Outcomes in the children exposed to chemotherapy in utero

The fetal risks related to chemotherapy appear to be greatest during the first trimester of pregnancy. Doll et al.²⁷ reviewed antineoplastic agents and fetal malformations in relation to the trimester of pregnancy. They reported that in utero exposure to systemic agents was associated fetal malformation risks of 14% and 19% for alkylating agents and antimetabolites, respectively. A similar review of second- and third-trimester exposure demonstrated a 1.3% incidence of fetal malformation. Thus, they concluded that single-agent or combination chemotherapy could be given during the second and third trimesters with low risk of fetal malformation, but these agents should be avoided during the first trimester of pregnancy. Similarly, in a review of cytotoxic agents used during pregnancy, Ebert et al.²⁶ collected 217 cases from the literature published between 1983 and 1995. They classified the use of the agents by disease category and analyzed outcome of pregnancy in relation to agent, dose, and gestational age at exposure. There were 94 cases of leukemia, 57 cases of lymphoma, 26 cases of breast or ovarian cancer, 16 cases of cytotoxic therapy used for rheumatic diseases, and the remainder of the malignancies. Eighteen newborns were reported to have congenital developmental abnormalities. Of these 18 newborns, 15 neonates had been exposed to cytotoxic drugs during the first trimester. Chromosomal abnormalities were noted in two neonates who had experienced exposure to cytotoxic agents during the first trimester.²⁶ Antimetabolite use was found in 50% of the neonates with congenital abnormalities following first trimester exposure to chemotherapy. Of the reviewed cases, 82.3% of leukemia patients, 75.4% of lymphoma patients, and 75% of breast or ovary cancer patients with associated pregnancies were reported to have live births with normally developed neonates. Germann et al.³¹ collected data involving 160 patients who received anthracyclines during pregnancy. In this group, five cases of fetal malformations (3%) were found, with three cases occurring with the use of chemotherapy in the first trimester. The remaining two cases of fetal malformation occurred after chemotherapy administration in the second trimester; one involved Down’s syndrome unrelated to chemotherapy, and the other involved a congenital adherence of the iris to the cornea that demonstrated no clinical consequence. The combination chemotherapy regimens associated with fetal malformations included cytosine arabinoside or cyclophosphamide. As these initial reports that there have been multiple case studies showing safety of systemic therapy with anthracyclines and taxanes as well as limited information regarding platinums when treated in the second and third trimesters.^32–34 Systemic treatment, especially with antimetabolites such as methotrexate, should be avoided during the first trimester of pregnancy except in circumstances in which delay in cancer treatment would jeopardize the life of the patient, such as acute leukemia.

A long-term report on children exposed to chemotherapy in utero during treatment of mothers for a variety of hematologic malignancies has been presented by Aviles and Neri.³⁵ They described 84 children followed a median of 18.7 years. Thirty-eight had been exposed to chemotherapy in utero during the first trimester of pregnancy. Fertility was reported to be preserved, some of the chemotherapy-exposed children having become parents. No learning, neurologic, or psychological problems were reported for any of the in utero chemotherapy-exposed subjects. Van Calsteren et al.³⁶ report on ten children from nine pregnancies exposed to chemotherapy in utero for differing primary cancers. The children who were born prematurely had multiple abnormalities ranging from speech delay to mental and motor retardation. These were children born at less than 33 weeks gestation. Echocardiograms were also obtained demonstrating a tendency towards a thinner ventricular wall. Abdel-Hady et al.³⁷ describe 118 children born to mothers who received chemotherapy during pregnancy with no significant difference when compared to a control group of children.

Much of the data in the children exposed to chemotherapy has come from studies of breast cancer diagnosed and treated during pregnancy. Murthy et al.³⁸ have updated on the outcomes of the children exposed to chemotherapy in utero. Complications for the neonate included prematurity, neutropenia, tachypnea of the newborn, and respiratory distress syndrome. One case of spontaneous cryptogenic intracranial hemorrhage occurred which all resolved. There were three congenital abnormalities reported which included Down syndrome (1), congenital ureteral reflux (1), and clubfoot (1).³⁸ Cardonick et al.³⁹ also described a voluntary registry of outcomes in children exposed to chemotherapy demonstrating a 3.8% rate of congenital malformations which is similar to the national average of pregnant patients without cancer. Loibl et al.⁴⁰ reviewed a registry of patients diagnosed with breast cancer during pregnancy from multiple different European sites. Of the 447 patients followed, 197 received chemotherapy during pregnancy from 2003 to 2011. Of these, 22 babies had reported complications and were delivered before the 37th week with four congenital malformations (trisomy 18, rectal atresia, polydactylia, and craniosynostosis). Nine of these babies were delivered after the 37th week with three malformations (asymmetric head, polydactyly, and Moebius syndrome). When evaluating for longer term outcomes in children exposed to chemotherapy in utero, Amant et al.⁴¹ described 70 children and evaluated that for neurocognitive and cardiac outcomes as well as general health, there was no significant finding except for those children who were born prematurely. Both of these studies highlight the need for to avoid iatrogenic preterm delivery whenever possible, with holding treatment past the 35th week of pregnancy in order to avoid blood nadirs and allowing the children to proceed full term.

Breast cancer

The diagnosis of breast cancer during pregnancy is often delayed, presumably due to the anatomical and physiologic changes in the pregnant breast.⁴² However, women with breast cancer during pregnancy have demonstrated the same survival rates, stage for stage, as non-pregnant patients with breast cancer.^{34, 43, 44} Imaging, local, and systemic therapies have been well described in the successful treatment of breast cancer diagnosed during pregnancy.

Imaging of the breast in women with a palpable mass or thickening is warranted, especially if it persists for 2 weeks or longer. Mammography and US may confirm the presence of a malignant mass. Although Max and Klamer reported normal mammograms in six of eight women with breast cancer during pregnancy, others have reported abnormal mammograms in the majority of women with pregnancy and breast cancer (18 of 23 and 5 of 8).^45–47 There are limited data on US; Liberman reported positive findings in six of six patients, and Samuels found positive findings in two of four patients.^{46, 47} Yang et al.⁴⁸ diagnosed 100% of the masses as well as axillary metastases in 18 of 20 women. US was also shown to be effective for restaging to evaluate response to pre-operative chemotherapy in the pregnant breast.⁴⁸ US may be useful for guiding either fine needle aspiration (FNA) or core biopsy in order to confirm a diagnosis of malignancy.^49–51 Chest radiography, liver US, and MRI of the thoracic/lumbar spine can be used to assess for extant organ metastasis.^{1, 9}

Lymph node evaluations can be tailored to clinical findings. If clinically suspicious regional nodes are identified on physical examination or by imaging techniques, an FNA that is guided by palpation or US can be utilized to confirm metastases. The theoretical dosage of radiation that would be absorbed by the fetus following sentinel lymph node biopsy has been calculated to be less than 5 cGy.^{52, 53} Khera et al.⁵⁴ have reported their experience with sentinel node procedures in the pregnant patient. Ten patients had sentinel node procedures, six with blue dye and Tc99m, two with Tc99m alone, and two with blue dye alone. No adverse sequelae were reported for nine neonates. One woman chose elective termination of pregnancy. Gropper et al.⁵⁵ have published their series of 25 women who underwent sentinel lymph node dissections during pregnancy with no procedure complications. Gentilini et al. have performed the technique on 12 patients with one child born with a ventricular septal defect.¹⁰

Breast-conserving surgery is possible with postpartum breast irradiation. Pre- or postoperative chemotherapy is used with the same criteria for selection of therapy as in the non-pregnant patient. However, breast-conserving therapy should be considered only when radiation can be given in a timely manner after delivery. Often, given the timing of chemotherapy, this will allow for postpartum radiation. Dominici et al.⁴⁹ have described a single institution experience of mastectomy versus breast-conserving surgery as well as biopsy procedures with no significant difference in wound complications or complications from FNA or core biopsies.

Other agents have been described in the literature to treat breast cancer and include vinorelbine, paclitaxel, docetaxel, and cisplatin.^{56, 57} The use of taxanes, both paclitaxel and docetaxel, has been described also in the second and third trimesters^{56, 58–65} with all available follow-up data reported healthy children.⁵⁶ Vinorelbine has been reported to be used in both adjuvant and metastatic settings, with five of the six children reported healthy at 6–35 months of follow-up. Information on one of the children was not available in the literature. Neonatal complications included one episode of grade 4 neutropenia and transient cytopenia at day 6 of life.^{63, 66–68} Multiple case reports of trastuzumab administered during pregnancy have been identified. This has been associated with oligo- and anhydramnios with its use was described in case reports.^{62, 66, 69–73} One case was of reversible heart failure in the mother with no anhydramnios in the fetus was reported.⁷¹ One of the children born developed respiratory failure, capillary leak syndrome, infections, and necrotizing enterocolitis, dying from multiple organ failure 21 weeks after delivery.⁷³ In addition, Bader et al.⁶² described a case of reversible renal failure in the fetus. One report of the use of lapatinib was recently described in a patient who conceived while on lapatinib. Despite approximately 11 weeks of exposure, the pregnancy was otherwise uncomplicated with the delivery of a healthy baby.⁷⁴ Routine administration of biologic agents is not recommended during pregnancy and trastuzumab now has an FDA Category D rating.

Tamoxifen is a standard treatment for hormone receptor positive tumors in pre-menopausal women. Although some case reports of tamoxifen fetal exposure demonstrated no effect on the newborn, there are other reports including Goldenhar syndrome (microtia, preauricular skin tags, and hemifacial microsomia),⁷⁵ ambiguous genitalia, and other birth defects. In addition, vaginal bleeding and spontaneous abortion have also been reported.^75–79 Braems et al.⁸⁰ described 11 babies with congenital malformations out of 44 live births and 3 stillbirths. Aromatase inhibitors are not indicated as a single agent in pre-menopausal women and should not be used in conjunction with ovarian suppression in a pregnant patient. Endocrine therapy should be delayed until after delivery.

Outcomes of pregnant breast cancer patients appear to be similar to non-pregnant cancer patients when treated with appropriate therapies in the second and third trimesters. Litton et al.⁸¹ have described the outcomes of a single institution cohort treated at the University of Texas MD Anderson Cancer Center since 1989 where all women presented for early-stage breast cancer and received chemotherapy with 5-fluoruracil, doxorubicin, and cyclophosphamide (FAC) in the second and third trimesters of pregnancy. There were all live births. Rouzier et al.⁸² reviewed 48 patients with pregnancy-associated breast cancer and have concluded that chemosensitivity and pathological response rates were modeled to be similar in pregnant and non-pregnant breast cancer patients. Amant et al. compared 311 women to 865 non-pregnant breast cancer patients with no statistically significant difference in OS.

Azim et al.³³ performed a meta-analysis of 30 studies of PABC which did show a higher risk of relapse and death. However, this did not hold true for the diagnosis during pregnancy which may further emphasize the importance of separating the situations of being diagnosed during versus after pregnancy. This analysis also included multiple older studies that either delayed or gave substandard therapy to pregnant patients that may also have affected survival outcomes.

Thyroid cancer

In pregnant women, thyroid cancer presents most often as an asymptomatic nodule in the neck. Ultrasound evaluation can confirm the size and solid character of the nodule. FNA biopsy is the most reliable diagnostic test and is safe and accurate during pregnancy.^83–85 Most often, pregnancy-associated thyroid cancers are differentiated thyroid cancers (DTC). Radioiodine scans and therapeutic radioiodine should not be given during pregnancy and can be safely delayed until after delivery.⁸⁶ Thyroid surgery can be delayed until after delivery for many patients, especially if the diagnosis is made during the third trimester of pregnancy.^{86, 87} If warranted, thyroid resection can be done under local anesthesia.⁸⁸ Moosa and Mazzaferi⁸⁹

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