Non.o.bstetric surgery Non.o.bstetric surgery is sometimes necessary during pregnancy, and ranges from 1 in 500 to 1 in 635 (Affleck et al et al., 1999). Maternal mortality non.o.bstetric surgery is no greater than mortality in the nonpregnant patient. Risks to the fetus from surgery are probably related more to the specific condition requiring the surgery than to the surgery itself. Among 2565 women who underwent surgery during the first or second trimester compared to controls, the frequency of spontaneous abortion in women undergoing surgery with general anesthesia was greater for gynecologic procedures compared to surgery in other anatomic regions (risk ratio of 2 versus 1.54). The frequency of congenital anomalies was not different (Duncan et al et al., 1986).

122.

Anaesthetic agents and surgery during pregnancy Appendicitis is the most common nontrauma indication for non.o.bstetric surgery during pregnancy, at approximately 1 in 3000 (Affleck et al et al., 1999), and occurs with equal frequency in all three trimesters (Black, 1960).

Cholecyst.i.tis and biliary tract disease are the most common surgical conditions following appendicitis and occur in approximately 110 per 10 000 pregnancies (Affleck et al et al., 1999; Hill et al. et al. , 1975). Laparoscopic surgery morbidity and mortality was no different from the open cholecystectomy (Affleck , 1975). Laparoscopic surgery morbidity and mortality was no different from the open cholecystectomy (Affleck et al et al., 1999; Barone et al et al., 1999).

Surgical procedures for intestinal obstruction, inflammatory bowel disease, breast disease, and diseases of the ovary are also relatively common. Surgery for cardiovascular disease during pregnancy is less common, but procedures such as mitral valvotomy (el-Maraghy et al et al., 1983) valve replacement, and cardiopulmonary bypa.s.s (Bernal and Miralles, 1986) have been performed in pregnant women with reasonably good results.

Anesthesia for non.o.bstetrical surgery may be delivered via either general endotracheal or regional techniques. The choice depends on: (1) procedure to be performed; (2) emergent nature of the procedure; (3) length of time the patient has been fasting; and (4) preferences of the surgeon and the patient. General anesthesia should be accomplished through a balanced technique using nitrous oxide, oxygen, thiopental, succinylcholine, and a halogenated agent. As surgical patients, pregnant women should receive antacid prophylaxis to prevent aspiration pneumonia. The patient should also fast for 1012 h prior to antic.i.p.ated surgery, but this may not be possible in all cases (e.g., emergency procedures). Endotracheal intubation with timely extubation when reflexes have returned will help prevent aspiration complications. High-concentration oxygen should be used and hypotension should be avoided in the pregnant surgical patient.

Choice of anesthetic depends on length of the procedure and preference of the anesthesiologist. To prevent maternal hypotension and decreased uteroplacental blood flow, adequate preload with a balanced salt solution is recommended prior to initiation of the actual block. Regional anesthetic techniques have some complications (Box 6.4), but they can be minimized using preventative techniques to decrease the incidence and severity of hypotension from regional blocks (Box 6.5).

Anesthesia for Caesarean section: the uncomplicated patient Regional anesthesia is the preferred method of anesthesia for the uncomplicated patient undergoing Caesarean section. Subarachnoid (spinal) or epidural block, or a combination, are suitable anesthetic techniques for these patients. The various agents which can Regional anesthesia is the preferred method of anesthesia for the uncomplicated patient undergoing Caesarean section. Subarachnoid (spinal) or epidural block, or a combination, are suitable anesthetic techniques for these patients. The various agents which can Box 6.4 Complications of regional anesthesia Box 6.4 Complications of regional anesthesia Subarachnoid block Total spinal block Arachnoiditis Epidural block Bladder dysfunction Hematoma or infection Headaches Hypotension Hypotension Subarachnoid or intravascular injection Meningitis From Gilstrap and Hankins, 1988.

Special considerations 123.

Box 6.5 Prevention and treatment of hypotension from regional anesthesia anesthesia Positioning Ephedrine Left lateral position 2550 mg IM prophylactically Left uterine displacement 1015 mg IV for hypotension Preanesthetic hydration 5001000 cc balanced salt solution From Gilstrap and Hankins, 1988.

Box 6.6 Anesthetic agents for regional anesthesia for Caesarean section section Subarachnoid block Bupivacaine (Marcaine, spinal), 7.510.5 mg Lidocaine (Xylocaine) 5% in 7.5% glucose, 6075 mg Tetracaine (Pontocaine) 1%, 810 mg Epidural block Bupivacaine (Marcaine) 0.5% Chloroprocaine (Nesacaine) 23% Lidocaine (Xylocaine) 12% be utilized in these patients are listed in Box 6.6. Hypotension is the most common complication of these techniques and the one that has the greatest impact on the fetus (Box 6.5).

A potentially serious complication resulting from the inadvertent intravascular injection of local anesthetic is central nervous system (CNS) toxicity. Epidural veins are engorged and large during pregnancy, and may be punctured with a needle or catheter.

Symptoms of CNS toxicity include: slurred speech, dizziness, metallic taste in the mouth, ringing in the ears, paresthesias of the face, seizures, and syncope. Epinephrine to detect intravascular injection has been discussed. Treatment of CNS toxicity is primarily supportive care: airway and ventilation support, oxygen, prevention and treatment of seizures (thiopental, diazepam), and treatment for hypotension (fluid, ephedrine, and lateral uterine displacement) (Gilstrap and Hankins, 1988).

General anesthesia is used even for uncomplicated Caesarean section. The estimated rate of general anesthesia is 2126 percent (Shroff et al et al., 2004). The previously described balanced general technique of nitrous oxide, oxygen, thiopental, succinylcholine and a halogenated agent provides satisfactory anesthesia for uncomplicated Caesarean sections. Patients should be preoxygenated and placed in the lateral position with left lateral uterine displacement. While avoiding hypotension, general anesthesia provides reliable and expeditious anesthesia. Aspiration pneumonitis is the major maternal risk and neonatal cardiorespiratory depression is the major fetal risk. As a precautionary rule, all pregnant women undergoing Caesarean section should be treated as if they have 'full stomachs,' hence the importance of endotracheal intubation.

124.

Anaesthetic agents and surgery during pregnancy Anesthesia for Caesarean section: The complicated patient Many women who require Caesarean section have other medical complications, such as hypertension, diabetes, or heart disease. It is, therefore, imperative for the obstetrician and anesthesiologist to communicate. Importantly, this is the critical path where communication frequently breaks down (Shroff Many women who require Caesarean section have other medical complications, such as hypertension, diabetes, or heart disease. It is, therefore, imperative for the obstetrician and anesthesiologist to communicate. Importantly, this is the critical path where communication frequently breaks down (Shroff et al et al., 2004).

Pregnancy-induced hypertension (PIH) occurs among about 5 percent of pregnancies and presents a significant challenge with regard to anesthesia when Caesarean section is required (Lopez-Jaramillo et al et al., 2005). Severe PIH, blood pressure 160/110 mmHg, is a.s.sociated with several cardiovascular changes, the most important of which is changes in blood volume. Blood volume in women with severe PIH generally does not expand much above the nonpregnant state, unlike the normotensive pregnant woman.

Severe PIH patients typically have low colloidal osmotic pressures and 'leaky vessels.'

Hence, they are more likely to develop pulmonary edema following the intravenous infusion of crystalloid solutions. A small percentage of women with PIH may also have hematologic abnormalities (thrombocytopenia, hemolytic anemia). Anesthetic choice for Caesarean section in women with severe PIH is controversial. General anesthesia, preferred by some, is not without risk. Significant hypertension may develop during intubation or extubation, with increased risk of cerebral hemorrhage or cardiac failure.

Hypertensive response to endotracheal intubation for general anesthesia may be damp-ened through antihypertensives such as nitroglycerin (Hodgkinson et al et al., 1980; Snyder et al et al., 1979). The efficacy and safety of general anesthesia in these patients is shown in one study of 245 cases of eclampsia in which no cases of cerebral hemorrhage, pulmonary edema, or mortality were observed (Pritchard et al et al., 1984).

Hypotension is a major problem with conduction anesthesia (spinal or epidural), secondary to sympathetic blockade. Hypotension is difficult to treat in women with severe PIH because they may be overly sensitive to pressor agents. Preloading with crystalloid solutions must be done with great caution, being careful to prevent fluid overload in a vasoconstricted but not underfilled vascular tree. The general consensus is that spinal block is contraindicated in women with severe PIH, but many clinicians do advocate epidural anesthesia for these women (Jouppila et al et al., 1982; Marx, 1974; Moir et al et al., 1972; Newsome and Branwell, 1984). Careful attention to fluid preload, prevention of hypotension, and test of coagulation status are of paramount importance if epidurals are to be used in these gravidas. Epidural or general anesthesia is effective for women with mild PIH.

Diabetes mellitus complicates approximately 2 percent of pregnancies and many of these women require Caesarean section. When necessary among pregnant diabetics, Caesarean section should be scheduled as the first case in the morning with blood glucose well controlled prior to surgery. General anesthesia or regional techniques (including spinal) may be used. If preload is required for regional techniques, a nondextrose solution should be used to prevent neonatal hypoglycemia.

No single anesthetic technique is ideal for women with heart disease during pregnancy. Anesthetic technique choice will depend on the specific type of heart lesion present and the patient's functional cardiac status (New York Heart a.s.sociation Cla.s.sification; Dunselman et al et al., 1988). Epidural anesthesia is preferred in pregnant women requiring surgery with most varieties of heart disease, and close attention must be paid to preload and hypotension.

Key references 125.

General anesthesia is indicated for certain cardiac lesions. Pregnant women with aortic stenosis are at significant risk for hypotension and hypovolemia, and are better served by general anesthesia when Caesarean section is required. Women who have pulmonary hypertension and diminished venous return to the heart are especially at risk for hypotension and hypovolemia. Hence, they do not receive regional anesthesia when surgery is required. For women with recent myocardial infarctions, epidural or general anesthesia is efficacious.

Key references Affleck DG, Handrahan DL, Egger MJ, Price RR. The laparoscopic management of appendicitis and cholelithiasis during pregnancy. Am J Surg 1999; 178 178: 523.

Barone JE, Bears S, Chen S et al. Outcome study of cholecystectomy during pregnancy. Am J Surg 1999; 177 177: 232.

Little BB. Pharmac.o.kinetics during pregnancy. Evidence-based maternal dose formulation.

Obstet Gynecol 1999; 93 93: 85868.

Lopez-Jaramillo P, Garcia RG, Lopez M. Preventing pregnancy-induced hypertension. Are there regional differences for this global problem? J Hypertens 2005; 23 23: 1121.

Shroff R, Thompson ACD, McCrum A, Rees SGO. Prospective multidisciplinary general anesthesia in a district general hospital. J Obstet Gynaecol 2004; 24 24: 641.

Further references are available on the book's website at http://www.drugsandpregnancy.com 7.Antineoplastic drugs during pregnancy Alkylating agents 129.

Special considerations 142.

Antibiotics 136.

Summary 148.

Plant alkaloids 138.

Key references 148.

Miscellaneous agents 139.

Cancer is uncommon during pregnancy and occurs in approximately one in 10006000 pregnant women (Haas, 1984; Kennedy et al et al., 1993; Pepe et al et al., 1989). It can be estimated that one in 118 women with cancer will be pregnant, because 12.8 percent of all cancers in women occur in the 1544 age group (Third National Cancer Survey, 1975).

Population- and hospital-based studies show that the most frequently occurring cancers that present during pregnancy are cervix, breast, and ovary (Haas, 1984; Pepe et al et al., 1989). The frequencies of nongenital-type cancers during pregnancy are shown in Table 7.1. The frequencies of the various forms of genital cancers in pregnancy are shown in Table 7.2, with cervical cancer being the most common.

Table 7.1 Frequencies of nongenital cancers in pregnancy Malignancy type Frequencies of nongenital cancers in pregnancy Malignancy type Incidence (per number Source of gestations) Malignant melanoma 1:100010 000 Pavlidis (2002) Breast carcinoma 1:30001:10 000 Lymphoma 1:10001:6000 Leukemia 1:75 0001:100 000 Colon cancer 1:13 000.

Hodgkin's lymphoma 1 in 6000 Others, see below Non-Hodgkin's lymphomas Extremely rare (< 1="" in="" 100="" 000)="" acute="" leukemia="" 1="" in="" 75="" 000="" to="" 1="" in="" 100="" 000="" gastrointestinal="" (colon,="" gastric,="" up="" to="" 1="" in="" 10="" 000="" pancreatic,="" carcinoid,="" hepatic)="" renal="" cell="" rare="" thyroid="" rare="" compiled="" from="" pavlidis,="" 2002="" and="" others="" (donegan,="" 1983,="" 1986;="" koren="" et="" al.,="" 1990;="" mclain,="" 1974;="" orr="" and="" shingleton,="" 1983;="" parente="" et="" al.,="" 1988;="" smith="" and="" randal,="" 1969;="" yazigi="" and="" cunningham,="">

Antineoplastic drugs during pregnancy 127.

Table 7.2 Frequency of genital cancers in pregnancy Type Frequency of genital cancers in pregnancy Type Frequency Cervix Carcinoma in situ 1.3 in 1000 to 1 in 770 Others Carcinoma of the cervix 1:200010 000 Pavlidis, 2002 Invasive carcinoma 0.5 in 1000 to 1 in 2200 Others Ovarian 1 in 18 000 to 1 in 25 000 Others Ovarian carcinoma 1:10 0001:100 000 Pavlidis, 2002 Data compiled from Pavlidis, 2002 and Others (Chung and Birnbaum, 1973; Hacker et al., 1982; Munnell, 1963; Yazigi and Cunningham, 1990).

When cancer is present during pregnancy, several dilemmas arise. Perhaps most important is whether the pregnancy should be continued or terminated. Several factors must be considered in this discussion: (1) the gestational age of the pregnancy; (2) the patient's desire to continue the pregnancy; (3) whether pregnancy per se per se affects the cancerous progression; and (4) the ultimate prognosis for the mother and infant. In general, pregnancies close to viability (i.e., 2428 weeks gestation) may be continued with mild to moderate adverse effects on the fetus. Of the various therapeutic modalities available, none are known to be safe for use during pregnancy. Some patients with pregnancies less than 24 weeks gestational age may best be managed by pregnancy termination. affects the cancerous progression; and (4) the ultimate prognosis for the mother and infant. In general, pregnancies close to viability (i.e., 2428 weeks gestation) may be continued with mild to moderate adverse effects on the fetus. Of the various therapeutic modalities available, none are known to be safe for use during pregnancy. Some patients with pregnancies less than 24 weeks gestational age may best be managed by pregnancy termination.

Decisions regarding pregnancy termination between 24 and 28 weeks are more difficult.

Management is most often dependent upon the patient's wishes, as well as the type and stage of the woman's cancer.

Available data suggest that pregnancy affects neither the progression nor prognosis for most cancers; the exception to this is the critical period of neural plate development (1018 days postconception). However, pregnancy may interfere with the diagnostic procedures for some types of malignancies.

The pharmac.o.kinetics of neoplastics is poorly studied, with only sufficient information to speculate on the effects of pregnancy on metabolism and clearance of cyclophosphamide. Of the five cytochrome P-450 enzymes that metabolize cyclophosphamide (Matalon et al et al., 2004), the activity of one, CYP3A4 (Little, 1999), is significantly increased during pregnancy. This implies that dose size or dose frequency should be adjusted for pregnant women by monitoring levels, and adjusting these parameters to maintain therapeutic levels.

A major consideration in treating cancer during pregnancy is finding the optimal regimen. This must include consideration of: (1) the effects of diagnostic tests; (2) surgical procedures; (3) radiotherapy; and (4) chemotherapy (Gilstrap and Cunningham, 1996; Koren et al et al., 1990; Yazigi and Cunningham, 1990). It is important to minimize the amount of fetal exposure to ionizing radiation. Many diagnostic tests can be performed safely during pregnancy because most diagnostic X-ray procedures expose the fetus to low doses of radiation, i.e., less than 1 rad per procedure; this holds true even for pelvic neoplasms. General 'rule of thumb' suggests that a fetal or embryonic radiation exposure of less than 5 'skin' rads is a.s.sociated with little to no risk the exception to this is the critical period of neural plate development (days 1018 postconception) with the threshold for significant risk being as high as 1520 'skin' rads (Brent, 1987). Skin rads 128 128 Antineoplastic drugs during pregnancy are the amount of radiation delivered to the mother's skin surface. Thus, procedures such as barium enemas, pyelography, chest films, and nonpelvic computerized tomography can be safely performed if deemed necessary during the initial diagnosis of malignancies during pregnancy. Other diagnostic modalities, such as magnetic resonance imaging and ultrasonography, can often provide the same diagnostic information as X-ray studies and carry no known risk to the fetus or embryo. Until the end of the second trimester, diagnostic techniques such as cystoscopy and sigmoidoscopy may be performed safely (Pentheroudakis and Pavlidis, 2006).

Most surgical oncology techniques can be used during pregnancy to treat life-threatening disease, especially if they do not involve the pelvis or pelvic organs (Miller and Bloss, 1995). Ovaries can generally be removed after 10 weeks gestational age (8 weeks postconception) without apparent adverse effects on pregnancy. However, progestational agents should be utilized if ooph.o.r.ectomy is necessary prior to this time (Gilstrap and Cunningham, 1996; Pentheroudakis and Pavlidis, 2006; Yazigi and Cunningham, 1990).

Most antineoplastic agents employed in chemotherapy have the capability to interfere with normal cell growth (hyperplasia, hypertrophy, and migration) in the embryo. Thus they are potentially teratogenic and may cause fetal growth r.e.t.a.r.dation and congenital abnormalities. In one review of 163 pregnancies exposed to antineoplastic drugs in the first trimester, the frequency of congenital anomalies was 25 percent for polytherapy chemotherapeutic regimens and 17 percent for single-agent exposure (Doll et al et al., 1989) (Table 7.3).

Table 7.3 Frequency of congenital anomalies a.s.sociated with first-trimester use of chemotherapy Frequency of congenital anomalies a.s.sociated with first-trimester use of chemotherapy Cla.s.s Congenital anomalies (%) Alkylating agents 6 in 44 (14) Antimetabolitesa 15 in 77 (19) Plant alkaloids 1 in 14 (7) Other Amsacrine Cisplatin Daunorubicin Procarbazine Total 24 in 139 (17%) a13 (24%) exposed to aminopterin or methotrexate.

Compiled from Doll et al., 1989.

The frequency of malformations in 131 pregnancies with second-trimester exposure was 1.5 percent, below the background risk for the human population (Doll et al et al., 1988). Hence it would be expected that exposures to antineoplastic agents after the period of embryogenesis (second and third trimesters of pregnancy) carry little risk to the fetus other than fetal growth r.e.t.a.r.dation (Gilstrap and Cunningham, 1996; Yazigi and Cunningham, 1990). Potential immediate fetal and neonatal effects are summarized in Box 7.1.

Alkylating agents 129.

Box 7.1 Potential immediate effects of chemotherapeutic agents on the fetus and newborn on the fetus and newborn Spontaneous abortion Premature birth Teratogenic effects Growth r.e.t.a.r.dation Organ toxicity Adapted from Doll et al., 1989.

Box 7.2 Potential long-term or delayed effects of antineoplastic agents on the neonate agents on the neonate Carcinogenesis Developmental r.e.t.a.r.dation Sterility Mutation Growth r.e.t.a.r.dation Teratogenic in future offspring Adapted from Doll et al., 1989.

Antineoplastic agents may also have long-term or delayed effects, such as sterility or carcinogenesis for the child exposed prenatally (Box 7.2). For the benefit of the patient, some treatments (for example, for acute leukemia) should begin as soon as the diagnosis is made, including the first trimester (Koren et al et al., 1990).

Finally, there is a risk to the fetus from spread of the maternal cancer by transplacental metastasis. It is well doc.u.mented that certain cancers may spread to the developing fetus, yielding a grave fetal prognosis (Read and Platzer, 1981). Malignant melanoma is the most common cancer to metastasize to the fetus and placenta (Anderson et al et al., 1989; Eltorky et al et al., 1995; Read and Platzer, 1981).

Management and treatment of specific types of cancers are discussed under Special Considerations below. Specific chemotherapeutic agents, considered below, can be divided into several cla.s.ses: alkylating agents, antibiotics, antimetabolites, plant alkaloids, and miscellaneous (Boice, 1986). Antineoplastic agents can also be cla.s.sified as cycle-specific and cycle-nonspecific agents. Cycle-specific agents (antimetabolites, antibiotics, and plant alkaloids) arrest cell division only during specific phases of the replication cycle. In contrast, cycle-nonspecific agents (alkylating agents) are cytotoxic during all phases of cell replication (Caliguri and Mayer, 1989).

ALKYLATING AGENTS.

A number of alkylating agents are available (Box 7.3). These agents act by transferring alkyl groups to such biological substrates as nucleic acids and proteins. Alkyl groups Box 7.3 The alkylating agents Box 7.3 The alkylating agents Busulfan (Myleran) Melphalan (Alkeran) Cyclophosphamide (Cytoxan, Neosar) Triethylene thiophosphoramide (Thiotepa) Chlorambucil (Leukeran) Carmustine (BCNU) Mechlorethamine (Mustargen) 130.

Antineoplastic drugs during pregnancy block replication of DNA via the cross-linking bioactive molecules (i.e., polymerases) needed for cell division.

Busulfan Busulfan (Myleran) is Food and Drug Administration (FDA)-approved for the palliative treatment of chronic myelogenous leukemia, and is the primary treatment for acute non-lymphacytic leukemia. Summary of 16 different reports of 22 infants born to busulfan-exposed patients found two infants with major congenital anomalies (2/22, 9.1 percent) (Doll et al et al., 1989). Subsequent reports of two exposed pregnancies resulted in normal neonates (Norhaya et al et al., 1994; Shalev et al et al., 1987). They also reported that six (14 percent) of 44 infants born to women who received an alkylating agent (30 different reports) had major congenital anomalies. Experimental animal studies also report an increased frequency of congenital anomalies with exposure to busulfan during gestation.

Cyclophosphamide Cyclophosphamide (Cytoxan and Neosar) is biotransformed princ.i.p.ally in the liver to active alkylating metabolites that cause crosslinking of tumor cell DNA. It is FDA-approved for treatment of a variety of cancers: (1) certain forms of acute and chronic leukemia; (2) ovarian; (3) multiple myeloma; (4) mycosis fungoides; and (5) breast carcinoma. This drug is also used to treat cancers of the bladder, cervix, color.e.c.t.u.m, endometrium, Ewing's sarcoma, head and neck, lymphomas, kidney, lung, osteosarcoma, pancreas, and trophoblastic tumors. In addition, cyclophosphamide is efficacious in combination with other agents for the treatment of Ewing's sarcoma, lymphomas, osteosarcoma, and trophoblastic tumors. Several studies of cyclophosphamide metabolism in in vitro in vitro cultures with rat embryos showed that the compound must be bioactivated by a monofunctional liver oxygenase system in order to be teratogenic (Fantel cultures with rat embryos showed that the compound must be bioactivated by a monofunctional liver oxygenase system in order to be teratogenic (Fantel et et al al., 1979; Kitchen et al et al., 1981; Mirkes et al et al., 1981, 1985). The morphologic changes found in vitro in vitro were very similar to those seen were very similar to those seen in vivo in vivo (Greenway (Greenway et al et al., 1982), suggesting cyclophosphamide metabolites are the teratogenic agents (Mirkes et al et al., 1985).

According to Mirkes et al et al. (1985), cyclophosphamide is 'one of the best studied teratogens'. There is no doubt that this agent produces skeletal and central nervous system anomalies in rats (Chaube et al et al., 1968), mice (Gibson and Becker, 1968), rabbits (Fritz and Hess, 1971), and monkeys (McClure et al et al., 1979). Available human data are minimal and include three case reports and one case series. A set of twins comprising one normal infant and one malformed twin exposed in utero in utero was reported. The malformed twin had multiple congenital abnormalities and subsequently developed thyroid cancer and neuroblastoma (Zemlickis was reported. The malformed twin had multiple congenital abnormalities and subsequently developed thyroid cancer and neuroblastoma (Zemlickis et al et al., 1993). In another case report, a fetus with multiple anomalies (cleft palate, absent thumbs, and multiple eye defects) was born to a mother who was treated with cyclophosphamide in the first trimester (Kirshon et al et al., 1988). A growth-r.e.t.a.r.ded infant with bilateral absence of the big toe, cleft palate, and hypoplasia of the fifth digit was born to a mother who received cyclophosphamide throughout pregnancy (Greenberg and Tanaka, 1964). No ill effects have been reported in a.s.sociation with second and third trimester exposure to cyclophosphamide (Matalon et al et al., 2004). Ten normal infants were reported following cyclophosphamide therapy during the first trimester (Blatt et al et al., 1980).

Alkylating agents 131.

Hematologic abnormalities, such as pancytopenia, were reported in infants whose mothers were treated with cyclophosphamide and other agents during pregnancy (Pizzuto et al et al., 1980), but not all neonates exhibited such effects, even when their mothers developed severe pancytopenia (Meador et al et al., 1987). The use of multiple agents seems more likely to be a.s.sociated with pancytopenia in the fetus and newborn than does monotherapy.

Chlorambucil Chlorambucil (Leukeran) is an oral bifunctional alkylating agent, nitrogen mustard type, FDA-approved to treat chronic leukemia and lymphomas. It is also used to treat breast, trophoblastic, and ovarian carcinomas. Several case reports of possible a.s.sociation of this agent with unilateral renal agenesis in the human have been published (Shotton and Monie, 1963; Steege and Caldwell, 1980), but no causal inference can be made. No epidemiological studies have been published. One of five fetuses exposed in the first trimester had a congenital anomaly (Doll et al et al., 1989). Central nervous system anomalies, postcranial skeleton, and palatal closure were increased in frequency among rodents whose mothers were given large doses of chlorambucil during pregnancy (Chaube and Murphy, 1968; Mirkes and Greenaway, 1982; Monie, 1961).

Ifosfamide Ifosfamide (Ifex) is a chemotherapeutic agent, chemically related to nitrogen mustards and a synthetic a.n.a.log of cyclophosphamide, which requires metabolic activation by microsomal liver enzymes to produce biologically active metabolites. The mechanism of action is typical for alkylating agents and is mediated by formation of DNA adducts.

Ifosfamide is particularly toxic to the urinary epithelium and must be given with mesna (Mesnex, Uromitexan). It is FDA-approved as third-line chemotherapy of germ cell testicular cancer. It is also used to treat acute leukemias and lung, pancreas, breast, cervix and endometrium cancers, as well as Ewing's sarcomas, lymphomas, osteosarcoma, soft tissue sarcoma, and ovarian cancer. No epidemiologic studies have been published of congenital anomalies in fetuses whose mothers used this agent during pregnancy. To date there are two case reports of fetuses exposed in utero in utero to ifosfamide-containing combination chemotherapy, of which one developed oligohydramnios (Barrenetexa to ifosfamide-containing combination chemotherapy, of which one developed oligohydramnios (Barrenetexa et al et al., 1995; Fernandez et al et al., 1989). The manufacturer reports that embryotoxic and teratogenic effects have been observed in mice, rats, and rabbits.

Mechlorethamine Another alkylating agent, mechlorethamine (Mustargen), is an FDA-approved treatment for Hodgkin's disease, polycythema vera, mycosis fungoides, chronic leukemia, lymphomas, and carcinoma of the lung. It is also used to treat brain, breast, and ovarian cancers. Two case reports of congenital anomalies after first-trimester combination chemotherapy (Garrett, 1974; Mennuti et al et al., 1975) are published, but no epidemiological studies of the use of this agent during pregnancy have been published.

Chemotherapy with mechlorethamine and other drugs that were discontinued prior to 132 132 Antineoplastic drugs during pregnancy conception did not increase the frequency of congenital anomalies among more than 40 infants above the 3.55 percent background rate expected in the general population (Andrieu and Ochoa-Molina, 1983; Schilsky et al et al., 1981; Whitehead et al et al., 1983).

However, this is probably unrelated to use of this drug during pregnancy. No birth defects were reported among the children of 12 women treated with mechlorethamine and other antineoplastic agents during pregnancy in one series (Aviles et al et al., 1991; Aviles and Neri, 2001), but the significance of these findings is unknown because most exposures were outside the first trimester.

Increased frequencies of congenital anomalies were found among the offspring of pregnant rodents that were given mechlorethamine in doses several times those normally used in humans (Beck et al et al., 1976; Gottschewski, 1964; Murphy et al et al., 1957; Nishimura and Takagaki, 1959).

Somatic chromosome breaks have been observed among embryos of pregnant animals who received this agent during gestation (Soukup et al et al., 1967). The relevance of this finding to human reproduction is unknown because gonadal cell lines were not a.n.a.lyzed.

Melphalan Melphalan (Alkeran) is a phenylalanine derivative of nitrogen mustard. It is a bifunctional alkylating agent, FDA-approved to treat multiple myeloma, ovarian, and breast carcinomas. It is also used for treatment of chronic myelocytic leukemia, melanoma, osteosarcoma, soft tissue sarcoma, and thyroid cancers. The manufacturer reports that oral melphalan is teratogenic and embryolethal in animals. Although there are no studies of the use of this drug during pregnancy in humans, its strong mutagenic and cytotoxic actions suggest that it is a likely human teratogen and should be avoided during pregnancy.

Triethylene thiophosphoramide The alkylating agent triethylene (Thiotepa) is FDA-approved for the treatment of ovarian, bladder and breast carcinomas, and malignant effusions. As with most antineoplastics, no epidemiological studies have been published of pregnancy outcome after the use of this agent during human pregnancy. None of four fetuses exposed in the first trimester developed malformations (Doll et al et al., 1989). One case was reported of fetal growth r.e.t.a.r.dation a.s.sociated with use of the drug in the latter half of pregnancy (Stevens and Fisher, 1965). An increased frequency of congenital anomalies and growth stunting was reported among the offspring of pregnant rodents that received this agent during pregnancy (KoroG.o.dina and Kaurov, 1984; Murphy et al et al., 1958; Tanimura, 1968).

Carmustine Carmustine (BCNU) is an alkylating agent, FDA-approved for chemotherapy of a variety of neoplasms including multiple myeloma, lymphomas, and brain tumors. A patient received carmustine throughout pregnancy and delivered a normal neonate (Schapira and Chudley, 1984). Carmustine must be suspected of being teratogenic because of its Alkylating agents Alkylating agents 133.

biochemical action (an alkylating agent). Rodents exposed to carmustine at several times the usual human dose during embryogenesis had increased frequency of birth defects (Wong and Wells, 1989). Otherwise, little information is published about the use of this agent during pregnancy in humans or animals.

Antimetabolites Antimetabolites can be divided into three groups: folate antagonists, purine antagonists, and pyrimidine antagonists (Box 7.4). One of the original antimetabolites is the folate antagonist aminopterin. This antineoplastic agent was previously used as an abortifacient, but is no longer widely used as an antineoplastic or abortifacient. It is a well-known teratogen, causing the fetal aminopterin syndrome. This finding is relevant to other folate antagonist antineoplastics that are commonly used.

Box 7.4 The antimetabolites Folate antagonist Pyrimidine antagonist Methotrexate (Folex, Mexate) Cytarabine (Cytosar) Fluorouracil (Efudex, Fluoroplex) Purine antagonist Mercaptopurine (Purinethol) Thioguanine (Thioguanine) Aminopterin/methylaminopterin A variety of congenital anomalies was observed among infants and children whose mothers used aminopterin or methylaminopterin throughout pregnancy, including short stature, craniosynostosis, hydrocephalus, micrognathia, hypertelorism, limb anomalies, and neural tube defects (Char, 1979; Reich et al et al., 1977; Thiersch, 1952; Thiersch and Phillips, 1950; Warkany, 1978). The precise risk of congenital anomalies following maternal exposure to this agent is unknown but is likely high (Warkany, 1978).

Malformations of the skull, face, eye, and abdominal wall were described among rodents born to mothers that were administered large doses of the aminopterin during pregnancy (Baranov, 1966; Puchkov, 1967). Even at doses lower than those used in humans, malformations were observed in rabbits (Goeringer and DeSesso, 1990). Fetal death occurred in another rat study (Thiersch and Phillips, 1950). As a group, folate antagonists appear to carry a substantially higher risk of congenital anomalies than other antineoplastic agents. Therefore, folate antagonists are uniformly contraindicated for use during pregnancy (Doll et al et al., 1989).

Methotrexate The folate antagonist methotrexate (Folex, Mexate) inhibits dihydrofolic acid reductase, interrupting DNA synthesis, repair, and cellular replication, including trophoblastic cells. It is used to treat a number of neoplasms, including acute leukemia, lymphoma, trophoblastic tumors, and carcinomas of the breast, cervix, ovary, bladder, kidney, prostate, lung, and 134 134 Antineoplastic drugs during pregnancy t.e.s.t.i.c.l.es. It is also used to treat nonneoplastic diseases: rheumatoid arthritis, psoriasis, and ectopic pregnancy. Methotrexate is particularly toxic to trophoblastic cells and is used frequently as an abortifacient. It has been used successfully to treat ectopic pregnancies (Grainger and Seifer, 1995; Sc.h.i.n.k, 1995) and to induce abortion (Hausknecht, 1995).

Methotrexate is a.s.sociated with a pattern of malformations similar to those in the aminopterin syndrome (Warkany, 1978). Congenital anomalies among more than a dozen children with first-trimester exposure to this agent included skeletal defects, ocular hypertelorism, and craniosynostosis (Adam et al et al., 2003; Chapa et al et al., 2003; Diniz et et al al., 1978; Milunsky et al et al., 1968; Nguyen et al et al., 2002; Powell and Ekert, 1971; Sosa-Munoz et al et al., 1983; Wheeler et al et al., 2002; Zand et al et al., 2003). The frequency of malformations seems to be dose-related, but some investigators speculate that the risk of congenital anomalies is lower than for aminopterin (Kozlowski et al et al., 1990; Roubenoff et et al al., 1988). The frequency of birth defects was not increased among the offspring of over 350 women who received methotrexate prior to conception (Rustin et al et al., 1984; Van Thiel et al et al., 1970). However, this finding is entirely irrelevant to exposure during embryogenesis or other times in pregnancy. Congenital anomalies were increased in frequency among the offspring of rodents given this folate antagonist during pregnancy (Darab et al et al., 1987; Jordan et al et al., 1977; Skalko and Gold, 1974; Wilson et al et al., 1979).

Mercaptopurine Mercaptopurine (Purinethol, 6-MP), a purine antagonist, is FDA-approved primarily for the treatment of acute leukemias. It is also used in the treatment of lymphomas. Although there are two published case reports of a possible a.s.sociation of congenital anomalies with the use of this agent during early pregnancy (Diamond et al et al., 1960; Sosa-Munoz et al et al., 1983), no controlled studies involving human pregnancies have been published. In a review of 12 case reports (Doll et al et al., 1989) of 20 infants born to women given this agent during pregnancy, none had congenital anomalies (Perucca et al et al., 1995). Among 34 infants born to women who were treated with mercaptopurine early in pregnancy, one infant had a birth defect (1/34, 2.9 percent), which does not seem unusually high compared to background risk (3.5 percent) (Francella et al et al., 2003). In addition, the one birth defect was probably not related to the drug as the neonate had a chromosomal aberration. Infants of eight women treated with mercaptopurine and other antineoplastic agents during pregnancy had no congenital anomalies (Aviles et al et al., 1991). Mercaptopurine is often a component of polydrug regimens, making it impossible to a.s.sess the teratogenic potential of an individual agent. This agent was a.s.sociated with neonatal pancytopenia in several case reports (McConnell and Bhoola, 1973; Okun et al et al., 1979; Pizzuto et al et al., 1980), but most instances involved a polydrug regimen. Congenital anomalies (limb, facial, and central nervous system) were increased in frequency among rodents whose mothers were given up to several times the usual human dose of mercaptopurine during gestation (Mercier-Parot and Tuchmann-Duplessis, 1967; Puget et al et al., 1975; Shah and Burdett, 1976).

Thioguanine Another purine antagonist, thioguanine (Tabloid), is FDA-approved for the treatment of acute nonlymphocytic leukemia. It was part of a multiple drug regimen to which a fetus Alkylating agents Alkylating agents 135.

was exposed in the first trimester and it had multiple abnormalities similar to BallerGerald syndrome (Artlich et al et al., 1994). An increased frequency of malformations was found in offspring of pregnant rats that were given thioguanine during embryogenesis (Thiersch, 1957).

Cytarabine Cytarabine (cytosine arabinoside) (Cytosar-U, Ara-C, Tarabine) is a pyrimidine antagonist antimetabolite that inhibits DNA polymerase. It is approved for the treatment of leukemia (acute and chronic). It is also used against lymphomas. A few reports of monotherapy with this agent during early pregnancy have been published. Wagner and a.s.sociates (1980) reported a newborn with limb and ear anomalies whose mother received this agent alone. In a review of leukemia treatment during pregnancy, 46 infants (summarized from 24 case reports) were born to mothers who received cytosine arabinoside (Ara-C) at some point during pregnancy, and several had received it during the first trimester (Caliguri and Mayer, 1989). Among exposed pregnancies, there were two spontaneous and six therapeutic abortions. Of the remaining 38 pregnancies, there were four intrauterine deaths (apparently grossly normal), one infant with polydactyly and one with adherence of the iris to the cornea; one newborn presented with neonatal pancytopenia (Caliguri and Mayer, 1989). Anecdotal reports seem to indicate an increased risk of birth defects following first trimester exposure to cytarabine, this kind of information cannot be used to attribute risk. However, this suspicion is bolstered by findings in experimental animal studies parallel to those in humans. In addition, it seems that treatment of leukemia during pregnancy given after the first trimester is not a.s.sociated with a high frequency of congenital abnormalities. It is important to note that the folate antagonist methotrexate was a component of the polydrug therapy in several of these gravidas.

When given during embryogenesis, cytarabine was a.s.sociated with an increased frequency of congenital anomalies in two rodent teratology studies (Chaube and Murphy, 1965; Percy, 1975).

Fluorouracil Fluorouracil (Adrucil, 5-FU, Efudex, Fluoroplex) is a fluorinated pyrimidine a.n.a.log that inhibits thymidine formation and blocks DNA and protein synthesis. Its FDA-approved indications are colon, r.e.c.t.u.m, breast, stomach, and pancreas neoplasms. Other uses include bladder, cervix, endometrium, esophagus, head and neck, liver, lung, ovary, prostate, and skin cancers.

Among 24 infants whose mothers were treated with intravenous fluorouracil in combination with doxorubicin and cyclophosphamide for breast cancer during the second and third trimesters of pregnancy, no congenital anomalies occurred (Berry et al et al., 1999).

However, it must be noted that these exposures occurred outside the period of embryogenesis, and do not indicate anything about the risk of birth defects that may be related to first trimester exposure to the drug. Multiple congenital anomalies in an abortus of a mother with colon malignancy who had received 5-fluorouracil during 11 and 12 weeks of gestation (910 weeks postconception) (600 mg IV five times weekly) has been 136 136 Antineoplastic drugs during pregnancy reported (Stephens et al et al., 1980). However, the patient had also undergone bowel resection and multiple diagnostic X-ray procedures during late embryogenesis.

Malformations included bilateral radial aplasia, absent thumbs, abnormal fingers, a single umbilical artery, hypoplastic aorta, and esophageal atresia, imperforate a.n.u.s, and renal dysplasia. These anomalies were probably not related to fluorouracil because of the gestational timing of the exposure (i.e., exposure occurred outside the period of morphogenesis of these organs).

Two normal infants were born following first-trimester maternal treatment with intrav.a.g.i.n.al 5-fluorouracil (Odom et al et al., 1990), which is known to be absorbed systemically by this route (Markman, 1985). Skeletal and other major anomalies (cleft palate, central nervous system) were increased in frequency among offspring of several species of pregnant nonprimate animals born to mothers exposed to this antineoplastic during pregnancy (Chaube and Murphy, 1968; Dagg, 1960; Shah and Mackay, 1978; Wilson et al et al., 1979).

ANTIBIOTICS.

These agents work through a variety of mechanisms, including alkylation and induction of DNA breakage to prevent DNA replication in neoplasias and other cells (Box 7.5).

Box 7.5 The antibiotic antineoplastic agents Anthracyclines Other Daunorubicin (Cerubidine) Bleomycin (Blenoxane) Doxorubicin (Adriamycin) Dactinomycina (Cosmegen) Mitomycin (Mutamycin) aAlso known as actinomycin-D.

Bleomycin Bleomycin (Blenoxane) inhibits DNA and, to a lesser extent, RNA and other protein synthesis. The drug is FDA-approved to treat a variety of carcinomas (renal, cervical, penile, testicular, v.u.l.v.ar, and neck), lymphomas, and sarcomas. No reports regarding the use of bleomycin monotherapy during organogenesis have been published. Reports of bleomycin polytherapy (Christman et al et al., 1990; Kim et al et al., 1989) reported two normal infants following maternal therapy for a malignant ovarian germ cell tumor during the second trimester with bleomycin in combination with cisplatin and vinblastine. Other reports are of second-trimester exposure (Nantel et al et al., 1990; Rodriguez and Haggag, 1995) to bleomycin-containing combinations for maternal lymphoma with normal infants. One newborn infant had profound but transient neonatal leukopenia (resolved by day of life 13) following maternal therapy for metastatic adenocarcinoma that was initiated very early in the third trimester with bleomycin in combination with etoposide and cisplatin (Raffles et al et al., 1989). Limb and tail anomalies were reported in nine rat teratology studies involving bleomycin (Nishimura and Tanimura, 1976).