Antineoplastic
PREGNANCY RECOMMENDATION: Contraindicated—1st Trimester
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
Carboplatin exhibits dose-related embryo toxicity and teratogenicity in one animal species. Treatment during human gestation has been reported in a number of cases, all of which were treated well after organogenesis. Moreover, there also are a large number of women who were treated with carboplatin several years before pregnancy. In both of these time periods, no fetal or neonatal toxicity due to carboplatin was noted. However, the absence of human exposures during organogenesis prevents an assessment of the actual teratogenic risk but, based on the animal data and the pharmacology of the drug, the risk appears to be high. Therefore, pregnant women should not be treated with this agent during the 1st trimester. Moreover, carboplatin is mutagenic and probably carcinogenic in experimental systems, but these effects have not been studied in human pregnancy.
FETAL RISK SUMMARY
The antineoplastic agent, carboplatin, is indicated for the treatment of ovarian cancer. It is closely related to cisplatin, another cancer chemotherapeutic agent. Carboplatin and cisplatin share the same cell-cycle nonspecific mechanism of action, producing inter-strand DNA cross-links. Carboplatin is not protein bound (1).
Carboplatin is mutagenic both in vitro and in vivo. Its carcinogenic potential has not been studied, but drugs with similar mechanisms of action are carcinogenic. Carboplatin is embryotoxic and teratogenic in rats given the drug during organogenesis (dose not specified) (1).
A 1989 study reported dose-related embryolethality and teratogenicity in rats treated in the early phase of organogenesis (2). Previous work by these researchers had found no teratogenicity at a dose of 4 mg/kg/day (relationship to human dose not stated). In their current study, however, a dose of 6 mg/kg/day produced a significant increase in embryo deaths and multiple malformations (e.g., gastroschisis, dilation of cerebral ventricles, cleft sternum, fused ribs, and malformed thoracic vertebrae) (2).
It is not known if carboplatin crosses the placenta early in pregnancy. The molecular weight (about 371) is low enough that passage to the fetal compartment should be expected. A 2002 review of cancer chemotherapy stated that carboplatin was widely distributed throughout all body tissues, including, presumably, the amniotic fluid (3).
A number of reports have described the use of carboplatin in human pregnancy (4–18). In a 1994 study, a 41-year-old primigravid woman at 14 weeks’ gestation had surgery for ovarian cancer (4). Beginning at 22 weeks, she received carboplatin every 4 weeks for three cycles. Nine weeks after the last dose, a cesarean section at 37 weeks gave birth to a normal-appearing 3245-g male infant with Apgar scores of 9 and 9. The neonate had normal renal function and no evidence of myelosuppression. Platinum–DNA adducts were found in maternal and cord blood lymphocytes, indicating that the drug crossed the placenta (4).
A 40-year-old woman was treated for ovarian cancer at 20 weeks’ gestation with cisplatin and cyclophosphamide (5). A second course of these agents was given a few weeks later. Further cisplatin doses were discontinued because the woman developed ototoxicity. At 30 weeks’ gestation carboplatin and cyclophosphamide were given. A normal-appearing 3600-g male infant was delivered by cesarean section 7 weeks later. Apgar scores were 9 and 9 at 1 and 5 minutes, respectively. The infant was developing normally, including normal audiograms and neurologic findings, at 12 months of age (5).
In a follow-up report to the above case, researchers used a modified cisplatin–DNA enzyme-linked immunosorbent assay (ELISA) test to determine if platinum–DNA adducts could be detected in amniotic fluid obtained at 36 weeks or in cord blood at 37 weeks (6). Platinum–DNA adducts were not detected in either sample, but insufficient DNA was extracted from the samples to assay at the limit of ELISA sensitivity. A less-sensitive assay (atomic absorbance spectrometry [AAS]) also failed to detect platinum drug binding to DNA in amniotic fluid or cord blood. In contrast, DNA from the placenta was positive for platinum–DNA adducts in both the ELISA and AAS assays (6).
A 2003 report described the pregnancy outcome of a 30-year-old woman treated with carboplatin and paclitaxel during the 2nd and 3rd trimesters (7). She was diagnosed with an advanced stage of serous papillary adenocarcinoma of the ovary in the 1st trimester. The woman underwent an exploratory laparotomy at 7.5 weeks’ gestation and then consented to chemotherapy beginning at 16–17 weeks. She received six cycles of carboplatin and paclitaxel, and was delivered by cesarean hysterectomy 3 weeks after the last cycle at 35.5 weeks. The newborn (sex not specified) had Apgar scores of 9, 9, and 9 at 1, 5, and 10 minutes, respectively. Birth weight was 2500 g (44th percentile), and the physical examination and laboratory tests were normal. In addition, the placenta appeared grossly normal. The infant was doing well at 15 months of age with no evidence of neurologic, renal, growth, or hematologic effects from the exposure (7).
A 28-year-old woman delivered a normal 3.88-kg male infant 4 years after treatment of a bilateral ovarian dysgerminoma (8). Treatment consisted of a laparotomy to remove the right tube and ovary and carboplatin (dose 735 mg). A 29-year-old woman conceived with the assistance of a donated ovum that had been fertilized in vitro, followed by embryo transfer (9). Five years earlier, both ovaries had been removed for stage III borderline ovarian adenocarcinoma. Her last course of carboplatin chemotherapy was given approximately 4 years before the pregnancy (9). In a retrospective study, the postsurgical reproductive histories of 50 women with ovarian cancer treated with unilateral oophorectomy from 1965 to 2000 were analyzed (10). Twenty-four women had attempted pregnancy and 17 (71%) had conceived 32 pregnancies. Six of the 17 had received prior chemotherapy (carboplatin or cisplatin plus paclitaxel in three; cisplatin plus cyclophosphamide in two; melphalan in one). The pregnancy outcomes were 1 on-going pregnancy, 5 spontaneous abortions (SABs), and 26 term gestations. There were no congenital anomalies in any of the offspring (10).
A large cohort study published in 2000 compared the pregnancy outcomes in survivors of various childhood cancers based on the type of treatment received (11). Among the total group of women, 340 had 594 pregnancies. The pregnancies were divided into five groups: 165 (nonsterilizing surgery or no treatment), 113 (chemotherapy with various agents, including an unknown number treated with carboplatin and cisplatin), 97 (abdominal–pelvic radiation), 53 (chemotherapy plus abdominal–pelvic radiation), and 166 (other treatments). The incidence of SABs and perinatal deaths did not differ among the groups. The proportion of live births with low birth weight (excluding preterm births) or congenital anomalies was highest in those treated only with radiation (16.0%) and those treated only with surgery only (9.5%), respectively. The rates of low birth weight (excluding preterm births) and congenital defects in the two chemotherapy groups were 2.3% and 2.3% (chemotherapy only) and 7.1% and 2.4% (chemotherapy plus radiation) (11).
In a novel case report, a 21-year-old woman was diagnosed with metastatic ovarian cancer that was initially treated with surgery that left her uterus, right fallopian tube, and ovary in situ(12). She then was enrolled into a phase I transplant protocol and received three cycles of carboplatin and paclitaxel. Subsequent high-dose chemotherapy was then given (carboplatin, paclitaxel, and/or cyclophosphamide). After her chemotherapy, the woman received a successful transplant of autologous peripheral blood stem cells. Approximately 16 months after the transplant she conceived but had a 1st trimester miscarriage. She conceived again several months later and eventually delivered a healthy full-term, 3000-g female infant. The child was developing normally at 17 months of age (12).
In a 2008 case report, a 34-year-old woman became pregnant after 12 years of infertility (13). Gestational diabetes was diagnosed at 5 weeks’ gestation (HbA1c 6.9%) and she was treated with insulin. At 16 weeks, bilateral ovarian cancer was diagnosed and, 2 weeks later, she underwent bilateral salpingo-oophorectomy. Four courses of carboplatin were given from 21 to 33 weeks’ gestation. At 33 weeks, a cesarean section was conducted to deliver a 2222-g normal male infant with Apgar scores of 9 and 10 at 1 and 5 minutes, respectively. After birth, the mother received five more courses of carboplatin. One year after the completion of therapy, the mother had no evidence of disease and her infant son was normal (13).
A 2008 review described data on seven patients who had received carboplatin during pregnancy (14). Three patients received carboplatin alone, three in combination with other antineoplastics (paclitaxel or cyclophosphamide) and one had received both carboplatin and cisplatin. All of the exposures occurred in the 2nd and 3rd trimesters. No fetal or neonatal toxicity was observed in the seven fetuses, although one neonate (exposed to both carboplatin and cisplatin) had anemia. The offspring were normal at a median follow-up of 13.5 months (range 9–20 months) (14).
Lung cancer with metastasis to the brain was diagnosed in a 33-year-old nonsmoking woman in the 19th week of pregnancy (15). The patient was treated with weekly paclitaxel and carboplatin every 3 weeks. In the 6th week of therapy, progressive disease in the brain was found with only partial response in the lungs. High-dose corticosteroids were given to induce fetal lung maturation and reduce cerebral edema. At 30 weeks, a cesarean section delivered a healthy baby boy (no other details provided). The mother died 4 weeks later. The infant was developing normally at 5 months of age (15).
A 32-year-old woman at about 29 weeks’ was treated with one cycle of carboplatin and paclitaxel for cervical cancer (16). Because she refused further chemotherapy, a cesarean section at about 33 weeks’ delivered a 2190-g male neonate with no signs of drug-induced toxicity. At 4 years of age, the child was developing normally (16).
A 38-year-old woman with breast cancer was treated with weekly trastuzumab in addition to carboplatin and docetaxel beginning at 15 weeks’ (17). Fetal renal insufficiency with anhydramnios and missing visualization of the fetal bladder occurred at 21 weeks. The condition reversed after trastuzumab was discontined and three instillations of amniotic fluid. The amount of amniotic stabilized after 24 weeks. Because of fetal growth restriction, a cesarean section was performed at 33 weeks to deliver a male infant with birth weight <3rd percentile. The neonate had normal renal function with normal urinalysis (17).
In a 2013 case report, a 36-year-old primigravid woman at 12 weeks was diagnosed with ovarian cancer (18). She underwent left salpingo-oophorectomy and fertility-sparing staging surgery. At 14 weeks, she was started on intraperitoneal carboplatin given on day 1 and IV paclitaxel given on days 1, 8, and 15 of a 28-day cycle. Mild preeclampsia developed at 32 weeks after four of the planned six cycles had been given. Chemotherapy was held because of persistent thrombocytopenia. At 37 weeks, she underwent a planned cesarean section to give birth to a viable 2126-g male neonate with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. The infant had congenital bilateral talipes equinovarus (clubfoot), but one parent had a family history of this defect. A complete blood count was normal. The infant was doing well at 7 months of age (18).
BREASTFEEDING SUMMARY
Consistent with its molecular weight (about 371), carboplatin is excreted into breast milk. In a 2012 case report, a 40-year-old woman at about 4 months postpartum was exclusively breastfeeding when she began treatment with 6 weekly doses of IV carboplatin and paclitaxel for recurrent papillary thyroid cancer (19). Her infant was fed donor milk during treatment. After the 6th dose, milk samples were collected at 0, 4, 28, 172, and 316 hours. For carboplatin, the relative infant dose was 2.0%, whereas the relative infant dose for paclitaxel was 16.7%. Carboplatin remained detectable (0.16 mg/L) at 316 hours. For paclitaxel, the level at 172 hours was 0.97 mg/L but was undetectable at 316 hours. The authors concluded that although these levels were probably too low to cause toxicity, potential toxicity could include myelosuppression (especially neutropenia and thrombocytopenia), severe hypersensitivity reactions, nephrotoxicity, and neurotoxicity (19). Because of the potential toxicity, women receiving these agents should not nurse.
References
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