC-LH nas pacientes com SOP, mas
esta correlação foi positiva nos controles. Houve uma correlação negativa entre o IMC e ASC-LH apenas nas pacientes com SOP.
CONCLUSÕES: os dados deste estudo comprovam haver hipersecreção de LH na SOP mesmo após a adoção dos critérios de Roterdã.
A magnitude da resposta do LH em mulheres com SOP tem correlação com a concentração basal do LH, e múltiplos fatores moduladores,
incluindo progesterona, insulina e IMC.
Avaliação de polimorfismos nos genes EGF e
EGFR e a susceptibilidade à pré-eclâmpsia severa
Assessment of polymorphisms in EGF and EGFR genes and
susceptibility to severe preeclampsia
Resumo de Tese
Palavras-chave
Pré-eclâmpsia
Polimorfismos
EGF
EGFR
Keywords
Preeclampsia
Polymorphisms
EGF
EGFR
Dissertação apresentada ao Programa de Pós-Graduação em Ciências Médicas, área de Concentração: Ciências Médicas, da
Universidade Federal Fluminense em 13 de junho de 2012.
OBJETIVO: avaliar a associação entre polimorfismos funcionais nos genes EGF (+61 G>A) e EGFR (-216 G>T e -191 C>A) e a
susceptibilidade à pré-eclâmpsia severa na população de gestantes do Estado do Rio de Janeiro. Como objetivos específicos, além
de analisarmos uma possível interação entre os polimorfismos no desenvolvimento da pré-eclâmpsia severa, buscamos associar os
polimorfismos ao histórico familiar da doença.
MÉTODOS: o estudo caso-controle foi composto por dois grupos, pareados por etnia: um grupo caso composto por 98 mulheres com
pré-eclâmpsia severa e um grupo controle com 98 mulheres saudáveis. Os polimorfismos EGF (+61 G>A) e EGFR (-216 G>T e -191 C>A)
foram avaliados pela reação em cadeia da polimerase seguida por análise de polimorfismos por tamanho de fragmentos de restrição
(PCR-RFLP). As variáveis categóricas, frequências alélicas e genotípicas foram comparadas através do teste exato de Fisher, e o teste t de
Student foi utilizado para comparação das variáveis contínuas em cada grupo, sendo o nível de significância fixado em 5% (p < 0,05).
RESULTADOS: os resultados demonstram que o alelo A do polimorfismo -191 C>A do gene EGFR, significativamente mais frequente no
grupo caso (p=0,036), está associado com a susceptibilidade à pré-eclâmpsia severa. Não houve diferença estatisticamente significativa
entre os genótipos e alelos dos polimorfismos EGF +61 G>A (p=0,762 e p=1,000, respectivamente) e EGFR -216 G>T (p=0,682
e p=0,438, respectivamente) e a susceptibilidade à pré-eclâmpsia severa. Assim como também não foi encontrada associação entre
a interação dos polimorfismos, histórico familiar e o desenvolvimento da pré-eclâmpsia severa. Além desses resultados, também foram
encontradas diferenças significativas ao avaliarmos as características demográficas e clínicas entre os grupos.
CONCLUSÃO: este é o primeiro estudo a avaliar associações entre pré-eclâmpsia severa e os polimorfismos -216 G>T e -191C>A
do gene EGFR e o primeiro estudo na população brasileira a investigar a associação do polimorfismo EGF +61 G>A e a doença.
Com esses achados, podemos sugerir que o polimorfismo, o -191C>A do gene EGFR possa desempenhar um papel importante na
susceptibilidade à pré-eclâmpsia severa em mulheres do Estado do Rio de Janeiro.
2013
ABRIL
de 11 a 13 de abril de 2013
XXXVII Congresso de Ginecologia e Obstetrícia
do Rio de Janeiro
Local: Centro de Convenções Sul América
Tel.: (21) 2285-0892 / 2265-1525
[email protected]
XVII Congresso Sul - Rio- Grandense de Ginecologia
e Obstetrícia – SOGIRGS
Local:Centro de Eventos do Hotel Serrano –
Gramado/RS
Plenarium Organização de Congressos
Tel.: (51) 3311-8969 / 3311-9456 / 3311-2578
[email protected]
www.plenariumcongressos.com.br
46º Congresso de Ginecologia e Obstetrícia do
DF e 7º Congresso Internacional de Ginecologia
e Obstetrícia do DF
Local: Centro de Convenções Ulysses Guimarães –
Brasília-DF
Informações: Secretaria Executiva da SGOB
Tel.: (61) 3245-3681 / 3245-4530 / 9622-1215
[email protected] / [email protected]
www.sgob.com.br
142
MAIO
de 1º a 04 de maio de 2013
VI Congresso Mineiro de Ginecologia e
Obstetrícia / 37º Encontro Mineiro de
Ginecologistas e Obstetras
Local: Minascentro – Belo Horizonte/MG
Realização: SOGIMIG
Organização: (31) 3291-9899 – Consult Eventos
http://cmgo2013.com.br
É comum mulheres
que utilizam COCs
terem sintomas
associados ao intervalo
livre de hormônios1
1º
CO
N
Reduz a severidade e frequência dos sintomas
relacionados ao intervalo livre de hormônios tais
como: cefaleia, dor pélvica, náusea, mastalgia e inchaço2
28 dias
Maior aderência ao tratamento3
Tomada contínua sem pausa
EPTIV
AC
O
TR
AL
R
O
Qlaira® associa
estradiol e dienogeste
em regime 26/22
COM
ESTRADIOL
Qlaira® é uma boa opção para mulheres com
sintomas associados ao intervalo livre de
hormônios no regime 21/72
QLAIRA®. DIENOGESTE E VALERATO DE ESTRADIOL. REG. MS – 1.7056.0049. INDICAÇÕES: CONTRACEPTIVO ORAL. CONTRAINDICAÇÕES: CONTRACEPTIVOS COMBINADOS ORAIS (CCOS) NÃO DEVEM SER UTILIZADOS NA PRESENÇA DAS CONDIÇÕES LISTADAS (DEVENDO-SE AVALIAR AS PARTICULARIDADES DE CADA SITUAÇÃO): TROMBOEMBOLISMO ARTERIAL OU VENOSO, ENXAQUECA, DIABETES MELLITUS, PANCREATITE, HIPERTRIGLICERIDEMIA, DOENÇA HEPÁTICA GRAVE, TUMORES HEPÁTICOS, NEOPLASIAS DEPENDENTES DE ESTEROIDES SEXUAIS, SANGRAMENTO VAGINAL NÃO DIAGNOSTICADO, SUSPEITA OU DIAGNÓSTICO DE GRAVIDEZ, HIPERSENSIBILIDADE A QUALQUER UM DOS COMPONENTES DO PRODUTO. ADVERTÊNCIAS E PRECAUÇÕES: NÃO EXISTEM ESTUDOS EPIDEMIOLÓGICOS SOBRE OS EFEITOS DE CCOS CONTENDO
ESTRADIOL/VALERATO DE ESTRADIOL. TODAS AS PRECAUÇÕES E ADVERTÊNCIAS A SEGUIR SÃO PROVENIENTES DE DADOS EPIDEMIOLÓGICOS E CLÍNICOS DE CCOS CONTENDO ETINILESTRADIOL. NÃO SE SABE SE ESTAS PRECAUÇÕES E ADVERTÊNCIAS SE APLICAM A QLAIRA®. AVALIAR
OS BENEFÍCIOS E RISCOS. CONSULTAS/EXAMES MÉDICOS REGULARES SÃO RECOMENDADOS. DISTÚRBIOS CIRCULATÓRIOS, TUMORES, HIPERTRIGLICERIDEMIA, HIPERTENSÃO, COLECISTOPATIA, PORFIRIA, LÚPUS ERITEMATOSO SISTÊMICO, SÍNDROME HEMOLÍTICO-URÊMICA, COREIA
DE SYDENHAM, HERPES GESTACIONAL, PERDA DA AUDIÇÃO RELACIONADA COM OTOSCLEROSE, PATOLOGIA INTESTINAL INFLAMATÓRIA CRÔNICA, ANEMIA FALCIFORME, ENXAQUECAS, ANGIOEDEMA HEREDITÁRIO, DISTÚRBIOS DA FUNÇÃO HEPÁTICA, PODE OCORRER CLOASMA.
QUANDO CCOS SÃO UTILIZADOS CORRETAMENTE O ÍNDICE DE FALHA É DE APROXIMADAMENTE DE 1% AO ANO. A EFICÁCIA DOS CCOS PODE SER REDUZIDA NOS CASOS DE ESQUECIMENTO DE TOMADA DOS COMPRIMIDOS, DISTÚRBIOS GASTRINTESTINAIS OU INTERAÇÃO MEDICAMENTOSA. PODEM SURGIR SANGRAMENTOS IRREGULARES, ESPECIALMENTE DURANTE OS PRIMEIROS MESES DE USO. É POSSÍVEL QUE EM ALGUMAS PACIENTES NÃO OCORRA O SANGRAMENTO POR PRIVAÇÃO DURANTE A INGESTÃO DOS COMPRIMIDOS BRANCOS (INATIVOS). CASO
A PACIENTE ENGRAVIDE DURANTE O USO DE QLAIRA®, DEVE-SE DESCONTINUAR O SEU USO. ENTRETANTO, ESTUDOS EPIDEMIOLÓGICOS ABRANGENTES COM CCOS CONTENDO ETINILESTRADIOL NÃO REVELARAM RISCO AUMENTADO DE MALFORMAÇÕES CONGÊNITAS EM CRIANÇAS
NASCIDAS DE MULHERES QUE TENHAM UTILIZADO CCOS ANTES DA GESTAÇÃO. TAMBÉM NÃO FORAM VERIFICADOS EFEITOS TERATOGÊNICOS DECORRENTES DA INGESTÃO ACIDENTAL DE CCOS NO INÍCIO DA GESTAÇÃO. O MEDICAMENTO NÃO DEVE SER UTILIZADO DURANTE A
GRAVIDEZ. OS CCOS PODEM AFETAR A AMAMENTAÇÃO. REAÇÕES ADVERSAS: CEFALEIA, DOR ABDOMINAL, ACNE, AMENORREIA, DESCONFORTO MAMÁRIO, DISMENORREIA, SANGRAMENTO INTERMENSTRUAL, SANGRAMENTO UTERINO DISFUNCIONAL, AUMENTO OU DIMINUIÇÃO DO
PESO CORPÓREO, INFECÇÃO VAGINAL ESPECIALMENTE POR FUNGO, AUMENTO DO APETITE, DEPRESSÃO, AUMENTO OU DIMINUIÇÃO DA LIBIDO, DISTÚRBIO MENTAL, ALTERAÇÃO DE HUMOR, TONTURA, HIPERTENSÃO, ENXAQUECA, DIARREIA, NÁUSEAS, VÔMITOS, ALOPECIA, PRURIDO,
ERUPÇÃO CUTÂNEA, AUMENTO DO TAMANHO DAS MAMAS, NÓDULO MAMÁRIO, DISPLASIA CERVICAL, DISPAREUNIA, DOENÇA FIBROCÍSTICA DAS MAMAS, CISTO OVARIANO, DOR PÉLVICA, SÍNDROME PRÉ-MENSTRUAL, MIOMA UTERINO, ALTERAÇÃO DA SECREÇÃO VAGINAL, IRRITABILIDADE, EDEMA, HERPES SIMPLES, SÍNDROME DE HISTOPLASMOSE OCULAR PRESUMIDA, TINEA VERSICOLOR, INFECÇÃO URINÁRIA, HIPERTRIGLICERIDEMIA, ANSIEDADE, DISFORIA, NERVOSISMO, AGITAÇÃO, DISTÚRBIO DO SONO, ESTRESSE, DISTÚRBIOS DA ATENÇÃO, PARESTESIA,
VERTIGEM, INTOLERÂNCIA A LENTES DE CONTATO, SANGRAMENTO DE VEIAS VARICOSAS, HIPOTENSÃO, DOR NOS VASOS, OBSTIPAÇÃO, DISPEPSIA, REFLUXO GATROESOFÁGICO, AUMENTO DA ALANINA AMINOTRANSFERASE, HIPERPLASIA NODULAR FOCAL DO FÍGADO, DERMATITE,
CLOASMA, HIRSUTISMO, HIPERTRICOSE, NEURODERMATITE, SEBORREIA, DOR NAS COSTAS, ESPASMOS MUSCULARES, SINUSORRAGIA, HIPOMENORREIA, ATRASO MENSTRUAL, RUPTURA DE CISTO OVARIANO, LINFADENOPATIA, DOR NO PEITO, FADIGA, MAL-ESTAR. INTERAÇÕES
MEDICAMENTOSAS: FENITOÍNAS, BARBITÚRICOS, PRIMIDONA, CARBAMAZEPINA, RIFAMPICINA, OXCARBAZEPINA, TOPIRAMATO, FELBAMATO, GRISEOFULVINA, ERVA-DE-SÃO-JOÃO, RITONAVIR, NEVIRAPINA, PENICILINAS, TETRACICLINAS, CIMETIDINA, VERAPAMIL, MACROLÍDEOS,
DILTIAZEM, ANTIDEPRESSIVOS, SUCO DE GRAPEFRUIT, CETOCONAZOL, ERITROMICINA. POSOLOGIA: OS COMPRIMIDOS DEVEM SER INGERIDOS NA ORDEM INDICADA NA CARTELA, TODOS OS DIAS. A INGESTÃO DOS COMPRIMIDOS É CONTÍNUA. DEVE-SE INGERIR UM COMPRIMIDO
POR DIA DURANTE 28 DIAS CONSECUTIVOS. CADA CARTELA SUBSEQUENTE É INICIADA NO DIA SEGUINTE À INGESTÃO DO ÚLTIMO COMPRIMIDO DA CARTELA ANTERIOR, SEM PAUSA ENTRE ELAS. EM GERAL, O SANGRAMENTO POR PRIVAÇÃO INICIA-SE DURANTE A INGESTÃO DOS
ÚLTIMOS COMPRIMIDOS DA CARTELA-CALENDÁRIO. PARA PROCEDIMENTOS SOBRE MUDANÇA DE CONTRACEPTIVO, CASO DE ESQUECIMENTO DE COMPRIMIDOS OU OCORRÊNCIA DE VÔMITOS E/OU DIARREIA, CONSULTAR A BULA DO PRODUTO. VENDA SOB PRESCRIÇÃO MÉDICA.
CONTRAINDICAÇÃO: TROMBOEMBOLISMO ARTERIAL OU VENOSO. INTERAÇÕES MEDICAMENTOSAS: ANTIBIÓTICOS E ANTICONVULSIVANTES.
REFERÊNCIAS BIBLIOGRÁFICAS: 1. SULAK ET AL. HORMONE WITHDRAWAL SYMPTONS IN ORAL CONTRACEPTIVES USERS. OBSTET GYNECOL. 2000;95(2):261-6. 2. MABEY RG, PARKE S, MELLINGER U, SERRANI M, JENSEN J. HORMONE WITHDRAWAL-ASSOCIATED SYMPTOMS:
COMPARISON OF E2V/DNG VERSUS EE/NGM. (POSTER PRESENTED AT THE ACOG 60TH ANNUAL CLINICAL MEETING 2012, SAN DIEGO). BOOK OF ABSTRACTS; MONDAY POSTERS SESSION, CONTRACEPTION/FAMILY PLANNING; P. 13. 3. PALACIOS S, ET AL. EFFICACY AND SAFETY OF
A NOVEL ORAL CONTRACEPTIVE BASED ON OESTRADIOL (OESTRADIOL VALERATE/DIENOGEST): A PHASE III TRIAL. EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY 2010; 149: 57-62.
Material destinado exclusivamente a profissionais de saúde.
L.BR.WH.2013-02-08.1032
.com.br
0800 7021241
É comum mulheres
que utilizam COCs
terem sintomas
associados ao intervalo
livre de hormônios1
1º
CO
N
Reduz a severidade e frequência dos sintomas
relacionados ao intervalo livre de hormônios tais
como: cefaleia, dor pélvica, náusea, mastalgia e inchaço2
28 dias
Maior aderência ao tratamento3
Tomada contínua sem pausa
EPTIV
AC
O
TR
AL
R
O
Qlaira® associa
estradiol e dienogeste
em regime 26/22
COM
ESTRADIOL
Qlaira® é uma boa opção para mulheres com
sintomas associados ao intervalo livre de
hormônios no regime 21/72
QLAIRA®. DIENOGESTE E VALERATO DE ESTRADIOL. REG. MS – 1.7056.0049. INDICAÇÕES: CONTRACEPTIVO ORAL. CONTRAINDICAÇÕES: CONTRACEPTIVOS COMBINADOS ORAIS (CCOS) NÃO DEVEM SER UTILIZADOS NA PRESENÇA DAS CONDIÇÕES LISTADAS (DEVENDO-SE AVALIAR AS PARTICULARIDADES DE CADA SITUAÇÃO): TROMBOEMBOLISMO ARTERIAL OU VENOSO, ENXAQUECA, DIABETES MELLITUS, PANCREATITE, HIPERTRIGLICERIDEMIA, DOENÇA HEPÁTICA GRAVE, TUMORES HEPÁTICOS, NEOPLASIAS DEPENDENTES DE ESTEROIDES SEXUAIS, SANGRAMENTO VAGINAL NÃO DIAGNOSTICADO, SUSPEITA OU DIAGNÓSTICO DE GRAVIDEZ, HIPERSENSIBILIDADE A QUALQUER UM DOS COMPONENTES DO PRODUTO. ADVERTÊNCIAS E PRECAUÇÕES: NÃO EXISTEM ESTUDOS EPIDEMIOLÓGICOS SOBRE OS EFEITOS DE CCOS CONTENDO
ESTRADIOL/VALERATO DE ESTRADIOL. TODAS AS PRECAUÇÕES E ADVERTÊNCIAS A SEGUIR SÃO PROVENIENTES DE DADOS EPIDEMIOLÓGICOS E CLÍNICOS DE CCOS CONTENDO ETINILESTRADIOL. NÃO SE SABE SE ESTAS PRECAUÇÕES E ADVERTÊNCIAS SE APLICAM A QLAIRA®. AVALIAR
OS BENEFÍCIOS E RISCOS. CONSULTAS/EXAMES MÉDICOS REGULARES SÃO RECOMENDADOS. DISTÚRBIOS CIRCULATÓRIOS, TUMORES, HIPERTRIGLICERIDEMIA, HIPERTENSÃO, COLECISTOPATIA, PORFIRIA, LÚPUS ERITEMATOSO SISTÊMICO, SÍNDROME HEMOLÍTICO-URÊMICA, COREIA
DE SYDENHAM, HERPES GESTACIONAL, PERDA DA AUDIÇÃO RELACIONADA COM OTOSCLEROSE, PATOLOGIA INTESTINAL INFLAMATÓRIA CRÔNICA, ANEMIA FALCIFORME, ENXAQUECAS, ANGIOEDEMA HEREDITÁRIO, DISTÚRBIOS DA FUNÇÃO HEPÁTICA, PODE OCORRER CLOASMA.
QUANDO CCOS SÃO UTILIZADOS CORRETAMENTE O ÍNDICE DE FALHA É DE APROXIMADAMENTE DE 1% AO ANO. A EFICÁCIA DOS CCOS PODE SER REDUZIDA NOS CASOS DE ESQUECIMENTO DE TOMADA DOS COMPRIMIDOS, DISTÚRBIOS GASTRINTESTINAIS OU INTERAÇÃO MEDICAMENTOSA. PODEM SURGIR SANGRAMENTOS IRREGULARES, ESPECIALMENTE DURANTE OS PRIMEIROS MESES DE USO. É POSSÍVEL QUE EM ALGUMAS PACIENTES NÃO OCORRA O SANGRAMENTO POR PRIVAÇÃO DURANTE A INGESTÃO DOS COMPRIMIDOS BRANCOS (INATIVOS). CASO
A PACIENTE ENGRAVIDE DURANTE O USO DE QLAIRA®, DEVE-SE DESCONTINUAR O SEU USO. ENTRETANTO, ESTUDOS EPIDEMIOLÓGICOS ABRANGENTES COM CCOS CONTENDO ETINILESTRADIOL NÃO REVELARAM RISCO AUMENTADO DE MALFORMAÇÕES CONGÊNITAS EM CRIANÇAS
NASCIDAS DE MULHERES QUE TENHAM UTILIZADO CCOS ANTES DA GESTAÇÃO. TAMBÉM NÃO FORAM VERIFICADOS EFEITOS TERATOGÊNICOS DECORRENTES DA INGESTÃO ACIDENTAL DE CCOS NO INÍCIO DA GESTAÇÃO. O MEDICAMENTO NÃO DEVE SER UTILIZADO DURANTE A
GRAVIDEZ. OS CCOS PODEM AFETAR A AMAMENTAÇÃO. REAÇÕES ADVERSAS: CEFALEIA, DOR ABDOMINAL, ACNE, AMENORREIA, DESCONFORTO MAMÁRIO, DISMENORREIA, SANGRAMENTO INTERMENSTRUAL, SANGRAMENTO UTERINO DISFUNCIONAL, AUMENTO OU DIMINUIÇÃO DO
PESO CORPÓREO, INFECÇÃO VAGINAL ESPECIALMENTE POR FUNGO, AUMENTO DO APETITE, DEPRESSÃO, AUMENTO OU DIMINUIÇÃO DA LIBIDO, DISTÚRBIO MENTAL, ALTERAÇÃO DE HUMOR, TONTURA, HIPERTENSÃO, ENXAQUECA, DIARREIA, NÁUSEAS, VÔMITOS, ALOPECIA, PRURIDO,
ERUPÇÃO CUTÂNEA, AUMENTO DO TAMANHO DAS MAMAS, NÓDULO MAMÁRIO, DISPLASIA CERVICAL, DISPAREUNIA, DOENÇA FIBROCÍSTICA DAS MAMAS, CISTO OVARIANO, DOR PÉLVICA, SÍNDROME PRÉ-MENSTRUAL, MIOMA UTERINO, ALTERAÇÃO DA SECREÇÃO VAGINAL, IRRITABILIDADE, EDEMA, HERPES SIMPLES, SÍNDROME DE HISTOPLASMOSE OCULAR PRESUMIDA, TINEA VERSICOLOR, INFECÇÃO URINÁRIA, HIPERTRIGLICERIDEMIA, ANSIEDADE, DISFORIA, NERVOSISMO, AGITAÇÃO, DISTÚRBIO DO SONO, ESTRESSE, DISTÚRBIOS DA ATENÇÃO, PARESTESIA,
VERTIGEM, INTOLERÂNCIA A LENTES DE CONTATO, SANGRAMENTO DE VEIAS VARICOSAS, HIPOTENSÃO, DOR NOS VASOS, OBSTIPAÇÃO, DISPEPSIA, REFLUXO GATROESOFÁGICO, AUMENTO DA ALANINA AMINOTRANSFERASE, HIPERPLASIA NODULAR FOCAL DO FÍGADO, DERMATITE,
CLOASMA, HIRSUTISMO, HIPERTRICOSE, NEURODERMATITE, SEBORREIA, DOR NAS COSTAS, ESPASMOS MUSCULARES, SINUSORRAGIA, HIPOMENORREIA, ATRASO MENSTRUAL, RUPTURA DE CISTO OVARIANO, LINFADENOPATIA, DOR NO PEITO, FADIGA, MAL-ESTAR. INTERAÇÕES
MEDICAMENTOSAS: FENITOÍNAS, BARBITÚRICOS, PRIMIDONA, CARBAMAZEPINA, RIFAMPICINA, OXCARBAZEPINA, TOPIRAMATO, FELBAMATO, GRISEOFULVINA, ERVA-DE-SÃO-JOÃO, RITONAVIR, NEVIRAPINA, PENICILINAS, TETRACICLINAS, CIMETIDINA, VERAPAMIL, MACROLÍDEOS,
DILTIAZEM, ANTIDEPRESSIVOS, SUCO DE GRAPEFRUIT, CETOCONAZOL, ERITROMICINA. POSOLOGIA: OS COMPRIMIDOS DEVEM SER INGERIDOS NA ORDEM INDICADA NA CARTELA, TODOS OS DIAS. A INGESTÃO DOS COMPRIMIDOS É CONTÍNUA. DEVE-SE INGERIR UM COMPRIMIDO
POR DIA DURANTE 28 DIAS CONSECUTIVOS. CADA CARTELA SUBSEQUENTE É INICIADA NO DIA SEGUINTE À INGESTÃO DO ÚLTIMO COMPRIMIDO DA CARTELA ANTERIOR, SEM PAUSA ENTRE ELAS. EM GERAL, O SANGRAMENTO POR PRIVAÇÃO INICIA-SE DURANTE A INGESTÃO DOS
ÚLTIMOS COMPRIMIDOS DA CARTELA-CALENDÁRIO. PARA PROCEDIMENTOS SOBRE MUDANÇA DE CONTRACEPTIVO, CASO DE ESQUECIMENTO DE COMPRIMIDOS OU OCORRÊNCIA DE VÔMITOS E/OU DIARREIA, CONSULTAR A BULA DO PRODUTO. VENDA SOB PRESCRIÇÃO MÉDICA.
CONTRAINDICAÇÃO: TROMBOEMBOLISMO ARTERIAL OU VENOSO. INTERAÇÕES MEDICAMENTOSAS: ANTIBIÓTICOS E ANTICONVULSIVANTES.
REFERÊNCIAS BIBLIOGRÁFICAS: 1. SULAK ET AL. HORMONE WITHDRAWAL SYMPTONS IN ORAL CONTRACEPTIVES USERS. OBSTET GYNECOL. 2000;95(2):261-6. 2. MABEY RG, PARKE S, MELLINGER U, SERRANI M, JENSEN J. HORMONE WITHDRAWAL-ASSOCIATED SYMPTOMS:
COMPARISON OF E2V/DNG VERSUS EE/NGM. (POSTER PRESENTED AT THE ACOG 60TH ANNUAL CLINICAL MEETING 2012, SAN DIEGO). BOOK OF ABSTRACTS; MONDAY POSTERS SESSION, CONTRACEPTION/FAMILY PLANNING; P. 13. 3. PALACIOS S, ET AL. EFFICACY AND SAFETY OF
A NOVEL ORAL CONTRACEPTIVE BASED ON OESTRADIOL (OESTRADIOL VALERATE/DIENOGEST): A PHASE III TRIAL. EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY 2010; 149: 57-62.
Material destinado exclusivamente a profissionais de saúde.
L.BR.WH.2013-02-08.1032
.com.br
0800 7021241
ISSN 0100-7203
Na endometriose
Revista Brasileira de Ginecologia e Obstetrícia
Tratamento simples e eficaz
Março
2013
Indicado especificamente para
o tratamento da endometriose
Março 2013
Reduz lesões
1
nº 3
2,4
volume 35
Reduz de forma eficaz a dor
Indicado para uso
a longo prazo
Adequada tolerabilidade
3
e segurança
2
CONTRAINDICAÇÕES: DISTURBIOS CARDIOVASCULARES, DIABETES MELLITUS COM ENVOLVIMENTO VASCULAR.
INTERAÇÕES MEDICAMENTOSAS: ANTICONVULSIVANTES, ANTIFÚNGICOS AZÓLICOS, ANTIDEPRESSIVOS.
número 3 p. 93 - 142
ALLURENE® (DIENOGESTE) RG MS-1.7056.0088
INDICAÇÃO: TRATAMENTO DA ENDOMETRIOSE. CONTRA-INDICAÇÕES: DISTÚRBIO TROMBOEMBÓLICO VENOSO EM ATIVIDADE, PRESENÇA OU HISTÓRICO DE DOENÇA CARDIOVASCULAR E ARTERIAL, DIABETES MELITUS COM ENVOLVIMENTO VASCULAR, PRESENÇA OU HISTÓRICO DE
DOENÇA HEPÁTICA GRAVE ENQUANTO OS VALORES DA FUNÇÃO HEPÁTICA NÃO RETORNAREM AO NORMAL, PRESENÇA OU HISTÓRICO DE TUMOR HEPÁTICO (BENIGNO OU MALIGNO), SUSPEITA OU DIAGNÓSTICO DE NEOPLASIAS DEPENDENTES DE HORMÔNIOS SEXUAIS, SANGRAMENTO
VAGINAL NÃO DIAGNOSTICADO, HIPERSENSIBILIDADE À SUBSTÂNCIA ATIVA OU A QUALQUER UM DOS COMPONENTES DA FORMULAÇÃO. ADVERTÊNCIAS E PRECAUÇÕES: ANTES DE INICIAR O TRATAMENTO COM ALLURENE®, DEVE-SE EXCLUIR A POSSIBILIDADE DE GRAVIDEZ. DURANTE O TRATAMENTO COM ALLURENE® A OVULAÇÃO É INIBIDA NA MAIORIA DAS PACIENTES. ENTRETANTO, ALLURENE® NÃO É UM CONTRACEPTIVO E CASO SEJA NECESSÁRIO PREVENIR A GRAVIDEZ, AS PACIENTES DEVEM SER ORIENTADAS A UTILIZAR MÉTODOS CONTRACEPTIVOS
NÃO HORMONAIS (POR EXEMPLO, MÉTODO DE BARREIRA). COM BASE NOS DADOS DISPONÍVEIS, O CICLO MENSTRUAL RETORNA AO NORMAL DENTRO DE 2 MESES APÓS O TÉRMINO DO TRATAMENTO COM ALLURENE®. EM MULHERES COM HISTÓRICO DE GRAVIDEZ EXTRAUTERINA
OU DE ALTERAÇÃO DA FUNÇÃO DAS TROMPAS, O USO DE ALLURENE® DEVE SER DECIDIDO APENAS APÓS CUIDADOSA AVALIAÇÃO DA RELAÇÃO RISCO/BENEFÍCIO. COMO ALLURENE® É UM MEDICAMENTO QUE CONTÉM SOMENTE PROGESTÓGENO, DEVEM SER CONSIDERADAS AS
PRECAUÇÕES E ADVERTÊNCIAS DE TODOS OS MEDICAMENTOS QUE CONTEM SOMENTE PROGESTÓGENO, EMBORA NEM TODAS ESTEJAM BASEADAS EM ACHADOS DOS ESTUDOS CLÍNICOS REALIZADOS COM ALLURENE®. CASO QUALQUER UMA DAS CONDIÇÕES/FATORES DE RISCO
DESCRITAS A SEGUIR ESTEJA PRESENTE OU SE AGRAVE, DEVE-SE REALIZAR UMA ANÁLISE INDIVIDUAL DA RELAÇÃO RISCO/BENEFÍCIO ANTES DE INICIAR OU CONTINUAR O USO DE ALLURENE®: DISTÚRBIOS CIRCULATÓRIOS; TUMORES; ALTERAÇÕES NO PADRÃO DE SANGRAMENTO;
HISTÓRICO DE DEPRESSÃO; DESENVOLVIMENTO DE HIPERTENSÃO CLINICAMENTE SIGNIFICATIVA DIABETES MELITUS (SOBRETUDO HISTÓRICO DE DIABETES MELITUS GESTACIONAL); E OCORRÊNCIA FOLÍCULOS OVARIANOS PERSISTENTES (CISTOS OVARIANOS FUNCIONAIS). RECORRÊNCIA
DE ICTERÍCIA COLESTÁTICA E/OU PRURIDO OCORRIDO ANTERIORMENTE DURANTE UMA GRAVIDEZ OU DURANTE O USO ANTERIOR DE ESTEROIDES SEXUAIS REQUER A DESCONTINUAÇÃO DE ALLURENE®. MULHERES COM TENDÊNCIA A MELASMA/CLOASMA DEVEM EVITAR EXPOSIÇÃO
AO SOL OU RADIAÇÃO ULTRAVIOLETA DURANTE O TRATAMENTO COM ALLURENE®. RECOMENDA-SE ACOMPANHAMENTO REGULAR, COM ATENÇÃO ESPECIAL À PRESSÃO ARTERIAL, MAMAS, ABDOME E ÓRGÃOS PÉLVICOS, INCLUINDO CITOLOGIA CERVICAL. ALLURENE® NÃO DEVE SER
ADMINISTRADO A MULHERES GRÁVIDAS UMA VEZ QUE NÃO HÁ NECESSIDADE DE TRATAR A ENDOMETRIOSE DURANTE A GRAVIDEZ - CATEGORIA B – “ESTE MEDICAMENTO NÃO DEVE SER UTILIZADO POR MULHERES GRÁVIDAS SEM ORIENTAÇÃO MÉDICA OU DO CIRURGIÃO-DENTISTA”. A
ADMINISTRAÇÃO DE ALLURENE® DURANTE A LACTAÇÃO NÃO É RECOMENDADA. INTERAÇÕES MEDICAMENTOSAS: INDUTORES OU INIBIDORES ENZIMÁTICOS INDIVIDUAIS (CITOCROMO P450); SUBSTÂNCIAS COM PROPRIEDADES DE INDUÇÃO ENZIMÁTICA (FENITOÍNA, BARBITÚRICOS,
PRIMIDONA, CARBAMAZEPINA, RIFAMPICINA E POSSIVELMENTE TAMBÉM OXCARBAZEPINA, TOPIRAMATO, FELBAMATO, GRISEOFULVINA, NEVIRAPINA E ERVA-DE-SÃO JOÃO); SUBSTÂNCIAS COM PROPRIEDADES DE INIBIÇÃO ENZIMÁTICA (ANTIFÚNGICOS AZÓLICOS, CIMETIDINA, VERAPAMIL, MACROLÍDEOS, DILTIAZEM, INIBIDORES DA PROTEASE, ANTI-DEPRESSIVOS E SUCO DE TORONJA). COM BASE EM ESTUDOS DE INIBIÇÃO IN VITRO, É IMPROVÁVEL QUE HAJA INTERAÇÃO CLINICAMENTE RELEVANTE ENTRE ALLURENE® E O METABOLISMO DE OUTROS MEDICAMENTOS
MEDIADO PELA ENZIMA DO CITOCROMO P450. O USO DE PROGESTÓGENOS PODE INFLUENCIAR OS RESULTADOS DE CERTOS EXAMES LABORATORIAIS, INCLUINDO PARÂMETROS BIOQUÍMICOS DO FÍGADO, TIREÓIDE, FUNÇÃO RENAL E ADRENAL, NÍVEIS PLASMÁTICOS DE PROTEÍNAS
(CARREADORAS), POR EXEMPLO, FRAÇÕES LIPOPROTEICAS/LIPÍDICAS, PARÂMETROS DO METABOLISMO DE CARBOIDRATADOS E PARÂMETROS DA COAGULAÇÃO E FIBRINÓLISE. DE MODO GERAL, AS ALTERAÇÕES PERMANECEM DENTRO DA FAIXA LABORATORIAL NORMAL. POSOLOGIA:
UM COMPRIMIDO POR DIA SEM INTERVALO DE PAUSA, TOMADO, PREFERENCIALMENTE, NO MESMO HORÁRIO TODOS OS DIAS, COM UM POUCO DE LÍQUIDO, SE NECESSÁRIO, INDEPENDENTEMENTE DE SANGRAMENTO VAGINAL. AO TÉRMINO DE UMA CARTELA, A PRÓXIMA DEVE SER
INICIADA, SEM INTERRUPÇÃO. A INGESTÃO DOS COMPRIMIDOS PODE SER INICIADA EM QUALQUER DIA DO CICLO MENSTRUAL. REAÇÕES ADVERSAS: FREQUENTES: CEFALEIA, DESCONFORTO NAS MAMAS, HUMOR DEPRIMIDO, ACNE, NÁUSEA, AUMENTO DE PESO, DOR ABDOMINAL,
CISTO OVARIANO, CONDIÇÕES ASTÊNICAS, FLATULÊNCIA, FOGACHOS, DISTÚRBIOS DO SONO, IRRITABILIDADE, SANGRAMENTO UTERINO/VAGINAL INCLUINDO GOTEJAMENTO, NERVOSISMO, PERDA DE LIBIDO, ALOPECIA, DOR NAS COSTAS, DISTENSÃO ABDOMINAL, VÔMITO, ENXAQUECA, HUMOR ALTERADO. POUCO FREQÜENTES: RESSECAMENTO VULVOVAGINAL, DESEQUILÍBRIO DO SISTEMA NERVOSO AUTÔNOMO, CANDIDÍASE VAGINAL, PELE SECA, ANSIEDADE, DEPRESSÃO, DISTÚRBIO DA ATENÇÃO, CONSTIPAÇÃO, DESCONFORTO ABDOMINAL, INFLAMAÇÃO
GASTRINTESTINAL, HIPERIDROSE, PRURIDO, DIARRÉIA, INFECÇÃO DO TRATO URINÁRIO, CORRIMENTO GENITAL, DOR PÉLVICA, EDEMA, ANEMIA, DIMINUIÇÃO DE PESO, AUMENTO DE APETITE, OLHO SECO, ZUMBIDO, DISTÚRBIOS INESPECÍFICOS DO SISTEMA CIRCULATÓRIO, PALPITAÇÕES,
HIPOTENSÃO, DISPNÉIA, HUMOR ALTERADO, GENGIVITE, HIRSUTISMO, ONICÓLISE, CASPA, DERMATITE, CRESCIMENTO ANORMAL DE PÊLOS, REAÇÃO DE FOTOSSENSIBILIDADE, DISTÚRBIO DE PIGMENTAÇÃO, DOR NOS OSSOS, ESPASMOS MUSCULARES, DOR NA EXTREMIDADE, PESO NAS
EXTREMIDADES, VULVOVAGINITE ATRÓFICA, MASSA MAMÁRIA, DOENÇA FIBROCÍSTICA DA MAMA, ENDURECIMENTO DA MAMA. VENDA SOB PRESCRIÇÃO MÉDICA. SAC 0800 7021241. VE0211-CCDS4. REFERÊNCIAS: 1. KÖHLER G, FAUSTMANN TA, GERLINGER C, SEITZ C, MUECK
AO. A DOSE-RANGING STUDY TO DETERMINE THE EFFICACY AND SAFETY OF 1, 2, AND 4MG OF DIENOGEST DAILY FOR ENDOMETRIOSIS. INT J GYNAECOL OBSTET 2010; 108: 21 -25. 2. KÖHLER G, GORETZLEHNER G, BRACHMANN K. LIPID METABOLISM DURING TREATMENT OF ENDOMETRIOSIS WITH THE PROGESTIN DIENOGEST. ACTA OBSTET GYNECOL SCAND 1989; 68. 3. PETRAGLIA F, ET AL. REDUCED PELVIC PAIN IN WOMEN WITH ENDOMETRIOSIS: EFICACY OF LONG-TERM DIENOGEST TREATMENT. ARCH GYNECOL OBSTET (2012) 285:167 -173 . 4. STROWITZKI
T, FAUSTMANN T,GERLINGER C, SEITZ C. DIENOGESTE IN THE TREATMENT OF ENDOMETRIOSIS- ASSOCIATED PELVIC PAIN: A 12-WEEK, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY. EUR J OBST GYNECOL REPROD BIOL 2010.
Material destinado exclusivamente aos profissionais da saúde
L.BR.WH.2012-07-30.0837
volume 35
VA
NO
CERAZETTE®, Desogestrel. APRESENTAÇÃO: cartucho com 1 cartela com 28 comprimidos. Cada comprimido contém: Desogestrel 75 mcg. INDICAÇÕES: contracepção. CONTRAINDICAÇÕES: CERAZETTE® não deve ser usado na
presença de qualquer das condições abaixo ou se as mesmas ocorrerem pela primeira vez, o produto deve ser descontinuado imediatamente: gravidez ou suspeita de gravidez; distúrbio tromboembólico venoso ativo; presença ou história de
doença hepática grave enquanto os valores de função hepática não tenham retornado ao normal; tumores progestagênio-dependentes; sangramento vaginal não diagnosticado; hipersensibilidade a qualquer componente do CERAZETTE®.
PRECAUÇÕES e ADVERTÊNCIAS: durante o uso de contraceptivos orais (COs) o risco de ter câncer de mama diagnosticado está levemente aumentado. Entretanto, para esses contraceptivos de progestagênio isolado, a evidência é menos
conclusiva. Avaliar risco-benefício no caso de câncer hepático. Investigações epidemiológicas associaram o uso de COC a uma maior incidência de tromboembolismo venoso (TEV, trombose venosa profunda e embolismo pulmonar). Embora a
relevância clínica deste achado para Desogestrel usado como contraceptivo na ausência de um componente estrogênico seja desconhecida, CERAZETTE® deve ser descontinuado em caso de trombose. A descontinuação de CERAZETTE®
deve também ser considerada e caso de imobilização prolongada devida à cirurgia ou doença. Mulheres com história de distúrbios tromboembólicos devem ser alertadas sobre a possibilidade de recorrência. Embora os progestagênios possam
apresentar efeito sobre a resistência à insulina e sobre a tolerância à glicose, não há evidência da necessidade de alterar o regime terapêutico em diabéticas usando contraceptivos de progestagênio isolado. Entretanto, mulheres diabéticas devem
ser cuidadosamente observadas enquanto usarem CERAZETTE®. O tratamento com CERAZETTE® leva à redução dos níveis séricos de estradiol para um nível correspondente à fase folicular inicial. Apesar do fato de CERAZETTE® inibir a
ovulação, a gravidez ectópica deve ser considerada no diagnóstico diferencial se a mulher tem amenorréia ou dor abdominal. Cloasma pode ocorrer ocasionalmente. As seguintes condições foram relatadas durante a gravidez e durante uso de
esteróide sexual, mas a associação com o uso de progestagênios não foi estabelecida: icterícia e/ou prurido relacionado a colestase; formação de cálculo de vesícula; porfiria; lúpus eritematoso sistêmico; síndrome urêmica hemolítica; corea de
Sydenham; herpes gestacional; perda da audição relacionada a otosclerose. Mesmo quando CERAZETTE® é tomado regularmente, podem ocorrer distúrbios de sangramento. As mulheres devem ser informadas de que CERAZETTE® não
protege contra HIV e outras doenças sexualmente transmissíveis. Com todos os contraceptivos hormonais de baixa dosagem, o desenvolvimento folicular ocorre e ocasionalmente o folículo pode continuar o desenvolvimento além do tamanho que
poderia atingir num ciclo normal. Geralmente, esses folículos aumentados desaparecem espontaneamente. A eficácia dos contraceptivos de progestagênio isolado pode ser reduzida no caso de esquecimento de tomar os comprimidos, distúrbios
gastrintestinais ou de utilização de medicação concomitante. Estudos epidemiológicos extensos mostraram que não há risco aumentado de malformações nas crianças de mães que utilizaram contraceptivos orais antes da gravidez, nem efeitos
teratogênicos quando os contraceptivos orais forem administrados inadvertidamente no início da gestação. Dados de farmacovigilância coletados com vários COCs contendo desogestrel também não indicam um risco aumentado. CERAZETTE®
não influencia a produção ou a qualidade do leite materno, mas uma pequena quantidade de etonogestrel é excretada no leite. REAÇÕES ADVERSAS: as reações adversas relatadas com maior freqüência nos estudos clínicos com CERAZETTE®
(>2,5%) foram sangramento irregular, acne, alterações de humor, dor nas mamas, náusea e aumento de peso. INTERAÇÕES MEDICAMENTOSAS: podem ocorrer interações com fármacos indutores de enzimas microsomais, resultando em
aumento da depuração dos hormônios sexuais. Foram estabelecidas interações com hidantoínas, barbitúricos, primidona, carbamazepina, rifampicina, oxcarbazepina, topiramato, rifabutina, felbamato, ritonavir, griseofulvina e produtos fitoterápicos
contendo Hypericum perforatum. Durante o tratamento com carvão medicinal, a absorção do esteróide do comprimido pode ser reduzida bem como sua eficácia contraceptiva. Contraceptivos orais podem interferir com o metabolismo de outros
fármacos (por ex., ciclosporina), consequentemente concentrações plasmáticas e tissulares podem ser afetadas. Dados obtidos com contraceptivos orais combinados mostraram que os esteróides contraceptivos podem influenciar os resultados
de certos testes de laboratório, incluindo parâmetros bioquímicos do fígado, tireóide, adrenal e de função renal, níveis séricos de proteínas (carregadoras). POSOLOGIA: deve-se tomar um comprimido ao dia durante 28 dias consecutivos na
ordem indicada pelas setas impressas na cartela, com pequena quantidade de líquido, aproximadamente no mesmo horário. Cada cartela subseqüente deve ser iniciada imediatamente após o término da anterior. Superdosagem: não há relatos de
reações adversas graves em decorrência de superdose. Nesta situação os sintomas que podem ocorrer são: náuseas, vômitos e, em meninas e adolescentes, discreto sangramento vaginal. Não há antídotos e o tratamento deve ser sintomático.
VENDA SOB PRESCRIÇÃO MÉDICA. Reg. MS: 1.0171.0089
CERAZETTE® não deve ser usado em casos de gravidez ou suspeita de gravidez e tumores progestagênio dependentes. Pode-se
esperar interações durante o uso concomitante de CERAZETTE® com hidantoínas, barbituratos, primidona, carbamazepina, rifampicina.
Antes de prescrever, recomendamos a leitura da Circular aos Médicos (bula) completa para informações detalhadas sobre o produto.
A PERSISTIREM OS SINTOMAS, O MÉDICO DEVE SER CONSULTADO.
Referência Bibliográfica: 1. Agência Nacional de Vigilância Sanitária. Lista de medicamentos de referência. Disponível em: http://portal.anvisa.gov.br/wps/wcm/connect/7b8223004db4095facf9bcd6059e5711/
Lista+A+Isolados_05_12.pdf?MOD=AJPERES. Acessado em 04 de janeiro de 2013.
Copyright © 2010 Merck Sharp & Dohme Corp., subsidiária de Merck & Co., Inc., Whitehouse Station, NJ, EUA.
Todos os direitos reservados.
MC 1150/12 01-2015-CER-13-BR-1150-J WOMN-1067094-0000 IMPRESSO EM JANEIRO/2013
CERAZETTE, CONSIDERADO
REfERêNCIA NO mERCADO DE
CONtRACEpçãO, AGORA VEm COm
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