When cancer is diagnosed in a pregnant woman, life-saving chemotherapy for the mother poses life-threatening concerns for the developing fetus. Depending on the type of cancer and the stage at diagnosis, chemotherapy cannot necessarily be delayed until after delivery. Women diagnosed with acute lymphoblastic leukaemia who decline both termination and chemotherapy often die with the previable fetus in utero. Safe use of chemotherapy, especially during the second and third trimester, have been reported, and pregnant women with cancer can accept therapy without definite neonatal harm. Here, we review the use of chemotherapy in pregnancy by trimester of exposure and summarise neonatal outcomes, including malformations, perinatal complications, and oldest age of neonatal follow-up. We will also discuss the modes of action of the drugs used and look at the multiagent regimens recommended for use during pregnancy.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(04)01466-4.pdf

Use of chemotherapy during human pregnancy

Rheumatic diseases in women of childbearing years may necessitate drug treatment during a pregnancy, to control maternal disease activity and to ensure a successful pregnancy outcome. This survey is based on a consensus workshop of international experts discussing effects of anti-inflammatory, immunosuppressive and biological drugs during pregnancy and lactation. In addition, effects of these drugs on male and female fertility and possible long-term effects on infants exposed to drugs antenatally are discussed where data were available. Recommendations for drug treatment during pregnancy and lactation are given.

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Anti-inflammatory and immunosuppressive drugs and reproduction.

Cancer complicating pregnancy is a rare coexistence. The incidence is approximately 1 in 1,000 pregnancies. The most common cancers are those more frequently seen during the reproductive age of a woman. Breast cancer, cervical cancer, Hodgkin's disease, malignant melanoma, and leukemias are the most frequently diagnosed malignancies during gestation. The diagnostic and therapeutic management of the pregnant patient with cancer is especially difficult because it involves two persons, the mother and the fetus. In this paper we review: A) the therapeutic and diagnostic management of these patients; B) the safety of diagnostic and therapeutic procedures; C) the metastatic pattern of the maternal tumors to the placenta and fetus, and D) the potential recommendations for therapeutic abortion.

Coexistence of pregnancy and malignancy.

Purpose To assess if cancers diagnosed during pregnancy or lactation are associated with increased risk of cause-specific death. Patients and Methods In this population-based cohort study using data from the Cancer Registry and the Medical Birth Registry of Norway, 42,511 women, age 16 to 49 years and diagnosed with cancer from 1967 to 2002, were eligible. They were grouped as not pregnant (reference), pregnant, or lactating at diagnosis. Cause-specific survival for all sites combined, and for the most frequent malignancies, was investigated using a Cox proportional hazards model. An additional analysis with timedependent covariates was performed for comparison of women with and without a postcancer pregnancy. The multivariate analyses were adjusted for age at diagnosis, extent of disease, and diagnostic periods. Results For all sites combined, no intergroup differences in cause-specific death were seen, with hazard ratio (HR) of 1.03 (95% CI, 0.86 to 1.22) and HR 1.02 (95% CI, 0.86 to 1.22) for the pregnant and lactating groups, respectively. Patients with breast (HR, 1.95; 95% CI, 1.36 to 2.78) and ovarian cancer (HR, 2.23; 95% CI, 1.05 to 4.73) diagnosed during lactation had an increased risk of cause-specific death. Diagnosis of malignant melanoma during pregnancy slightly increased this risk. For all sites combined, the risk of cause-specific death was significantly decreased for women who had postcancer pregnancies. Conclusion In general, the diagnosis of most cancer types during pregnancy or lactation does not increase the risk of cause-specific death. Breast and ovarian cancer diagnosed during lactation represents an exception. We confirmed the “healthy mother effect” for women with a postcancer pregnancy. J Clin Oncol 27:45-51. © 2008 by American Society of Clinical Oncology

Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study.

Cancer associated with obstetric delivery: results of linkage with the California cancer registry

Background.— Cancer is the second leading cause of death of women during the reproductive years, and its occurrence in pregnancy is between 0.07% and 0.1%. Methods.— To analyze the effect of cancer on pregnancy, we compared 21 pregnancies occurring during 30 years in women who received chemotherapy for their cancer with a control group matched for maternal age and composed of women not exposed to known teratogens or reproductive risks during pregnancy. Results.— Of 13 women exposed to chemotherapy during the first trimester, two of five whose pregnancies continued to term had major malformations in their infants, four had spontaneous abortions, and four had therapeutic abortions. Of four women with second-trimester exposure to chemotherapy, two had normal live births, one had a stillbirth, and one had a therapeutic abortion. All four pregnancies exposed to chemotherapy during the third trimester resulted in healthy live births. Infants exposed to chemotherapy had statistically significantly lower birth weights than their matched controls (2227±558 g vs 3519±272 g,P Conclusions.— This study confirms the increased likelihood of spontaneous abortions and major birth defects when chemotherapy is used during embryogenesis, whereas such a risk is not apparent beyond the first trimester. Because of the higher risk of stillbirth and intrauterine growth retardation, women with cancer should be monitored closely by a high-risk obstetric unit to define the optimal time of delivery. (Arch Intern Med.1992;152:573-576)

Fetal outcome after in utero exposure to cancer chemotherapy.

Maternal and fetal outcome after breast cancer in pregnancy

The peak incidence of Hodgkin's disease occurs during the reproductive age, and its association with pregnancy is at a rate of between 1:1,000-1:6,000. We studied the effects of Hodgkin's Disease on the course and survival of 48 women who had Hodgkin's Disease and who were pregnant, and compared their outcome with non-pregnant matched women who were of similar stage of disease, age at diagnosis, and calenderic year of treatment. Twenty-year survival of pregnant women with Hodgkin's Disease was not different from that of their matched controls. Pregnant women with Hodgkin's Disease had similar distribution of stages to the controls.

Maternal and foetal outcome following Hodgkin's disease in pregnancy.

Invasive carcinoma of the cervix is the most common gynecologic malignancy to occur during the reproductive years. To analyze the effects of pregnancy on the course and survival of invasive cervical cancer, we compared 40 women with invasive cervical cancer to 89 nonpregnant controls matched for age, calendric year of diagnosis, stage, and tumor type. Additionally, we compared the distribution of invasive cervical cancer stages among the 40 pregnant women with that among the 1,963 cases of invasive cervical cancer treated during the same 30 years in women less than 45 years of age registered in the same hospital. To evaluate pregnancy outcome, we compared babies born to women with invasive cervical cancer to babies born of women matched for maternal age and not exposed to known teratogens or reproductive risks during pregnancy. Thirty-year survival of pregnant women with invasive cervical cancer was identical to that of their matched controls. Women having invasive cervical cancer were 3.1 times more like...

Maternal and fetal outcome after invasive cervical cancer in pregnancy.

A 29-year-old pregnant woman diagnosed with acute lymphocytic leukemia maintained remission with daily cyclophosphamide and intermittent prednisone treatment. She delivered a male twin with multiple congenital abnormalities who was diagnosed with papillary thyroid cancer at 11 years of age and stage III neuroblastoma at 14 years of age. The female twin was unaffected and has exhibited normal development to date. First trimester exposure to cylcophosphamide has been associated with major malformations. Metabolites of cyclophosphamide have been demonstrated to be teratogens and carcinogens in animals. Differences in placental or fetal hepatic cytochrome P-450 may account for the variability in response between the twins. In addition, disparity between the twins may be the result of differences in metabolite inactivating enzymes present either in fetal liver or placenta. The risk of second malignancies caused by alkylating agents such as cyclophosphamide has been well documented in adults and children but to the best of our knowledge this is the first description of transplacental second cancer. ©1993 Wiley-Liss, Inc.

D. Zemlickis

Papers

Fetal outcome after in utero exposure to cancer chemotherapy.

Maternal and fetal outcome after breast cancer in pregnancy

Maternal and foetal outcome following Hodgkin's disease in pregnancy.

Maternal and fetal outcome after invasive cervical cancer in pregnancy.

Teratogenicity and carcinogenicity in a twin exposed in utero to cyclophosphamide