Antineoplastic/Immunologic Agent (Antirheumatic)
PREGNANCY RECOMMENDATION: Human Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
The use of rituximab in human pregnancy has been described in more than 200 cases. All of the live births were healthy, and none had structural anomalies that were thought to be related to rituximab. These outcomes are consistent with the reproduction studies with monkeys in which exposures that were nearly equivalent to human exposures were not associated with congenital defects. However, a functional deficit (depletion of B lymphocytes) was observed in monkey offspring and has occurred in at least two human newborns. The immunosuppression was reversible, with normal B-cell counts measured in monkey offspring by 6 months and in the infants. No increase in infectious disease was seen in any of the in utero exposed infants. Nevertheless, there is a risk for severe infections in immunosuppressed individuals, and this should be considered in all infants exposed in utero to rituximab.
FETAL RISK SUMMARY
Rituximab is a genetically engineered chimeric murine/human monoclonal immunoglobulin G1 (IgG1) kappa antibody that is directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. It has three indications: (a) for the treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell, non-Hodgkin’s lymphoma (NHL); (b) for the first-line treatment of diffuse large B-cell, CD20-positive, non-Hodgkin’s lymphoma in combination with CHOP or other anthracycline-based chemotherapy regimens; and (c) in combination with methotrexate to reduce signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies. The elimination half-life of rituximab is dose-related. In patients with NHL, the mean serum half-life after the first of four weekly infusions was 76.3 hours (range 31.5–152.6 hours), whereas the mean half-life after the fourth infusion was 205.8 hours (range 83.9–407.0 hours). In patients with rheumatoid arthritis, the mean terminal elimination half-life after two doses, 2 weeks apart, was 19 days (1).
Rituximab may cause severe infusion-related toxicity, including hypotension and other adverse effects. Premedication with acetaminophen and an antihistamine is recommended before each infusion (1). Hypotension in a pregnant woman could have deleterious effects on placental perfusion, resulting in embryo or fetal harm.
Reproduction studies have been conducted in cynomolgus monkeys. During organogenesis, monkeys were given three daily IV loading doses, then four weekly doses. The highest weekly dose resulted in exposures that were 0.8 times the human exposure from a 2-g dose based on AUC. There was no evidence of teratogenicity. However, the antibody did produce a decrease in B cells in the offspring. Subsequent studies showed that the decreased B cells and immunosuppression noted in the offspring returned to normal levels and functions within 6 months of birth. Long-term studies for carcinogenicity, mutagenicity, or effects on fertility have not been conducted (1).
Even though the molecular weight is high (about 145,000), the antibody crosses the monkey placenta (1). Rituximab also crosses the human placenta, at least near term. Very high levels of the antibody have been measured in cord blood and the young infant (2).
A 35-year-old woman was diagnosed with Burkitt’s lymphoma of the left breast at 15 weeks’ gestation (2). Starting at week 16, she was treated with four weekly infusions of rituximab 375 mg/m2. Then at 3-week intervals, she was treated with four courses of the R-CHOP regimen followed by two courses of CHOP. The patient was in complete remission at 37 weeks. At 41 weeks’, a healthy female infant was delivered via cesarean section. At birth, rituximab serum levels in the cord blood and mother were 32,095 and 9750 ng/mL (cord blood:mother ratio 3.3), respectively. Serum levels in the infant at 4 and 18 weeks of age were 5399 and 700 ng/mL, respectively, whereas the mother’s serum level at 18 weeks was 500 ng/mL (infant:mother ratio 1.4). No CD19 B-cells were found in the mother or newborn. In the infant at 4 and 18 weeks of age, B-cell counts were 70 and 1460 cells/micro-L) (normal range for infants 3–6 months: 200–1100 cells/micro-L), respectively. At 20 months of age, the infant’s B-cell count was normal and no infectious complications, malformations, or other immune dysfunction have been observed in the now 26-month-old child (2).
A brief 2001 correspondence described the use of rituximab in the 2nd trimester (3). The 29-year-old woman, with diffuse large B-cell NHL, in her 21st week of pregnancy was treated with rituximab 375 mg/m2 on day 1, doxorubicin 50 mg/m2 on day 3, vincristine 2 mg on day 3, and prednisolone 100 mg on days 3–7, given in 4-week cycles. At 35 weeks’ gestation, 2 weeks after the last of four cycles, she delivered a healthy female infant (birth weight or other details not given) via cesarean section. The child was developing normally and a normal peripheral B-cell population was noted at 4 months of age (3).
A 37-year-old woman with an 8-year history of follicular NHL was treated with weekly infusions (375 mg/m2) of rituximab for 4 weeks (4). Pregnancy was detected 1 week after the last dose with conception occurring between the first and second infusions. No further rituximab treatment was given. The woman delivered a normal, healthy 3610-g female infant at 40 weeks’ gestation. No hematological or immunological adverse effects were detected in the infant. At 18 months of age, the child has normal immunity and has had no major infections (4).
A 31-year-old woman at 15 weeks’ gestation was diagnosed with B-cell NHL (5). She was treated with six cycles of R-CHOP on a 14-day schedule (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, and prednisone 100 mg/day on days 1–5). Filgrastim 300 mcg/day was given on days 6–11. At 33 weeks’ gestation, 2 months after the last cycle, the woman spontaneously delivered a healthy female infant (weight and size within the 50th–90th percentiles) with Apgar scores of 8, 10, and 10 at 1, 5, and 10 minutes, respectively. The 16-month-old child has been closely evaluated every 3 months since birth and has had no infections or evidence of physiological or developmental abnormalities (5).
A 2006 report briefly mentioned the use of weekly infusions of rituximab (375 mg/m2) for severe thrombotic thrombocytopenic purpura (TTP) (6). The woman had a left-sided stroke and seizure at 16 weeks’ gestation and was diagnosed with acute TTP. Rituximab infusions were started at 27 weeks’ to reduce the risk of further complications by reducing IgG antibodies. The woman suffered another seizure in the 30th week of pregnancy and an emergency cesarean section delivered a 1045-g male infant. The infant has had no infectious complications (6).
A 41-year-old woman, with a history of cardiac valvulopathy responsible for left ventricular failure, was treated for recurrent autoimmune hemolytic anemia with four weekly IV doses of rituximab (375 mg/m2) and daily corticosteroids (7). Unbeknownst to her physicians, the patient also was pregnant, receiving the four rituximab doses between 7 and 10 weeks of gestation. No other exposures occurred during the remainder of a normal pregnancy and she delivered a normal, 3060-g female infant at 38 weeks’ gestation. Apgar scores were 10 at 1, 5, and 10 minutes. Mature B-cells and B-cell precursors were present at birth, as well as during the first 55 days after birth. A mild bone depression at the sacrum–coccyx level was noted, but an evaluation completely excluded spina bifida occulta. Other than a possible mild infection at 24 hours of age, and a transient and slight lymphopenia on days 2 and 3, no other alterations in the infant were detected (7).
Treatment during pregnancy of a 36-year-old woman with long-standing immune-mediated thrombocytopenia was discussed in a 2008 report (8). Her initial treatment during pregnancy consisted of corticosteroids and IV immunoglobulins, but only a small rise was noted in the platelet count and she had persisting hemorrhagic diathesis. Treatment was changed to prednisone 60 mg/day and continued to 36 weeks’. At week 30, she was given rituximab weekly for 4 consecutive weeks followed by additional IV immunoglobulins. At 38 weeks’, 4 weeks after the last dose of rituximab, labor was induced and a 3780-g female infant was born with Apgar scores of 7, 8, and 8 at 1, 5, and 10 minutes, respectively. The rituximab concentration in the newborn was 6.7 mg/L. The number of B-cells in the neonate was 0, but a rise was detected at 3 months of age so that at 6 months they were in the normal range. At 10 months of age, growth and development were normal. She did not have any infections and the vaccination titers were normal (8).
A 2011 study, authored by investigators from Stanford University School of Medicine and the manufacturer, described 231 pregnancies gathered worldwide that were exposed to rituximab in the 1st and 2nd trimesters (9). More than half of the pregnancies were also exposed to other potentially teratogenic agents. Of the 231 pregnancies, 67 outcomes were unknown, 11 were ongoing, and 153 outcomes were known. In the latter group, there were 90 live births, 1 maternal death (cerebral hemorrhage from preexisting autoimmune thrombocytopenia), 1 stillbirth (20 weeks’ due to fetal hypoxemia from umbilical card knot), 33 spontaneous abortions (all in 1st trimester), and 28 elective abortions (1 for trisomy 13). Among the live births, there were 22 premature infants, 1 neonatal death at 6 weeks, and 11 neonates with hematologic abnormalities, but none had corresponding infections. Four neonates had infection (fever, bronchlolitis, cytomegalovirus hepatitis, and chorioamnionitis). Two infants had a structural anomaly, clubfoot in one twin, and a cardiac malformation in a singleton birth (9).
A brief 2011 report described the outcome of a pregnancy that was exposed to rituximab given 6 weeks before conception (10). The 32-year-old woman was treated with rituximab for long-standing rheumatoid arthritis resistant to other therapies. After an uncomplicated pregnancy, she gave birth to twin females at 37 weeks’, one with a clubfoot and the other with transient erythema toxicum neonatorum. Normal B-cell counts and normal immunoglobulin levels were measured during 8 months of follow-up, but one girl had transient mild leucocytosis without signs of infection. Both were developing normally, without serious infectious complications, although one had mild asthma (10).
A 2012 case report described the pregnancy of a 34-year-old woman at 27 weeks’ with systemic lupus erythematosus who developed severe thrombocytopenia (11). She was treated with high-dose corticosteroids, IV immunoglobulin, rituximab (weekly for 4 doses starting at about 27 weeks’), one dose of cyclophosphamide, eltrombopag, and anti-D immunoglobulin, but the thrombocytopenia was resistant to these agents. Romiplostim (weekly for 3 doses) was then given and the platelet count rose from 4 × 109/L to 91 × 109/L. Because her platelet count began to fall, she was given the third dose of romiplostim 1 day before induction of labor at 34 weeks’. A healthy normal female baby was born with a normal platelet count (no additional details provided) (11).
In a second 2012 case report, a 22-year-old woman during the 12th week of pregnancy was diagnosed with primary mediastinal large B-cell lymphoma (12). In the 13th week, she was started on standard doses of R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) given every 3 weeks for six cycles. Her last cycle was at her 31st week of pregnancy. At 34 weeks’, she underwent labor induction and gave birth to a healthy male baby with Apgar scores of 9 and 9 (no other details given). At 1 year of age, the infant has shown no developmental delays or physical abnormalities (12).
A 2013 case report described the outcomes of two pregnancies exposed to rituximab in the 1st trimester (13). In the first case, a 25-year-old woman with rheumatoid arthritis conceived while receiving rituximab (500 mg on days 1 and 15 of each cycle) and methotrexate (10 mg/week). Rituximab was given at weeks 2 and 4. Both drugs were then stopped. The previous cycle had been given 6 months before the current cycle. A cesarean section was performed at week 37 to give birth to a healthy 3110-g neonate (sex not specified) with Apgar scores of 10 and 10 at 5 and 10 minutes, respectively. The child was doing well at 4.5 years follow-up. The second case involved a 31-year-old woman with multiple relapsing TTP. Her last dose of rituximab occurred 9 weeks before conception. Serum concentrations of rituximab at 11 and 31 weeks’ were 0.11 mcg/mL and undetected, respectively. Based on the pharmacokinetics, the theoretical concentration at conception was estimated to be 1 mcg/mL. At 39 weeks’, a healthy 3024-g neonate (sex not specified) was born vaginally with Apgar scores of 10 and 10 at 5 and 10 minutes, respectively. The infant was doing well at 1.5 years of age (13).
A 2013 review summarized seven reports on the use of rituximab in pregnancy (14). The seven studies (2,5–9,11) are discussed above. The authors concluded that, although the drug could not be considered completely safe, it could be given if the maternal benefit outweighed the potential embryo–fetal risk (14). Another 2013 review examined the available evidence on drugs used for dermatologic diseases in pregnancy (15). Based on case reports or clinical experience, the authors classified rituximab as safe in pregnancy.
BREASTFEEDING SUMMARY
No reports describing the use of rituximab during human lactation have been located. The molecular weight (about 145,000) is very high, but human IgG is excreted into milk, and therefore, rituximab also may be excreted. The effects of this potential exposure on a nursing infant are unknown, but immunosuppression and other severe adverse effects are potential complications.
References
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