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TERATOLOGY 65:240 –261 (2002)
Teratogen Update: Azathioprine and
6-Mercaptopurine
JANINE E. POLIFKA1* AND J.M. FRIEDMAN2
1TERIS Project, University of Washington, Seattle, Washington 98195-7920
2Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z3
TERATOGEN UPDATE: AZATHIOPRINE AND
some patients who become ill with an immunopathic or 6-MERCAPTOPURINE
malignant disease while pregnant, treatment with6-MP or AZA may be initiated during gestation.
Azathioprine (AZA) and its active metabolite, 6-mer- The use of cytotoxic immunosuppressants during captopurine (6-MP), are purine analogues that inter- pregnancy raises concern about possible adverse effects fere with the synthesis of adenine and guanine ribo- in the developing embryo or fetus, but the potential nucleosides. These ribonucleosides are important teratogenicity of AZA and 6-MP is difficult to evaluate precursors of DNA and RNA. Because AZA and 6-MP in humans. These agents are used to treat patients who act predominantly on rapidly dividing cells such as the have severe illness, and it is often impossible to deter- T lymphocytes, these drugs are not only cytotoxic but mine if adverse effects that occur in the embryo/fetus also immunosuppressive and anti-inflammatory. The resulted from a particular treatment, the maternal ill- effects are dose-related, small doses of either drug are ness, or some other factor (Brent et al., ’97). Also, anti-inflammatory, but larger doses are immunosup- because of the severity of the illness and the complica- pressive and cytotoxic (Goldstein, ’87).
tions that ensue, combination therapy is common. Use 6-MP has been used in cancer chemotherapy, pri- of drug combinations as well as variations in dose marily in childhood and adult leukemias and usually in further hamper efforts to attribute an observed adverse combination with other drugs. 6-MP is also used to effect to a particular treatment. This article will review treat autoimmune diseases, such as inflammatory human and animal data regarding the pharmacology of bowel disease (IBD), systemic lupus erythematosus 6-MP and AZA and their adverse effects on the embryo (SLE), and rheumatoid arthritis (RA) (Bermas and Hill, ’95; Ramsey-Goldman and Schilling, ’97). Initialoral doses for treatment of leukemia range between METABOLISM AND PHARMACOLOGY
2.5–5 mg/kg/d. For maintenance therapy of leukemia,doses range between 1.5–2.5 mg/kg/d. Similar doses AZA and 6-MP are structurally very similar, differ- (1.5–2.5 mg/kg/d) are used to treat IBD (Present et al., ing only in that AZA has a methyl-nitro-imidazolyl ’80; Botoman et al., ’98; USP DI, ’01), but the use of group attached to the sulfur atom at the 6-position of 6-MP as an immunosuppressant has been largely su- the purine ring of 6-MP (Van Scoik et al., ’85; Diasio perseded by AZA, which has been shown to possess a and LoBuglio, ’96). On the average, 47% of an orally- better therapeutic index (Van Scoik et al., ’85; Gold- administered dose of AZA is available to the systemic stein, ’87; Chabner et al., ’96). AZA is no longer used as circulation (Van Os et al., ’96; Sandborn, ’98). AZA is a prodrug that, after absorption, is extensively cleaved to ployed in the treatment of autoimmune disorders at 6-MP in the blood by the enzyme glutathione-S-trans- doses between 1–2.5 mg/kg/d and at doses between 1–5 ferase (Van Scoik et al., ’85). More than 80% of AZA is mg/kg/d as part of immunosuppressive regimens to converted to 6-MP (Sandborn, ’98; Cuffari et al., ’00).
prevent transplant rejection (Botoman et al., ’98; USP AZA may also be metabolized by the enzyme aldehyde oxidase to 8-hydroxyAZA, which in turn is converted to The majority of patients affected by autoimmune an inactive metabolite, 6-thiouric acid, by xanthine diseases are women, in whom the peak incidence oc- curs between 16 and 55 years of age (Weterman, ’89; In contrast to AZA, the bioavailability of 6-MP is low Brent et al., ’97; Esplin and Branch, ’97). Successful and highly variable, with only 16% of an orally-admin- treatment with cytotoxic and immunosuppressantdrugs such as AZA has greatly improved the feasibilityof pregnancy in affected women, many of whom must *Correspondence to: Janine E. Polifka, PhD, TERIS Box 357920, continue to take the medications throughout gestation University of Washington, Seattle, WA 98195-7920.
to prevent relapse. Similarly, women who become preg- nant after organ transplantation continue immunosup- Received 13 July 2001; Accepted 22 December 2001 pressive therapy to prevent rejection if they have been Published online in Wiley InterScience (www.interscience.wiley.com).
on immunosuppressive therapy before pregnancy. In AZATHIOPRINE AND 6-MERCAPTOPURINE
istered dose of 6-MP gaining access to the systemic born et al., ’95). This delayed clearance of thioguanine circulation, on the average (Zimm et al., ’83). This is from body tissues suggests that active metabolites of because most of an oral dose is metabolized in the AZA and 6-MP may accumulate in cells with chronic intestine and liver by the enzyme xanthine oxidase to administration even if plasma concentrations are low the inactive metabolite 6-thiouric acid, which is ex- creted in the urine (Andersen et al., ’98). In addition, After oral administration, 6-MP may be anabolized the oral bioavailability of 6-MP is inversely propor- intracellularly, as described above, or catabolized in tional to the dose (Sandborn, ’98). Relative bioavailabil- the liver, depending on the enzyme and cell type the ity of 6-MP after an oral dose of 500 mg/m2 was 55% of drug first encounters (Van Scoik et al., ’85; Chrza- that after an oral dose of 75 mg/m2 (Arndt et al., ’88).
nowska et al., ’99). 6-MP can be degraded through two Nevertheless, cytocidal 6-MP plasma levels (Ͼ1–10 catabolic pathways. One is inactivation by xanthine ␮mol/L) were achieved in all six patients given 500 oxidase to 6-thiouric acid. The other catabolic pathwaymg/m2 of 6-MP but in only one of these patients after is through methylation of the 6-MP sulfur atom by thiopurine methyltransferase (TPMT).
The half-lives of AZA and 6-MP in plasma are short, There is a wide range of interindividual variability in ranging from 1–3 hr (Lennard, ’92; Gaffney & Scott, the activity of TPMT due to genetic polymorphism ’98). Steady state levels of 6-thioguanine in the red (Weinshilboum, ’92). Approximately 1 in 300 people blood cells can be reached after 2– 8 weeks of oral inherits two nonfunctional TPMT alleles and conse- treatment in most patients (Ewe et al., ’93; Sandborn et quently lacks the enzyme activity altogether. About al., ’99); however, therapeutic effects are achieved more 5–10% of people are heterozygotes for the nonfunc- slowly, requiring up to 16 weeks in some individuals tional TPMT allele and have intermediate enzyme ac- (Present et al., ’80; Lennard et al., ’84).
tivity (Collie-Duguid et al., ’99; Marathias et al., ’99; 6-MP itself is biologically inactive as an inhibitor of Relling et al., ’99). Individuals who carry a variant of purine synthesis (Van Scoik et al., ’85). It must be TPMT or lack the enzyme altogether can have high anabolized by the enzyme hypoxanthine guanine phos- cellular concentrations of 6-thioguanine nucleotides phoribosyl transferase to thioguanine nucleotides to and experience severe and sometimes fatal hematopoi- exert its cytotoxic effects (Van Scoik et al., ’85; McLeod etic toxicity when given conventional doses of 6-MP or et al., ’00). These active metabolites of 6-MP alter cel- lular metabolism in a number of ways, including inhi- There is some evidence that the methylated thiopu- bition of de novo purine ribonucleotide synthesis and rines produced by the action of TMPT on 6-MP are also interconversion and incorporation into cellular RNA capable of inhibiting de novo purine synthesis and may and DNA. Incorporation of thioguanine nucleotides play a role in cytotoxicity (Bokkerink et al., ’93; Stet et into DNA is four times greater than into RNA (Tidd al., ’93; Janka-Schaub et al., ’94; Stolk et al., ’98). The and Paterson, ’74; Nelson et al., ’75), but cell types metabolism of 6-MP in humans is complex, and its role differ with respect to whether the effect on RNA syn- in the production of active drug metabolites remains thesis or the effect on DNA synthesis is of greater poorly understood (Rowland et al., ’99).
importance to the pharmacologic response. For exam- AZA, 6-MP, and their inactive metabolite, thiouric ple, thioguanylate incorporation into cellular RNA has acid, can pass through the human placenta. All three a much larger inhibitory effect on bone marrow cells compounds were found in fetal blood after oral admin- than on circulating T-lymphocytes (Van Scoik et al., istration of radioactively-labeled AZA (35S-AZA) to ’85). Thioguanine nucleotides do not traverse cell mem- three women during the 9th, 14th, and 15th weeks of branes, circulate in the plasma, or appear in the urine pregnancy in one study (Saarikoski and Seppa¨la¨, ’73).
(Ding and Benet, ’79; Kurowski and Iven, ’91; Bostrom Higher concentrations of thiouric acid than of AZA or 6-MP were found in placenta, amniotic fluid, and fetal Incorporation of thioguanine nucleotides into cellu- lar nucleic acids is the mechanism of 6-MP’s cytotoxic-ity, whereas inhibition of de novo purine ribonucleotide ANIMAL TERATOLOGY STUDIES
synthesis and interconversion is responsible for thedrug’s inhibition of cellular proliferation (Nelson et al., The teratogenic effects of AZA and 6-MP have been ’75; Van Scoik et al., ’85). Treatment usually aims to studied in mice, rats, rabbits, and hamsters, but the minimize one effect (e.g., cytotoxicity) to achieve the treatments used in these animal studies differ from other (e.g., immunosuppression). Because the cytotoxic those given to pregnant women. Humans usually take and immunosuppressive effects of AZA and 6-MP are AZA or 6-MP orally, whereas most animal studies em- nonspecific, undesired effects such as bone marrow ploy parenteral AZA or 6-MP treatments. As discussed suppression, hepatotoxicity, and an increased risk of above, the bioavailability of these two drugs is substan- neoplasia may occur with use of these drugs (Van Scoik tially reduced when they are administered orally. In the animal studies reviewed below, parenteral AZA Although the half-lives of AZA and 6-MP in plasma and 6-MP doses are compared to the maximum human are very short, the half-life of thioguanine is quite long, therapeutic doses (5 mg/kg/d) adjusted to account for ranging between 3 and 13 days. (Lennard, ’92; Sand- reduced bioavailability (47% for AZA and 16% for POLIFKA AND FRIEDMAN
6-MP) after oral administration. Application of these Tuchmann-Duplessis, ’67). No malformations were in- adjustment factors yields a parenteral-equivalent max- duced in the offspring of rats treated orally at various imum human therapeutic dose of 2.35 mg/kg/d for AZA times during organogenesis with 6-MP at the equiva- and 0.8 mg/kg/d for 6-MP. In this adjustment, equiva- lent of Ͻ1–12 times the maximum human dose lent bioavailability and activity in both species is as- (Thiersch, ’54). A high rate of embryonic death occurred when 6-MP was administered to pregnant rats at thetime of implantation at doses equivalent to 2–12 times the human dose; these doses were also toxic to the Increased frequencies of cleft palate, open-eye, and skeletal anomalies as well as a significant decrease in In mice, treatment with 6-MP during the period of thymic size were observed in the offspring of mice organogenesis at doses equivalent to Ͻ1–125 times the injected intraperitoneally (i.p.) during the period of maximum used in humans induced increased frequen- organogenesis with the equivalent of 4 –13 times the cies of fetal death and central nervous system, facial, maximum human therapeutic dose of AZA (Githens et and limb defects in the offspring (Mercier-Parot and al., ’65; Rosenkrantz et al., ’67). No anomalies were Tuchmann-Duplessis, ’67; Puget et al., ’75; Reimers et observed in the offspring of mice treated similarly in another study (Tuchmann-Duplessis and Percier-Pa- Increased frequencies of fetal death and central ner- rot, ’64). The rate of malformations was not increased vous system, tail, and limb defects were also observed among the offspring of mice injected i.p. during the among the offspring of pregnant rabbits treated with period of organogenesis with AZA in doses that were 6-MP at doses within the human therapeutic range within the human therapeutic range or twice as great, (Mercier-Parot and Tuchmann-Duplessis, ’67; Puget et although increased frequencies of fetal loss and growth al., ’75). Cleft palate, facial, limb, and abdominal anom- retardation were observed (Tuchmann-Duplessis and alies were produced in the offspring of pregnant ham- Mercier-Parot, ’64; Githens et al., ’65; Rosenkrantz et sters given a single i.p. injection equivalent to 29 –162 al., ’67). Fetal hydrops, anemia, and hematopoietic de- times the maximum human therapeutic dose of 6-MP pression were observed without significant maternal hematopoietic depression in the offspring of mice Treatment of pregnant mice with 6-MP has been treated for 3 days during the latter stages of pregnancy found to impair the reproductive function of surviving with the equivalent of 13 times the maximum human offspring (Reimers et al., ’80). Decreased fertility oc- dose of AZA (Rosenkrantz et al., ’67).
curred among both male and female offspring of mice Increased frequencies of limb malformations, ocular treated subcutaneously during pregnancy with 6-MP in anomalies, and cleft palate occurred among the off- doses equivalent to Ͻ1– 4 times those used in humans.
spring of pregnant rabbits injected i.p. with AZA in Although the external appearance of these offspring at doses equivalent to 2– 6 times those used in humans the time of mating was normal, their gonads contained (Tuchmann-Duplessis and Mercier-Parot, ’64).
fewer germ cells than expected. In some cases, the No malformations occurred in the offspring of rats gonads were completely devoid of germ cells. The fre- injected i.p. during the period of organogenesis with quency of fetal loss was also increased in the pregnan- AZA in doses equivalent to up to four times the human cies of daughters of treated females.
therapeutic dose (Tuchmann-Duplessis and Mercier-Parot, ’64). Fetal loss and growth retardation, however, HUMAN STUDIES
were significantly increased at these doses (Tuchmann-Duplessis and Mercier-Parot, ’64; Scott, ’77; Fein et al., Although controlled epidemiological studies are not available, information regarding the outcome of preg- nancy in women who were treated with AZA during 6-MP is teratogenic in experimental animals at doses pregnancy has been reported in a large number of similar to or greater than those used therapeutically in clinical series (see Table 1). A list of the congenital humans. An increased incidence of cleft palate, skele- anomalies described among the infants of women who tal, and urogenital anomalies, diaphragmatic hernia, took AZA during pregnancy is presented in Table 2.
and other malformations was observed among fetuses The frequency of congenital anomalies among in- of rats given a single i.p. injection equivalent to 37.5– fants of renal transplant recipients who were treated 156 times the maximum human therapeutic dose of 6-MP on the 11th or 12th day of gestation (Murphy, ’60; 0.0 –11.8% in 27 clinical series (Table 1). The number of Bragonier et al., ’64; Chaub and Murphy, ’68; Kury et infants included in each series varies from 6 –110. No al., ’68; Puget et al., ’75). In another study, increased recurrent pattern of congenital anomalies emerges frequencies of fetal death and central nervous system, from these studies (Table 2). The incidence of congen- facial, and limb anomalies were observed among the ital anomalies did not appear to be increased among offspring of rats treated at various times during orga- 314 infants of female kidney transplant recipients nogenesis with the equivalent of Ͻ1– 62.5 times the whose pregnancies were reported to the National maximum human dose of 6-MP (Mercier-Parot and Transplantation Pregnancy Registry (Armenti et al., AZATHIOPRINE AND 6-MERCAPTOPURINE
’94). It is difficult to determine if the rate of congenital twins died of cardiomyopathy. The authors attributed anomalies in some of these studies is higher than what the neonatal cardiomyopathy to maternal treatment would be expected because the mothers usually took with tacrolimus, a recognized cause of cardiomyopathy other drugs besides AZA and often had azotemia, hy- in transplant recipients (Atkison et al., ’95; Baruch et pertension, and other illnesses. No congenital anoma- al., ’96). Five other infants listed among the case re- lies occurred in two small series among ten infants ports in Table 3 were either stillborn or died shortly born to heart/lung or liver transplant recipients who after birth (Lower et al., ’71; Zerner et al., ’81; Williams were treated with AZA and other immunosuppressants and Johnstone, ’82; Laifer and Guido, ’95). No congen- during pregnancy (Talaat et al., ’94; Pruvot et al., ’97).
ital anomalies were observed in any of these babies.
One infant with a cardiovascular defect, one with pes Maternal AZA therapy early in gestation was asso- equinovarus, and one with undescended testicle were ciated with an increased frequency of fetal death reported among 33 infants born to women who were among women with SLE (Martı´nez-Rueda et al., ’96), treated with AZA during pregnancy for rheumatic dis- but the women in this study had severe SLE, which ease in a study conducted through the Swedish na- could account for the poor fetal survival (Georgiou et tional medical record system (Ka¨lle´n, ’98). No congen-ital anomalies were observed among 17 liveborn al., ’00). High frequencies of premature delivery, fetal infants whose mothers were treated with AZA during growth retardation and neonatal death have been re- the first trimester of pregnancy for severe SLE (Mar- ported in pregnancies of AZA-treated renal transplant tı´nez-Rueda et al., ’96) or among nine liveborn infants recipients in some series (Penn et al., ’80; Registration whose mothers were treated with AZA during preg- Committee of the European Dialysis and Transplant nancy for various immunopathic diseases in other se- Association [EDTA], ’80; Pirson et al., ’85; Marushak et ries (Symington et al., ’77). The infant of a woman al., ’86; Brown et al., ’91; Sturgiss and Davison, ’91; treated with AZA for SLE during the 2nd and 3rd Armenti et al., ’93, ’95; Cararach et al., ’93; Pahl et al., trimesters of pregnancy was reported to have double ’93; Huynh and Min, ’94; Ka¨lle´n, ’98). The infants of outlet right ventricle, but this defect is unrelated to the such women often have adrenocortical insufficiency, AZA exposure because cardiac development was com- bacterial infections, or respiratory distress (Penn et al., plete by the time treatment began (Tincani et al., ’92).
’80; Pahl et al., ’93). Many of these transplant recipi- Six normal infants were born to other AZA-treated ents were maintained on cyclosporine and prednisone mothers in this series. No congenital anomalies were as well as AZA; therefore it is impossible to separate seen among 22 infants of women treated with AZA the effects of AZA from those of other medications or during pregnancy for IBD in two clinical series (Al- stead et al., ’90; Khan et al., ’00) or among 14 infants of Fatal neonatal anemia, thrombocytopenia, and lym- women treated with AZA during pregnancy for auto- phopenia occurred in an infant born to a renal trans- immune hepatitis (Heneghan et al., ’01).
plant recipient treated with AZA and prednisone dur- Case reports of 117 infants born to women who were treated with AZA at various times during pregnancy lymphopenia and thrombocytopenia have been ob- have been published (see Table 3). First-trimester ex- served in several other children born to women who posures occurred in 96% of the cases. No major congen- received similar therapy (Lower et al., ’71; Cote´ et al., ital anomalies were found in 112 of these infants. Con- ’74; Price et al., ’76; Rudolph et al., ’79; Penn et al., ’80; genital anomalies were observed in two infants of renal Davison et al., ’85; Talaat et al., ’94). It seems likely transplant recipients who had been treated with AZA that these hematologic abnormalities resulted from a during pregnancy (Rasmussen et al., ’81; Burleson et toxic effect of AZA similar to that which occasionally al., ’83). One of these children, whose mother was not treated with AZA until the second trimester of preg- Pregnancy in renal transplant recipients is fre- nancy, had an atrial septal defect. The other affected quently complicated by hypertension (Armenti et al., child had a mild combined valvular aortic anomaly, ’95). Furthermore, immunosuppression by AZA may possibly in combination with a ventricular septal defect predispose to bacterial, viral, and fungal infections and delayed psychomotor development (Burleson et al., (O’Donnell et al., ’85; Pahl et al., ’93; Castiglione et al., ’83). An anencephalic fetus was delivered to a third ’00). These factors may also have adverse effects on the renal transplant recipient who was treated with AZA throughout pregnancy but who also had insulin-depen-dent diabetes mellitus (Vinicor et al., ’84). Congenital anomalies were also reported in two infants whose Although 6-MP is effective in the treatment of auto- mothers were treated for SLE throughout pregnancy immune disorders such as IBD and SLE, it is more with AZA (Williamson and Karp, ’81; Ostrer et al., ’84).
widely used as an antineoplastic agent, especially in Preaxial polydactyly was found in one of these infants the treatment of leukemia (Goldstein, ’87; Pearson et and microcephaly, facial dysmorphology, and micrope- al., ’95). Malignancy during pregnancy poses substan- nis in the other. In another case report, both infants in tial risks to maternal and fetal survival, so treatment a pair of twins born at 32 weeks gestation exhibited with potentially teratogenic drugs is sometimes justi- dilated heart chambers (Vyas et al., ’99). One of the POLIFKA AND FRIEDMAN
pregnancies
reporting
Clinical
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TABLE 2. Congenital anomalies observed among infants of women who were treated
with AZA during pregnancy
Plagiocephaly with neurological damage (1) Registration Committee of the European Dialysis Registration Committee of the European Dialysis aSlight impairment in psychomotor development (2) Rasmussen et al., ’81; Marushak et al., ’86 Registration Committee of the European Dialysis Burleson et al., ’83; McGrory et al., ’99 Probable peripheral pulmonary arterial stenosis (mild) (1) Mild combined valvular aortic anomaly, possibly in combination Hyperflexion of 5th digits, large toenail deformity (1) Williamson and Karp, ’81; Cararach et al., ’93 Salant et al., ’76; O’Donnell et al., ’85 Hadi et al., ’86; Cararach et al., ’93 Registration Committee of the European Dialysis & Transplant Association, ’80; Ogburn et al.,’86; Cararach et al., ’93 Registration Committee of the European Dialysis & Transplant Association, ’80; Ka¨lle´n, ’98 Microcephaly, unusual facial features, micropenis (1) “Severe multiple malformations incompatible with life” (1) aSome infants had more than one anomaly.
No congenital anomalies were observed among the cleft palate, hypoplastic thyroid and ovaries, thoracic infants of 14 women who were treated with 6-MP and kyphosis, and growth retardation (Diamond et al., ’60).
other antineoplastic agents during pregnancy in two The infant died at 10 weeks of age. Macrocephaly, small series (Pizzuto et al., ’80; Aviles et al., ’91). Pan- hypertelorism, and “probable” phocomelia were ob- cytopenia was observed in one infant who died of sep- served in one twin infant whose mother took 6-MP for ticemia at 21 days of age (Pizzuto et al., ’80). A second infant in the same series died of gastroenteritis at ’83). The other twin was normal. Two of the infants three months of age. The frequency of congenital anom- listed in Table 4 were stillborn, and one of these babies alies did not appear to be increased among the children had polydactyly (Parekh et al., ’59; Mulvihill et al., ’87).
of 72 women with IBD who were treated with 6-MP Transient neonatal anemia and pancytopenia were during pregnancy (Francella et al., ’96).
observed in three infants of women treated with 6-MP Case reports of 53 women who took 6-MP at various and other antineoplastic agents during pregnancy (Mc- times during pregnancy have been published (Table 4).
Connell and Bhoola, ’73; Okun et al., ’79; Pizzuto et al., Forty-nine (92%) of these women were treated with ’80). These short-term effects may be the result of di- 6-MP and other medications for leukemia and the re- maining mothers were treated with 6-MP for non-Hodgkin lymphoma (1), SLE (1), or IBD (2). 6-MP MECHANISMS OF TERATOGENICITY
treatment occurred in the first trimester in 46% of thepregnancies for which there are data regarding time of The mechanisms by which AZA and 6-MP or their exposure. Four (7.5%) of the 53 reported pregnancies metabolites induce teratogenicity are not known. Two resulted in spontaneous abortions; one of the fetuses (a mechanisms have been proposed: 1) inhibition of nu- twin) had major malformations. Congenital anomalies cleic acid synthesis, or 2) alteration of maternal zinc were also reported in two (4.1%) of 49 liveborn infants.
metabolism. Laboratory investigations of these mech- One child whose mother took 6-MP for leukemia anisms have focused on the effects of 6-MP, but the “around conception” and 1 month before delivery was conclusions probably apply to AZA as well because AZA born with bilateral microphthalmia, corneal opacity, AZATHIOPRINE AND 6-MERCAPTOPURINE
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Inhibition of Nucleic Acid Synthesis
(Hirsch and Hurley, ’78). Several studies have foundthat 6-MP is capable of altering the metabolism of zinc Numerous in vivo and in vitro studies have demon- and other minerals in pregnant rats and their fetuses strated that 6-MP is incorporated into the nucleic acids (Hirsch and Hurley, ’78; Amemiya et al., ’86, ’89;).
of human and other mammalian cells and that this Therefore, it has been suggested that the teratogenic incorporation is the key mechanism of cytotoxicity effect of 6-MP may be mediated through embryonic (Bieber et al., ’61; Elion, ’67; Lepage and Whitecar, ’71; zinc deficiency (Amemiya et al., ’86, ’89; Hirsch and Tidd and Paterson, ’74; Nelson et al., ’75; Breter, ’85).
6-MP inflicts damage on rapidly dividing cells, such as Amemiya and associates (’86) found that the zinc bone marrow, intestinal epithelium, and the reproduc- concentrations of whole fetuses and fetal liver were tive organs in adults (Sokal and Lessmann, ’60). Most consistently lower after treatment of pregnant rats on embryonic tissues proliferate rapidly, especially during gestational day (GD) 11 with a teratogenic dose of organogenesis, so embryonic tissue would be expected 6-MP. The increased rate of fetal anomalies produced to be particularly sensitive to the cytotoxic actions of by this 6-MP treatment could be partially alleviated by 6-MP. Several attempts have been made to test the supplementing the maternal diet with zinc. Similar hypothesis that the teratogenicity of 6-MP results from protective effects on embryogenesis were found in an- cytotoxicity caused by an incorporation of 6-thiogua- other study in which rats were fed diets supplemented with zinc and injected with a teratogenic dose of 6-MP Bragonier and Carver (’68) administered a terato- on GD 11 (Hirsch and Hurley, ’78). Although it is clear genic i.p. dose of 6-MP to pregnant rats on gestation that supplemental levels of zinc in the maternal diet day 12. Placental purine synthesis was decreased 6 can reduce the teratogenicity of 6-MP in animals, the hours after treatment, and fetal DNA content was re- mechanism by which zinc supplementation does this is duced 48 hr after treatment. No evidence of fetal mal- formation was seen at this stage of development, butskeletal defects consistently occurred in 20-day-old fe-tuses after such treatment.
GENETIC EFFECTS OF AZA AND 6-MP
Platzek et al. (’85, ’94) found a correlation between The mechanisms of teratogenicity and mutagenicity, incorporation of S35-labeled 6-MP-riboside (an active and the risks associated with them, are distinct (Alex- metabolite of 6-MP) into embryonic DNA and the fre- androv, ’73; Bishop et al., ’97). Teratogenesis occurs quency of skeletal abnormalities in the offspring of when an initially normal embryo or fetus is damaged pregnant mice treated on the 11th day of gestation.
while it is developing, usually by an exposure that the This observation is consistent with the hypothesis that mother sustains while she is pregnant. Teratogenicity the embryotoxicity of 6-MP riboside is due to its incor- affects many cells of the developing organism, and the poration, probably as 6-thioguanine, into the DNA of incidence and severity of teratogenic effects increase with the dose and the number of cells affected (Brent, In another study, Burdett et al. (’88) found that ma- ’86). Cells that are damaged by a teratogen may be ternal treatment with the equivalent of 87.5 times the replaced by normal cells in early embryonic develop- maximum human therapeutic dose of 6-MP on Day 9 of ment, so a teratogen must damage a threshold number gestation depressed DNA synthesis and reduced mes- of cells to produce a disruptive effect. Consequently, a enchymal cell number and density in the maxillary threshold dose exists for teratogenic exposures, below processes of treated 10 –12-day-old hamster embryos.
Although these studies provide convincing evidence In contrast, mutation results from DNA damage that 6-MP-induced modifications in DNA are associ- within a single cell. Germ cell mutations occur when ated with increased frequencies of fetal malformations, there is damage to the DNA of the sperm or oo¨cyte. If they do not prove that the inhibition of DNA synthesis an individual is conceived from a sperm or oo¨cyte con- was directly involved in the pathogenesis of the anom- taining a mutation, the mutation will be copied into every cell of that individual’s body. The likelihood ofmutation increases with the magnitude of mutagen Alteration of Maternal Zinc Metabolism
exposure, but only a single event is required for muta- Zinc is essential to many enzyme systems that influ- tion to occur. A potential mutagenic risk may therefore ence DNA synthesis, RNA synthesis, and cell division exist at any dose, and there is no threshold for a mu- and proliferation (Ploysangam et al., ’97; MacDonald, ’00). Maternal zinc deficiency decreases fetal incorpo- Because AZA and 6-MP interfere with nucleic acid ration of 3H-thymidine (Swenerton et al., ’69; Eckhert synthesis, treatment with these drugs might produce and Hurley, ’77; Hirsch and Hurley, ’78; Shrader et al., germ cell mutations as well as teratogenic effects. Mu- ’78) and reduces the activity of fetal thymidine kinase tations that occur in the germ cells of a treated parent and DNA polymerase (Dreosti and Hurley, ’75; Duncan could result in constitutional chromosomal abnormali- and Hurley, ’77; Shrader et al., ’78). In rats, maternal ties or new dominant diseases in children who are zinc deficiency can produce fetal anomalies very simi- subsequently conceived. Such effects would be more lar to those caused by maternal treatment with 6-MP likely after treatment of a man than of a woman be- AZATHIOPRINE AND 6-MERCAPTOPURINE
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POLIFKA AND FRIEDMAN
cause DNA synthesis in oo¨genesis is restricted to em- comes was significantly higher when the fathers were bryonic and fetal life. Mutation of germ cell precursors treated with 6-MP within 3 months of conception than could also occur during embryogenesis (and therefore when they were not (OR ϭ 19.6, 95% confidence inter- be associated with treatment of the mother during val 3.1–122) (Rajapakse et al., ’00). There were two pregnancy), but any constitutional chromosomal ab- spontaneous abortions and two infants born with con- normalities or new dominant diseases produced would genital anomalies in 13 pregnancies fathered by men in occur in her grandchildren, not in her children.
the 6-MP-treated group. The congenital anomalies ob- Both AZA and 6-MP have been found to be muta- served were a missing thumb in one child and acrania, genic in various mammalian in vitro and in vivo assays digital malformations, and limb anomalies in a fetus (Voogd, ’89; Mosesso and Palitti, ’93; Bishop et al., ’97).
that was therapeutically aborted. Two spontaneous Dominant lethal effects, which usually result from abortions and no congenital anomalies were observed chromosomal or genic mutations, were observed when among 90 pregnancies fathered by men with IBD who male mice were injected i.p. with the equivalent of were not treated with 6-MP. The difference between 5– 602 times the maximum human therapeutic dose of the groups is largely attributable to lower than ex- 6-MP (Ray et al., ’73; Generoso et al., ’75a, b; Schenck- pected frequencies of spontaneous abortions and con- ing and Frohberg, ’75; Sykora, ’81). Similar effects were genital anomalies in the pregnancies fathered by men observed after protracted oral administration of 6-MP who were not treated with 6-MP. No significant differ- at doses that were 5–10 times the maximum human ence in the frequency of adverse pregnancy outcomes dose in one study (Sykora, ’81), but not in another (Ray was observed between a third group of fathers with et al., ’73). Damage occurred in the early stages of IBD who conceived at least 3 months after stopping spermatogenesis, mainly affecting the late differenti- 6-MP treatment and the fathers with IBD who were ating spermatogonia and early spermatocytes (Gen- eroso et al., ’75b; Schencking and Frohberg, ’75). Sim- Wilms tumor was reported in one 4-year-old boy ilarly, the dominant-lethal test was positive when AZA whose father took 6-MP for IBD at the time of concep- was administered orally to male mice at 5–20 times the maximum human therapeutic dose (Clark, ’75; Racineand Schmid, ’84). Both AZA and 6-MP have also been Preconception exposures to AZA in Humans
found to increase the frequencies of chromosome aber- Very few studies have investigated the pregnancy rations, micronuclei, and sister chromatid exchange in outcomes for spouses of men treated with AZA before rodent bone marrow cells (Holden et al., ’73; Maier and conception. Golby (’70) found 38 normal pregnancies Schmid, ’76; van Went, ’79; Matter et al., ’82; Sono et and two spontaneous abortions among the spouses of 40 male renal transplant recipients who conceivedwhile receiving long-term immunosuppressive therapy Preconception Exposures to 6-MP in humans
with AZA. In two other studies, congenital anomalies The largest experience with respect to the mutagenic were found in nine (3.3%) of 273 and two (4.8%) of 42 effects of 6-MP in humans is with men and women who infants of male renal and cardiac transplant recipients, were given the drug for treatment of malignant disease respectively (Ahlswede et al., ’94; Wagoner et al., ’94).
before conception. Congenital anomalies did not appear Most of the men were treated with AZA in addition to to be unusually frequent in two series of 11 and 49 other immunosuppressants before conception. No re- children whose parents had previously received 6-MP current pattern of anomalies was apparent in either of as part of their treatment for leukemia (Pajor et al., ’91; these studies. The rates of miscarriage and other ad- Green et al., ’97). Similarly, only 1/38 (2.6%) liveborn verse outcomes in pregnancies fathered by renal trans- infants of women who had been successfully treated plant recipients were similar to those of the general with 6-MP and other medications for trophoblastic tu- population (Ahlswede et al., ’94). One case report de- mors before pregnancy was reported to have congenital scribes an infant with lumbar myelomeningocele born anomalies (Walden and Bagshawe, ’79). This affected to a male renal transplant recipient who was treated infant had spina bifida and hydrocephalus. Spontane- with AZA (125 mg/d) and prednisone (15 mg/d) (Tallent ous abortions occurred in 13% of the pregnancies in this series; this is about the expected frequency. In Increased frequencies of acquired chromosomal addition, published case reports include 21 normal in- breaks and rearrangements have been observed in the fants (Hinkes and Plotkin, ’73; Bacon and Kernahan, lymphocytes of renal transplant recipients receiving ’75; Wegelius, ’75; Barkhan and Evans, ’76; Kroner and AZA therapy and, transiently, in the infants of women Tschumi, ’77; Moe et al., ’79; Blatt et al., ’80; Gasser, who were given such treatment during pregnancy ’80; Sanz and Rafecas, ’82; Evenson et al., ’84), two (Gevers et al. ’71; Leb et al., ’71; Sharon et al., ’74; Price children with minor anomalies (Moe et al., ’79; Blatt et et al., ’76; Henahan, ’83). The clinical significance, if al., ’80), and one child with multiple congenital anom- any, of these observations is unknown.
alies (Evenson et al., ’84) born to men or women who One child with two separate de novo constitutional were treated with 6-MP before conception.
chromosomal anomalies has been reported whose In a retrospective cohort study of pregnancies fa- mother was treated before and during pregnancy with thered by men with IBD, the incidence of adverse out- AZA and prednisone (Ostrer et al., ’84). Another re- AZATHIOPRINE AND 6-MERCAPTOPURINE
ported child whose father was treated with AZA for tional doses of AZA or 6-MP. The occurrence of higher Crohn disease for 4 years before conception had a de circulating concentrations of drug in women with such novo deletion of chromosome 11p13 and aniridia and genetic variants seems likely to increase their risk of psychomotor delay consistent with the WAGR syn- an adverse pregnancy outcome, but this has not been drome (Ben-Neriah and Ackerman, ’01). These obser- vations raise the possibility that parental AZA treat- It is important to remember that many of the women treated with cytotoxic immunosuppressants such as constitutional cytogenetic abnormalities in subse- AZA and 6-MP have serious illnesses. Poor pregnancy quently conceived children. If this does occur, it must outcomes are common among women with chronic ill- be infrequent because most children born to men or nesses, such as cancer and rheumatic diseases. Never- women treated with AZA appear to be normal (EDTA, theless, these medications may permit a woman to ’80; Penn et al., ’80; Pirson et al., ’85).
become pregnant who otherwise would be too ill to do The number of reported children conceived by men or so. These chronic diseases may pose very serious risks women treated with AZA or 6-MP is too small to draw to both the mother and fetus during pregnancy. In conclusions regarding the possible mutagenic effects of many cases, the risk associated with effective treat- ment using AZA or 6-MP may be smaller than the riskthat accompanies an untreated pregnancy in a seri-ously ill woman.
Because AZA and 6-MP inhibit the synthesis of nu- Maternal AZA or 6-MP treatment during pregnancy cleic acids, it is possible that treatment with these is clearly teratogenic in animals at doses similar to or drugs interfere with DNA replication in the germ cells.
greater than those used in humans, but information on Although cytogenetic abnormalities and congenital the teratogenicity of these medications in human preg- anomalies have been described in a few of the offspring nancy is limited. Most available information is from of patients treated with AZA or 6-MP before concep- single cases or clinical series of organ transplant recip- tion, too little information is available to draw any firm ients or women undergoing treatment for cancer. Less conclusions regarding the germ-cell mutagenicity of information is available on the use of AZA or 6-MP for these drugs. Large populations are required to detect treatment of other diseases in pregnant women. With- even a small increase in germ cell mutation (Byrne, out the benefit of well-controlled studies, it is difficult ’99). The limited available data suggest that the risk of to determine if the risk of birth defects is higher among birth defects associated with preconceptional treat- infants whose mothers are treated with AZA or 6-MP ment with these drugs is likely to be increased only during pregnancy than in the general population.
Given the animal and mechanistic data, however, onemust assume that some risk exists with chemothera- COUNSELING THE PREGNANT PATIENT
peutic doses of 6-MP early in pregnancy. The availablehuman data, although limited, suggest that this risk is Women of reproductive age who must be treated with AZA or 6-MP should be advised about the potential In addition, prenatal exposure to these drugs may teratogenic and mutagenic risks of these drugs in hu- cause bone marrow suppression in neonates. It is likely mans. In addition to the factors mentioned above, a that women treated with AZA or 6-MP for malignan- woman’s risk of giving birth to an infant with congen- cies have a higher risk of adverse pregnancy outcomes ital anomalies will depend on her state of health, other than women treated for other diseases because of the potentially adverse exposures, previous and current higher doses used to treat cancer. The evidence from pregnancy history, and family history. In general, an clinical series suggests that the risk of congenital individual’s risk should be presented with reference to anomalies among infants of transplant recipients who the background risk of congenital anomalies that at- are treated with AZA throughout pregnancy is minimal tends every pregnancy; but because of her illness, the to small. One might expect a greater risk on the basis “background” risk for a woman who requires treatment of the animal studies, but the poor bioavailability of with AZA or 6-MP will probably be higher than the AZA and 6-MP after oral administration may produce 3–5% that is usually quoted for the general population.
levels that are too low to have a substantial teratogenic Women who must be treated during the first trimester of pregnancy with AZA or 6-MP will have a higher risk Both AZA and 6-MP are often used in conjunction of teratogenic effects than women treated in the 2nd or with other medications. The teratogenic risks associ- ated with polydrug therapy that includes AZA or 6-MP Pregnancies in women who require AZA or 6-MP may be greater than the risks associated with maternal treatment require careful management and coordi- nated perinatal and medical care. Detailed fetal ultra- Genetic variations may influence the teratogenicity sound examination can be used to screen for many of AZA or 6-MP. Women with polymorphic variants serious fetal malformations and to monitor fetal that reduce the activity of TPMT may experience po- growth and well-being (Framarino di Malatesta et al., tentially toxic drug levels when treated with conven- POLIFKA AND FRIEDMAN
Although potentially teratogenic, drugs such as AZA Ben Hamida F, Ben Abdallah T, Barbouch S, Laabidi J, Abderrahim and 6-MP enable some chronically ill women to have E, Goucha R, Hedri H, el Younsi F, Ben Moussa F, Kheder MA, Ben healthy children. The risks and benefits of treatment Maı¨z H. 1999. Four successful pregnancies following kidney trans-plantation. Transplant Proc 31:3146 –3147.
must be carefully balanced by the patient in consulta- Ben-Neriah Z, Ackerman Z. 2001. WAGR syndrome in a baby—the tion with her doctor and partner. More research is result of 6-MP treatment in a father affected by Crohn disease? needed to develop alternative therapeutic agents that can be used safely during pregnancy.
Bererhi L, Bedrossian J, Metivier F, Duboust A, Fornairon S, Marrast AC, Idatte JM. 1997. Pregnancy in kidney transplantation: pastand present experience. Transplant Proc 29:2478.
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