Chemotherapy in Pregnancy

Monique A. Hartley-Brown

Donald C. Doll

Cancer during pregnancy is fairly uncommon. It is the leading cause of death in women of childbearing age with an incidence between 0.07% and 0.1% and approximately 1 in 1,000 pregnancies.¹^,²^,³ The common malignancies complicating pregnancy include those of the breast, cervix, ovary, leukemia, lymphoma, melanoma, and thyroid⁴^,⁵^,⁶^,⁷; however, other cancers have been reported as well. An international study of 215 patients identified between 1998 and 2008 found breast cancer to be the most common at 46%, followed by hematologic malignancies at 18%. The mean maternal age at diagnosis was 33.2 ± 4.8 years, with mean gestational age of 21.0 ± 10.8 weeks.⁸

A diagnosis of malignancy in a pregnant patient creates a unique dilemma for the mother, her family, and the oncologist. The balance of treating the mother while preventing harmful effects to the fetus is a difficult feat to accomplish. Maternal interest may lie in immediate institution of cancer therapy; however, such therapy may endanger the life of the fetus. A delay or modification of cancer therapy to ensure the birth of a healthy infant could adversely affect maternal prognosis. Substantial harm to the fetus exists whether or not the mother is treated. One study observed an increased risk of small-forgestational-age children (birth 8 [length] <10th percentile) in infants exposed to chemotherapy in utero.⁸ Most of these children were born preterm, 54.2%, with a high rate of admissions to the neonatal ICU. Many of these preterm deliveries were medically induced⁸ because of the maternal malignancy, 89.7%. This exposes the infants to many early and late complications associated with preterm birth, as well as increased mortality and morbidities later in life such as impaired cognitive and behavioral outcomes. Delay of therapy to allow for fetal maturity may be an option in patients with early-stage disease, especially in those patients with advanced fetal age at the time of diagnosis. In patients with late-stage disease, the option of delaying therapy is much less feasible, posing a significant threat to maternal life.⁸^,⁹^,¹⁰^,¹¹ In addition, few chemotherapeutic agents have been tested in pregnant patients, thus the arsenal of drugs available for treatment is limited.

Various ethical, moral, cultural, and religious issues may complicate clinical decision-making. With the increasing trend for women to delay childbearing, the concurrence of cancer and pregnancy may increase in the future, and the progress in both curative cancer chemotherapy and neonatal care will only increase the difficulty of the decision to use chemotherapy.

The adverse effect of pregnancy on the biology of maternal cancer is unclear.¹²^,¹³^,¹⁴^,¹⁵^,¹⁶ In breast cancer, two studies reveal that pregnancy is associated with advanced stage at presentation, higher likelihood of receptor-negative tumors, and poorer disease-free and overall survival when compared with stagematched controls.¹⁷^,¹⁸ Conversely, other studies reveal essentially no difference between the two cohorts of patients.¹⁹^,²⁰^,²¹ Because of the relatively rare occurrence and lack of definitive studies, the effects of cancer and the complications of therapy on the fetus are not well-defined. For these reasons, it is best for pregnant cancer patients to be treated in a tertiary setting with access to appropriate gynecologic, oncologic, and neonatal care.⁸

PHARMACOKINETICS DURING PREGNANCY

Pregnancy associated physiologic changes may change drug pharmacokinetics and may therefore require altering dosing and schedule of chemotherapy.

Changes in Renal Function and Plasma Volume

The increase in cardiac output and plasma volume increases renal plasma flow and glomerular filtration rate.²² This increase in renal function results in lowering of serum creatinine concentration.²³ Therefore, pregnancy may amplify the renal excretion of chemotherapeutic agents.²⁴^,²⁵^,²⁶^,²⁷

Volume Distribution

The increase in total body water,²⁸ and plasma volume²⁹ seen in pregnancy, may increase the distribution volume for water-soluble drugs. This may decrease the peak drug concentration, and the half-lives may be prolonged,³⁰ altering the therapeutic to toxicity ratio of individual chemotherapeutic agents.³¹ Furthermore, amniotic fluid as a pharmacologic third space for drugs, such as methotrexate, may delay elimination and increase toxicity.³²

Changes in Plasma Protein Levels

During pregnancy, increased serum levels of certain proteins such as fibrinogen, globulins, and decline of serum albumin levels may affect plasma concentration and distribution of drugs with low lipid solubility and increased affinity for plasma proteins.³³ This may increase the concentration of unbound (active) drugs that can then freely move across different fluid compartments.

Changes in Hepatic Drug Metabolism

Hepatic blood flow and hepatic oxidation are enhanced during pregnancy.³⁴ Therefore, along with the increased renal excretion³⁵ there could be increased drug clearance from the body.

Gastrointestinal Absorption

A decrease in gastrointestinal motility could affect the oral drug absorption.³⁶^,³⁷ However, this phenomenon is not changed until late in pregnancy and may be affected by autonomic neuropathy because of vinca alkaloids.³⁸

Placental Transfer

Several mechanisms govern the movement of drugs across the placenta and the drug levels in placental and fetal circulation. Protein binding appears to be different in maternal and fetal circulation.³³ Moreover, maternal and fetal serum albumin levels may differ at different time periods during pregnancy. Because free drugs cross the placenta more easily, they can achieve higher concentrations in placental and fetal circulation. Other important determinants of drug movement across the placenta are lipid solubility, water solubility, fetal blood pH, and molecular weight of the drug.³⁰^,³¹^,³³

Except for high-molecular-weight proteins such as asparaginase and interferon a, most antineoplastic agents possess these properties and easily enter the fetal circulation, where they are subject to the same pharmacokinetic principles. However, the multidrug resistant P-glycoprotein in the gravid endometrium may provide a natural barrier for certain antineoplastic agents, such as vinca alkaloids and the anthracycline antibiotics.³⁸

Fetal Pharmacokinetics

Fetal liver can metabolize drugs through oxidation, dehydrogenation, reduction, glucuronidation, methylation, and acetylation as early as 7 to 8 weeks of pregnancy.³⁹ Fetal kidney may also aid in drug elimination, but the extent to which fetal liver and kidney participate in drug elimination is marginal compared with adult liver. If the drugs are excreted into the amniotic fluid, they may be ingested by the fetus and reabsorbed from the gastrointestinal tract, thereby potentially increasing any adverse side effects of drugs such as antimetabolites that are excreted in active form.

Placental Excretion

The placenta is an important route of fetal drug elimination; transplacental passage of antineoplastic agents has been documented with doxorubicin and cisplatin.⁴⁰^,⁴¹^,⁴² In general, because the metabolites are more polar than the parent compound, they may not cross the placenta as easily as the parent compound. As a result, metabolites may accumulate in fetal tissues or amniotic fluid.³³

Despite these known maternal, placental, and fetal factors, in the absence of proper pharmacokinetic studies, it is difficult to ascertain the correct dosing of antineoplastic agents in pregnant patients. Therefore, we must assume that drug doses used in the nonpregnant state are adequate in pregnancy.

ADVERSE EFFECTS OF ANTINEOPLASTIC AGENTS ON THE FETUS AND NEONATE

Chemotherapy drugs by damaging rapidly dividing cells could endanger fetal tissues as well and may therefore be associated with deleterious effects. The timing of such exposure is critical in determining the immediate and delayed effect on the embryo and fetus.

Drugs administered in the first week after conception probably produce an “all or nothing” phenomenon—that is, a spontaneous abortion or a normal fetus. During the first trimester of organogenesis, drugs can produce congenital malformations and/or result in an abortion.⁴³ In the second and third trimesters, the drug may impair fetal growth and development. In particular, neuronal growth in the brain continues during this period and exposure to chemotherapy can produce microcephaly, mental retardation, and impaired learning.

Teratogenicity

The teratogenic and mutagenic effects of chemotherapeutic agents have been well-described in animals,⁴⁰^,⁴¹^,⁴²^,⁴³^,⁴⁴^,⁴⁵^,⁴⁶ but extrapolation of animal data to human organogenesis is dangerous because of differences in species susceptibility.⁴⁷ For instance, many drugs that produce defects in animals appear to be harmless to the human embryo (e.g., aspirin). Conversely, the absence of teratogenicity in animals is no guarantee of safety in humans as observed with thalidomide. More than 2,500 elements have been cataloged as being potentially teratogenic in animal experiments.⁴⁸ However, clear evidence of toxicity to the human fetus is available only for a few of these. Risk factors have been assigned to all drugs based on the level of risk a drug poses to the fetus during pregnancy. These risk categories are A, B, C, D, and × as defined by U.S. Food and Drug Administration (FDA)⁴⁹ and are shown in Table 25-1. Table 25-2 lists some commonly used chemotherapeutic agents, with the pregnancy risk category according to the FDA risk category.

Multiple factors influence the probability of teratogenesis. As noted, the timing of exposure is critical but drug doses, frequency of administration, and duration of exposure are important variables.⁵⁰^,⁵¹^,⁵²^,⁵³^,⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷ Individual and genetic susceptibility may also be important variables.⁴⁴ To be teratogenic, it appears that the dose must lie within a narrow range between that which causes death of the fetus and that which has no discernible effect. Synergistic teratogenic interactions may occur with combination chemotherapy⁵⁶^,⁵⁷ or with radiotherapy.⁵⁸^,⁵⁹^,⁶⁰

Table 25-3 shows data regarding fetal malformations associated with the use of chemotherapy during the first trimester.⁶¹^,⁶²^,⁶³^,⁶⁴^,⁶⁵^,⁶⁶^,⁶⁷^,⁶⁸ Such data have been extensively reviewed.⁶¹^,⁶²^,⁶³ In addition, a case report of multiple congenital anomalies associated with the sequential administration of 6-mercaptopurine and busulfan in the first trimester has been described.⁵⁸ It is apparent, then, that a number of antineoplastic agents— given alone or in combination—may be teratogenic when administered early in pregnancy. This interpretation should be tempered by the fact that the overall incidence of major congenital malformations is approximately 3% of all births,⁶⁹ and the incidence of minor malformations may be as high as 9%. Furthermore, in several reported cases of congenital malformations, the mothers were also treated with radiation,⁷⁰^,⁷¹ which is well-recognized as a potent teratogen in humans and animals.⁷²

Table 25-1 FDA Drug-Risk Factors During Pregnancy

Category A	Controlled studies in women do not show risk to the fetus during the first trimester, there is no evidence of risk in later trimesters, and possibility of fetal harm is remote.
Category B	Animal reproduction studies have not shown a fetal risk, but there are no controlled studies in pregnant women, or animal reproduction studies have shown an adverse effect (other than a decrease in fertility), but this has not been confirmed in controlled studies in women in the first trimester (no evidence of a risk in later trimesters).
Category C	Studies in animals have revealed adverse effects on the fetus (teratogenic, embryocidal, or both), there are no controlled studies in women, or studies in animals and women are not available; drug should be given only if potential benefit justifies the risk to the fetus.
Category D	There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (if the drug is needed in life-threatening situation for which other safer drugs are not available).
Category X	Studies in humans and animals have shown fetal malformations, or 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.
From Federal Register. 1980;44:37434-3746, with permission.

ANTIMETABOLITES

Methotrexate

In animals, the folic acid antagonists aminopterin and methotrexate have been shown to cause fetal death and dose-dependent malformations, including cleft palate and CNS malformations.⁷³^,⁷⁴^,⁷⁵ In humans, these agents have been extensively reported to be associated with fetal abnormalities when given during the first trimester.⁶¹^,⁶²^,⁶⁸^,⁷⁶^,⁷⁷ Indeed, a conundrum of cranial dysostosis, hypertelorism, a wide nasal bridge, anomalies of the external ears, and micrognathia had been recognized as aminopterin syndrome.⁷⁸ Intelligence may be below normal, with poor speech development. Several of the infants have had limb deformities, and most of the abortuses and infants who died shortly after birth have cerebral anomalies. Kozlowski et al.⁷⁹ reported 8 women experiencing 10 pregnancies after low-dose exposure to methotrexate during the first trimester for the treatment for rheumatic disease. The outcome of pregnancies included five full-term babies, three spontaneous abortions, and two elective abortions. All offspring were normal, with no abnormalities noted at a mean age of 11.5. Such findings suggest that methotrexate is not always teratogenic when given in the first trimester and that there may be a critical dose above which fetal malformations occur. Second trimester and later exposure to methotrexate has not been shown to cause significant malformations.⁵¹^,⁸⁰^,⁸¹ Furthermore, methotrexate, when used as a treatment for ectopic pregnancies alone or in combination with other agents, has been associated with a very high success rate.⁸²^,⁸³^,⁸⁴

PURINE AND PYRIMIDINE ANALOGS

5-Fluorouracil

When administered during the first trimester, 5-fluorouracil (5-FU) was associated with multiple anomalies: radial dysplasia, absent digits, and hypoplasia of thoracic and abdominal organs.⁸⁵ In another case, 5-FU and radiotherapy combination during 11 to 12 weeks of gestation resulted in severe congenital anomalies.⁷¹ Local application of 5-FU cream to treat human papilloma virus infection of the lower genital tract during the first trimester resulted in a genotypic abnormality with 47 chromosomes with XXX genotype.⁸⁵ Conversely, there have been at least six other reports of first-trimester use of local 5-FU cream with favorable obstetric outcome.⁸⁵^,⁸⁶ Second-trimester exposure to 5-FU in combination with other agents has not resulted in adverse effects.⁸⁷ One case of toxicity from 5-FU, with cyanosis and jerking extremities, has been reported after exposure late in the third trimester.⁸⁸

6-Mercaptopurine

Of the 20 patients exposed to 6-mercaptopurine alone, no fetal anomalies were documented.⁶¹^,⁶² However, first-trimester use of single-agent 6-mercaptopurine for the treatment for malignant lymphoma resulted in spontaneous abortion.⁶⁶

Cytosine Arabinoside

Cytosine arabinoside used as a single agent once during the first trimester for acute lymphocytic leukemia, resulted in multiple congenital anomalies including otic anomalies, auditory canal atresia, lobster claw hand, and other digital anomalies, as well
as lower limb defects.⁸⁰^,⁸⁹^,⁹⁰ Moreover, fetal growth inhibition has been well-documented.

Table 25-2 Commonly Used Chemotherapeutic Agents and Their Pregnancy Risk Category^a

Drug	FDA Pregnancy Category
Methotrexate	X
Aminopterin	X
Cytosine arabinoside	D
5-FU	D
6-Mercaptopurine	D
6-Thioguanine	D
Gemcitabine	D
Hydroxyurea	D
Chlorambucil	D
Cyclophosphamide	D
Ifosfamide	D
Melphalan	D
Thiotepa	D
Busulfan	D
Cisplatin	D
Carboplatin	D
Oxaliplatin	D
Dacarbazine	C
Procarbazine	D
Daunorubicin	D
Doxorubicin	D
Idarubicin	D
Epirubicin	D
Dactinomycin	C
Bleomycin	D
Mitoxantrone	D
Vinorelbine	D
Vincristine	D
Vinblastine	D
Paclitaxel	D
Docetaxel	D
Etoposide	D
Teniposide	D
Trastuzumab	C
Imatinib	D
ATRA	D
Tamoxifen	D
Prednisone	B
Interferon^a	C
Bevacizumab	C
Cetuximab	C
Rituximab	C
Erlotinib	D
Azacytidine	D
Thalidomide	X
Lenalidomide	X
Arsenic	D
Fludarabine	D
Cytarabine	D
Alemtuzumab	C
Gemtuzumab	D
^aThe pregnancy risk category is identified according to the FDA risk category as outlined in Table 25-1.

Gemcitabine

Gemcitabine can potentially harm the fetus when administered to a pregnant woman. It is toxic to fetal tissue in animal studies, causing fetal malformations (cleft palate and incomplete ossification), fetotoxic causing fetal malformations (fused pulmonary artery and absence of gall bladder) and embryotoxic (decreased fetal viability, reduced live litter sizes, and developmental delays).⁹¹ However, there are no studies of gemcitabine in pregnant women.

Similarly fludarabine and cladarabine has no human data. In a case of hairy cell leukemia, therapy with cladarabine was deferred until after the delivery of the baby.⁹²

ALKYLATING AGENTS

Cyclophosphamide and Ifosfamide

Cyclophosphamide and ifosfamide appear to be less teratogenic agents than antimetabolites, with few reports of fetal malformations.⁶¹^,⁶² Four of these six mothers had received radiation therapy as well. A very unique case of a twin pregnancy has
been reported by Zemlickis et al.,⁹³ in which the mother was exposed to daily cyclophosphamide with intermittent prednisone throughout the pregnancy. The female offspring was normal but the male child had multiple congenital anomalies and was diagnosed with papillary thyroid cancer at age 11 and a neuroblastoma at age 14. Moreover, cyclophosphamide has been reported to be absorbed through skin or air as an aerosol.⁹⁴ Therefore, pregnant women who administer chemotherapy should take special precautions.

Table 25-3 Chemotherapy During the First Trimester of Pregnancy

Class		Number of Exposed Patients	Number of Fetal Malformations
Alkylating agents
	Busulfan	24	2
	Chlorambucil	6	1
	Cyclophosphamide	7	3
	Nitrogen mustard	6	0
	Triethylenemelamine	4	0
Antimetabolites
	Aminopterin	52	10
	Methotrexate	9	3
	6-Mercaptopurine	20	0
	Cytarabine	1	1
	5-FU	1	1
	Hydroxyurea	3	0
Plant alkaloids
	Vinblastine	14	1
Antibiotics
	Daunorubicin	1	0
Miscellaneous
	Procarbazine	1	1
	Amsacrine	1	1
	Cisplatin	1	0
Total		151	24 (15%)
Combinations		54	9 (16%)