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Fertility preservation for people with cancer

Risk of pregnancy complications

Clinical Question One

Are women with a history of cancer at increased risk of complications during pregnancy, birth and breastfeeding?

Pregnancy imposes substantial physiological demands on mothers. Women with existing medical problems may be at increased risk of complications in pregnancy, on account of the condition itself or its treatment. These complications generally arise due to the challenges in meeting the increased physiological demands of the pregnancy, and can include miscarriage, stillbirth, premature birth, premature rupture of the membranes, fetal growth restriction, hypertensive disorders of pregnancy (including pre-eclampsia), gestational diabetes, and an increased requirement for interventions in labour such as operative delivery (e.g. forceps or caesarean section).

In the case of cancer, it is the effects of cancer treatment, especially on the uterus and ovaries, that are of particular concern, not only with respect to pregnancy complications, but also the potential risks of physical and developmental abnormalities to the offspring. This latter concern clearly applies to men as well and is addressed in clinical question two.

The literature in this field is largely composed of registry-based cohort studies (that often use sibling controls) or case control studies. It is relatively heterogeneous in terms of the types of malignancies and treatments studied, and the reported outcomes of interest. Most studies have found an increased rate of pregnancy and birth complications among women with a history of cancer. A systematic review and meta-analysis by van der Kooi et al. found that the offspring of women with a history of cancer are at increased risk of prematurity (relative risk [RR]: 1.56; 95% confidence interval [CI] 1.37-1.77) and low birth weight (RR 1.47; 95% CI 1.24-1.73) but not of being small for gestational age. The same systematic review found that women with a history of cancer have higher rates of elective (RR: 1.38; 95% CI 1.13-1.70) and emergency caesarean section (RR: 1.22; 95% CI 1.15-1.30) as well as assisted vaginal delivery (RR: 1.10; 95% CI 1.02-1.18) and are at increased risk of postpartum haemorrhage (RR: 1.18; 95% CI 1.02-1.36).[1]

In a study limited to women with cancer in remission who required oocyte donation owing to iatrogenic ovarian dysfunction, Munoz et al. identified no differences in pregnancy, implantation, miscarriage, or delivery rates when compared to women without a history of cancer.[2] Green et al. addressed the impact of paternal cancer survivorship on pregnancy outcomes. Partners of male survivors had a lower proportion of pregnancies that resulted in a live birth (RR 0.79, 95% CI 0.65 – 0.96) when compared to partners of their siblings.[3]

No study identified in this review specifically addressed the risk of complications with breastfeeding among cancer survivors.

Radiotherapy may also have an impact on pregnancy outcome. The review by van der Kooi et al found that radiotherapy was associated with an increased risk of prematurity (RR 2.27; 95% CI 1.34-3.82) and low birth weight.[1] Another systematic review addressed the impact of radiotherapy specifically, comparing perinatal outcomes of women with a history of childhood cancer who had received radiotherapy with those who had not. This review found increased risks of stillbirth (RR=1.19, 95% CI=1.02–1.39) and low birth weight (RR=2.22, 95% CI=1.55–3.17), but the risk of spontaneous abortion was not increased for women who received radiotherapy.[4]


Evidence Summary One

Evidence summaryLevelReferences
Women with a history of cancer are at increased risk of pregnancy and birth complications, including preterm birth, low birth weight, caesarean section and assisted delivery, and postpartum haemorrhage.III-2[1], [4]


Recommendation One

Evidence-based recommendationGrade
Women with a history of cancer should be informed of the increased risk of pregnancy and birth complications, and care should be provided in an appropriate facility.C


Clinical Question Two

Are children of people with a history of cancer at increased risk of physical and developmental abnormalities?

A systematic review of the perinatal issues for people diagnosed with cancer before the age of 40 included 22 studies and identified an apparent increase in the risk of congenital anomalies (RR 1.10; 95% CI 1.02-1.20). The authors concluded that this was likely to be a statistical artefact as only one of the 12 studies used in the analysis reported a higher prevalence of congenital abnormalities in children of people with a history of cancer.[1]

Individual cohort studies not included in the analysis by van der Kooi et al. also identified a slight increase in the risk of anomalies among the offspring of people with a history of cancer. Boice et al. employed a person-years approach in their cohort study, to accommodate the reporting of congenital defects later in life, and found a relative risk of 1.22 (95% CI 0.99 – 1.49) that did not differ from the risk for sibling offspring (RR 1.03, 95% CI 0.91 – 1.17).[5]

In a study limited to chromosomal anomalies, including those identified prenatally in pregnancies that did not continue, Winther et al. found that the proportion of live born children in survivor families with abnormal karyotypes (0.21%) was the same as that among sibling families.[6]

Approaching this topic from another perspective, the case-control study by Dodds et al. compared parents of children with congenital anomalies diagnosed within the first year of life with parents of unaffected children, and found no difference in the rate of prior cancer among mothers (RR 1.04, 95% CI 0.7 – 1.5) or fathers (RR 0.9, 95% CI 0.7 – 1.4).[7]

In contrast, a smaller number of studies have found significant associations between parental cancer diagnoses and congenital anomalies among offspring. Ji et al. found an adjusted odds ratio of 1.11 (95% CI 1.04 – 1.2) for congenital malformations among the children of cancer survivors compared to controls, however this was only significant in mothers diagnosed with bladder and kidney cancer and nervous system tumours.[8] A cohort study limited to the offspring of men with a cancer diagnosis by Stahl et al. also found a statistically significant increase in the rate of congenital anomalies (RR 1.17, 95% CI 1.05 – 1.31) when compared with controls. The absolute risk difference in this study was relatively small (3.7% vs 3.2%), however the large number of subjects included in this study justifies consideration of this effect.[9]

Overall, it would appear that the children of cancer survivors are potentially at a very slightly increased risk of congenital malformations, the small magnitude of which (and lack of statistical significance thereof in most studies) is reassuring. Attending pre-pregnancy counselling may permit a more accurate assessment of a patient’s specific risks in pregnancy. It also provides an opportunity to optimise general health and mitigate additional risk factors for these adverse outcomes (e.g. smoking cessation).

Evidence Summary Two

Evidence summaryLevelReferences
Some studies suggest a very slightly increased risk of congenital malformations in the children of people with a history of cancer.III-2[1], [5], [6], [7], [8], [9]


Recommendation Two

Evidence-based recommendationGrade
It is recommended that cancer patients be reassured that their children are unlikely to have an increased risk of congenital anomalies. It is advisable that cancer patients be offered pre-pregnancy counselling.C


References

  1. van der Kooi ALF, Kelsey TW, van den Heuvel-Eibrink MM, Laven JSE, Wallace WHB, Anderson RA. Perinatal complications in female survivors of cancer: a systematic review and meta-analysis. Eur J Cancer 2019 Apr;111:126-137 Available from: http://www.ncbi.nlm.nih.gov/pubmed/30849686.
  2. Muñoz E, Fernandez I, Martinez M, Tocino A, Portela S, Pellicer A, et al. Oocyte donation outcome after oncological treatment in cancer survivors. Fertil Steril 2015 Jan;103(1):205-13 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25439848.
  3. Green DM, Whitton JA, Stovall M, Mertens AC, Donaldson SS, Ruymann FB, et al. Pregnancy outcome of partners of male survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 2003 Feb 15;21(4):716-21 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12586811.
  4. Gao W, Liang JX, Yan Q. Exposure to radiation therapy is associated with female reproductive health among childhood cancer survivors: a meta-analysis study. J Assist Reprod Genet 2015 Aug;32(8):1179-86 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25940112.
  5. Boice JD Jr, Tawn EJ, Winther JF, Donaldson SS, Green DM, Mertens AC, et al. Genetic effects of radiotherapy for childhood cancer. Health Phys 2003 Jul;85(1):65-80 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12852473.
  6. Winther JF, Boice JD Jr, Mulvihill JJ, Stovall M, Frederiksen K, Tawn EJ, et al. Chromosomal abnormalities among offspring of childhood-cancer survivors in Denmark: a population-based study. Am J Hum Genet 2004 Jun;74(6):1282-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15106125.
  7. Dodds L, Marrett LD, Tomkins DJ, Green B, Sherman G. Case-control study of congenital anomalies in children of cancer patients. BMJ 1993 Jul 17;307(6897):164-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8343744.
  8. Ji J, Sundquist J, Sundquist K. Congenital malformation in offspring of female cancer survivors: a national cohort study. Eur J Cancer Prev 2018 May;27(3):274-278 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29369836.
  9. Ståhl O, Boyd HA, Giwercman A, Lindholm M, Jensen A, Kjær SK, et al. Risk of birth abnormalities in the offspring of men with a history of cancer: a cohort study using Danish and Swedish national registries. J Natl Cancer Inst 2011 Mar 2;103(5):398-406 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21303994.

Body of evidence

Are cancer survivors at increased risk of complications during pregnancy, birth and breastfeeding?Are children of cancer survivors at increased risk of physical and developmental abnormalities?

CitationLevel of EvidenceQuality of EvidenceSize of EffectNumber of PatientsRelevance of Evidence
Boice JD Jr, Tawn EJ, Winther JF, Donaldson SS, Green DM, Mertens AC, et al. Genetic effects of radiotherapy for childhood cancer. Health Phys 2003 Jul;85(1):65-80 Available from:http://www.ncbi.nlm.nih.gov/pubmed/12852473 III-3Low53,1013
Byrne J, Rasmussen SA, Steinhorn SC, Connelly RR, Myers MH, Lynch CF, et al. Genetic disease in offspring of long-term survivors of childhood and adolescent cancer. Am J Hum Genet 1998 Jan;62(1):45-52 Available from:http://www.ncbi.nlm.nih.gov/pubmed/9443870 III-3Medium56,7422
Dodds L, Marrett LD, Tomkins DJ, Green B, Sherman G. Case-control study of congenital anomalies in children of cancer patients. BMJ 1993 Jul 17;307(6897):164-8 Available from:http://www.ncbi.nlm.nih.gov/pubmed/8343744 III-3Medium5172,7161
Gao W, Liang JX, Yan Q. Exposure to radiation therapy is associated with female reproductive health among childhood cancer survivors: a meta-analysis study. J Assist Reprod Genet 2015 Aug;32(8):1179-86 Available from:http://www.ncbi.nlm.nih.gov/pubmed/25940112 IHigh521,8452
Green DM, Whitton JA, Stovall M, Mertens AC, Donaldson SS, Ruymann FB, et al. Pregnancy outcome of partners of male survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 2003 Feb 15;21(4):716-21 Available from:http://www.ncbi.nlm.nih.gov/pubmed/12586811 III-3Low51,2273
Haggar FA, Pereira G, Preen D, Holman CD, Einarsdottir K. Adverse obstetric and perinatal outcomes following treatment of adolescent and young adult cancer: a population-based cohort study. PLoS One 2014;9(12):e113292 Available from:http://www.ncbi.nlm.nih.gov/pubmed/25485774 III-2Medium56,0321
Hartnett KP, Ward KC, Kramer MR, Lash TL, Mertens AC, Spencer JB, et al. The risk of preterm birth and growth restriction in pregnancy after cancer. Int J Cancer 2017 Dec 1;141(11):2187-2196 Available from:http://www.ncbi.nlm.nih.gov/pubmed/28836277 III-2LowN/AN/AN/A
Ji J, Sundquist J, Sundquist K. Congenital malformation in offspring of female cancer survivors: a national cohort study. Eur J Cancer Prev 2018 May;27(3):274-278 Available from:http://www.ncbi.nlm.nih.gov/pubmed/29369836 III-2High52,714,1671
Melin J, Heinävaara S, Malila N, Tiitinen A, Gissler M, Madanat-Harjuoja L. Adverse Obstetric Outcomes Among Early-Onset Cancer Survivors in Finland. Obstet Gynecol 2015 Oct;126(4):803-10 Available from:http://www.ncbi.nlm.nih.gov/pubmed/26348187 III-2LowN/AN/AN/A
Mueller BA, Chow EJ, Kamineni A, Daling JR, Fraser A, Wiggins CL, et al. Pregnancy outcomes in female childhood and adolescent cancer survivors: a linked cancer-birth registry analysis. Arch Pediatr Adolesc Med 2009 Oct;163(10):879-86 Available from:http://www.ncbi.nlm.nih.gov/pubmed/19805705 III-2Medium516,1761
Muñoz E, Fernandez I, Martinez M, Tocino A, Portela S, Pellicer A, et al. Oocyte donation outcome after oncological treatment in cancer survivors. Fertil Steril 2015 Jan;103(1):205-13 Available from:http://www.ncbi.nlm.nih.gov/pubmed/25439848 III-2Low517,9863
Sabeti Rad Z, Friberg B, Henic E, Rylander L, Ståhl O, Källén B, et al. Deliveries After Malignant Disease Before Pregnancy: Maternal Characteristics, Pregnancy, and Delivery Complications. J Adolesc Young Adult Oncol 2016 Sep;5(3):240-7 Available from:http://www.ncbi.nlm.nih.gov/pubmed/27111543 III-2MediumN/AN/AN/A
Seppänen VI, Artama MS, Malila NK, Pitkäniemi JM, Rantanen ME, Ritvanen AK, et al. Risk for congenital anomalies in offspring of childhood, adolescent and young adult cancer survivors. Int J Cancer 2016 Oct 15;139(8):1721-30 Available from:http://www.ncbi.nlm.nih.gov/pubmed/27280956 III-2Medium542,5522
Ståhl O, Boyd HA, Giwercman A, Lindholm M, Jensen A, Kjær SK, et al. Risk of birth abnormalities in the offspring of men with a history of cancer: a cohort study using Danish and Swedish national registries. J Natl Cancer Inst 2011 Mar 2;103(5):398-406 Available from:http://www.ncbi.nlm.nih.gov/pubmed/21303994 III-2Medium517,699,4651
van der Kooi ALF, Brewster DH, Wood R, Nowell S, Fischbacher C, van den Heuvel-Eibrink MM, et al. Perinatal risks in female cancer survivors: A population-based analysis. PLoS One 2018;13(8):e0202805 Available from:http://www.ncbi.nlm.nih.gov/pubmed/30138451 III-3High510,5282
van der Kooi ALF, Kelsey TW, van den Heuvel-Eibrink MM, Laven JSE, Wallace WHB, Anderson RA. Perinatal complications in female survivors of cancer: a systematic review and meta-analysis. Eur J Cancer 2019 Apr;111:126-137 Available from:http://www.ncbi.nlm.nih.gov/pubmed/30849686 III-2High5N/A1
Winther JF, Boice JD Jr, Frederiksen K, Bautz A, Mulvihill JJ, Stovall M, et al. Radiotherapy for childhood cancer and risk for congenital malformations in offspring: a population-based cohort study. Clin Genet 2009 Jan;75(1):50-6 Available from:http://www.ncbi.nlm.nih.gov/pubmed/19021636 III-2High59,6201
Winther JF, Boice JD Jr, Mulvihill JJ, Stovall M, Frederiksen K, Tawn EJ, et al. Chromosomal abnormalities among offspring of childhood-cancer survivors in Denmark: a population-based study. Am J Hum Genet 2004 Jun;74(6):1282-5 Available from:http://www.ncbi.nlm.nih.gov/pubmed/15106125 III-2Medium511,1171
Winther JF, Boice JD Jr, Svendsen AL, Frederiksen K, Stovall M, Olsen JH. Spontaneous abortion in a Danish population-based cohort of childhood cancer survivors. J Clin Oncol 2008 Sep 10;26(26):4340-6 Available from:http://www.ncbi.nlm.nih.gov/pubmed/18779621 III-2High521,1251
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