Hematopoietic
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
Several reports have described the use of darbepoetin alfa in human pregnancy, apparently all ending in normal outcomes. The absence of major toxicity in animals and the experience with epoetin alfa (see Epoetin Alfa) suggest that darbepoetin does not represent a significant embryo or fetal risk. Because anemia and the need for frequent blood transfusions present significant risks to the mother and fetus, the benefits derived from darbepoetin probably outweigh the known risks.
FETAL RISK SUMMARY
Darbepoetin is an erythropoiesis 165-amino acid protein produced by recombinant DNA technology in Chinese hamster ovary cells. It is indicated for the treatment of anemia and is closely related to epoetin alfa. The half-life after SC administration is 49 hours (range 27–89 hours) that is reflective of its slow absorption, whereas after IV administration the terminal half-life is 21 hours.
Reproduction studies have been conducted in pregnant rats and rabbits. No evidence of direct embryotoxic, fetotoxic, or teratogenic effects was observed at IV doses up to 20 mcg/kg/day. (Note: dose is about 300 times the recommended human dose of 0.45 mcg/kg once weekly based on body weight in patients with chronic renal failure [RHD-CRF] or about 60 times the recommended human dose of 2.25 mcg/kg once weekly based on body weight in cancer patients receiving chemotherapy [RHD-C]). A slight reduction in fetal weight was observed at doses that were ≥1 mcg/kg/day (≥15 times RHD-CRF; ≥3 times RHD-C), but this was a maternal toxic dose. In rats, IV doses of ≥2.5 mcg/kg every other day (about ≥20 times the RHD-CRF or about ≥4 times the RHD-C) from day 6 of gestation through day 23 of lactation caused decreased body weights and delayed eye opening and preputial separation. Darbepoetin had no adverse effect on uterine implantation in rats or rabbits. However, an increase in postimplantation fetal loss was observed in rats given doses ≥0.5 mcg/kg three times weekly (about ≥3 times the RHD-CRF; about ≥0.7 times the RHD-C) (1).
It is not known if darbepoetin alfa crosses the human placenta. The very high molecular weight (about 37,000) of this glycoprotein argues against transfer across the placenta. A closely related drug, epoetin alfa, has a lower molecular weight (about 30,000) and it does not cross to the fetus. (See Epoetin Alfa.)
A 2005 case report described the use of darbepoetin alfa in a 20-year-old woman at 28 weeks’ gestation (2). Darbepoetin was given weekly. She had received a kidney transplant about 4 years earlier and had been maintained on rapamycin and iron therapy until 22 weeks’ gestation, at which time the rapamycin was discontinued and replaced with cyclosporine. A cesarean section was performed at 37 weeks’ because of fetal distress to deliver a healthy 6-pound (about 2.224 kg) female infant with Apgar scores of 7 and 8 at 1 and 5 minutes, respectively (2).
A 2006 report described two pregnancies that were treated with darbepoetin alfa (3). The women, a 33-year-old with chronic renal failure of unknown cause, and a 31-year-old with insulin-dependent diabetes complicated by hypertension and nephropathy, were treated with weekly doses of darbepoetin alfa from the 22nd and 20th week of gestation, respectively. The first mother gave birth at 37 weeks’ to a healthy, 2.010-kg infant (sex not specified) with an Apgar score of 10, whereas the second gave birth by cesarean section at 32 weeks’ to a 1.730-kg female infant with Apgar scores of 9 and 10. The status of the first infant was not specified, but the second infant was doing well (3).
A 21-year-old woman with nephrotic syndrome was treated with weekly doses of darbepoetin alfa starting at 26 weeks’ (4). Because of worsening renal failure, labor was induced and she gave birth at 36 weeks’. No information of the infant was included in the report.
A 27-year-old woman with HbH disease, an intermediate clinical form of alpha thalassemia, was treated with two doses of epoetin at 15 weeks’ then darbepoetin alfa 500 IU every 3 weeks from 16 weeks’ until delivery by an emergency cesarean section for fetal distress (umbilical cord around the neck of the fetus) at 38 weeks’. The healthy, 3.13-kg male infant had Apgar scores of 8 and 10 (5).
BREASTFEEDING SUMMARY
No reports describing the use of darbepoetin in human lactation have been located. Darbepoetin is a 165-amino acid glycoprotein with a molecular weight of 37,000. Passage into milk is not expected, but in the event that some transfer did occur, digestion in the nursing infant’s gastrointestinal tract would occur. Moreover, preterm infants have been treated with epoetin alfa, a closely related agent. (See Epoetin Alfa.) Thus, the risk to a nursing infant from ingestion of the drug via the milk appears to be nonexistent.
References
1.Product information. Aranesp. Amgen, 2004.
2.Goshom J, Youell TD. Darbepoetin alfa treatment for post-renal transplantation anemia during pregnancy. Am J Kidney Dis 2005;46:e81–6.
3.Sobito-Jarek L, Popowska-Drojecka J, Muszytowski M, Wanic-Kossowska M, Kobelski M, Czekalski S. Anemia treatment with darbepoetin alpha in pregnant female with chronic renal failure: report of two cases. Adv Med Sci 2006;51:309–11.
4.Ghosh A, Ayers KJ. Darbepoetin alfa for treatment of anaemia in a case of chronic renal failure during pregnancy—case report. Clin Exp Obstet Gynecol 2007;34:193–4.
5.Maccio A, Madeddu C, Chessa P, Mantovani G, Galanello R. Use of erythropoiesis stimulating agents for the treatment of anaemia and related fatigue in a pregnant woman with HbH disease. Br J Haematol 2009;146:335–7.