ginecologia / obstetricia

#Suplementação de ferro na gravidez?

Postado em

gestante na sala de médico

Suplementação de ferro na gravidez?

É comum que durante a gestação as mulheres sejam estimuladas a fazer uso de multivitamínicos, e quando não o fazem, geralmente é preconizado a suplementação de ferro. Mas em 2018, com taxas de desnutrição mais baixas, continua sendo recomendado suplementar ferro na gravidez?

De acordo com o Ministério da Saúde, a suplementação de ferro na gravidez deve ser universal. A Febrasgo também indica a suplementação a fim de evitar a anemia gestacional. Já de acordo com o US Task Force, essa suplementação tem benefício incerto. Mulheres que não recebem a suplementação tem as mesmas taxas de complicações maternas e fetais ao fim gravidez do que as que recebem.

As diferentes opiniões das entidades só reforçam que a decisão da suplementação deve ser direcionada ao perfil da paciente. Em mulheres com alimentação equilibrada e com ingesta satisfatória de alimentos ricos em ferro, ela pode ser dispensada, mas entre aquelas com ingestão de ferro reduzida, ela terá um benefício muito maior.

Importante destacar que essa tomada de decisão pode ser feita junto com a paciente, que também pode tolerar a suplementação oral de ferro ou não, de acordo com efeitos colaterais e custo das medicações.

 

 

Anúncios

#El inicio de la #menstruación antes de los 12 años se relaciona con un mayor #riesgo de enfermedad cardiaca e #ictus en la edad adulta (Heart)

Postado em

La menstruación de inicio temprano, antes de los 12 años, está relacionada con un mayor riesgo de enfermedad cardiaca e ictus en etapas posteriores de la vida, según sugiere un análisis de datos del Biobanco de Reino Unido, publicado en Heart.

Es uno de varios factores de riesgo reproductivos, como la menopausia precoz, las complicaciones del embarazo y la histerectomía, que parecen estar asociados a la enfermedad cardiovascular.

En un intento por aclarar cualquier asociación potencial, el equipo de investigación se basó en datos del Biobanco de Reino Unido, un amplio estudio basado en la población de más de medio millón de hombres y mujeres hasta la edad de 69 años, y reclutados entre 2006 y 2010.

Los participantes completaron cuestionarios sobre su estilo de vida, entorno e historial médico, que incluyeron una amplia gama de factores reproductivos, además de que se les tomaron pruebas para evaluar su salud física y funcional, y proporcionaron muestras de orina, sangre y saliva.

En total, se siguió la salud de 267.440 mujeres y 215.088 hombres, ninguno de los cuales presentaba enfermedad cardiovascular cuando ingresaron en el estudio, hasta marzo de 2016 o hasta que tuvieron su primer ataque cardiaco o accidente cerebrovascular, lo que ocurriera primero. La edad promedio de las mujeres al inicio del estudio fue de 56, y alrededor de la mitad (51%) provenía del tercio más acomodado de la población de Reino Unido. Seis de cada diez nunca habían fumado.

La edad promedio a la que comenzaron a tener periodos fue de 13 años; la mayoría (85%) habían estado embarazadas, y casi la mitad (44%) habían tenido dos hijos. En promedio, tenían 26 años cuando dieron a luz a su primer hijo. Una de cada cuatro mujeres había abortado y el 3% había tenido un bebé muerto. Casi dos tercios de ellas habían llegado a la menopausia, a una edad promedio de 50 años.

Aproximadamente, cuatro de cada diez hombres (42%) tuvieron dos hijos antes del inicio del estudio. Durante un periodo de monitorización, que abarcó alrededor de 7 años, se registraron 9.054 casos de enfermedad cardiovascular, un tercio (34%) de los cuales fueron en mujeres. Esto incluyó 5.782 casos de enfermedad arterial coronaria (28% en mujeres) y 3.489 casos de accidente cerebrovascular (43% en mujeres).

El análisis de los datos mostró que, después de tener en cuenta factores potencialmente influyentes, las mujeres que habían comenzado a tener la menstruación antes de la edad de 12 presentaban un 10% más de riesgo de enfermedad cardiovascular que aquellas que la tuvieron a los 13 años o más.

De manera similar, aquellas que atravesaron la menopausia temprano (antes de la edad de 47 años) registraron un 33% más de riesgo de enfermedad cardiovascular, aumentando a 42% su riesgo de accidente cerebrovascular, después de tener en cuenta otros factores potencialmente influyentes.

Los abortos espontáneos previos se vincularon con un mayor riesgo de enfermedad cardiaca, con cada aborto aumentando el riesgo en un 6%. Y la muerte fetal se relación con un mayor riesgo de enfermedad cardiovascular en general (22%) y de accidente cerebrovascular en particular (44%).

La histerectomía se relacionó con un mayor riesgo de enfermedad cardiovascular (12%) y de enfermedad cardiaca (20%). Y aquellas a las que se les habían extirpado los ovarios antes de una histerectomía registraban el doble de probabilidades de desarrollar patología cardiovascular que las que no se habían sometido a estos procedimientos.

La edad temprana en la primera paternidad parece ser otro factor de riesgo, con cada año adicional de edad disminuyendo el riesgo de enfermedad cardiovascular en alrededor del 3%. Pero la asociación entre el número de niños y la enfermedad cardiovascular fue similar para hombres y mujeres, lo que sugiere que los factores sociales, psicológicos y de comportamiento pueden ser más importantes que los biológicos.

#La #diabetes gestacional comporta un mayor riesgo de #enfermedad cardiaca (PLoS Medicine)

Postado em

Las mujeres que desarrollan diabetes gestacional durante el embarazo tienen un riesgo mayor de lo habitual de desarrollar diabetes tipo 2, hipertensión y cardiopatía isquémica en el futuro, según un estudio publicado en PLOS Medicine por Krishnarajah Nirantharakumar, de la Universidad de Birmingham, Reino Unido, y colegas.

Las tasas de diabetes gestacional están aumentando en la mayoría de los países desarrollados y la investigación previa ha encontrado que las mujeres diagnosticadas con diabetes gestacional presentan mayor riesgo de desarrollar diabetes tipo 2 durante toda la vida. En el nuevo trabajo, los autores estudiaron la incidencia de diabetes tipo 2, hipertensión y cardiopatía isquémica y enfermedades cerebrovasculares en una base de datos de atención primaria de Reino Unido que incluyó a más de 9.000 mujeres diagnosticadas con diabetes gestacional entre 1990 y 2016.

Las mujeres diagnosticadas con diabetes gestacional registraban más de 20 veces más probabilidades de ser diagnosticadas con diabetes tipo 2 más adelante en la vida, más de dos veces y media más probabilidades de desarrollar cardiopatía isquémica y casi el doble de probabilidades de desarrollar hipertensión.

Aunque las pautas actuales recomiendan la detección anual de la diabetes en las mujeres diagnosticadas con diabetes gestacional, el estudio encontró que la evaluación de seguimiento de la diabetes y los factores de riesgo cardiovascular fue baja, con la excepción de la presión arterial; menos del 60% de las mujeres fueron evaluadas durante el primer año postparto y las tasas disminuyeron a partir de entonces.

“Los hallazgos añaden una visión importante sobre la trayectoria del desarrollo de diabetes tipo 2, hipertensión y enfermedad cardiovascular en los periodos posparto temprano y posterior”, concluyen los autores.

#Early Puberty Puts Women at Higher Risk for Heart Disease and Stroke

Postado em

Imagem relacionada

Early Puberty Puts Women at Higher Risk for Heart Disease and Stroke

By Lisa Rapaport

(Reuters Health) – Girls who start menstruating before they’re 12 years old may have a greater risk of heart disease and stroke later in life than their peers who go through puberty later, a UK study suggests.

For the study, researchers examined data on more than 500,000 middle-aged adults who didn’t have a history of heart disease, including more than 267,000 women. Researchers followed half of the participants for at least seven years, and during that time about 9,000 men and women developed heart disease or experienced a heart attack or stroke.

Women typically started menstruating when they were 13 years old. When they got their first period before age 12, women were 10% more likely to develop cardiovascular disease than when they started menstruating at age 13 or older, the study found.

Obesity might explain some of this connection, said study co-author Sanne Peters of the George Institute for Global Health at the University of Oxford in the UK. Previous studies have linked early puberty to obesity in both children and adults, Peters said by email.

“However, there is no straightforward link,” Peters said. “Our findings show that the risk of developing cardiovascular disease increases for both women of healthy weight and women who are overweight or obese, which suggests we need more research to understand the association between an early first menstrual cycle and a greater risk of heart disease and stroke later in life.”

Other reproductive health factors also appeared to influence the risk of heart disease in women, researchers report online January 15 in the journal Heart.

Women who went through menopause early, before age 47, were 33% more likely to develop cardiovascular disease and 42% more likely to have a stroke than women who went through menopause later, the study found.

A history of miscarriages was also linked to a higher risk of cardiovascular disease, with each miscarriage tied to a 6% increase in the odds of heart problems.

In addition, those who had a hysterectomy were 12% more likely to get cardiovascular disease, and the increased risk was even higher for women who had their ovaries removed in addition to the uterus.

The study wasn’t a controlled experiment designed to prove whether or how puberty timing might directly impact the odds of cardiovascular disease, a heart attack or stroke decades later.

Even so, the results add to the evidence linking earlier maturation with obesity, high blood pressure and other risk factors for cardiovascular disease, said Jane Mendle, a human development researcher at Cornell University in Ithaca, New York, who wasn’t involved in the study.

“Early puberty is correlated with many risks and experiences that are independently important for cardiovascular health – such as obesity, smoking, socioeconomic status, and higher life stress,” Mendle said by email. “Likely, it’s a combination of these factors that explain why earlier development is related to heart health.”

SOURCE: http://bit.ly/2ENG9Ns

Heart 2018.

Reuters Health Information © 2018

#Breastfeeding May Halve #Diabetes Risk in Women

Postado em

Women who breastfed for at least 6 months across all births reduced their risk for type 2 diabetes throughout their childbearing years by almost half compared with those who did not breastfeed, a 30-year study has found.

“We found a very strong association between breastfeeding duration and lower risk of developing diabetes, even after accounting for all possible confounding risk factors,” lead author Erica P. Gunderson, PhD, senior research scientist at the Kaiser Permanente Division of Research in Oakland, California, said in a news release.

“The incidence of diabetes decreased in a graded manner as breastfeeding duration increased, regardless of race, gestational diabetes, lifestyle behaviors, body size, and other metabolic risk factors measured before pregnancy, implying the possibility that the underlying mechanism may be biological,” she explained.

Dr Gunderson and colleagues published their findings online January 16 in JAMA Internal Medicine.

The researchers analyzed data from the 30-year Coronary Artery Disease Risk Development in Young Adults (CARDIA) study, a study of black and white women treated at one of four geographically diverse centers in the United States. The analysis included 1238 women (n = 615 black and 623 white) without diabetes prior to pregnancy who delivered at least one live singleton birth (n = 2302) after baseline.

During a mean follow-up of 24.7 years, 155 (12.5%) reported gestational diabetes (GD) status for those births. All participants underwent systematic testing that included “multiple assessments of glucose tolerance and other risk factors” up to seven times during the study, the authors write.

The adjusted relative hazard (aRH) for incident diabetes was 0.75 (95% confidence interval [CI], 0.51 – 1.09) for women who breastfed for 0 to 6 months; 0.52 (95% CI, 0.31 – 0.87) for those who breastfed for more than 6 months to fewer than 12 months; and 0.53 (95% CI, 0.29 – 0.98) for women who breastfed for 12 months or more, compared with women who did not breastfeed (P for trend = .01).

“For the full sample of 1238 women, models with continuous months of lactation yielded consistent lower RHs of incident diabetes in unadjusted and adjusted race-stratified models and combined models,” the researchers write.

During 27,598 person-years, the overall incidence rate of diabetes was 6.6 cases per 1000 person-years, with 132 cases in 13,369 person-years among black women and 50 cases in 14,229 person-years among white women. The incidence of diabetes per 1000 person-years was significantly higher among black women compared with white women (9.9% vs 3.5; P < .001).

Women with GD also had a higher incidence of diabetes per 1000 person-years compared with women who did not have GD (18.0 vs 5.1; P < .001).

Most (93%) of the postbaseline births occurred within 15 years after baseline, and 86% of incident diabetes cases were diagnosed from 15 to 30 years postbaseline.

“We have known for a long time that breastfeeding has many benefits both for mothers and babies; however, previous evidence showed only weak effects on chronic disease in women,” Tracy Flanagan, MD, director of women’s health for Kaiser Permanente Northern California, said in the news release.

“Now we see much stronger protection from this new study showing that mothers who breastfeed for months after their delivery may be reducing their risk of developing type 2 diabetes by up to one half as they get older. This is yet another reason that doctors, nurses, and hospitals as well as policymakers should support women and their families to breastfeed as long as possible.”

The researchers say several mechanisms could explain their findings, including the effects of lactation-associated hormones on pancreatic cells, which could result in decreased circulating glucose and reduced insulin secretion, even though glucose production increases during lactation.

“These processes for milk production have been associated with lower basal and glucose-stimulated β-cell secretory activity for a standardized glucose load and beneficial effects that unload the pancreatic β-cells. Higher basal and sporadic increased prolactin levels in lactating women may preserve pancreatic β-cell mass and function” they explain.

Limitations of the study include the variable time of health assessments relative to pregnancies and the fact that women self-reported pregnancy complications. The researchers note that accurate reporting of GD and other perinatal outcomes is a strength of the study.

“Unlike previous studies of breastfeeding, which relied on self-reporting of diabetes onset and began to follow older women later in life, we were able to follow women specifically during the childbearing period and screen them regularly for diabetes before and after pregnancies,” Dr Gunderson said in the news release.

“Lactation is a natural biological process with the enormous potential to provide long-term benefits to maternal health, but has been underappreciated as a potential key strategy for early primary prevention of metabolic diseases in women across the childbearing years and beyond,” the researchers conclude.

Dr Gunderson reports receiving funding from Janssen Pharmaceuticals and Dr Quesenberry reports receiving research funding from Takeda, Merck & Company Inc, Sanofi-Aventis, Eli Lilly, Genentech, Valeant, and Pfizer. The remaining study authors have disclosed no relevant financial relationships.

JAMA Int Med. Published online January 16, 2018. Full text

#Ácido fólico em gestantes em tratamento com #antiepiléticos associado a menor #risco de autismo

Postado em

A suplementação com ácido fólico, tanto pré quanto perigestacional, pode abrandar o risco de autismo na prole de mulheres em tratamento com drogas antiepiléticas (DAE), mostra uma nova pesquisa.

Pesquisadores noruegueses estudaram o risco de características autistas na prole de quase 105.000 mulheres com epilepsia e descobriram que aquelas que foram tratadas com DAEs durante a gestação tinham risco de cinco a oito vezes maior de dar à luz uma criança autista se não receberam ácido fólico durante o período de concepção.

Um terço das crianças cujas mães não haviam sido tratadas com suplementação de ácido fólico durante o período periconcepcional tinha traços autistas aos 18 e 36 meses. Maiores concentrações de folato no plasma materno entre a 17a e 19a semanas gestacionais foram associadas a menos traços autistas aos 36 meses.

“Filhos de mulheres que usaram drogas antiepiléticas acompanhadas de suplementos de ácido fólico antes da gestação, ou no primeiro trimestre, tiveram um risco bastante reduzido de traços autistas comparados aos filhos de mulheres que não usaram tais suplementos,” relatou ao Medscape a Dra. Marte Bjørk, principal pesquisadora e neurologista do Departamento de Medicina Clínica do Haukeland University Hospital, em Bergen (Noruega).

Mulheres que estejam em tratamento com DAEs, e que tenham possibilidade de engravidar, devem ser suplementadas com baixas doses de ácido fólico ou, como alternativa, ter o folato sérico checado regularmente, aconselha ela.

O estudo foi publicado on-line em 26 de dezembro no JAMA Neurology.

“Magnitude surpreendente”

Crianças expostas a DAEs durante a gestação têm risco aumentado de traços autistas, provavelmente devido a “mecanismos embriotóxicos e interações genético-ambientais”, escrevem os autores.

“A exposição intra-uterina às DAEs tem sido associada a traços de autismo e de transtorno do espectro autista (TEA), e estas drogas interferem com o metabolismo do folato, ou seja, mulheres portadoras de epilepsia têm maior risco de baixo folato durante a gravidez,” explica a Dra. Marte.

A administração adequada de ácido fólico reduz levemente o risco de TEA na população geral, mas estudos anteriores ainda não haviam examinado se a redução de risco com tal suplementação também se aplicaria a mulheres em tratamento com DAEs, observa ela.

“Nós então pensamos em investigar se o nível de folato materno e a suplementação de ácido fólico reduziriam o risco de traços autistas em crianças expostas a DAEs na gestação.”

Para explorar a questão, os pesquisadores analisaram mulheres (n=104.946; idade média de 29,8; desvio-padrão de 4,6 anos) que participavam do registro Norwegian Mother and Child Cohort Study.

As mães receberam questionários para serem preenchidos entre a 17a e 19a semanas gestacionais (Q1), e aos 18 e 36 meses de idade da criança (Q3 e Q4, respectivamente).

O estudo incluiu filhos de mulheres com epilepsia tratadas com DAEs durante a gestação (n=335), filhos de mulheres com epilepsia porém sem tratamento com DAEs (n=389), e filhos de mulheres sem diagnóstico da doença, que funcionaram como grupo controle (n=104.222).

A monoterapia com DAEs incluiu lamotrigina, carbamazepina, valproato de sódio, levetiracetam, topiramato, oxcarbazepina, clonazepam, fenitoína ou fenitoína sódica, fenobarbital, gabapentina, primidona e clobazam. Valproato foi incluído em 19 combinações politerapêuticas.

A administração “periconcepcional” foi definida como “suplementação de ácido fólico desde quatro semanas antes até 12 semanas após a concepção.”

Dentre as mães com epilepsia em tratamento com DAEs, 139 reportaram a dose, e, destas, 84 (60,4%) relataram o uso de alta dose de ácido fólico (>0,4 mg/d).

Amostras de sangue materno foram obtidas entre a 17a e 19a semanas gestacionais, e o sangue do cordão umbilical imediatamente após o parto em mulheres com epilepsia em tratamento com DAEs, e, nestas, foram analisados o metabólitos ativo 5-metiltetrahidrofolato (mTHF), os produtos de degradação 4-α-hidroxi-mTHF, p-aminobenzoilglutamato, p-acetamidobenzoilglutamato e ácido fólico não metabolizado. Foram analisadas também em ambas amostras as concentrações de DAEs.

Para medir os traços autistas nas crianças, foram utilizadas as escalas Modified Checklist for Autism in Toddlers e o Social Communication Questionnaire (SCQ) aos 18 e 36 meses, respectivamente.

As variáveis incluídas na análise de regressão logística foram idade materna, condição sócio-econômica, baixa renda familiar, paridade, tabagismo, uso de álcool, sintomas depressivos na mãe e politerapia com DAEs.

Os pesquisadores concluíram que a odds ratio ajustada (ORA) para traços autistas entre crianças de 18 meses cujas mães foram tratadas com DAEs sem suplementação de ácido fólico foi de 5,9 (IC de 95%, 2,2-15,8), comparada com aquelas cujas mães foram suplementadas. Em crianças de 36 meses de idade, a ORA correspondente foi 7,9 (IC de 95%, 2,5-24,9).

As ORAs correspondentes em filhos de mulheres sem epilepsia aos 18 e 36 meses de idade foram 1,3 IC de 95%, 1,2-1,4) e 1,7 (IC de 95%, 1,5-1,9), respectivamente.

Não foi observado aumento significativo de traços autistas aos 18 e 36 meses de idade em filhos de mulheres com epilepsia não tratada com DAEs, independente de suplementação.

Foi observada uma associação inversa em crianças expostas a DAEs entre escore médio de SCQ e concentração de folato no plasma materno entre a 17a e 19a semanas gestacionais. O quartil com as menores concentrações de folato apresentaram um escore de SCQ mais alto do que o quartil com as concentrações mais altas, onde escore alto significa mais traços autistas.

Da mesma forma, as análises ad hoc ajustadas para fatores de confusão mostraram uma associação inversa linear entre escore médio de SCQ e dose de ácido fólico em qualquer semana gestacional, mas a associação foi mais pronunciada para suplementação no primeiro trimestre (β = -0,45; P<0,001).

O tempo médio para início da suplementação foi idade gestacional de 6,5 semanas para mães de crianças com traços autistas aos 18 meses, e de 12,5 semanas para aquelas cujos filhos apresentaram os mesmos traços aos 36 meses.

Mães de crianças sem traços autistas mais frequentemente iniciaram suplementação com ácido fólico antes da gravidez em comparação com aquelas que tiveram filhos com traços autistas aos 18 e 36 meses (mediana 6,5 semanas, P=0,007, e 12,5 semanas P=0,01, respectivamente).

A associação entre suplementação com ácido fólico periconcepcional e traços autistas em crianças expostas a DAEs parece existir com todas as DAEs.

A análise post hoc revelou uma interação “altamente significativa” de tratamento com DAEs acrescida de suplementação com ácido fólico e número de traços autistas (B = -3,1; erro padrão = 1,1; β = -0,42; P = 0,004).

A Dra. Marte reconhece que apesar da “direção dos achados” ter sido esperada, ela foi surpreendida pela “magnitude do efeito.”

“Nossos resultados se mantiveram mesmo após o ajuste para fatores de confusão relevantes”, acrescenta ela.

“Mistério sem solução”

Comentando os achados com o Medscape, Darrell Wiens, PhD e professor de biologia da University of Northern Iowa, em Cedar Falls (Estados Unidos), que não participou do estudo, considerou esta “uma importante contribuição pois, até o momento, havíamos estudado muito pouco a questão das DAEs durante a gestação e a possibilidade de o ácido fólico oferecer alguma proteção nestes casos.”

Ele salienta alguns pontos fortes do estudo: a quantidade de mulheres estudadas, o fato de ter sido realizado em longo prazo, testando para autismo em duas idades diferentes, e o controle de múltiplas variáveis.

Disto isto, porém, ele observa que não ficou claro se a suplementação foi de ácido fólico puro ou como componente de um multivitamínico.

“Isso faria diferença, pois o multivitamínico garantiria a ingesta de várias vitaminas, fazendo com que a correlação possa ser entre nutrição completa versus incompleta.”

E mais, as diferentes DAEs “podem provavelmente ter mecanismos de ação diferentes, mas foram todas incluídas no estudo como uma categoria na maioria das análises.”

Embora os dados suplementares que acompanham o estudo tenham acrescentado uma análise mais detalhada, “os autores concluíram simplesmente que a associação entre traços autistas e DAEs estava presente para todos.”

Sua própria pesquisa mostrou que o ácido fólico é um fator de risco para transtorno do espectro autista, e que “existem fortes razões para se ter cuidado com altas doses de ácido fólico em grávidas, especialmente durante a época perinatal e no decorrer da gestação,” adverte ele.

No editorial de acompanhamento, o Dr. Kimford J. Meador, professor de neurologia e neurociência da Stanford University, e diretor clínico do Stanford Comprehensive Epilepsy Center, na California (Estados Unidos), recomenda que as “mulheres com possibilidade de engravidar”, especialmente aquelas sendo tratadas com DAEs, “tomem suplementos de folato continuamente.”

Não está claro, porém, que dose deve ser utilizada, já que “alguns estudos na população geral sugerem risco adverso com folato em altas doses,” observa ele, acrescentando que as doses mais seguras e eficazes “podem ser diferentes entre mulheres na população geral e aquelas tomando DAEs.”

A Dra. Marte concorda que a dose ideal ainda requer mais estudo. “Apesar de termos visto o efeito de altas doses de suplementos de ácido fólico, a dose correta para os vários tipos de DAEs ainda é uma questão não resolvida que deve ser estudada em pesquisas futuras.”

Este estudo foi financiado pela Norwegian Epilepsy Association. O Norwegian Mother and Child Cohort Study é financiado pelos ministérios da saúde e educação noruegueses, National Institute of Environmental Health Science, National Institute of Neurological Disorders and Stroke, e o Norwegian Research Council/Functional Genomics. A Dra. Marte informa ter recebido honorários como palestrante e consultora da Novartis. Nenhum outro conflito de interesse da autora. O Dr Wiens não informou relações financeiras relevantes. O Dr. Meador informou ter recebido financiamento para pesquisa dos National Institutes of Health, e de Sunovion Pharmaceuticals, e pagamentos para a Stanford University do Epilepsy Study Consortium por consultorias prestadas a Eisai, GW Pharmaceuticals, Neuro-Pace, Novartis, Supernus, Upsher-SmithLaboratories, UCB Pharma e Vivus Pharmaceuticals.

JAMA Neurol, Publicado on-line em 26 de dezembro, 2017, Resumo, Editorial.

#Pregnancy and Labor Complications in Female Survivors of #Childhood Cancer

Postado em

The British Childhood Cancer Survivor Study

Raoul C. Reulen; Chloe J. Bright; David L. Winter; Miranda M. Fidler; Kwok Wong; Joyeeta Guha; Julie S. Kelly; Clare Frobisher; Angela B. Edgar; Roderick Skinner; W. Hamish B. Wallace; Mike M. Hawkins

Abstract and Introduction

Abstract

Background Female survivors of childhood cancer treated with abdominal radiotherapy who manage to conceive are at risk of delivering premature and low-birthweight offspring, but little is known about whether abdominal radiotherapy may also be associated with additional complications during pregnancy and labor. We investigated the risk of developing pregnancy and labor complications among female survivors of childhood cancer in the British Childhood Cancer Survivor Study (BCCSS).

Methods Pregnancy and labor complications were identified by linking the BCCSS cohort (n = 17 980) to the Hospital Episode Statistics (HES) for England. Relative risks (RRs) of pregnancy and labor complications were calculated by site of radiotherapy treatment (none/abdominal/cranial/other) and other cancer-related factors using log-binomial regression. All statistical tests were two-sided.

Results A total of 2783 singleton pregnancies among 1712 female survivors of childhood cancer were identified in HES. Wilms tumor survivors treated with abdominal radiotherapy were at threefold risk of hypertension complicating pregnancy (relative risk = 3.29, 95% confidence interval [CI] = 2.29 to 4.71), while all survivors treated with abdominal radiotherapy were at risk of gestational diabetes mellitus (RR = 3.35, 95% CI = 1.41 to 7.93) and anemia complicating pregnancy (RR = 2.10, 95% CI = 1.27 to 3.46) compared with survivors treated without radiotherapy. Survivors treated without radiotherapy had similar risks of pregnancy and labor complications as the general population, except survivors were more likely to opt for an elective cesarean section (RR = 1.39, 95% CI = 1.16 to 1.70).

Conclusions Treatment with abdominal radiotherapy increases the risk of developing hypertension complicating pregnancy in Wilms tumor survivors, and diabetes mellitus and anemia complicating pregnancy in all survivors. These patients may require extra vigilance during pregnancy.

Introduction

Survival from childhood cancer has improved considerably over the last few decades, and currently nearly 80% of children diagnosed with cancer survive at least five years.[1] This dramatic improvement in survival is mainly attributable to advances in multimodality therapy with combination chemotherapy and improved radiotherapy delivery. However, various studies have shown that previous cancer treatment, particularly following radiotherapy, increases the long-term risk of developing adverse health outcomes, including second primary cancer, cardiovascular disease, infertility, and adverse pregnancy outcomes.[2,3]

Female survivors of childhood cancer who have been treated with abdominal radiotherapy and who subsequently managed to conceive are at risk of premature delivery and delivering low-birthweight offspring.[4–10] The exact mechanism underlying this risk is not entirely clear, but it has been postulated that exposure to abdominal irradiation increases myometrial fibrosis and negatively affects vascular and/or muscular development of the uterus.[11,12] Although the risks of premature delivery and delivering low-birthweight offspring in survivors of childhood cancer are well documented,[4–10] it is unclear whether previous treatment with abdominal radiotherapy for childhood cancer may also be associated with additional complications during pregnancy and labor. Green et al.[5,13] reported that female survivors of unilateral Wilms’ tumor treated with flank irradiation are at risk of fetal malposition, early or threatened labor, and developing hypertension complicating pregnancy, but to the best of our knowledge, no other large-scale study has investigated the risk of specific pregnancy and labor complications in women treated with abdominal radiotherapy for childhood cancer.

The principal aim of this study was to investigate the risks of developing pregnancy and labor complications ascertained through linkage with hospital electronic health records in female survivors treated with abdominal radiotherapy for childhood cancer.

Methods

British Childhood Cancer Survivor Study

The British Childhood Cancer Survivor Study is a large-scale population-based cohort of 17 980 five-year survivors of childhood cancer who were diagnosed with cancer between age 0 to 14 years from 1940 to 1991 in Britain.[14] The cohort was ascertained through the National Registry of Childhood Tumours. The BCCSS cohort was linked to the population-based Hospital Episode Statistics (HES) for England—an electronic database that records data on patients’ hospital admissions (inpatient), outpatient appointments, and accident and emergency attendances at National Health Service (NHS) or private hospitals (if care was commissioned by the NHS). HES is managed by NHS digital and developed as a system for hospitals to get paid for administered patient care. For this study, the BCCSS cohort was linked to the inpatient HES data set from April 1, 1997, to December 31, 2012, by a third party (Northgate Solutions) using NHS number, date of birth, and postcode. Approval to link the BCCSS cohort to HES without prior individual patient consent was obtained from the Confidentiality Advisory Group and the National Research Ethics Service.

As HES only covers England, 2116 (11.8%) five-year survivors who were alive and residing in Scotland or Wales were excluded from analyses. Among the 6192 female survivors in the cohort who were alive as of April 1, 1997, 5126 (82.8%) had at least one recorded hospital admission in the HES inpatient data set.

The HES inpatient data set includes any records relating to care given for births that took place in NHS hospitals. Although home deliveries and births in private hospitals should be recorded in HES, practically few are,[15] and hence these deliveries were excluded (n = 35). Pregnancies that resulted in a multiple birth (n = 85) were also excluded as the risk of pregnancy and labor outcomes is likely to differ from singleton births.

For comparisons with the general population, a random sample of 25 000 deliveries was extracted from the entire (anonymized) HES database (n = 8 821 531 deliveries). A sample of 25 000 was decided upon because at that size the sample was sufficiently large to provide ample statistical power, and, moreover, larger samples (eg, n = 100 000) resulted in similar results (results not shown).

Pregnancy and Labor Complications

Pregnancy and labor complications were only evaluated if there were at least 50 affected pregnancies. Medical conditions and complications are recorded in HES using the International Classification of Diseases (ICD), revision 10. Specifically, we investigated the risk of: hypertension complicating pregnancy (ICD-10: O10-O11/O13-O16), gestational diabetes mellitus (O24.4), anemia complicating pregnancy (O99.0), malpresentation of fetus (O32), maternal care due to uterine scar from previous surgery (O34.2), fetal problems (O36), premature rupture of membranes (ie, rupture of the amniotic sac; O42), prolonged pregnancy (O48), abnormalities of forces of labor (O62), long labor (O63), obstructed labor due to malposition of fetus (064), delivery complicated by fetal stress (O68), umbilical cord complications (O69), perineal laceration (O70), and postpartum hemorrhage (O72). In addition, the likelihood of the delivery method being elective or emergency cesarean and whether there were any high-risk pregnancies that needed supervision (ICD-10: Z35) was also evaluated. Adverse pregnancy outcomes evaluated in this study included low-birthweight baby, preterm delivery, and stillbirth.

Statistical Analysis

A log-binomial regression model—with a population-averaged generalized estimating equation modification accounting for correlation between pregnancies of the same survivor—was used to calculate relative risk (RR) estimates of pregnancy and labor complications by type of childhood cancer, site of radiotherapy treatment (none/cranial/abdominal/other), age at childhood cancer, and calendar period of treatment (<1980/1980–1984/1985–1991). Abdominal radiotherapy was defined as any radiotherapy received for a tumor in the abdomen or pelvic volume. All models included the potential confounders maternal age and parity unless otherwise specified. Relative risks were also calculated for Wilms tumor survivors as these would have received some of the highest doses of abdominal irradiation and also comprise a sufficiently large group to consider separately. To determine whether survivors differed in their risk of developing pregnancy and labor complications from the general population independent of an effect of radiotherapy, survivors treated without radiotherapy were chosen for comparisons with the general population.

Although the completeness of HES ascertainment increased over calendar years, not all deliveries may have been recorded within HES, particularly before 2002.[15,16] A recent exercise whereby HES delivery records from 2002 to 2010 were linked with the Office of National Statistics (ONS) birth registrations found that 96.8% of all births recorded by ONS were also recorded in HES, suggesting that—at least for the period 2002 to 2010—the majority of deliveries are captured by HES.[17] To ascertain whether potential underreporting of deliveries and adverse pregnancy and labor outcomes in the years 1997 to 2001 could have potentially introduced bias, we conducted a sensitivity analysis by fitting HES calendar year (1997–2001 vs 2002–2012) as an interaction term in our model. Such an interaction term should detect whether there is statistically significant variation in the risk of developing a specific pregnancy or labor complication by HES calendar year.

For factors with multiple categories, a test for homogeneity of the relative risks across the levels of the factor was also performed, and Pheterogeneitywas used to indicate the statistical significance of the overall test. All analyses were performed using Stata 14 (StataCorp, College Station, Texas).[18] Statistical significance was defined at a two-sided P value of less than .05.

 

Results

Cohort Characteristics

A total of 2783 singleton deliveries among 1712 female survivors of childhood cancer were available for analysis (Table 1). The mean maternal age at the delivery-related admission was 28.7 years (SD = 5.4 years). The majority of recorded deliveries were among survivors of leukemia (32.9%, n = 915), central nervous system tumor (12.1%, n = 336), and Wilms tumor (11.6%, n = 322). In terms of site of radiotherapy treatment, 205 (12.0%) survivors had received abdominal radiotherapy (of whom 127, 62.0%, were Wilms tumor survivors), 543 (31.7%) had received radiotherapy to the brain, 529 (30.9%) had not been treated with any radiotherapy, and 146 (8.5%) had received radiotherapy to sites other than the abdomen or brain.

Hypertension, Diabetes Mellitus, and Anemia in Pregnancy

The relative risk of developing hypertension complicating pregnancy was substantially elevated among Wilms tumor survivors treated with abdominal radiotherapy (RR = 3.29, 95% confidence interval [CI] = 2.29 to 4.71) vs those treated without radiotherapy (Table 2). Twenty-three point seven percent of all Wilms tumor survivors treated with abdominal radiotherapy experienced hypertension that complicated the pregnancy vs only 7.1% of all survivors not treated with radiotherapy and 6.0% of women in the general population. Wilms tumor survivors not treated with abdominal radiotherapy were, however, not at statistically significant risk of developing hypertension complicating pregnancy (RR = 1.36, 95% CI = 0.68 to 2.71). Other survivors (ie, non-Wilms tumor) treated with abdominal radiotherapy were not at statistically significant risk either (RR = 1.09, 95% CI = 0.52 to 2.28). Similar relative risks as reported above were observed when excluding preexisting hypertension (ICD10: O10-O11), that is, for gestational hypertension only (Table 2).

Survivors treated with abdominal radiotherapy were at 3.35-fold (95% CI = 1.41 to 7.93) risk of gestational diabetes mellitus compared with survivors treated without radiotherapy (Table 2), and this relative risk was increased for both Wilms tumor (RR = 2.73, 95% CI = 1.00 to 7.62) and non-Wilms tumor (RR = 4.27, 95% CI = 1.54 to 11.83) survivors. Overall, 4.9% of all survivors treated with abdominal radiotherapy developed diabetes mellitus during pregnancy, whereas this was only 1.5% in all survivors not treated with radiotherapy and 1.6% in the general population.

The relative risk of having developed anemia that complicates pregnancy was statistically significantly elevated among survivors treated with abdominal radiotherapy compared with survivors treated without radiotherapy (RR = 2.10, 95% CI = 1.27 to 3.46) and elevated for both Wilms (RR = 2.00, 95% CI = 1.13 to 3.57) and non-Wilms tumor (RR = 2.25, 95% CI = 1.13 to 4.49) survivors (Table 2). Eight point three percent of all survivors treated with abdominal radiotherapy experienced a pregnancy that was complicated by anemia, compared with 4.0% of survivors treated without radiotherapy and 4.4% in the general population.

Maternal Care for Known or Suspected Disorder

Prior treatment with radiotherapy did not affect the likelihood of receiving specific maternal care for a known or suspected malpresentation of the fetus (P heterogeneity = .96), a uterine scar from previous surgery (P heterogeneity = .14), fetal problems such as poor fetal growth (P heterogeneity = .66), or a prolonged pregnancy (P heterogeneity = .58) (Table 3). Previous treatment with radiotherapy to the brain was associated with a small increased risk of premature rupture of the membranes (RR = 1.49, 95% CI = 1.07 to 2.08).

Complications of Labor and Delivery

No statistically significant associations could be detected between any of the factors under study and the labor complications: abnormalities of forces of labor, long labor, obstructed labor, umbilical cord complications, delivery complicated by fetal stress (except for Wilms tumor survivors having a reduced risk of a delivery being complicated by fetal stress (RR = 0.73, 95% CI = 0.57 to 0.94) (Table 4)) perineal laceration, or postpartum hemorrhage (Table 5).

Cesarean Delivery and Supervision High-Risk Pregnancy

Compared with the general population, survivors treated without radiotherapy were 39% more likely to opt for an elective cesarean (RR = 1.39, 95% CI = 1.16 to 1.70). Particularly survivors of a bone tumor (RR = 1.52, 95% CI = 1.05 to 2.20) and those treated with abdominal radiotherapy (RR = 1.46, 95% CI = 1.07 to 1.99) (Table 5) were more likely to opt for a cesarean. Survivors treated longer ago were more likely to undergo an elective cesarean than more recently treated survivors (22.3% before 1980 vs 12.7% in 1985 to 1991, P trend = .004). The risk of an emergency cesarean was not elevated among survivors compared with the general population (P = .21), although survivors of Hodgkin lymphoma appeared to be at reduced risk (RR = 0.59, 95% CI = 0.36 to 0.97). Pregnancies in survivors treated with abdominal radiotherapy were not identified as high-risk pregnancies requiring greater supervision than pregnancies in survivors treated without radiotherapy (RR = 1.04, 95% CI = 0.58 to 1.87).

Adverse Pregnancy Outcomes

Wilms tumor survivors treated with abdominal radiotherapy were at threefold risk of delivering offspring with a low birthweight compared with survivors treated without radiotherapy (RR = 2.85, 95% CI = 1.79 to 4.48) (Supplementary Table 1, available online). The RR for preterm delivery was also statistically significantly increased for Wilms tumor survivors (RR = 1.89, 95% CI = 1.30 to 2.74). Only 19 hospital admissions were related to a stillbirth, and no stillbirths were recorded among women treated with abdominal radiotherapy.

Sensitivity Analysis by HES Calendar Year

No statistically significant variation was found in the relative risk of developing a pregnancy or labor complication by HES calendar year (Supplementary Table 2, available online), suggesting that if there was potential underreporting of any pregnancy or labor outcomes before HES year 2002, the effect would have been minimal.

Discussion

To our knowledge, this is the largest study investigating the risks of pregnancy and labor complications in childhood cancer survivors. This study shows that treatment with abdominal radiotherapy increases the risk of developing hypertension complicating pregnancy in Wilms tumor survivors, as well as diabetes mellitus and anemia complicating pregnancy in all survivors. In addition, female survivors as a whole are more likely to opt for an elective cesarean than the general population. Our results of increased risks of preterm delivery and babies born with low birthweight among female survivors of childhood cancer treated with abdominal radiotherapy concur with previously reported data.[4–10]

In this study, hypertensive disorders complicated 23.7% of all pregnancies among Wilms tumor survivors treated with abdomino-pelvic radiotherapy. Consistent with these findings, Green et al.[13] reported that 23.7% of all pregnancies among Wilms tumor survivors treated with flank irradiation were complicated by hypertension. There is a possibility that the risk of hypertension complicating pregnancy may be related to a previous nephrectomy rather than actual abdominal radiotherapy; however, because the vast majority of Wilms tumor survivors would have undergone a nephrectomy,[19,20] the risks should then, in theory, also be increased among those Wilms tumor survivors not treated with radiotherapy. However, this was not supported by our data—only 8.9% of Wilms tumor survivors not treated with abdominal radiotherapy developed hypertension complicating pregnancy; not statistically significantly different than that observed in the general population (6.2%) or than other survivors not treated with radiotherapy (7.2%).

The exact biological mechanism explaining the risk of hypertension and anemia complicating pregnancy after abdominal radiotherapy is poorly understood. Hypertension, anemia, and varying degrees of chronic glomerular impairment are well documented features of chronic radiation-induced renal injury, which may also reduce a survivor’s reserve against future renal stresses. Statistically significant glomerular impairment has been reported in 25% to 56% of children receiving renal doses of 12 to 24 Gy.[21] It is plausible that hypertension and anemia may be recognized for the first time during pregnancy in some female survivors with less severe degrees of chronic radiation-induced renal damage as a result of the greater physiological stresses and increased medical surveillance during pregnancy.

To our knowledge, this is the first study to report an elevated risk of developing diabetes in pregnancy among survivors treated with abdominal radiotherapy. A linked cancer-birth registry analysis from four US centers[8]showed in an exploratory analysis that female bone cancer survivors were at risk of diabetes during pregnancy (RR = 4.92, 95% CI = 1.60 to 15.13), but this was based on small observed numbers. Other studies have found that survivors of childhood cancer treated with abdominal radiation are at risk of developing diabetes,[22–25] but not specifically during pregnancy. The mechanism for developing diabetes mellitus is unclear but may relate to a radiation-induced effect on the pancreas, perhaps causing inflammation and fibrosis, which may reduce subsequent insulin secretion from the islet cells.

In this study, survivors were more likely to opt for an elective cesarean than the general population. In a recent smaller study, Melin et al.[26] observed a 50% increased odds among 456 survivors of childhood cancer for undergoing a cesarean delivery compared with siblings which is consistent with our findings. It is not clear why survivors are more likely to opt for an elective cesarean, but it could be indicative of the obstetrician aiming to reduce any theoretical risk that a vaginal delivery might have. For example, survivors previously exposed to treatment modalities known to be associated with cardiomyopathy (eg, chest irradiation and high-dose cumulative doses of anthracycline)[27] might have opted for a cesarean delivery to decrease the potential risk relating to cardiomyopathy during labor and puerperium.

Several potential limitations should be considered. First, large-scale linkage exercises may suffer from inaccuracies with regard to linking the correct patient to the corresponding health records. However, because linkage of the BCCSS cohort with HES was done using NHS number, date of birth, and postcode of each patient, such inaccuracies in linkage are likely to be minimal. Lack of detailed treatment exposure, such as administered chemotherapy and radiation treatment charts, did not allow for conducting detailed dose-response analyses. However, we did consider Wilms tumor survivors separately who, if treated with radiotherapy, would have received one of the highest doses of radiation to the abdomen of all childhood cancer survivors. Evaluation of potential confounding of the association between abdominal irradiation and specific pregnancy and labor complications by chemotherapy was also not possible. Investigation of pregnancy and labor complications by detailed treatment exposure would require a nested case-control study. Last, we acknowledge that information on site of radiotherapy was missing for 16.9% of all survivors.

A major strength of the current study is the population-based design, which overcomes a variety of potential limitations including the issue of selection bias related to ascertainment of survivors of childhood cancer into the cohort. Hospital-based studies are probably more likely to include those survivors who were treated more intensely, and any absolute risk estimates of adverse late effects—including pregnancy outcomes—are therefore more likely to be overestimated than within a population-based study. It also provided us with the opportunity to compare the risks of pregnancy and labor outcomes with the general population in an entirely population-based way. Additionally, record linkage of our cohort with the population-based HES provides ascertainment of pregnancy and labor outcomes in a systematic way, unlike studies that ascertain adverse outcomes through either (postal) questionnaires or hospital records, which may suffer from nonresponse or selection bias, respectively.

It has previously been shown that uterine damage, manifested by impaired growth and blood flow, is a likely consequence of abdomino-pelvic irradiation[12,28,29] and that uterine volume correlates with age at irradiation.[30] Exposure of the pelvis to radiation is associated with risk of miscarriage, delivering prematurely, and low-birthweight offspring, and in this study we have shown further evidence that there is a risk of hypertension complicating pregnancy in Wilms tumor survivors, and diabetes mellitus and anemia complicating pregnancy in all survivors who have received abdominal radiotherapy. Although survivors treated with abdominal radiotherapy were more likely to opt for an elective cesarean, the risks of specific complications during labor were not statistically significantly increased, and there is thus no evidence base for suggesting that an elective cesarean should be the optimum mode of delivery in survivors of childhood cancer treated with abdominal radiotherapy.

In conclusion, the results of this study into pregnancy and labor complications among female survivors of childhood cancer show that treatment with abdominal radiotherapy increases the risk of developing hypertension complicating pregnancy in Wilms tumor survivors, and diabetes mellitus and anemia complicating pregnancy in all survivors. These patients may require extra vigilance during pregnancy.