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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

Open AccessPublished:June 02, 2020DOI:https://doi.org/10.1016/j.ajog.2020.05.058
      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.

      Key words

      Introduction

      Five-year survival rates for childhood, adolescent, and young adult (CAYA) cancer patients now approach 80%.
      • Howlader N.
      • NA K.M.
      • Miller D.
      • et al.
      SEER cancer statistics review 1975-2016.
      Consequently, an increasing number of CAYA cancer survivors are at risk for adverse physical and psychosocial complications from their cancer or its treatment.
      • Gibson T.M.
      • Mostoufi-Moab S.
      • Stratton K.L.
      • et al.
      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.
      • Thouvenin-Doulet S.
      • Berger C.
      • Casagranda L.
      • et al.
      Fecundity and quality of life of women treated for solid childhood tumors between 1948 and 1992 in France.
      • Langeveld N.E.
      • Grootenhuis M.A.
      • Voûte P.A.
      • de Haan R.J.
      • van den Bos C.
      Quality of life, self-esteem and worries in young adult survivors of childhood cancer.
      • Duffy C.
      • Allen S.
      Medical and psychosocial aspects of fertility after cancer.
      • Zebrack B.J.
      • Block R.
      • Hayes-Lattin B.
      • et al.
      Psychosocial service use and unmet need among recently diagnosed adolescent and young adult cancer patients.
      • Carter J.
      • Raviv L.
      • Applegarth L.
      • et al.
      A cross-sectional study of the psychosexual impact of cancer-related infertility in women: third-party reproductive assistance.
      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,
      • Melin J.
      • Heinävaara S.
      • Malila N.
      • Tiitinen A.
      • Gissler M.
      • Madanat-Harjuoja L.
      Adverse obstetric outcomes among early-onset cancer survivors in Finland.
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      • Signorello L.B.
      • Cohen S.S.
      • Bosetti C.
      • et al.
      Female survivors of childhood cancer: preterm birth and low birthweight among their children.
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      • van der Kooi A.L.F.
      • Brewster D.H.
      • Wood R.
      • et al.
      Perinatal risks in female cancer survivors: a population-based analysis.
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      and these risks are further increased in survivors treated with abdominopelvic radiotherapy.
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      • Signorello L.B.
      • Cohen S.S.
      • Bosetti C.
      • et al.
      Female survivors of childhood cancer: preterm birth and low birthweight among their children.
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      • Green D.M.
      • Whitton J.A.
      • Stovall M.
      • et al.
      Pregnancy outcome of female survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
      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,
      Children’s Oncology Group
      Long-term follow-up guidelines for survivors of childhood, adolescent and young adult cancers. Version 5.0.
      Dutch Childhood Oncology Group
      Guidelines for follow-up in survivors of childhood cancer 5 years after diagnosis.
      • Skinner R.W.W.
      Therapy based on long term follow up practice statement, Uk Children’s Cancer Study Group Late Effects Group.
      Scottish Intercollegiate Guidelines Network
      Long term follow up of survivors of childhood cancer: Scottish Intercollegiate Guidelines Network.
      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.
      • Kremer L.C.M.
      • Mulder R.L.
      • Oeffinger K.C.
      • et al.
      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.
      For this guideline, concordances and discordances across existing survivorship guidelines of the North American Children’s Oncology Group,
      Children’s Oncology Group
      Long-term follow-up guidelines for survivors of childhood, adolescent and young adult cancers. Version 5.0.
      the Dutch Childhood Oncology Group,
      Dutch Childhood Oncology Group
      Guidelines for follow-up in survivors of childhood cancer 5 years after diagnosis.
      the Scottish Intercollegiate Guidelines Network,
      Scottish Intercollegiate Guidelines Network
      Long term follow up of survivors of childhood cancer: Scottish Intercollegiate Guidelines Network.
      and the UK Children’s Cancer and Leukaemia Group
      • Skinner R.W.W.
      Therapy based on long term follow up practice statement, Uk Children’s Cancer Study Group Late Effects 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)
      • Guyatt G.
      • Oxman A.D.
      • Akl E.A.
      • et al.
      GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables.
      (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.
      • Atkins D.
      • Best D.
      • Briss P.A.
      • et al.
      Grading quality of evidence and strength of recommendations.
      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.
      • Kremer L.C.M.
      • Mulder R.L.
      • Oeffinger K.C.
      • et al.
      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.
      ,
      • Atkins D.
      • Best D.
      • Briss P.A.
      • et al.
      Grading quality of evidence and strength of recommendations.
      ,

      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.
      Figure thumbnail gr1
      FigureFlowchart of selected studies
      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.
      Table 1Overall conclusions of evidence for obstetrical risks in female childhood and adolescent cancer survivors (key outcomes)
      Who needs preconception counseling? Who needs high-risk pregnancy surveillance?
      Risk of miscarriage in female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      Citations refer to papers on which the GRADE level of evidence was based on and do not necessarily support the overall conclusion.
      No increased risk in CAYA cancer survivors vs controls⊕⊕⊕⊖ Moderate
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Lantinga G.M.
      • Simons A.H.
      • Kamps W.A.
      • Postma A.
      Imminent ovarian failure in childhood cancer survivors.
      ,
      • Nielsen S.N.
      • Andersen A.N.
      • Schmidt K.T.
      • et al.
      A 10-year follow up of reproductive function in women treated for childhood cancer.
      ,
      • Sudour H.
      • Chastagner P.
      • Claude L.
      • et al.
      Fertility and pregnancy outcome after abdominal irradiation that included or excluded the pelvis in childhood tumor survivors.
      ,
      • Winther J.F.
      • Boice Jr., J.D.
      • Svendsen A.L.
      • Frederiksen K.
      • Stovall M.
      • Olsen J.H.
      Spontaneous abortion in a Danish population-based cohort of childhood cancer survivors.
      ,
      • Reinmuth S.
      • Liebeskind A.K.
      • Wickmann L.
      • et al.
      Having children after surviving cancer in childhood or adolescence—results of a Berlin survey.
      Increased risk after (abdominopelvic) radiotherapy vs no radiotherapy⊕⊕⊕⊖ Moderate
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Green D.M.
      • Whitton J.A.
      • Stovall M.
      • et al.
      Pregnancy outcome of female survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
      ,
      • Hawkins M.M.
      Is there evidence of a therapy-related increase in germ cell mutation among childhood cancer survivors?.
      • Lantinga G.M.
      • Simons A.H.
      • Kamps W.A.
      • Postma A.
      Imminent ovarian failure in childhood cancer survivors.
      • Nielsen S.N.
      • Andersen A.N.
      • Schmidt K.T.
      • et al.
      A 10-year follow up of reproductive function in women treated for childhood cancer.
      • Reulen R.C.
      • Zeegers M.P.
      • Wallace W.H.
      • Frobisher C.
      British Childhood Cancer Survivor Study
      Pregnancy outcomes among adult survivors of childhood cancer in the British Childhood Cancer Survivor Study.
      • Sudour H.
      • Chastagner P.
      • Claude L.
      • et al.
      Fertility and pregnancy outcome after abdominal irradiation that included or excluded the pelvis in childhood tumor survivors.
      • van de Loo L.E.X.M.
      • van den Berg M.H.
      • Overbeek A.
      • et al.
      Uterine function, pregnancy complications, and pregnancy outcomes among female childhood cancer survivors.
      • Winther J.F.
      • Boice Jr., J.D.
      • Svendsen A.L.
      • Frederiksen K.
      • Stovall M.
      • Olsen J.H.
      Spontaneous abortion in a Danish population-based cohort of childhood cancer survivors.
      Increased risk with increasing doses of abdominopelvic and pituitary radiotherapy vs no radiotherapy⊕⊕⊖⊖ Low
      • Winther J.F.
      • Boice Jr., J.D.
      • Svendsen A.L.
      • Frederiksen K.
      • Stovall M.
      • Olsen J.H.
      Spontaneous abortion in a Danish population-based cohort of childhood cancer survivors.
      ,
      • Chiarelli A.M.
      • Marrett L.D.
      • Darlington G.A.
      Pregnancy outcomes in females after treatment for childhood cancer.
      No significant effect of chemotherapy vs no chemotherapy⊕⊕⊕⊖ Moderate
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Green D.M.
      • Whitton J.A.
      • Stovall M.
      • et al.
      Pregnancy outcome of female survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
      ,
      • Nielsen S.N.
      • Andersen A.N.
      • Schmidt K.T.
      • et al.
      A 10-year follow up of reproductive function in women treated for childhood cancer.
      ,
      • Reulen R.C.
      • Zeegers M.P.
      • Wallace W.H.
      • Frobisher C.
      British Childhood Cancer Survivor Study
      Pregnancy outcomes among adult survivors of childhood cancer in the British Childhood Cancer Survivor Study.
      ,
      • Chiarelli A.M.
      • Marrett L.D.
      • Darlington G.A.
      Pregnancy outcomes in females after treatment for childhood cancer.
      Increased risk after chemotherapy and radiotherapy (no specific field) vs no chemotherapy and radiotherapy⊕⊕⊖⊖ Low
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Green D.M.
      • Whitton J.A.
      • Stovall M.
      • et al.
      Pregnancy outcome of female survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
      ,
      • Lantinga G.M.
      • Simons A.H.
      • Kamps W.A.
      • Postma A.
      Imminent ovarian failure in childhood cancer survivors.
      ,
      • Nielsen S.N.
      • Andersen A.N.
      • Schmidt K.T.
      • et al.
      A 10-year follow up of reproductive function in women treated for childhood cancer.
      ,
      • Chiarelli A.M.
      • Marrett L.D.
      • Darlington G.A.
      Pregnancy outcomes in females after treatment for childhood cancer.
      No significant effect of age at diagnosis⊕⊕⊖⊖ Low
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      Risk of terminations in female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      No increased risk in CAYA cancer survivors vs controls⊕⊖⊖⊖ Very low
      • Winther J.F.
      • Boice Jr., J.D.
      • Svendsen A.L.
      • Frederiksen K.
      • Stovall M.
      • Olsen J.H.
      Spontaneous abortion in a Danish population-based cohort of childhood cancer survivors.
      ,
      • Reinmuth S.
      • Liebeskind A.K.
      • Wickmann L.
      • et al.
      Having children after surviving cancer in childhood or adolescence—results of a Berlin survey.
      Increased risk after radiotherapy vs no radiotherapy⊕⊕⊖⊖ Low
      • Green D.M.
      • Whitton J.A.
      • Stovall M.
      • et al.
      Pregnancy outcome of female survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
      ,
      • Reulen R.C.
      • Zeegers M.P.
      • Wallace W.H.
      • Frobisher C.
      British Childhood Cancer Survivor Study
      Pregnancy outcomes among adult survivors of childhood cancer in the British Childhood Cancer Survivor Study.
      Increased risk after chemotherapy vs no chemotherapy⊕⊖⊖⊖ Very low
      • Green D.M.
      • Whitton J.A.
      • Stovall M.
      • et al.
      Pregnancy outcome of female survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
      ,
      • Reulen R.C.
      • Zeegers M.P.
      • Wallace W.H.
      • Frobisher C.
      British Childhood Cancer Survivor Study
      Pregnancy outcomes among adult survivors of childhood cancer in the British Childhood Cancer Survivor Study.
      Increased risk after chemotherapy or radiotherapy (to any field or gonadal) vs no chemotherapy and radiotherapy⊕⊕⊖⊖ Low
      • Green D.M.
      • Whitton J.A.
      • Stovall M.
      • et al.
      Pregnancy outcome of female survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
      ,
      • Hawkins M.M.
      Is there evidence of a therapy-related increase in germ cell mutation among childhood cancer survivors?.
      Risk of stillbirth in female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      No increased risk in CAYA cancer survivors vs controls⊕⊕⊕⊖ Moderate
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Winther J.F.
      • Boice Jr., J.D.
      • Svendsen A.L.
      • Frederiksen K.
      • Stovall M.
      • Olsen J.H.
      Spontaneous abortion in a Danish population-based cohort of childhood cancer survivors.
      No significant effect of radiotherapy vs no radiotherapy⊕⊕⊖⊖ Low
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Green D.M.
      • Whitton J.A.
      • Stovall M.
      • et al.
      Pregnancy outcome of female survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
      ,
      • Reulen R.C.
      • Zeegers M.P.
      • Wallace W.H.
      • Frobisher C.
      British Childhood Cancer Survivor Study
      Pregnancy outcomes among adult survivors of childhood cancer in the British Childhood Cancer Survivor Study.
      ,
      • Chiarelli A.M.
      • Marrett L.D.
      • Darlington G.A.
      Pregnancy outcomes in females after treatment for childhood cancer.
      ,
      • Winther J.F.
      • Olsen J.H.
      • Wu H.
      • et al.
      Genetic disease in the children of Danish survivors of childhood and adolescent cancer.
      Increased risk after high-dose ovarian-abdominal radiotherapy vs no radiotherapy⊕⊕⊖⊖ Low
      • Chiarelli A.M.
      • Marrett L.D.
      • Darlington G.A.
      Pregnancy outcomes in females after treatment for childhood cancer.
      ,
      • Signorello L.B.
      • Mulvihill J.J.
      • Green D.M.
      • et al.
      Stillbirth and neonatal death in relation to radiation exposure before conception: A retrospective cohort study.
      ,
      • Winther J.F.
      • Olsen J.H.
      • Wu H.
      • et al.
      Genetic disease in the children of Danish survivors of childhood and adolescent cancer.
      Increased risk after abdominopelvic radiotherapy (>1.00 Gy) given before menarche vs no radiotherapy, but no significant effect when given after menarche⊕⊕⊖⊖ Low
      • Signorello L.B.
      • Mulvihill J.J.
      • Green D.M.
      • et al.
      Stillbirth and neonatal death in relation to radiation exposure before conception: A retrospective cohort study.
      No significant effect of chemotherapy vs no chemotherapy⊕⊕⊖⊖ Low
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Green D.M.
      • Whitton J.A.
      • Stovall M.
      • et al.
      Pregnancy outcome of female survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
      ,
      • Reulen R.C.
      • Zeegers M.P.
      • Wallace W.H.
      • Frobisher C.
      British Childhood Cancer Survivor Study
      Pregnancy outcomes among adult survivors of childhood cancer in the British Childhood Cancer Survivor Study.
      ,
      • Chiarelli A.M.
      • Marrett L.D.
      • Darlington G.A.
      Pregnancy outcomes in females after treatment for childhood cancer.
      No significant effect of alkylating agent dose⊕⊕⊖⊖ Low
      • Signorello L.B.
      • Mulvihill J.J.
      • Green D.M.
      • et al.
      Stillbirth and neonatal death in relation to radiation exposure before conception: A retrospective cohort study.
      No significant effect of alkylating agents in combination with abdominal-pelvic radiation vs no alkylating agents and abdominal-pelvic radiation⊕⊕⊖⊖ Low
      • Green D.M.
      • Whitton J.A.
      • Stovall M.
      • et al.
      Pregnancy outcome of female survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
      ,
      • Hawkins M.M.
      Is there evidence of a therapy-related increase in germ cell mutation among childhood cancer survivors?.
      ,
      • Chiarelli A.M.
      • Marrett L.D.
      • Darlington G.A.
      Pregnancy outcomes in females after treatment for childhood cancer.
      Risk of gestational hypertension in female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      No increased risk in CAYA cancer survivors vs controls⊕⊖⊖⊖ Very low
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      ,
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      Increased risk after abdominopelvic radiotherapy vs no radiotherapy⊕⊖⊖⊖ Very low
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      ,
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      ,
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      Increased risk with increasing doses of flank radiotherapy in CAYA Wilms tumor survivors⊕⊖⊖⊖ Very low
      • Green D.M.
      • Lange J.M.
      • Peabody E.M.
      • et al.
      Pregnancy outcome after treatment for Wilms tumor: A report from the National Wilms tumor long-term follow-up Study.
      No significant effect of chemotherapy vs no chemotherapy.⊕⊖⊖⊖ Very low
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      No significant effect of age at diagnosis⊕⊕⊖⊖ Low
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      Risk of preeclampsia in female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      Increased risk in CAYA cancer survivors vs controls⊕⊕⊖⊖ Low
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      No significant effect of abdominopelvic radiotherapy vs no radiotherapy⊕⊖⊖⊖ Very low
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      Risk of maternal anemia in female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      No increased risk in CAYA cancer survivors vs controls⊕⊕⊕⊖ Moderate
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      Increased risk after (abdominopelvic) radiotherapy vs no radiotherapy⊕⊕⊖⊖ Low
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      Increased risk after chemotherapy vs no chemotherapy⊕⊕⊖⊖ Low
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      No significant effect of radiotherapy and chemotherapy vs controls⊕⊕⊖⊖ Low
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      No significant effect of age at diagnosis⊕⊕⊕⊖ Moderate
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      Risk of gestational diabetes in female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      Increased risk in CAYA cancer survivors vs controls⊕⊕⊖⊖ Low
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      Increased risk after (abdominopelvic) radiotherapy vs no radiotherapy⊕⊕⊖⊖ Low
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      ,
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      No significant effect of chemotherapy vs no chemotherapy⊕⊕⊕⊖ Moderate
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      Increased risk after chemotherapy in combination with radiotherapy vs controls⊕⊖⊖⊖ Very low
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      No significant effect of age at diagnosis⊕⊕⊕⊕ High
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      Risk of malposition in female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      No increased risk in CAYA cancer survivors vs controls⊕⊖⊖⊖ Very low
      • Melin J.
      • Heinävaara S.
      • Malila N.
      • Tiitinen A.
      • Gissler M.
      • Madanat-Harjuoja L.
      Adverse obstetric outcomes among early-onset cancer survivors in Finland.
      No significant effect of radiotherapy vs no radiotherapy⊕⊕⊖⊖ Low
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      Increased risk with increasing doses flank radiation⊕⊖⊖⊖ Very low
      • Green D.M.
      • Lange J.M.
      • Peabody E.M.
      • et al.
      Pregnancy outcome after treatment for Wilms tumor: A report from the National Wilms tumor long-term follow-up Study.
      No significant effect of age at diagnosis⊕⊕⊕⊕ High
      • Melin J.
      • Heinävaara S.
      • Malila N.
      • Tiitinen A.
      • Gissler M.
      • Madanat-Harjuoja L.
      Adverse obstetric outcomes among early-onset cancer survivors in Finland.
      ,
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      Risk of postpartum hemorrhage in female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      Increased risk in CAYA cancer survivors vs controls⊕⊕⊖⊖ Low
      • van der Kooi A.L.F.
      • Brewster D.H.
      • Wood R.
      • et al.
      Perinatal risks in female cancer survivors: a population-based analysis.
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      • Melin J.
      • Heinävaara S.
      • Malila N.
      • Tiitinen A.
      • Gissler M.
      • Madanat-Harjuoja L.
      Adverse obstetric outcomes among early-onset cancer survivors in Finland.
      ,
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      ,
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      Increased risk after abdominopelvic radiotherapy vs no radiotherapy⊕⊖⊖⊖ Very low
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      ,
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      No significant effect of age at diagnosis⊕⊕⊖⊖ Low
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      Risk of premature birth in female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      Increased risk in CAYA cancer survivors vs controls⊕⊕⊕⊖ Moderate
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      • Melin J.
      • Heinävaara S.
      • Malila N.
      • Tiitinen A.
      • Gissler M.
      • Madanat-Harjuoja L.
      Adverse obstetric outcomes among early-onset cancer survivors in Finland.
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      • Signorello L.B.
      • Cohen S.S.
      • Bosetti C.
      • et al.
      Female survivors of childhood cancer: preterm birth and low birthweight among their children.
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      ,
      • Sudour H.
      • Chastagner P.
      • Claude L.
      • et al.
      Fertility and pregnancy outcome after abdominal irradiation that included or excluded the pelvis in childhood tumor survivors.
      ,
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      Increased risk after (abdominopelvic) radiotherapy vs no radiotherapy⊕⊕⊕⊕ High
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      ,
      • van de Loo L.E.X.M.
      • van den Berg M.H.
      • Overbeek A.
      • et al.
      Uterine function, pregnancy complications, and pregnancy outcomes among female childhood cancer survivors.
      ,
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      ,
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      Increased risk with increasing doses of ovarian-abdominal radiotherapy (>5/15 Gy)⊕⊕⊖⊖ Low
      • Signorello L.B.
      • Cohen S.S.
      • Bosetti C.
      • et al.
      Female survivors of childhood cancer: preterm birth and low birthweight among their children.
      ,
      • Green D.M.
      • Lange J.M.
      • Peabody E.M.
      • et al.
      Pregnancy outcome after treatment for Wilms tumor: A report from the National Wilms tumor long-term follow-up Study.
      Increased risk after chemotherapy vs no chemotherapy⊕⊕⊖⊖ Low
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      No significant effect of alkylating agent dose⊕⊕⊖⊖ Low
      • Signorello L.B.
      • Cohen S.S.
      • Bosetti C.
      • et al.
      Female survivors of childhood cancer: preterm birth and low birthweight among their children.
      Increased risk after radiotherapy and chemotherapy vs no radiotherapy and chemotherapy⊕⊕⊕⊖ Moderate
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      Increased risk in survivors aged >5 years at cancer diagnosis vs controls, but no significant effect in survivors aged <5 years at cancer diagnosis⊕⊕⊖⊖ Low
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      Risk of low birthweight in female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      Increased risk in CAYA cancer survivors vs controls⊕⊕⊕⊖ Moderate
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      • Melin J.
      • Heinävaara S.
      • Malila N.
      • Tiitinen A.
      • Gissler M.
      • Madanat-Harjuoja L.
      Adverse obstetric outcomes among early-onset cancer survivors in Finland.
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      • Signorello L.B.
      • Cohen S.S.
      • Bosetti C.
      • et al.
      Female survivors of childhood cancer: preterm birth and low birthweight among their children.
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      ,
      • Sudour H.
      • Chastagner P.
      • Claude L.
      • et al.
      Fertility and pregnancy outcome after abdominal irradiation that included or excluded the pelvis in childhood tumor survivors.
      ,
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      Increased risk after (abdominopelvic) radiotherapy vs no radiotherapy⊕⊕⊕⊕ High
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      ,
      • van de Loo L.E.X.M.
      • van den Berg M.H.
      • Overbeek A.
      • et al.
      Uterine function, pregnancy complications, and pregnancy outcomes among female childhood cancer survivors.
      ,
      • Chiarelli A.M.
      • Marrett L.D.
      • Darlington G.A.
      Pregnancy outcomes in females after treatment for childhood cancer.
      ,
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      ,
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      Increased risk after increasing doses of abdominopelvic radiotherapy (>2.5/25 Gy)⊕⊕⊕⊖ Moderate
      • Signorello L.B.
      • Cohen S.S.
      • Bosetti C.
      • et al.
      Female survivors of childhood cancer: preterm birth and low birthweight among their children.
      ,
      • Sudour H.
      • Chastagner P.
      • Claude L.
      • et al.
      Fertility and pregnancy outcome after abdominal irradiation that included or excluded the pelvis in childhood tumor survivors.
      ,
      • Chiarelli A.M.
      • Marrett L.D.
      • Darlington G.A.
      Pregnancy outcomes in females after treatment for childhood cancer.
      ,
      • Green D.M.
      • Lange J.M.
      • Peabody E.M.
      • et al.
      Pregnancy outcome after treatment for Wilms tumor: A report from the National Wilms tumor long-term follow-up Study.
      Increased risk after chemotherapy vs no chemotherapy⊕⊖⊖⊖ Very low
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Chiarelli A.M.
      • Marrett L.D.
      • Darlington G.A.
      Pregnancy outcomes in females after treatment for childhood cancer.
      ,
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      No significant effect alkylating agent dose⊕⊖⊖⊖ Very low
      • Signorello L.B.
      • Cohen S.S.
      • Bosetti C.
      • et al.
      Female survivors of childhood cancer: preterm birth and low birthweight among their children.
      Increased risk after radiotherapy and chemotherapy vs no radiotherapy and chemotherapy⊕⊖⊖⊖ Very low
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Chiarelli A.M.
      • Marrett L.D.
      • Darlington G.A.
      Pregnancy outcomes in females after treatment for childhood cancer.
      Increased risk in survivors aged ≥20 years at cancer diagnosis vs controls, but no significant effect in survivors aged <20 years at cancer diagnosis⊕⊖⊖⊖ Very low
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      Risk of delivery of a child small for gestational age in female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      No increased risk in CAYA cancer survivors vs controls⊕⊕⊖⊖ Low
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Signorello L.B.
      • Cohen S.S.
      • Bosetti C.
      • et al.
      Female survivors of childhood cancer: preterm birth and low birthweight among their children.
      ,
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      No significant effect of (abdominopelvic) radiotherapy vs no radiotherapy⊕⊕⊖⊖ Low
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      ,
      • van de Loo L.E.X.M.
      • van den Berg M.H.
      • Overbeek A.
      • et al.
      Uterine function, pregnancy complications, and pregnancy outcomes among female childhood cancer survivors.
      ,
      • Chiarelli A.M.
      • Marrett L.D.
      • Darlington G.A.
      Pregnancy outcomes in females after treatment for childhood cancer.
      ,
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      Increased risk after increasing doses of abdominopelvic radiotherapy⊕⊕⊖⊖ Low
      • Signorello L.B.
      • Cohen S.S.
      • Bosetti C.
      • et al.
      Female survivors of childhood cancer: preterm birth and low birthweight among their children.
      ,
      • Chiarelli A.M.
      • Marrett L.D.
      • Darlington G.A.
      Pregnancy outcomes in females after treatment for childhood cancer.
      No significant effect of chemotherapy vs no chemotherapy.⊕⊖⊖⊖ Very low
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      No significant effect of alkylating agent dose⊕⊕⊖⊖ Low
      • Signorello L.B.
      • Cohen S.S.
      • Bosetti C.
      • et al.
      Female survivors of childhood cancer: preterm birth and low birthweight among their children.
      No significant effect of radiotherapy and chemotherapy vs surgery only⊕⊖⊖⊖ Very low
      • Chiarelli A.M.
      • Marrett L.D.
      • Darlington G.A.
      Pregnancy outcomes in females after treatment for childhood cancer.
      Risk of intrauterine growth restriction in female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      No increased risk in CAYA cancer survivors vs controls⊕⊖⊖⊖ Very low
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      Likelihood of vaginal delivery in female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      Decreased likelihood of vaginal birth in in CAYA cancer survivors vs controls⊕⊕⊕⊕ High
      • van der Kooi A.L.F.
      • Brewster D.H.
      • Wood R.
      • et al.
      Perinatal risks in female cancer survivors: a population-based analysis.
      ,
      • Melin J.
      • Heinävaara S.
      • Malila N.
      • Tiitinen A.
      • Gissler M.
      • Madanat-Harjuoja L.
      Adverse obstetric outcomes among early-onset cancer survivors in Finland.
      Likelihood of assisted vaginal delivery in female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      No increased likelihood of in CAYA cancer survivors vs controls⊕⊕⊕⊖ Moderate
      • van der Kooi A.L.F.
      • Brewster D.H.
      • Wood R.
      • et al.
      Perinatal risks in female cancer survivors: a population-based analysis.
      ,
      • Melin J.
      • Heinävaara S.
      • Malila N.
      • Tiitinen A.
      • Gissler M.
      • Madanat-Harjuoja L.
      Adverse obstetric outcomes among early-onset cancer survivors in Finland.
      ,
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      No significant effect of radiotherapy vs no radiotherapy⊕⊖⊖⊖ Very low
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      No significant effect of age at diagnosis⊕⊕⊖⊖ Low
      • Melin J.
      • Heinävaara S.
      • Malila N.
      • Tiitinen A.
      • Gissler M.
      • Madanat-Harjuoja L.
      Adverse obstetric outcomes among early-onset cancer survivors in Finland.
      Risk of any cesarean delivery in female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      Increased likelihood of any cesarean delivery in in CAYA cancer survivors vs controls⊕⊕⊖⊖ Low
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      • Melin J.
      • Heinävaara S.
      • Malila N.
      • Tiitinen A.
      • Gissler M.
      • Madanat-Harjuoja L.
      Adverse obstetric outcomes among early-onset cancer survivors in Finland.
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      Increased likelihood after radiotherapy vs no radiotherapy⊕⊕⊖⊖ Low
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      Increased likelihood after chemotherapy vs no chemotherapy,⊕⊕⊖⊖ Low
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      Significant effect of age at diagnosis (increased effect if 0–14 years at diagnosis)⊕⊖⊖⊖ Very low
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Melin J.
      • Heinävaara S.
      • Malila N.
      • Tiitinen A.
      • Gissler M.
      • Madanat-Harjuoja L.
      Adverse obstetric outcomes among early-onset cancer survivors in Finland.
      Likelihood of an elective or primary cesarean delivery in female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      Increased likelihood in CAYA cancer survivors vs controls⊕⊕⊕⊕ High
      • van der Kooi A.L.F.
      • Brewster D.H.
      • Wood R.
      • et al.
      Perinatal risks in female cancer survivors: a population-based analysis.
      ,
      • Melin J.
      • Heinävaara S.
      • Malila N.
      • Tiitinen A.
      • Gissler M.
      • Madanat-Harjuoja L.
      Adverse obstetric outcomes among early-onset cancer survivors in Finland.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      Increased likelihood after radiotherapy vs no radiotherapy, specifically after abdominal radiotherapy in Wilms survivors⊕⊕⊕⊖ Moderate
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      No significant effect of age at diagnosis⊕⊕⊕⊕ High
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      Likelihood of an emergency/secondary/urgent cesarean delivery in female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      No increased likelihood in CAYA cancer survivors vs controls⊕⊕⊕⊖ Moderate
      • van der Kooi A.L.F.
      • Brewster D.H.
      • Wood R.
      • et al.
      Perinatal risks in female cancer survivors: a population-based analysis.
      ,
      • Melin J.
      • Heinävaara S.
      • Malila N.
      • Tiitinen A.
      • Gissler M.
      • Madanat-Harjuoja L.
      Adverse obstetric outcomes among early-onset cancer survivors in Finland.
      ,
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      ,
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      No significant effect of radiotherapy vs no radiotherapy⊕⊕⊕⊕ High
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      ,
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      No significant effect of age at diagnosis⊕⊕⊕⊖ Moderate
      • van der Kooi A.L.F.
      • Brewster D.H.
      • Wood R.
      • et al.
      Perinatal risks in female cancer survivors: a population-based analysis.
      ,
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      Risk of congenital anomalies or abnormalities in female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      No increased risk in CAYA cancer survivors vs controls⊕⊕⊕⊕ High
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      ,
      • Reinmuth S.
      • Liebeskind A.K.
      • Wickmann L.
      • et al.
      Having children after surviving cancer in childhood or adolescence—results of a Berlin survey.
      ,
      • Winther J.F.
      • Boice Jr., J.D.
      • Frederiksen K.
      • et al.
      Radiotherapy for childhood cancer and risk for congenital malformations in offspring: a population-based cohort study.
      • Byrne J.
      • Rasmussen S.A.
      • Steinhorn S.C.
      • et al.
      Genetic disease in offspring of long-term survivors of childhood and adolescent cancer.
      • Nygaard R.
      • Clausen N.
      • Siimes M.A.
      • et al.
      Reproduction following treatment for childhood leukemia: a population-based prospective cohort study of fertility and offspring.
      • Kenney L.B.
      • Nicholson H.S.
      • Brasseux C.
      • et al.
      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].
      • Hawkins M.M.
      • Draper G.J.
      • Winter D.L.
      Cancer in the offspring of survivors of childhood leukaemia and non-Hodgkin lymphomas.
      No significant effect of (ovarian-abdominal) radiotherapy vs no radiotherapy⊕⊕⊕⊕ High
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      ,
      • Chiarelli A.M.
      • Marrett L.D.
      • Darlington G.A.
      Pregnancy outcomes in females after treatment for childhood cancer.
      ,
      • Winther J.F.
      • Boice Jr., J.D.
      • Frederiksen K.
      • et al.
      Radiotherapy for childhood cancer and risk for congenital malformations in offspring: a population-based cohort study.
      ,
      • Nygaard R.
      • Clausen N.
      • Siimes M.A.
      • et al.
      Reproduction following treatment for childhood leukemia: a population-based prospective cohort study of fertility and offspring.
      ,
      • Kenney L.B.
      • Nicholson H.S.
      • Brasseux C.
      • et al.
      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].
      ,
      • Winther J.F.
      • Olsen J.H.
      • Wu H.
      • et al.
      Genetic disease in the children of Danish survivors of childhood and adolescent cancer.
      ,
      • Signorello L.B.
      • Mulvihill J.J.
      • Green D.M.
      • et al.
      Congenital anomalies in the children of cancer survivors: a report from the Childhood Cancer Survivor Study.
      No significant effect of radiotherapy dose⊕⊕⊕⊖ Moderate
      • Chiarelli A.M.
      • Marrett L.D.
      • Darlington G.A.
      Pregnancy outcomes in females after treatment for childhood cancer.
      ,
      • Winther J.F.
      • Boice Jr., J.D.
      • Frederiksen K.
      • et al.
      Radiotherapy for childhood cancer and risk for congenital malformations in offspring: a population-based cohort study.
      ,
      • Winther J.F.
      • Olsen J.H.
      • Wu H.
      • et al.
      Genetic disease in the children of Danish survivors of childhood and adolescent cancer.
      ,
      • Signorello L.B.
      • Mulvihill J.J.
      • Green D.M.
      • et al.
      Congenital anomalies in the children of cancer survivors: a report from the Childhood Cancer Survivor Study.
      ,
      • Green D.M.
      • Lange J.M.
      • Peabody E.M.
      • et al.
      Pregnancy outcome after treatment for Wilms tumor: A report from the National Wilms tumor long-term follow-up Study.
      No significant effect of alkylating agents vs no alkylating agents⊕⊕⊕⊖ Moderate
      • Chiarelli A.M.
      • Marrett L.D.
      • Darlington G.A.
      Pregnancy outcomes in females after treatment for childhood cancer.
      ,
      • Nygaard R.
      • Clausen N.
      • Siimes M.A.
      • et al.
      Reproduction following treatment for childhood leukemia: a population-based prospective cohort study of fertility and offspring.
      ,
      • Kenney L.B.
      • Nicholson H.S.
      • Brasseux C.
      • et al.
      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].
      ,
      • Winther J.F.
      • Olsen J.H.
      • Wu H.
      • et al.
      Genetic disease in the children of Danish survivors of childhood and adolescent cancer.
      ,
      • Signorello L.B.
      • Mulvihill J.J.
      • Green D.M.
      • et al.
      Congenital anomalies in the children of cancer survivors: a report from the Childhood Cancer Survivor Study.
      ,
      • Green D.M.
      • Fiorello A.
      • Zevon M.A.
      • Hall B.
      • Seigelstein N.
      Birth defects and childhood cancer in offspring of survivors of childhood cancer.
      No significant effect of alkylating agent dose⊕⊖⊖⊖ Very low
      • Signorello L.B.
      • Mulvihill J.J.
      • Green D.M.
      • et al.
      Congenital anomalies in the children of cancer survivors: a report from the Childhood Cancer Survivor Study.
      No significant effect of alkylating agents in combination with abdominal-pelvic radiation vs no alkylating agents and abdominal-pelvic radiation⊕⊕⊕⊖ Moderate
      • Hawkins M.M.
      Is there evidence of a therapy-related increase in germ cell mutation among childhood cancer survivors?.
      ,
      • Chiarelli A.M.
      • Marrett L.D.
      • Darlington G.A.
      Pregnancy outcomes in females after treatment for childhood cancer.
      ,
      • Winther J.F.
      • Olsen J.H.
      • Wu H.
      • et al.
      Genetic disease in the children of Danish survivors of childhood and adolescent cancer.
      No significant effect of age at diagnosis⊕⊖⊖⊖ Very low
      • Kenney L.B.
      • Nicholson H.S.
      • Brasseux C.
      • et al.
      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].
      Rate of supervision of high-risk pregnancy in female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      No increased rates in CAYA cancer survivors vs controls⊕⊕⊖⊖ Low
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      No significant effect of radiotherapy vs no radiotherapy⊕⊕⊖⊖ Low
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      Risk of retained placenta/manual removal of the placenta in female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      No increased risk in CAYA cancer survivors vs controls⊕⊕⊖⊖ Low
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      Risk of placental pathologies in female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      No increased risk in CAYA cancer survivors vs controls⊕⊖⊖⊖ Very low
      • Melin J.
      • Heinävaara S.
      • Malila N.
      • Tiitinen A.
      • Gissler M.
      • Madanat-Harjuoja L.
      Adverse obstetric outcomes among early-onset cancer survivors in Finland.
      Risk of resuscitation of the neonate born to female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      Increased risk in CAYA cancer survivors vs controls⊕⊖⊖⊖ Very low
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      Likelihood of admission to a special care unit in neonates born to female cancer survivors diagnosed before the age of 25 yearsLevel of evidence
      Increased likelihood in CAYA cancer survivors vs controls⊕⊖⊖⊖ Very low
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      CAYA, childhood, adolescent, and young adult.
      van der Kooi. IGHG recommendations for management of obstetrical risks for female CAYA survivors. Am J Obstet Gynecol 2021.
      a Citations refer to papers on which the GRADE level of evidence was based on and do not necessarily support the overall conclusion.

      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.
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Green D.M.
      • Whitton J.A.
      • Stovall M.
      • et al.
      Pregnancy outcome of female survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
      ,
      • Hawkins M.M.
      Is there evidence of a therapy-related increase in germ cell mutation among childhood cancer survivors?.
      • Lantinga G.M.
      • Simons A.H.
      • Kamps W.A.
      • Postma A.
      Imminent ovarian failure in childhood cancer survivors.
      • Nielsen S.N.
      • Andersen A.N.
      • Schmidt K.T.
      • et al.
      A 10-year follow up of reproductive function in women treated for childhood cancer.
      • Reulen R.C.
      • Zeegers M.P.
      • Wallace W.H.
      • Frobisher C.
      British Childhood Cancer Survivor Study
      Pregnancy outcomes among adult survivors of childhood cancer in the British Childhood Cancer Survivor Study.
      • Sudour H.
      • Chastagner P.
      • Claude L.
      • et al.
      Fertility and pregnancy outcome after abdominal irradiation that included or excluded the pelvis in childhood tumor survivors.
      • van de Loo L.E.X.M.
      • van den Berg M.H.
      • Overbeek A.
      • et al.
      Uterine function, pregnancy complications, and pregnancy outcomes among female childhood cancer survivors.
      • Winther J.F.
      • Boice Jr., J.D.
      • Svendsen A.L.
      • Frederiksen K.
      • Stovall M.
      • Olsen J.H.
      Spontaneous abortion in a Danish population-based cohort of childhood cancer survivors.
      However, this association was only borderline significant in a large cohort from the British Childhood Cancer Survivor Study (BCCSS)
      • Reulen R.C.
      • Zeegers M.P.
      • Wallace W.H.
      • Frobisher C.
      British Childhood Cancer Survivor Study
      Pregnancy outcomes among adult survivors of childhood cancer in the British Childhood Cancer Survivor Study.
      and not significant in 2 smaller studies.
      • Lantinga G.M.
      • Simons A.H.
      • Kamps W.A.
      • Postma A.
      Imminent ovarian failure in childhood cancer survivors.
      ,
      • van de Loo L.E.X.M.
      • van den Berg M.H.
      • Overbeek A.
      • et al.
      Uterine function, pregnancy complications, and pregnancy outcomes among female childhood cancer survivors.
      There is only low-level evidence for a dose-response relationship.
      • Winther J.F.
      • Boice Jr., J.D.
      • Svendsen A.L.
      • Frederiksen K.
      • Stovall M.
      • Olsen J.H.
      Spontaneous abortion in a Danish population-based cohort of childhood cancer survivors.
      ,
      • Chiarelli A.M.
      • Marrett L.D.
      • Darlington G.A.
      Pregnancy outcomes in females after treatment for childhood cancer.
      The evidence indicated no significant effect owing to chemotherapy.
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Reulen R.C.
      • Zeegers M.P.
      • Wallace W.H.
      • Frobisher C.
      British Childhood Cancer Survivor Study
      Pregnancy outcomes among adult survivors of childhood cancer in the British Childhood Cancer Survivor Study.
      ,
      • Chiarelli A.M.
      • Marrett L.D.
      • Darlington G.A.
      Pregnancy outcomes in females after treatment for childhood cancer.
      ,
      • Green D.M.
      • Peabody E.M.
      • Nan B.
      • Peterson S.
      • Kalapurakal J.A.
      • Breslow N.E.
      Pregnancy outcome after treatment for Wilms tumor: A report from the National Wilms Tumor Study Group.

      Termination of pregnancy

      There is no data indicating an increased risk of medically induced terminations (very–low-level evidence)
      • Green D.M.
      • Whitton J.A.
      • Stovall M.
      • et al.
      Pregnancy outcome of female survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
      ,
      • Hawkins M.M.
      Is there evidence of a therapy-related increase in germ cell mutation among childhood cancer survivors?.
      ,
      • Reulen R.C.
      • Zeegers M.P.
      • Wallace W.H.
      • Frobisher C.
      British Childhood Cancer Survivor Study
      Pregnancy outcomes among adult survivors of childhood cancer in the British Childhood Cancer Survivor Study.
      ,
      • Winther J.F.
      • Boice Jr., J.D.
      • Svendsen A.L.
      • Frederiksen K.
      • Stovall M.
      • Olsen J.H.
      Spontaneous abortion in a Danish population-based cohort of childhood cancer survivors.
      ,
      • Reinmuth S.
      • Liebeskind A.K.
      • Wickmann L.
      • et al.
      Having children after surviving cancer in childhood or adolescence—results of a Berlin survey.
      among CAYA cancer survivors in general. However, there is (very) low-level evidence for an increased risk for termination of pregnancy after any radiotherapy
      • Green D.M.
      • Whitton J.A.
      • Stovall M.
      • et al.
      Pregnancy outcome of female survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
      ,
      • Reulen R.C.
      • Zeegers M.P.
      • Wallace W.H.
      • Frobisher C.
      British Childhood Cancer Survivor Study
      Pregnancy outcomes among adult survivors of childhood cancer in the British Childhood Cancer Survivor Study.
      and chemotherapy.
      • Green D.M.
      • Whitton J.A.
      • Stovall M.
      • et al.
      Pregnancy outcome of female survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
      ,
      • Reulen R.C.
      • Zeegers M.P.
      • Wallace W.H.
      • Frobisher C.
      British Childhood Cancer Survivor Study
      Pregnancy outcomes among adult survivors of childhood cancer in the British Childhood Cancer Survivor Study.
      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
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Winther J.F.
      • Boice Jr., J.D.
      • Svendsen A.L.
      • Frederiksen K.
      • Stovall M.
      • Olsen J.H.
      Spontaneous abortion in a Danish population-based cohort of childhood cancer survivors.
      and low-level evidence for increased risk of stillbirth after moderate to high doses of ovarian-uterine radiotherapy (>10 Gy)
      • Signorello L.B.
      • Mulvihill J.J.
      • Green D.M.
      • et al.
      Stillbirth and neonatal death in relation to radiation exposure before conception: A retrospective cohort study.
      or abdominopelvic radiotherapy (>25 Gy).
      • Chiarelli A.M.
      • Marrett L.D.
      • Darlington G.A.
      Pregnancy outcomes in females after treatment for childhood cancer.

      Gestational hypertension

      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,
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      whereas 2 smaller studies did not find this association.
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      ,
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      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
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      but not in 2 other studies.
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      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.
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      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,
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      whereas the effect was not observed in another equally sized cohort.
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.

      Gestational diabetes

      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
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      and 2 that did not find an association.
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      There is low-level evidence for an effect of abdominopelvic radiotherapy,
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      ,
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      moderate-level evidence that there is no effect of chemotherapy,
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      and high-level evidence that there is no effect of age at diagnosis
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      on the risk of gestational diabetes.

      Malposition of the fetus

      There is no increased risk of malposition of the fetus (low-level evidence) and no effect of radiotherapy on this outcome (very–low-level evidence).
      • Melin J.
      • Heinävaara S.
      • Malila N.
      • Tiitinen A.
      • Gissler M.
      • Madanat-Harjuoja L.
      Adverse obstetric outcomes among early-onset cancer survivors in Finland.
      ,
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.

      Evidence for gestational length and birthweight

      Premature birth

      CAYA cancer survivors are at increased risk of premature birth (before 37 weeks’ gestation) compared with siblings and the general population (moderate-level evidence).
      • Melin J.
      • Heinävaara S.
      • Malila N.
      • Tiitinen A.
      • Gissler M.
      • Madanat-Harjuoja L.
      Adverse obstetric outcomes among early-onset cancer survivors in Finland.
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      • Signorello L.B.
      • Cohen S.S.
      • Bosetti C.
      • et al.
      Female survivors of childhood cancer: preterm birth and low birthweight among their children.
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Sudour H.
      • Chastagner P.
      • Claude L.
      • et al.
      Fertility and pregnancy outcome after abdominal irradiation that included or excluded the pelvis in childhood tumor survivors.
      ,
      • van de Loo L.E.X.M.
      • van den Berg M.H.
      • Overbeek A.
      • et al.
      Uterine function, pregnancy complications, and pregnancy outcomes among female childhood cancer survivors.
      ,
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      High-level evidence indicated that radiotherapy to volumes exposing the uterus increases the risk of premature birth.
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      ,
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      ,
      • van de Loo L.E.X.M.
      • van den Berg M.H.
      • Overbeek A.
      • et al.
      Uterine function, pregnancy complications, and pregnancy outcomes among female childhood cancer survivors.
      ,
      • Reulen R.C.
      • Bright C.J.
      • Winter D.L.
      • et al.
      Pregnancy and labor complications in female survivors of childhood cancer: the British Childhood Cancer Survivor Study.
      ,
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      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.
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      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.
      • Green D.M.
      • Whitton J.A.
      • Stovall M.
      • et al.
      Pregnancy outcome of female survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
      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.
      • Signorello L.B.
      • Cohen S.S.
      • Bosetti C.
      • et al.
      Female survivors of childhood cancer: preterm birth and low birthweight among their children.
      One study reported that chemotherapy was associated with an increased risk of premature birth (low-level evidence).
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.
      However, this effect was not found in a small Japanese study
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      or in a large Australian population-based study.
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      One study did not observe a significant effect of alkylating agent dose on the risk of premature birth (very–low-level evidence).
      • Signorello L.B.
      • Cohen S.S.
      • Bosetti C.
      • et al.
      Female survivors of childhood cancer: preterm birth and low birthweight among their children.

      Low birthweight

      There is moderate-level evidence for an increased risk of low birthweight (below 2500 grams) delivery in CAYA cancer survivors compared with controls
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      • Lie Fong S.
      • van den Heuvel-Eibrink M.M.
      • Eijkemans M.J.C.
      • Schipper I.
      • Hukkelhoven C.W.P.M.
      • Laven J.S.E.
      Pregnancy outcome in female childhood cancer survivors.
      ,
      • Sudour H.
      • Chastagner P.
      • Claude L.
      • et al.
      Fertility and pregnancy outcome after abdominal irradiation that included or excluded the pelvis in childhood tumor survivors.
      ,
      • Sekiguchi M.
      • Miyoshi Y.
      • Kikuchi N.
      • Sago H.
      Pregnancy outcomes in female childhood cancer survivors: nationwide survey in Japan.
      and high-level evidence for this outcome after radiotherapy to volumes exposing the uterus.
      • Haggar F.A.
      • Pereira G.
      • Preen D.
      • D’Arcy Holman C.D.
      • Einarsdottir K.
      Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study.
      ,
      • Mueller B.A.
      • Chow E.J.
      • Kamineni A.
      • et al.
      Pregnancy outcomes in female childhood and adolescent cancer survivors: A linked cancer-birth registry analysis.