Hematopoietic
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
Neither the animal nor the human pregnancy data suggest a major risk for the human embryo or fetus from maternal filgrastim therapy. Although the human pregnancy experience is limited, no congenital malformations or other toxicities attributable to filgrastim have been observed. The cases submitted to the manufacturer suggest selective reporting (i.e., preferentially reporting of abnormal outcomes). Amounts sufficient to produce a biological effect in the fetus apparently cross the human placenta, at least in the 2nd and 3rd trimesters. Additional study is warranted, but filgrastim treatment should not be withheld because of pregnancy.
FETAL RISK SUMMARY
The human granulocyte colony-stimulating factor (G-CSF) filgrastim is a 175-amino acid glycoprotein produced by recombinant DNA technology. Filgrastim is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive chemotherapy associated with a significant incidence of severe neutropenia with fever. The agent is administered either SC or IV. The elimination half-life is approximately 3.5 hours (1).
Reproduction studies with filgrastim have been conducted in rats and rabbits. No effects on fertility were observed in male and female rats at doses ≤500 mcg/kg. (Note: The human dose is 5–10 mcg/kg/day.) In pregnant rats treated during organogenesis, IV injections ≤575 mcg/kg/day were not associated with fetal death, teratogenicity, or behavioral effects. In offspring of pregnant rats treated with doses >20 mcg/kg/day, a delay of external differentiation (detachment of auricles and descent of testes) and slight growth restriction were observed. These effects may have been due to lower maternal body weight during rearing and nursing. At 100 mcg/kg/day, newborn pups had decreased body weights and a slightly decreased 4-day survival rate. Treating pregnant rabbits during organogenesis with doses of 80 mcg/kg/day resulted in increased resorptions and embryolethality but not external defects. This dose, however, was maternally toxic (genitourinary bleeding and decreased body weight and food consumption) (1).
Filgrastim crosses the rat placenta late in gestation (2). In a rat study, filgrastim (50 mcg/kg) was given twice daily for 2, 4, and 6 days before delivery. Filgrastim crossed the placenta within 30 minutes, reaching peak fetal serum levels 4 hours after the dose. Peak serum levels in the fetuses were 1000-fold lower than levels measured in the dams, but the agent still induced bone marrow and spleen myelopoiesis in the fetus and neonate (2). In a continuation of this study, the investigators demonstrated that the 6-day course of filgrastim administered before delivery significantly increased the survival of pups that were infected at birth with Group B β-hemolytic Streptococcus (3).
Although it has a very high molecular weight (18,800), filgrastim also crosses the human placenta, at least in the 2nd and 3rd trimesters. A single IV dose of filgrastim (25 mcg/kg) was given to 11 women (1 set of twins) with an imminent delivery at ≤30 weeks’ gestation (4). Ten infants were delivered within 30 hours of the dose (mean 10.8 hours) (“early delivery”), and two infants were delivered at 54 and 108 hours (“late delivery”). Three of 10 cord blood samples in the “early delivery” group had G-CSF levels higher than those of 10 untreated controls, but there was no difference in cord blood neutrophil concentrations. Cord blood from the two infants in the “late delivery” group had G-CSF levels similar to those of controls but much higher neutrophil levels that remained elevated for 1 week. The investigators concluded that filgrastim crossed the placenta in amounts sufficient to produce a biologic effect in the fetus, and that this effect was most noticeable in cases where delivery was delayed at least 30 hours after a dose (4).
A 1998 study by the same investigators as above evaluated the effects of filgrastim therapy in women in preterm labor (5). Of the 26 women enrolled in the study, 16 (eight G-CSF subjects and eight controls) delivered within 3 weeks of the dose and were eligible for evaluation. G-CSF cases received a single 25 mcg/kg dose administered as an IV infusion over 4 hours, whereas controls received an IV infusion without the drug. No adverse effects on pregnancy duration or maternal discomfort were noted. Neutrophil production was assessed by bone marrow aspiration in neonates 24 hours after delivery. The mean time between G-CSF or placebo administration and delivery was 3.9 and 6.3 days, respectively. Compared with controls, the neonates of case mothers had a significantly greater marrow proliferative pool and a significant improvement in Scores for Neonatal Acute Physiologic State (5).
A 27-year-old patient at 26 weeks’ gestation was diagnosed with acute myeloid leukemia (6). Because she was otherwise well, she decided to hold chemotherapy to allow the fetus to mature. The woman became neutropenic and, at 27 weeks’ gestation, developed fever secondary to a systemic infection. In addition to antibiotics, a 12-day course of filgrastim (dose not specified) was given to allow further time for fetal maturation. A cesarean section was performed at 32 weeks’ gestation to deliver a healthy baby boy (weight and other details not provided). The infant was doing well at 5 months of age (6).
A brief 1996 report described the use of filgrastim in a pregnant woman with acute promyelocytic leukemia (7). In addition to other treatment, filgrastim (75 mcg/day SC) was given for 7 days early in the 2nd trimester. She eventually delivered a healthy female infant at term (7).
A number of other studies have reported the use of filgrastim in human pregnancy (8–12). In four studies, the outcomes of 15 pregnancies were (period of exposure shown in parentheses) as follows: one normal infant (3rd trimester) (8); two normal infants (throughout); one with bilateral hydronephrosis (throughout); two with cyclic neutropenia (throughout and 3rd trimester; mothers also had the disorder); one normal infant (1st trimester); three elective abortions (EABs) (1st trimester; one fetus with “abnormal embryogenesis”); and one infant with cardiac septal defects (3rd trimester) (9); one normal infant (2–3 weeks’ gestation); one normal infant and one spontaneous abortion (SAB) (treatment before pregnancy in both) (10); and one normal infant (3rd trimester) (11).
Two reports from the Severe Chronic Neutropenia International Registry (SCNIR), one in 2002 (12) and the other in 2003 (13), discussed the outcomes of 23 pregnancies in women who were treated with filgrastim. Three women became pregnant during clinical trials and, although they were excluded from the study, continued to receive commercially available filgrastim (12). Two of the women with cyclic neutropenia had normal infants (one with cyclic neutropenia; one electively aborted her first pregnancy, then carried a second pregnancy to term). The third woman had idiopathic neutropenia and she had an EAB because of abnormal bleeding but subsequently died (12). The Registry also collected data on 20 pregnancies in women who had been exposed to filgrastim and 105 pregnancies in women who were not exposed to the agent (historical controls) (13). The outcomes of the exposed group, treated for an average of two trimesters (range one to three), were 13 normal infants, 3 SABs, and 4 EABs (nonmedical). Among the 105 historical controls, there were 75 live births (includes two sets of twins and five infants with medical conditions—primarily respiratory), 24 SABs, and 8 EABs (12,13).
The SCNIR also reported the outcomes of nine pregnancies based on information submitted to the manufacturer (12). Of the nine cases, there were four normal infants, one SAB, and four infants with congenital renal and/or cardiac malformations (12).
BREASTFEEDING SUMMARY
No reports describing the use of filgrastim during human lactation have been located. Filgrastim is a glycoprotein and, although it may be excreted into breast milk, it would probably be digested in a nursing infant’s stomach. The risk to a nursing infant is unknown but appears to be low to nonexistent. Therefore, treatment with filgrastim should not be held because of breastfeeding.
References
1.Product information. Neupogen. Amgen, 2004.
2.Medlock ES, Kaplan DL, Cecchini M, Ulich TR, del Castillo J, Andresen J. Granulocyte colony-stimulating factor crosses the placenta and stimulates fetal rat granulopoiesis. Blood 1993;81:916–22.
3.Novales JS, Salva AM, Mondanlou HD, Kaplan DL, del Castillo J, Andresen J, Medlock ES. Maternal administration of granulocyte colony-stimulating factor improves neonatal rat survival after a lethal group B streptococcal infection. Blood 1993;81:923–7.
4.Calhoun DA, Ross C, Christensen RD. Transplacental passage of recombinant human granulocyte colony-stimulating factor in women with an imminent preterm delivery. Am J Obstet Gynecol 1996;174:1306–11.
5.Calhoun DA, Christensen RD. A randomized pilot trial of administration of granulocyte colony-stimulating factor to women before preterm delivery. Am J Obstet Gynecol 1998;179:766–71.
6.Cavenagh JD, Richardson DS, Cahill MR, Bernard T, Kelsey SM, Newland AC. Treatment of acute myeloid leukaemia in pregnancy. Lancet 1995;346:441–2.
7.Lin C-P, Huang M-J, Liu H-J, Chang IY, Tsai C-H. Successful treatment of acute promyelocytic leukemia in a pregnant Jehovah’s Witness with all-trans-retinoic acid, rhG-CSF, and erythropoietin. Am J Hematol 1996;51:251–2.
8.Arango HA, Kalter CS, Decesare SL, Fiorica JV, Lyman GH, Spellacy WN. Management of chemotherapy in a pregnancy complicated by a large neuroblastoma. Obstet Gynecol 1994;84:665–8.
9.Welter K, Boxer LA. Severe chronic neutropenia: pathophysiology and therapy. Semin Hematol 1997;34:267–78.
10.Cavallaro AM, Lilleby K, Majolino I, Storb R, Appelbaum FR, Rowley SD, Bensinger WI. Three- to six-year follow-up of normal donors who received recombinant human granulocyte colony-stimulating factor. Bone Marrow Transplant 2000;25:85–9.
11.Sangalli MR, Peek M, McDonald A. Prophylactic granulocyte colony-stimulating factor treatment for acquired chronic severe neutropenia in pregnancy. Aust N Z J Obstet Gynaecol 2001;41:470–1.
12.Cottle TE, Fier CJ, Donadieu J, Kinsey SE. Risk and benefit of treatment of severe chronic neutropenia with granulocyte colony-stimulating factor. Semin Hematol 2002;39:134–40.
13.Dale DC, Cottle TE, Fier CJ, Bolyard AA, Bonilla MA, Boxer LA, Cham B, Freedman MH, Kannourakis G, Kinsey SE, Davis R, Scarlata D, Schwinzer B, Zeidler C, Welte K. Severe chronic neutropenia: treatment and follow-up of patients in the Severe Chronic Neutropenia International Registry. Am J Hematol 2003;72:82–93.