If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Counseling and surveillance of obstetrical risks for female childhood, adolescent, and young adult cancer survivors: recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Erasmus University Medical Center, Rotterdam, the NetherlandsPrincess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
Princess Máxima Center for Pediatric Oncology, Utrecht, the NetherlandsDepartment of Pediatrics, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Department of Pediatric and Adolescent Haematology and Oncology and Children’s Haematopoietic Stem Cell Transplant Unit, Great North Children’s Hospital, and Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Erasmus University Medical Center, Rotterdam, the Netherlands
Princess Máxima Center for Pediatric Oncology, Utrecht, the NetherlandsDepartment of Pediatric Oncology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Department of Obstetrics, Birth Center Wilhelmina Children’s Hospital, and Division of Woman and Baby, University Medical Center Utrecht, Utrecht, the Netherlands
Department of Paediatric Oncology and Haematology, Centre Hospitalier Universitaire d’Angers, France, and Cancer and Radiation Team, Centre for Research in Epidemiology and Population Health, University of Paris-Sud, Villejuif, France
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Erasmus University Medical Center, Rotterdam, the Netherlands
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Erasmus University Medical Center, Rotterdam, the Netherlands
Princess Máxima Center for Pediatric Oncology, Utrecht, the NetherlandsInstitute of Biostatistics and Registry Research, Brandenburg Medical School, Neuruppin, Germany
Female childhood, adolescent, and young adult cancer survivors have an increased risk of adverse pregnancy outcomes related to their cancer- or treatment-associated sequelae. Optimal care for childhood, adolescent, and young adult cancer survivors can be facilitated by clinical practice guidelines that identify specific adverse pregnancy outcomes and the clinical characteristics of at-risk subgroups. However, national guidelines are scarce and vary in content. Here, the International Late Effects of Childhood Cancer Guideline Harmonization Group offers recommendations for the counseling and surveillance of obstetrical risks of childhood, adolescent, and young adult survivors. A systematic literature search in MEDLINE database (through PubMed) to identify all available evidence published between January 1990 and December 2018. Published articles on pregnancy and perinatal or congenital risks in female cancer survivors were screened for eligibility. Study designs with a sample size larger than 40 pregnancies in childhood, adolescent, and young adult cancer survivors (diagnosed before the age of 25 years, not pregnant at that time) were eligible. This guideline from the International Late Effects of Childhood Cancer Guideline Harmonization Group systematically appraised the quality of available evidence for adverse obstetrical outcomes in childhood, adolescent, and young adult cancer survivors using Grading of Recommendations Assessment, Development, and Evaluation methodology and formulated recommendations to enhance evidence-based obstetrical care and preconception counseling of female childhood, adolescent, and young adult cancer survivors. Healthcare providers should discuss the risk of adverse obstetrical outcomes based on cancer treatment exposures with all female childhood, adolescent, and young adult cancer survivors of reproductive age, before conception. Healthcare providers should be aware that there is no evidence to support an increased risk of giving birth to a child with congenital anomalies (high-quality evidence). Survivors treated with radiotherapy to volumes exposing the uterus and their healthcare providers should be aware of the risk of adverse obstetrical outcomes such as miscarriage (moderate-quality evidence), premature birth (high-quality evidence), and low birthweight (high-quality evidence); therefore, high-risk obstetrical surveillance is recommended. Cardiomyopathy surveillance is reasonable before pregnancy or in the first trimester for all female survivors treated with anthracyclines and chest radiation. Female cancer survivors have increased risks of premature delivery and low birthweight associated with radiotherapy targeting the lower body and thereby exposing the uterus, which warrant high-risk pregnancy surveillance.
Consequently, an increasing number of CAYA cancer survivors are at risk for adverse physical and psychosocial complications from their cancer or its treatment.
Temporal patterns in the risk of chronic health conditions in survivors of childhood cancer diagnosed 1970–99: a report from the Childhood Cancer Survivor Study cohort.
Reproductive health and specifically pregnancy and delivery outcomes represent a critical area for long-term follow-up because having children is an important determinant of quality of life for CAYA cancer survivors.
Previous research indicates difficulty conceiving or carrying a pregnancy to term and increased risk of adverse pregnancy outcomes among CAYA cancer survivors. For example, the risks of premature birth and postpartum hemorrhage are higher in CAYA cancer survivors than in women who did not have cancer,
Evidence-based clinical guidelines on surveillance in pregnancy can identify the type and prevalence of specific obstetrical and perinatal complications, characterize the clinical features of those at risk, help survivors make informed decisions, facilitate counseling and timely referral to high-risk obstetrical care, and enable opportunities for interventions to optimize pregnancy outcomes.
Objective
Published clinical practice guidelines by North American and European cancer groups reference general obstetrical risks,
but do not comprehensively assess the clinical features of those who could benefit from high-risk obstetrical follow-up. Herein, we summarize the results of a systematic review undertaken by the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) and present a critical appraisal of available evidence on obstetrical risks in CAYA cancer survivors, synthesizing these findings into evidence-based recommendations for surveillance and counseling of CAYA cancer survivors during pregnancy and delivery owing to their cancer or cancer treatment.
Materials and Methods
This guideline focuses on facilitating timely identification of CAYA cancer survivors at high risk of obstetrical complications diagnosed as having cancer before the age of 25 years (and not pregnant at that time) who would benefit from preconception counseling and surveillance during pregnancy. Management of obstetrical complications is beyond the scope of the present guideline, which should defer to standards established by local or national health systems. Standardized definitions used in this guideline are presented in Appendix 1.
The obstetrical guideline panel consisted of 33 experts from the United States of America, United Kingdom, Denmark, Germany, France, New Zealand, Australia, Japan, and the Netherlands from relevant disciplines, such as gynecology, obstetrics, midwifery, endocrinology, pediatric oncology, radiation oncology, epidemiology, and guideline methodology, and CAYA survivor or family representatives.
Methods of the IGHG have been described previously.
A worldwide collaboration to harmonize guidelines for the long-term follow-up of childhood and young adult cancer survivors: A report from the International Late Effects of Childhood Cancer Guideline Harmonization Group.
were evaluated. We defined the major outcomes for obstetrical problems in survivors and congenital problems in offspring (Appendix 1). For all discordances and relevant outcomes, focused clinical questions were formulated to determine whether specific preconception consultation or surveillance was indicated. Four working groups evaluated the following topics: (1) adverse fetal outcomes in pregnancy (such as miscarriage), (2) adverse maternal outcomes in pregnancy, (3) delivery outcomes, and (4) congenital anomalies of the neonate.
A systematic literature search was performed in MEDLINE database (through PubMed) to identify all available evidence published between January 1990 and December 2018, using the search terms “childhood cancer,” “survivors,” “late effects,” and “obstetric problems.” Details of the full search strategy are included in Appendix 2. All study designs with a sample size larger than 40 pregnancies in female childhood cancer survivors were eligible. To ensure rigorous review of manuscripts by at least 2 individuals, studies published in English were selected for analysis. All abstracts were screened by 2 independent reviewers (A.L.L.F.K. and 1 working group member). Disagreements were resolved through consensus. Cross-reference checking was performed to identify additional studies overlooked during the initial search. Relevant articles were summarized in 1 evidence table by 2 reviewers (A.L.L.F.K. and 1 working group member), such as a critical appraisal of risks of bias (Appendix 3). The evidence tables were subsequently assembled into summary of findings tables (A.L.L.F.K.) and revised where necessary (R.L.M. and L.C.M.K.). We assessed the quality of the body of evidence for each clinical question according to criteria based on Grading of Recommendations Assessment, Development, and Evaluation (GRADE)
(Appendix 4). The quality of the total body of evidence is graded according to the following 4 levels: high (⊕⊕⊕⊕), further research is unlikely to change the confidence in the estimate of effect; moderate (⊕⊕⊕⊖), further research is likely to have an important impact on the confidence in the estimate of effect and may change the estimate; low (⊕⊕⊖⊖), further research is very likely to have an important impact on the confidence in the estimate of effect and is likely to change the estimate; and very low (⊕⊖⊖⊖), any estimate of effect is very uncertain. The level of evidence decreased in the presence of study limitations (risk of bias in the studies), inconsistency of results between studies, indirectness of the study populations or outcomes, or imprecision of the effect estimates. The level of evidence increased if the effect sizes were large or there was evidence for a dose-response relationship.
Translating evidence into recommendations
Recommendations were drafted considering the level of the evidence, other effects of the expected risks (such as unnecessary medicalization), and the need for flexibility across healthcare systems.
Terminology employed for radiotherapy and obstetrical outcomes can be found in Appendix 5. Decisions were made through iterative group discussions; final recommendations represent unanimous consensus. The strength of the recommendations was graded according to published evidence-based methods (Appendix 4). Recommendations were classified into strong or moderate recommendations and based on high-quality evidence, moderate-quality evidence, or expert opinion.
A worldwide collaboration to harmonize guidelines for the long-term follow-up of childhood and young adult cancer survivors: A report from the International Late Effects of Childhood Cancer Guideline Harmonization Group.
Gibbons RJ, Smith S, Antman E; American College of Cardiology, American Heart Association. American College of Cardiology/American Heart Association clinical practice guidelines: Part I: where do they come from? 2003;107:2979–2986.
Pregnancy care-related recommendations from the IGHG cardiomyopathy guideline were adopted in this guideline to provide a complete overview of recommendations for pregnancy surveillance. The final harmonized recommendations were critically appraised by 4 independent external experts in the field and 2 survivor representatives.
Results
Discordances across existing long-term follow-up guidelines
Identification of concordances and discordances among existing surveillance recommendations is presented in Appendix 6. The literature search yielded 2772 abstracts for pregnancy- and delivery-related risks and 2492 abstracts for congenital anomalies. In total, 98 full texts were reviewed, and 28 articles were included (Figure, included articles in Appendix 7). The evidence tables and summary of findings are presented in Appendix 8. The conclusions of evidence tables such as GRADE assessment are summarized in Table 1 and Appendix 9 and depicted in a color scheme in Appendix 10.
Articles could be included for multiple working groups (WGs). Four working groups respectively evaluated the following topics: (1) adverse fetal outcomes in pregnancy (such as miscarriage), (2) adverse maternal outcomes in pregnancy, (3) delivery outcomes, and (4) congenital anomalies of the neonate.
CAYA, childhood, adolescent, and young adult; WG, working group.
van der Kooi. IGHG recommendations for management of obstetrical risks for female CAYA survivors. Am J Obstet Gynecol 2021.
Increased risk after abdominopelvic radiotherapy (>1.00 Gy) given before menarche vs no radiotherapy, but no significant effect when given after menarche
Birth defects in offspring of adult survivors of childhood acute lymphoblastic leukemia. A Childrens Cancer Group/National Institutes of Health Report [A Childrens Cancer Group/National Institutes of Health Report].
Birth defects in offspring of adult survivors of childhood acute lymphoblastic leukemia. A Childrens Cancer Group/National Institutes of Health Report [A Childrens Cancer Group/National Institutes of Health Report].
Birth defects in offspring of adult survivors of childhood acute lymphoblastic leukemia. A Childrens Cancer Group/National Institutes of Health Report [A Childrens Cancer Group/National Institutes of Health Report].
Birth defects in offspring of adult survivors of childhood acute lymphoblastic leukemia. A Childrens Cancer Group/National Institutes of Health Report [A Childrens Cancer Group/National Institutes of Health Report].
Who Needs Preconception Consultation or Specific Obstetrical Surveillance?
Evidence for risks during pregnancy
Miscarriage
There is moderate-level evidence that CAYA cancer survivors treated with radiotherapy to volumes exposing the uterus are at increased risk of miscarriage compared with the general population.
among CAYA cancer survivors in general. However, there is (very) low-level evidence for an increased risk for termination of pregnancy after any radiotherapy
Of note, these findings are compromised by terminology in the relevant reports, which limits the distinction between medically indicated and elective termination of pregnancy.
Stillbirth
There is no data indicating an increased risk of stillbirth (moderate-level evidence) in CAYA cancer survivors in general
There is very–low-level evidence for an effect of radiotherapy on the risk of gestational hypertension in CAYA cancer survivors compared with survivors treated without radiotherapy. The increased risk was only reported in the abdominopelvic irradiated survivors who had been diagnosed as having Wilms tumor in the BCCSS,
A paper from the National Wilms Tumor Study Group observed an increased risk of any hypertensive disorder of pregnancy with increasing doses of flank radiotherapy, but because this was the only identified study assessing radiotherapy dose, the level of evidence is very low.
Preeclampsia
There is low-level evidence for an increased risk of preeclampsia in CAYA cancer survivors compared with controls, because this association was reported in 1 large population-based Australian study
Of note, 1 of these studies concerned a small subcohort of 6 CAYA cancer survivors exposed to radiotherapy to the abdomen, none of whom developed preeclampsia.
No studies were identified that evaluated the risk of preeclampsia after chemotherapy.
Maternal anemia
There is low-level evidence that abdominopelvic radiotherapy increases the risk of maternal anemia in CAYA cancer survivors compared with nonirradiated survivors. This is based on increased risks observed in 1 large study,
There is low-level evidence overall for an increased risk of gestational diabetes in CAYA cancer survivors compared with controls, based on 1 report that found the association
CAYA cancer survivors are at increased risk of premature birth (before 37 weeks’ gestation) compared with siblings and the general population (moderate-level evidence).
Although 2 reports did not delineate specific radiotherapy volumes, categorizing groups only as treated with or without any type of radiotherapy, but both also indicated increased risk after treatment with radiotherapy.
We found low-level evidence for a dose-response relationship with radiotherapy, including 1 study that found a trend for increasing risk with increasing flank radiation dose, specifically with doses >15 Gy.
Another study reported increased risks specifically with doses >5 Gy to the uterus and, in a smaller subcohort treated before menarche, an even lower threshold of 2.5 Gy.
30614-1&id=gr1.jpg){kind=link}