Immunologic Agent (Immunomodulator)
PREGNANCY RECOMMENDATION: Compatible
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
The extensive human pregnancy experience has not shown an increase in structural anomalies, spontaneous abortions (SABs), or fetal death. However, a study described below did find that exposure in the second half of pregnancy impaired the immune system of two newborns, a finding similar to the effect observed in adults treated with the drug. The clinical significance of this impairment requires supportive data. In 2011, the World Congress of Gastroenterology stated, “The safety of natalizumab during pregnancy is unknown. Although human data show no increased risk of birth defects, the agent is too new for adequate supportive data and there are no drugs of similar mechanism with which to compare.” (1). Nevertheless, if the maternal condition indicates that the drug is required, it should not be withheld because of pregnancy. If natalizumab is used in pregnancy, physicians are encouraged to enroll patients in the Tysabri pregnancy exposure registry by calling 800-456-2255.
FETAL RISK SUMMARY
Natalizumab is a recombinant humanized immunoglobu lin G4-kappa (IgG4K) monoclonal antibody produced in murine myeloma cells. It is an α-4 integrin inhibitor that is indicated as monotherapy for the treatment of relapsing forms of multiple sclerosis (MS) to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations. It also is indicated for inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn’s disease and evidence of inflammation, and who have had an inadequate response to, or are unable to tolerate, conventional therapies. The recommended dose is 300 mg IV every 4 weeks. The elimination half-life is approximately 10–11 days (2).
Reproduction studies have been conducted in pregnant guinea pigs and cynomolgus monkeys. In these species, there was no evidence of teratogenicity at doses up to seven times the human clinical dose based on body weight (HCD). In guinea pigs given a dose seven times the HCD during the second half of pregnancy, a small reduction in pup survival was noted at postnatal day 14. At doses seven times the HCD, a doubling of abortions (33% vs. 17%) was observed in one of five studies with monkeys, but no association with abortion was seen in guinea pigs. At this dose in both species, serum levels in fetal animals at delivery were approximately 35% of maternal levels. A dose that was 2.3 times the HCD in monkeys produced drug-related changes in the fetuses: mild anemia, reduced platelet count, increased spleen weights, and reduced liver and thymus weights associated with increased splenic extramedullary hematopoiesis, thymic atrophy, and decreased hepatic hematopoiesis. Reduced platelet counts also were observed in offspring of mothers given seven times the HCD, but this effect was reversed upon clearance of the drug. Offspring exposed in utero had no drug-related changes in the lymphoid organs and had normal immune response (2).
No carcinogenic, clastogenic, or mutagenic effects were observed in various assays and tests conducted with natalizumab. The drug had no effect on male guinea pig fertility, but, at a dose seven times the HCD, a 47% decrease in pregnancy rate relative to controls was observed in females. No such effect was observed at a dose that was 2.3 times the HCD (2).
A series of four research reports, conducted by the manufacturer, on the effects of natalizumab in guinea pigs and cynomolgus monkeys was published in 2009 (3–6). One concern was that the drug would interfere with pregnancy because α-4 integrins and their ligands appear to be critically involved in mammalian fertilization, implantation, and placental and cardiac development (3–6). The results and conclusions of the four studies were similar to those described above. However, the increase in monkey abortions in one cohort was 39.3% vs. 7.1% in controls but, in a second cohort, no increase was observed (33.3% vs. 37.5%). In cynomolgus monkeys treated with doses up to seven times the HCD, no adverse effects on the general health, survival, development, or immunologic structure and function of exposed offspring were observed (6).
Natalizumab crosses the placentas of guinea pigs and monkeys producing fetal drug concentrations approximately 35% of maternal concentrations at birth (2). Because of the similarity to the human placenta and the very long elimination half-life, passage to the fetus should be expected, regardless of the very high molecular weight (about 149,000). Moreover, immune globulin crosses the human placenta in significant amounts near term (see Immune Globulin Intravenous).
Several reports have described the use of natalizumab during pregnancy (1,7–12).
A 2011 review mentioned 164 pregnancies treated with natalizumab during the 1st trimester for either Crohn’s disease (N = 35) or MS (N = 129) (1). There was no increase in the rate of birth defects compared with the expected background occurrence.
In another 2011 report, 35 women with MS became accidentally pregnant while receiving natalizumab (7). Six of the women received the last dose before the last menstrual period (21.3 ± 13.7 days) and 29 after the last menses (22.6 ± 20 days). All of the women stopped the drug when they became aware of the pregnancy. The mean number of doses before pregnancy was 11.7 (range 2–35). The pregnancy outcomes were 28 healthy children, 1 case of hexadactyly, 5 SABs, and 1 elective abortion. There were no significant differences between the outcomes of those exposed and a control group of 23 women with MS who were not exposed to disease-modifying treatments (7).
In a 2011 case report, a 17-year-old patient, who had been treated with natalizumab for MS since she was 16, received seven doses of the drug during an unknown pregnancy (8). Pregnancy was diagnosed in the 31st gestational week. She gave birth to a healthy 2830-g female infant at term with Apgar scores of 10. The infant was doing well at 10 months of age (8).
The outcomes of two planned pregnancies were reported in 2011 (9). In the first case, a 28-year-old woman with MS became pregnant while receiving natalizumab; her last dose was on day 9 of the menstrual cycle. At 37 3/7 weeks, she gave birth to a healthy 3160-g baby girl with Apgar scores of 10 and 10. No abnormalities in the infant were found. The second case involved a 24-year-old woman with MS who did not notify her physician of her pregnancy until 20 weeks’ gestation. Natalizumab, 300 mg every 4 weeks, was continued throughout pregnancy. A cesarean section at 41 weeks’ delivered a 2940-g female infant with Apgar scores of 5 and 8 at 1 and 5 minutes, respectively. The infant was doing well at 6 weeks of age (9).
A preliminary report from the Tysabri (Natalizumab) Pregnancy Register was described in two references (10,11). As of May 2011, 341 pregnant patients had been prospectively enrolled with 277 known outcomes. There did not appear to be a pattern of drug-related malformations and the rate of SAB (11%) were consistent with the background rate (15%) in the US general population (10,11). Several other pregnancy outcomes following use of natalizumab were also described in one of the references (11).
A 2013 report described the effect of natalizumab on the immune system of two neonates, both born at 38 weeks, whose mothers received the drug until 34 weeks’ for MS (12). In the first case, the mother received four doses starting at 21 weeks’ gestation. The 2640-g infant had Apgar scores of 9, 10, and 10. No structural anomalies were evident, but a minor intracerebral hemorrhage was detected by ultrasound that later resolved. The infant was anemic and had moderate thrombocytopenia. At age of 6 weeks, the infant was admitted to the hospital with respiratory syncitial virus bronchiolitis that resolved within a few days with symptomatic treatment. The infant was still anemic but the platelet count had normalized. At 12 weeks of age, the infant had mild anemia but otherwise was doing well. The mother in the second case was treated with methylprednisolone up to 13 weeks but, because of relapsing MS, was given four doses of natalizumab starting at 21 weeks’ similar to the first case. The 2755-g newborn had Apgar scores of 9, 10, and 10. Because adults treated with natalizumab have a significant decrease in T-lymphocyte chemotaxis, both infants were examined for this decrease. The impaired effects on the immune system were found in both infants at 2 weeks of age but, in both cases, the impairment had resolved by 12 weeks of age. The authors concluded that the clinical relevance of the impaired chemotaxis in the context of host defense, especially against viral pathogens, was unclear because chemotaxis was just one of several features of altered immune cell functions under treatment with natalizumab (12).
BREASTFEEDING SUMMARY
No reports describing the use of natalizumab during human lactation have been located. The molecular weight is very high (about 149,000), but immunoglobulins are excreted into breast milk. Although given once every 4 weeks, the long elimination half-life (10–11 days) will assure that the drug is available for excretion throughout the dosing period. The effects of this potential exposure on a nursing infant are unknown.
References
1.Mahadevan U, Cucchiara S, Hyams JS, Steinwurz F, Nuti F, Travis SPL, Sandborn WJ, Colombel IH. The London position statement of the World Congress of Gastroenterology on biological therapy for IBD with the European Crohn’s and Colitis Organization: pregnancy and pediatrics. Am J Gastroenterol 2011;106:214–23.
2.Product information. Tysabri. Biogen Idec, 2008.
3.Wehner NG, Shopp G, Rocca MS, Clarke J. Effects of natalizumab, an α4 integrin inhibitor, on the development of Hartley guinea pigs. Birth Defects Res B Dev Reprod Toxicol 2009;86:98–107.
4.Wehner NG, Skov M, Shopp G, Rocca MS, Clarke J. Effects of natalizumab, an α4 integrin inhibitor, on fertility in male and female guinea pigs. Birth Defects Res B Dev Reprod Toxicol 2009;86:108–16.
5.Wehner NG, Shopp G, Oneda S, Clarke J. Embryo/fetal development in cynomolgus monkeys exposed to natalizumab, an α4 integrin inhibitor. Birth Defects Res B Dev Reprod Toxicol 2009;86:117–30.
6.Wehner NG, Shopp G, Osterburg I, Fuchs A, Buse E, Clarke J. Postnatal development in cynomolgus monkeys following prenatal exposure to natalizumab, an α4 integrin inhibitor. Birth Defects Res B Dev Reprod Toxicol 2009;86:144–56.
7.Hellwig K, Haghikia A, Gold R. Pregnancy and natalizumab: results of an observational study in 35 accidental pregnancies during natalizumab treatment. Mult Scler 2011;17:958–63.
8.Bayas A, Penzien J, Hellwig K. Accidental natalizumab administration to the third trimester of pregnancy in an adolescent patient with multiple sclerosis. Acta Neurol Scand 2011;124:290–2.
9.Hoevenaren IA, de Vries LC, Rijnders RJP, Lotgering FK. Delivery of healthy babies after natalizumab use for multiple sclerosis: a report of two cases. Acta Neurol Scand 2011;123:430–3.
10.Bayas A, Penzien J, Hellwig K. Accidental natalizumab administration in pregnancy in multiple sclerosis. Acta Neurol Scand 2012;126:e5–6. doi:10.1111/j.1600-0404.2011.01636.x.
11.Houtchens MK, Kolb CM. Multiple sclerosis and pregnancy: therapeutic considerations. J Neurol 2013;260:1202–14.
12.Schneider H, Weber CE, Hellwig K, Schroten H, Tenenbaum T. Natalizumab treatment during pregnancy—effects on the neonatal immune system. Acta Neurol Scand 2013;127:e1–4. doi:10.1111/ane.12004.