By Ahizechukwu C. Eke, MD, PhD, MPH
Associate Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore
SYNOPSIS: This study demonstrated that women with a prior history of chemotherapy exposure have a higher prevalence of adverse pregnancy outcomes compared to those without a previous history, with no differences in neonatal outcomes.
SOURCE: Sorokine A, Czuzoj-Shulman N, Abenhaim HA. Maternal and neonatal outcomes in women with a history of chemotherapy exposure: A population-based study of 8 million obstetric admissions. Arch Gynecol Obstet 2022; May 7. doi: 10.1007/s00404-022-06566-5. [Online ahead of print].
Pregnancy following cancer chemotherapy can be challenging because of the negative effect of cancer chemotherapy on the female reproductive system.1,2 Although fertility can be affected after cancer chemotherapy, long-term data are lacking.3 Although maternal and fetal outcomes in future pregnancies among cancer survivors are dependent on several factors, including maternal age, type of cancer therapy, and dose of chemotherapy received, fertility and favorable pregnancy outcomes seem to be higher in younger women (< 35 years of age) and those who receive vinca alkaloids compared to other agents.4
Although there are no evidence-based recommendations on how long to defer pregnancy after cancer treatment, most practice guidelines recommend deferring pregnancy between six months to two years after completing cancer chemotherapy to allow damaged eggs to be eliminated from the ovaries, to enable maternal tissues to recover from the toxic effects of chemotherapy, and to allow for intermediate metabolites to be cleared from body tissues (mainly from muscle and fat).5
With advancements in cancer chemotherapy and new developments in fertility preservation, many cancer survivors seek to become pregnant after chemotherapy.6 However, little is known about the maternal and neonatal outcomes in women with a prior history of chemotherapy exposure. In this paper, Sorokine and colleagues sought to evaluate the effects of prior chemotherapy exposure on maternal and neonatal outcomes.7 This study was a retrospective cohort conducted using the Healthcare Cost and Utilization Project-Nationwide Inpatient Sample (HCUP-NIS) between 2006-2015. Pregnant women with a personal history of prior chemotherapy captured in the HCUP-NIS database were included. The remainder of pregnant patients in the HCUP-NIS database served as the control group. Pregnancy and postpartum outcomes included preeclampsia, venous thromboembolism, disseminated intravascular coagulation, placental abruption, chorioamnionitis, postpartum hemorrhage requiring blood transfusion, and maternal death. Fetal outcomes included intrauterine growth restriction, small for gestational age, preterm birth (< 37 weeks’ gestation), neonatal intensive care unit admission, intrauterine fetal death, neonatal death, and infant death.
Statistical analyses were performed in three steps. First, the overall and prevalence of chemotherapy exposure in the population were estimated. Second, basic demographic and clinical characteristics were compared between exposed and unexposed groups, and third, using multivariate logistic regression models, the adjusted effects of chemotherapy exposure on maternal and neonatal outcomes were estimated. All models were adjusted for maternal baseline characteristics.7
A total of 7,907,139 deliveries were identified during the study period. Of these, 613 had prior exposure to cancer chemotherapy, resulting in an overall prevalence rate of approximately 0.008%. Women with a prior history of cancer chemotherapy were more likely to be white, be older, be obese, smoke, have preexisting diabetes, have a higher household income, and have private insurance. The most common types of cancers identified were Hodgkin’s lymphomas (32%), breast cancers (26%), non-Hodgkin’s lymphomas (17%), and leukemias (15%). All the other types of cancers constituted the remaining 10%. Thyroid and skin cancers were rare (< 1% of all cancers).
Women with a history of prior chemotherapy were at increased risk for adverse pregnancy outcomes, including a greater risk for preeclampsia (adjusted odds ratio [aOR], 1.75; confidence interval [CI], 1.28, 2.39; P < 0.001), placental abruption (odds ratio, 2.07; CI, 1.22, 3.52; P < 0.01), chorioamnionitis (aOR, 2.31; CI, 1.52, 3.51; P < 0.0001), postpartum hemorrhage requiring blood transfusion (aOR, 2.11; CI, 1.49, 2.98; P < 0.0001), venous thromboembolism (aOR, 10.60; CI, 6.90, 16.30; P < 0.0001), disseminated intravascular coagulation (aOR, 6.37; CI, 1.60, 25.44; P < 0.01), and maternal death (aOR, 9.39; CI, 1.31, 67.32; P < 0.05). There were no statistically significant differences in fetal and neonatal outcomes between women who had prior chemotherapy and those who did not.
COMMENTARY
Cancer survivors are known to have higher rates of cardiovascular disease, thromboembolism, diabetes, and other adverse outcomes when compared to the general population.8,9 Therefore, the findings from this study are not surprising, since cancer survivors with a history of cardiovascular disease and thromboembolism prior to pregnancy will be at higher risk of developing preeclampsia, venous thromboembolism, and other pregnancy complications compared to women without this history.
Cancer survivors also can develop recurrence of malignancies during pregnancy that would necessitate cancer chemotherapy. Although surgery and chemotherapy are acceptable treatment options during pregnancy, radiation therapy typically is absolutely contraindicated in pregnant women.10 Although most cytotoxic chemotherapy is small enough to traverse the placenta and affect the fetus, vinca alkaloids are an exception, since they rarely cross the placenta because of their high molecular weight and high protein-binding. This characteristic makes them especially useful during the first trimester.11 Hence, when chemotherapy is indicated during pregnancy for recurrent cancers, vinca alkaloids and doxorubicin/cisplatin/carboplatin usually are the preferred cytotoxic agents. The findings from this study indicate that chemotherapy increased the risk for adverse pregnancy outcomes, similar to findings from other studies.12,13 Adverse long-term outcomes following exposure to cancer chemotherapy to the fetus are rare, as evidence demonstrates no significant adverse effects of cancer chemotherapy on intellectual development in neonates and infants.13 Also, data do not demonstrate an increased risk for malignancies in fetuses exposed to chemotherapy during pregnancy.13
In women undergoing active chemotherapy during pregnancy, delivery timing typically occurs three to four weeks after a chemotherapy treatment cycle (the last treatment cycle usually is timed to occur between 32-36 weeks’ gestation), since this practice decreases the risk for myelosuppression and susceptibility to infection.14 After delivery, histopathological examination of the placenta for evidence of metastases is good practice.15 Breastfeeding typically is contraindicated in women on active chemotherapy, since transfer to the neonate can increase the risk for infection. The American College of Obstetricians and Gynecologists (ACOG) recommends pretreatment fertility conservation counseling, use of effective contraception, and discussion of risks associated with pregnancy prior to cancer treatment in sexually active young women diagnosed with cancer.16
In addition, ACOG recommends risk assessment during pregnancy in women, including those with malignancies, for concerns regarding the benefits of chemotherapy to the pregnant woman and the fetus, the probability of adverse effects to the pregnant woman and her fetus, and the risks and benefits of cancer chemotherapy.17
REFERENCES
- Waimey KE, Smith BM, Confino R, et al. Understanding fertility in young female cancer patients. J Womens Health (Larchmt) 2015;24:812-818.
- Tang M, Webber K. Fertility and pregnancy in cancer survivors. Obstet Med 2018;11:110-115.
- Rodriguez-Wallberg KA, Oktay K. Fertility preservation during cancer treatment: Clinical guidelines. Cancer Manag Res 2014;6:105-117.
- Lee SJ, Schover LR, Partridge AH, et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 2006;24:2917-2931.
- Hartnett KP, Mertens AC, Kramer MR, et al. Pregnancy after cancer: Does timing of conception affect infant health? Cancer 2018;124:4401-4407.
- Matthews ML, Hurst BS, Marshburn PB, et al. Cancer, fertility preservation, and future pregnancy: A comprehensive review. Obstet Gynecol Int 2012;2012:953937.
- Sorokine A, Czuzoj-Shulman N, Abenhaim HA. Maternal and neonatal outcomes in women with a history of chemotherapy exposure: A population-based study of 8 million obstetric admissions. Arch Gynecol Obstet 2022; May 7. doi: 10.1007/s00404-022-06566-5. [Online ahead of print].
- Strongman H, Gadd S, Matthews A, et al. Medium and long-term risks of specific cardiovascular diseases in survivors of 20 adult cancers: A population-based cohort study using multiple linked UK electronic health records databases. Lancet 2019;394:1041-1054.
- Xiao Y, Wang H, Tang Y, et al. Increased risk of diabetes in cancer survivors: A pooled analysis of 13 population-based cohort studies. ESMO Open 2021;6:100218.
- Folsom SM, Woodruff TK. Good news on the active management of pregnant cancer patients. F1000Res 2020;9:F1000 Faculty Rev-487.
- Miyamoto S, Yamada M, Kasai Y, et al. Anticancer drugs during pregnancy. Jpn J Clin Oncol 2016;46:795-804.
- Esposito S, Tenconi R, Preti V, et al. Chemotherapy against cancer during pregnancy: A systematic review on neonatal outcomes. Medicine (Baltimore) 2016;95:e4899.
- Hahn KME, Johnson PH, Gordon N, et al. Treatment of pregnant breast cancer patients and outcomes of children exposed to chemotherapy in utero. Cancer 2006;107:1219-1226.
- Wolters V, Heimovaara J, Maggen C, et al. Management of pregnancy in women with cancer. Int J Gynecol Cancer 2021;31:314-322.
- Botha MH, Rajaram S, Karunaratne K. Cancer in pregnancy. Int J Gynaecol Obstet 2018;143 Suppl 2:137-142.
- [No authors listed]. ACOG Committee Opinion No. 747 summary: Gynecologic issues in children and adolescent cancer patients and survivors. Obstet Gynecol 2018;132:535-536.
- [No authors listed]. Committee Opinion No. 664: Refusal of medically recommended treatment during pregnancy. Obstet Gynecol 2016;127:e175-e182.
This study demonstrated that women with a prior history of chemotherapy exposure have a higher prevalence of adverse pregnancy outcomes compared to those without a previous history, with no differences in neonatal outcomes.
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