EPOETIN ALFA

Fetal Risk Summary

Recombinant human erythropoietin (epoetin alfa), a 165-amino acid glycoprotein produced by a recombinant DNA method with the same biologic effects as endogenous erythropoietin, is used to stimulate red blood cell production.

Fetal toxicity (decreased growth, delays in appearance of abdominal hair, delayed eyelid opening, delayed ossification, and decreases in the number of caudal vertebrae) was observed in the offspring of pregnant rats dosed with 500 U/kg (five times the human dose) (1). In addition, a trend toward increased fetal wastage occurred in pregnant rats dosed with 100 and 500 U/kg. No fetal adverse effects were seen in rabbits at doses up to 500 U/kg from day 6 to 18 of gestation (1).

Epoetin alfa crosses the placenta in significant amounts to the fetus in pregnant mice (2) but not from the mother to the fetus (3) or from the fetus to the mother in sheep (4). Another study also found no transfer of recombinant epoetin alfa to the fetus in sheep and monkeys, in spite of high maternal concentrations (5). The question of human placental transfer of endogenous erythropoietin and epoetin alfa was examined in a 1993 review (6). Five reasons arguing against transfer were presented: poor correlation between maternal and fetal levels, high correlation between fetal plasma and amniotic fluid levels, high molecular weight, animals studies, and one human in vitro study (6). Since then, several studies have investigated whether or not epoetin alfa is transferred across the human placenta (7,10,11,12,13,14 and 15).

A 1992 study measured an elevated cord erythropoietin level (62 mIU/mL; normal <19) in an infant whose mother was receiving 150 U/kg/week (9000 U/week) of the drug (7). However, because the mother had insulin-dependent diabetes, a disease known to display elevated cord levels of erythropoietin (8,9 and 10), the investigators could not determine whether the cord concentrations were due to exogenous or endogenous erythropoietin (7). The lack of correlation between maternal and fetal erythropoietin concentrations, at least between 19 and 28 weeks' gestation, suggests that endogenous maternal erythropoietin does not cross the placenta to the fetus (10). At 7–12 weeks' gestation, however, mean maternal and extraembryonic coelomic fluid concentrations of endogenous erythropoietin were nearly identical, 15.4 mU/mL (range 6.8–32.1 mU/mL) compared to 15.45 mU/mL (range 5.6–29.4 mU/mL), respectively (11). Passage of maternal erythropoietin to the coelomic fluid via the decidualized endometrium was offered as a possible explanation for the identical levels. This latter study also found low amniotic fluid levels of erythropoietin, mean 5.0 mU/mL (range <5.0–5.8 mU/mL), at 7–12 weeks of gestation, but their samples may have been contaminated with coelomic fluid (11). An earlier study was unable to find endogenous erythropoietin in amniotic fluid before the 11th week of gestation (12). More recent investigations have demonstrated the lack of placental passage of recombinant epoetin alfa across the human placenta (13,14 and 15).

In the fetus, erythropoietin is primarily produced by the fetal liver during most of pregnancy (16). Erythropoietin binding sites have been found in the 1st trimester of pregnancy in the human fetal liver and lung (17) and in cultures of umbilical vein endothelial cells derived at cesarean section (18). A 1994 report compared the levels of endogenous erythropoietin measured in the umbilical serum in normal women at term and in premature labor, and in those with preeclampsia or diabetes (19). Women with preeclampsia had the highest concentrations (95.8 mU/mL), followed by those with diabetes (38.0 mU/mL), women in premature labor (25.2 mU/mL) and normal women (21.1 mU/mL), demonstrating that fetal hypoxia was not the only factor that determines levels of this glycoprotein (19).

The first published report on the use of epoetin alfa in human pregnancy appeared in a 1990 abstract (20). A 28-year-old Japanese woman with chronic glomerulonephritis became pregnant 8 years after the start of dialysis and approximately 22 months after the initiation of weekly doses of epoetin alfa. She had been amenorrheic prior to epoetin alfa therapy; her menses returned 17 months after start of treatment. The duration of her dialysis treatments (in hours per week) was gradually increased throughout gestation. She received 4500–9000 U/week of epoetin alfa from the 20th gestational week (doses prior to this time were not specified) until delivery at 36 weeks' gestation. Her blood pressure was normal throughout pregnancy, as was intrauterine fetal growth. The 2396-g, healthy, male infant was normal at birth with Apgar scores of 9 and 9 at 1 and 5 minutes, respectively. He was discharged with his mother 12 days after birth.

A report published in 1991 described a 32-year-old hypertensive woman with end-stage renal disease of unknown origin, who had been on hemodialysis for 4 years (21). She was started on epoetin alfa early in the 1st trimester and continued until delivery (36 weeks by dates, 34 weeks by ultrasound). No transfusions were required during pregnancy. An emergency cesarean section was performed because of fetal distress secondary to severe maternal hypertension. The 1140-g male infant had Apgar scores of 7 and 8 at 1 and 5 minutes, respectively. No congenital malformations were noted in the infant, who was discharged home at 35 days of age.

A second 1991 publication involved a 37-year-old woman who was treated throughout pregnancy with escalating doses of epoetin alfa (22). The patient had received a renal transplant 9 years before pregnancy because of reflux nephropathy, but the onset of chronic rejection caused progressive renal failure. Due to persistent anemia, she was started on a regimen of epoetin alfa, 4,000 U/week, and supplemental iron shortly before conception. The dose was increased at 18 weeks' gestation to 8,000 U/week, and then to 12,000 U/week at 27 weeks. Hemodialysis was started during the 25th week of pregnancy because of severe renal failure, polyhydramnios, and fetal intrauterine growth retardation. Her blood pressure was controlled with atenolol and nifedipine. Severe intrauterine growth retardation and fetal distress were diagnosed at 31 weeks and, after betamethasone therapy for fetal lung maturation, a cesarean section was performed to deliver a 780-g female infant. Birth weight was below the 3rd percentile for gestational age. Although the growth retardation was attributed to the mother's renal disease, the use of atenolol was probably a factor (see Atenolol). Except for transient coagulopathy and thrombocytopenia found at birth, both thought to be due to the mother's condition or premature delivery, the infant progressed normally and was discharged home at 66 days of age with a weight of 2140 g.

A 1992 report described the use of epoetin alfa, combined with supplemental oral iron, in three human pregnancies that resulted in the birth of four (one set of twins) infants (7). The birth weights of the newborns were all at approximately the 50th percentile for gestational age (7). Two of the women developed polyhydramnios after starting treatment with epoetin alfa, and all developed preeclampsia or worsening renal impairment, but the authors could not determine whether these were effects of the drug treatment or the underlying disease (7). Hematocrit values were maintained in the targeted 30%–33% range, and no coagulation problems or significant changes in platelet counts were observed. The three pregnancies are described below.

A 30-year-old woman, with onset of renal disease secondary to immunoglobulin A nephropathy and chronic hypertension before pregnancy, was treated with epoetin alfa 50–65 U/kg/week starting in the 20th gestational week (7). Polyhydramnios was noted at 32 weeks' gestation. Because of worsening renal failure, labor induction was initiated at 35 weeks resulting in the delivery of a 2570-g male infant with Apgar scores of 8 and 8 at 1 and 5 minutes, respectively. The newborn had mild hyperbilirubinemia and required oxygen, but no other problems were noted. He was doing well at 3 months.

The second patient, a 33-year-old woman with hypertension, diabetes, and renal impairment, was treated with 150 U/kg/week of epoetin alfa beginning at 26 weeks' gestation (7). Polyhydramnios developed, and labor was induced at 32 weeks because of worsening renal function and superimposed preeclampsia. After maternal betamethasone therapy to accelerate fetal lung maturity, a 2020-g male infant was delivered, with Apgar scores of 4 and 7 at 1 and 5 minutes, respectively. The infant had mild hypoglycemia and hyperbilirubinemia and, initially, required oxygen therapy. He was discharged home at 2 weeks of age.

The third patient was a 26-year-old with renal disease secondary to crescentic segmental necrotizing glomerulonephritis following streptococcal pharyngitis (7). She was treated with azathioprine and prednisone throughout a twin gestation to control her renal disease. Beginning at 14 weeks' gestation, she was treated with epoetin alfa, 85–160 U/kg/week, continuously until 33 weeks' gestation, except for a 4-week period at 23–27 weeks. Therapy was halted during that time because of a low ferritin level, and therapy was discontinued when it recurred at 33 weeks. Labor was induced at 35 weeks for worsening renal function. A cesarean section was required because of failure to descend, resulting in the delivery of a 2220-g female (Apgar scores of 4 and 8, respectively) and a 2410-g male (Apgar scores of 2 and 5, respectively). The infants were developing normally at 7 months of age (7).

The pregnancies of six women who became pregnant while on dialysis for end-stage renal disease and who were treated with epoetin alpha have been described (23,24). No effects on the mothers' blood pressure control were observed in these cases, and in one of the reports, the investigators found no evidence that the drug crossed the placenta to the fetuses (24).

A number of additional studies have been published describing the use of epoetin alfa during human pregnancy (25,26,27,28,29,30,31 and 32). In most of the studies or reports, the drug was used to treat the maternal anemia associated with severe renal disease (25,26,27,28 and 29), but in three reports, epoetin alfa was used in women with either heterozygous b thalassemia (30), hypoproliferative anemia and a low serum erythropoietin level (31), or acute promyelocytic leukemia (32). Except for a single complication in which abruptio placentae with resulting fetal death occurred at 23 weeks' gestation and drug therapy could not be excluded as a contributing factor (28), no other fetal and/or newborn adverse effects attributable to epoetin alfa were observed.

In summary, the use of recombinant human erythropoietin (epoetin alfa) does not seem to present a major risk to the fetus. The glycoprotein does not cross the human placenta to the fetus. The severe maternal hypertension or worsening of renal disease requiring delivery of the fetus that occurred in four pregnancies may be an adverse effect of the drug therapy, a consequence of the preexisting renal disease or current pregnancy, or a combination of these factors. The contribution of epoetin alfa to the case of abruptio placentae in a woman with severe hypertension and chronic renal insufficiency is unknown. No cases of thrombosis were reported in the pregnant women treated with epoetin alfa, but this is a potentially serious complication. Because anemia and the need for frequent blood transfusions also present significant risks to the mother and fetus, it appears that the benefits derived from the use of epoetin alfa outweigh the known risks.

Breast Feeding Summary

Epoetin is a 165-amino acid glycoprotein produced by recombinant DNA technology that has the same biologic activity as endogenous erythropoietin. No reports describing its use during lactation have been located. Passage into milk is not expected, but in the event that some transfer did occur, digestion in the nursing infant's gastrointestinal system would occur. Moreover, preterm infants have been treated directly with the drug (33). Thus, the risk to a nursing infant from ingestion of the agent via the milk appears to be nonexistent.

References

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