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).
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. 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.
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. 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.
Evidence Summary One
|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||, |
|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.
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).
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.
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).
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. 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.
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
|Some studies suggest a very slightly increased risk of congenital malformations in the children of people with a history of cancer.||III-2||, , , , , |
|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|
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.