Radiation can be divided into ionizing and nonionizing radiation. Ionizing radiation has the ability to penetrate tissue and damage cellular DNA, resulting in mutation and ultimately affecting the development and viability of the fetus. Numerous studies of radiation exposure after the atomic bomb detonations in Japan confirmed that this effect is dependent on radiation dose and stage of fetal development at the time of exposure (Table 64-1).³ Fetal abnormalities associated with exposure to excessive ionizing radiation include microcephaly, eye malformation, and growth retardation.⁴ The American College of Obstetricians and Gynecologists recommendations for imaging during pregnancy state that 5-cGy exposure to the fetus is not associated with any increased risk of fetal loss or birth defects.⁵ Radiation exposure is well below this amount for most procedures except for the maximum dose with computed tomography (CT) scanning of the abdomen and pelvis (Table 64-2). A more relevant concern is an increased risk of childhood cancer. After a gestational age of 3 to 4 weeks, the number of excess cancer cases (leukemia and solid tumors) up to age 15 years after radiation in utero is estimated to be 1 in 17,000 per 0.1 cGy. The baseline cancer risk in the first 15 years is about 1 in 650, and thus fetal doses of 2.5 cGy will approximately double the risk; however, this represents an excess lifetime fatal cancer risk of less than 0.5%.

Table 64-1

Estimates of Threshold Doses for Effects After Fetal Radiation in Utero

	Minimal Dose (mGy)
Age (wk)	Death	Gross Malformations	Mental Retardation
0-1	No threshold at day 1; 100 thereafter	No threshold at day 1?	Analysis of Japanese data suggest a dose-related reduction of about 3 IQ points per 10 cGy for children who undergo radiation in utero from 8 to 15 weeks after fertilization; the threshold is ill defined and may lie between 6 and 30 cGy
2-5	250-500	200
5-7	500	500
7-21	>500	Very few observed
To term	>1000	Very few observed

Table 64-2

Typical Ranges of Fetal Doses * After Common Diagnostic Procedures

Examination	Mean Dose (cGy)	Maximum Dose (cGy)
CONVENTIONAL RADIOGRAPH
Abdomen	0.14	0.42
Chest	<0.01	<0.01
Cervical spine	<0.01	<0.01
Lumbar spine	0.17	1.0
Pelvis	0.11	0.4
Thoracic spine	<0.01	<0.01
COMPUTED TOMOGRAPHY
Abdomen	0.8	4.9
Pelvis	2.5	7.9
Chest	0.006	0.096
Cervical spine	<0.01
Brain	<0.005	<0.005
NUCLEAR MEDICINE
Technetium-99m bone scan (phosphate)	0.33	0.46
Gallium-67 tumors and abscesses	—	1.2
Iodine-131 thyroid metastases	—	2.2

^*The radiation doses have been estimated from surveys conducted in the United Kingdom for a range of diagnostic radiology.

Ultrasound, CT Scan, and Magnetic Resonance Imaging

Ultrasound is believed to be safe during pregnancy and can be particularly useful in assessing the breasts and liver.⁶ CT scans and noncontrast magnetic resonance imaging (MRI) scans are being used with increasing frequency during pregnancy and lactation. Radiation doses from CT of the head and chest are minimal.⁷ CT should be used as the initial study for suspected pulmonary embolism. Noncontrast MRI does not expose the patient to ionizing radiation, and there has been no indication that noncontrast MRI during pregnancy has produced deleterious effects. Contrast agents such as gadolinium cross the placenta and are contraindicated. MRI of the abdomen is limited by motion artifact of the bowel.

Position Emission Tomography Scanning

Pregnancy is a relative contraindication to positron emission tomography (PET) scanning with use of fluorine-18 fluorodeoxyglucose as a radiomarker, but termination is not generally recommended if a patient is found to be pregnant after undergoing a PET scan. A PET/CT scan has a representative dose of 8 mGy (PET) and 0.3 cGy (CT). The dose to the fetus may be higher because of close proximity of the mother’s bladder, where ¹⁸F-fluorodeoxyglucose is excreted.

Teratogenicity of Chemotherapy

The U.S. Food and Drug Administration (FDA) has defined risk categories for all drugs based in part on the evidence in animals of fetal harm (Table 64-3). The majority of chemotherapeutic agents are category D, for which there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Extrapolation of teratogenic and mutagenic effects of chemotherapeutic agents from animals to human organogenesis is difficult, however, because of differences in susceptibility between species.⁸ The timing of fetal drug exposure is critical. Administration of drugs within 1 week of conception may result in a spontaneous abortion or a healthy fetus. During the first trimester, when organogenesis occurs, drugs may produce congenital malformations and/or result in spontaneous abortion. Other factors that may influence the probability of teratogenesis include the frequency of drug administration, duration of exposure, synergistic effects of multiple drugs, use of radiation, and individual genetic susceptibility.

Table 64-3

Food and Drug Administration Risk Categories for Drugs Administered During Pregnancy

Category	Description
A	Controlled studies in women do not show risk to the fetus during the first trimester; there is no evidence of risk in late trimesters, and the possibility of fetal harm is remote
B	Animal reproduction studies have not shown a fetal risk, but no controlled studies in pregnant women have been performed; or animal reproduction studies have shown an adverse effect (other than a decrease in fertility), but this effect has not been confirmed in controlled studies in women in the first trimester (no evidence exists of a risk in later trimesters)
C	Studies in animals have revealed adverse effects on the fetus (teratogenic, embryocidal, or both), and no controlled studies have been performed in women, or studies in animals and women are unavailable; drugs should be given only if potential benefit justifies the risk to the fetus
D	Positive evidence of human fetal risk exists, but the benefits from use in pregnant women may be acceptable despite the risk (if the drug is needed in a life-threatening situation for which other safer drugs are not available)
X	Studies in humans and animals have shown fetal malformations; there is evidence of fetal risk based on human experience or both; the risk of use in a pregnant woman clearly outweighs any potential benefit; this drug is contraindicated in women who are or may become pregnant

Most human data about chemotherapy during pregnancy involve small series or case reports, which are prone to reporting bias. Specific or systemic information about the teratogenicity of individual cytotoxics or modern multiagent chemotherapy regimens is limited, particularly in the first trimester. Many reported malformations have occurred after exposure to multiple agents, making it difficult to assign blame to a single causative agent. It is important to note that the overall incidence of major congenital malformations with chemotherapy use after the first trimester is approximately 3% (close to the risk of the general population), although the incidence of minor malformations may be as high as 9%, and between 10% to 15% of all pregnancies result in a miscarriage or spontaneous abortion.⁹ Extrapolation from older data also might not be appropriate, because many of these drugs (e.g., alkylating agents such as nitrogen mustard and busulfan and antimetabolites such as aminopterin) are now rarely used. Limited experience in the first trimester with regimens such as Adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine (ABVD) and cyclophosphamide, hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), and prednisolone (CHOP) suggests low rates of teratogenicity.¹⁰ In the second and third trimesters, drugs very rarely cause significant malformations but could impair fetal growth and development. The current available literature suggests that chronic prenatal chemotherapy exposure does not result in learning or behavioral problems (also known as functional teratogenesis).^10,11 Overall, the use of systemic antineoplastic therapy alone appears to be accompanied by significantly lower risk than is commonly appreciated.

Specific Chemotherapy Drugs

Table 64-4 details the available experience on the use of some of the more commonly used chemotherapy drugs in animals and at various stages of human pregnancy, together with the FDA category.^12–37 The recommendations are those published by Briggs and colleagues,¹³ with some additional comments from the authors. The choice of chemotherapy agents should be based on the most current available literature.

Table 64-4

Summary and Recommendations for Chemotherapy Drug Experience in Pregnancy

Drug	First Trimester	Second Trimester	Recommendations	Risk Category	Comments
Alkylators	Inadequate data; teratogenic in animals	Case reports without apparent fetal harm	Contraindicated in first trimester	D
Anthracyclines	Teratogenic in rats; little human data as single agent	No reports of specific fetal abnormalities; idarubicin associated with neonatal cardiomyopathy	Contraindicated in first trimester	D	Doxorubicin preferred
Bleomycin	Teratogenic in rats; use in combination not associated with fetal malformations	Use in combination has not been clearly associated with fetal abnormalities	Not specified	D	Oxygen during delivery may aggravate pulmonary toxicity
Cisplatin	Teratogenic in animals; little human data	Case reports suggest safety	Contraindicated in first trimester	D
Cyclophosphamide	Yes: cyclophosphamide embryopathy	Main concern is neonatal myelosuppression	Contraindicated in first trimester	D
Cytarabine	Yes: limb abnormalities	Main concern is maternal myelosuppression and sepsis with secondary effects on the fetus	Not specified; relatively contraindicated in first trimester	D
Etoposide	Teratogenic in animals; no human data	Intrauterine growth retardation and myelosuppression when used in aggressive combination regimens	Not specified	D
Imatinib	Associated with exomphalos, cardiac and renal abnormalities	50% neonates without abnormalities	Contraindicated during early pregnancy	D	Consider in second or third trimester if poor disease control
Methotrexate	Yes: methotrexate embryopathy; minimal risk at 6-8 wk after conception at doses ≥10 mg/wk	Neonatal myelosuppression; accumulates in ascetic fluid	Contraindicated at all stages	X
Rituximab	Not teratogenic in animals; limited data suggest no adverse effects	Limited case reports suggest safety	Not contraindicated but use with caution	C	Benefit outweighs risk in most circumstances
Taxanes	Teratogenic in animals; no human data	Reports suggest no significant risk to the fetus	Not specified	D	Consider in second/third trimester if clear maternal benefit
Trastuzumab	No fetal harm in monkeys	One report of reversible anhydramnios	Not contraindicated but use with caution	B
Vinca alkaloids	Teratogenic in rats, but limited human data suggest relatively safe	No reports of specific fetal abnormalities	Not specified	D	Vinblastine has been recommended as a single agent in women with Hodgkin lymphoma in the first trimester

Refer to the text for additional comments.

Adapted from Briggs GG, Freeman RK, Yaffe ST. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 7th ed. Philadelphia: Lippincott Williams and Wilkins; 2005.

Antimetabolites

Methotrexate is widely distributed, including into fluid spaces such as amniotic fluid, and when given during the first trimester it is closely associated with fetal abnormalities, characterized by cranial dysostosis, hypertelorism, micrognathia, limb deformities, and mental retardation. In fact, methotrexate is commonly used in combination with misoprostol during the first trimester to medically induce abortions. However, methotrexate does not uniformly cause malformations, and a critical dose and timing may exist above which fetal malformations occur.²⁴ Exposure to methotrexate in the latter trimesters has not been associated with significant malformations,¹³ but its elective use at this time, particularly in high doses, is still not recommended.

5-Fluorouracil (5-FU) was associated with multiple congenital malformations in the fetus of a patient who was found to be pregnant at week 14 after she began receiving chemotherapy for colon cancer at week 12 and hence is not recommended for use during the first trimester.³⁸ Multiple studies have shown safe use beyond the first trimester in combination therapy.^39,40 Use of cytosine arabinoside during the first trimester, alone and in combination with other drugs, has also been associated with congenital anomalies.³⁶ Capecitabine is an oral drug akin to 5-FU that is used in persons with bowel and breast cancer. Capecitabine is embryotoxic in animals, is classified as a category D drug, and is not recommended for use during pregnancy.

Use of hydroxyurea is believed to be unsafe during pregnancy because of a case series of 31 patients in which an increased risk of intrauterine growth retardation, intrauterine fetal demise, and prematurity was noted.⁴¹ Whether this finding was due to underlying disease is unclear. No data for cladribine or fludarabine exist in the literature.

Alkylating Agents

Alkylating agents are commonly used in the treatment of lymphoma, acute lymphocytic leukemia, multiple myeloma, ovarian cancer, and breast cancer. Cyclophosphamide is the most widely used and the best studied. Use in the first trimester has been associated with some fetal abnormalities, tempered with several reports with no abnormalities. Second and third trimester use is believed to be safe. Regarding dacarbazine use during pregnancy, congenital abnormalities were seen in two cases during the first trimester, consisting of isolated microphthalmos with secondary severe hypermetropia and a unilateral floating thumb malformation and one fetal death. In the second or third trimester exposure, one fetus died and one case of minor malformation (syndactyly) was observed. In all cases, dacarbazine was administered with several other cytotoxic drugs.⁴² Exposure to chlorambucil during the first trimester has been reported to cause renal aplasia, cleft palate, and skeletal abnormalities.⁴³

Platinum Derivatives

Regarding cisplatin and carboplatin, a number of case reports documenting platinum use after the first trimester have not noted any congenital malformations.22,33 Oxaliplatin is embryotoxic in animals, is classified as a category D drug, and is not recommended for use during pregnancy, although one case has been reported without adverse outcomes.⁴⁴

Taxanes

Although data are limited, the use of taxanes appears feasible and safe during pregnancy based on placental expression of drug-extruding transporters such as P-glycoprotein and BCRP-1, which result in low fetal exposure.⁴⁵ Forty cases have been reported in the literature, including use of paclitaxel (21 cases), docetaxel (16 cases), and both drugs (3 cases).⁴⁶ Ninety-five percent were treated after the first trimester and 95% received taxanes concomitantly with other chemotherapy. Despite the inherent bias in case reports, the pharmacokinetics of paclitaxel and docetaxel and available data suggest that these drugs appear safe for use in the second and third trimesters in cases where benefit is believed to outweigh risk.

Vinca Alkaloids

Although vinblastine is highly teratogenic in animal models, the literature suggests that its use in the first trimester may be relatively safe. In a series of patients treated with single agent vinblastine for Hodgkin lymphoma, no adverse outcomes to the pregnancy or in infants who were followed up afterward were reported.⁴⁷ No congenital malformations were reported in 11 pregnancies when exposure to vincristine occurred, with exposure in three pregnancies occurring in the first trimester.¹⁹ Vinorelbine, vinblastine, and vincristine had been used during the latter trimesters without harm to the fetus.^10,14

Anthracyclines

Little information is available about the effects of anthracyclines during pregnancy when they are used as single agents. Few malformations have been reported when anthracyclines are used in combination regimens in the first trimester. A few studies have shown acute myocardial dysfunction after anthracycline use in a minority of fetuses.48,49 However, a study of 81 children with in utero chemotherapy exposure, including anthracylines, who were followed up until age 9 to 29 years, showed that cardiac function did not differ from the general population.¹¹ Idarubicin is more lipophilic, which favors placental transfer; it has been associated with neonatal cardiomyopathy, and its use during pregnancy is not recommended.³² Doxorubicin is preferred to daunorubicin and has been used in combination therapy in a prospective single-arm study of 57 pregnant women with breast cancer in the second or third trimester. No stillbirths, miscarriages, or perinatal deaths were observed.⁵⁰ Similar findings have been reported in smaller series.

Supportive Care

Regarding the prevention of nausea and vomiting, consensus on the safe use of metoclopramide, 5-HT3 antagonists, NK1 antagonists, and corticosteroids during pregnancy have been established.⁵⁸ For corticosteroids, methylprednisolone or hydrocortisone are extensively metabolized in the placenta, and thus relatively little crosses into the fetal side.⁵⁹ Methylprednisolone and hydrocortisone are preferred over dexamethasone/betamethasone both for use as an antiemetic and for the prevention of anaphylaxis.

Granulocyte colony-stimulating factor (G-CSF) is not teratogenic in rats, and no congenital malformations or toxicities attributable to G-CSF have been reported in humans.⁹ G-CSF is a category B drug and should not be withheld during pregnancy if there is significant potential benefit to the mother. Safe use in pregnancy has been documented,⁶⁰ as well as in the prevention of recurrent miscarriage.⁶¹

Recombinant human erythropoietin (category C) does not cross the human placenta and does not appear to present a major risk to the fetus.¹³

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