EXPERT ANALYSIS AT THE CMSC ANNUAL MEETING
NEW ORLEANS (FRONTLINE MEDICAL NEWS) – Multiple sclerosis has little to no impact on the ability to conceive, on pregnancy, or on fetal status, according to Patricia K. Coyle, MD.
“That’s very reassuring,” Dr. Coyle said at the annual meeting of the Consortium of Multiple Sclerosis Centers. “We don’t see an increase in birth defects just because the mother has MS. There is no consistent increase in abortions, ectopic pregnancies, or assisted vaginal/cesarean deliveries.”
Dr. Coyle , director of the MS Comprehensive Care Center at Stony Brook (N.Y.) University Medical Center , said that the most dramatic changes for pregnant patients with MS occur in the final trimester and mainly involve rising levels of multiple hormones: estrogens, cortisol, progesterone, norepinephrine, and 1,25-dihydroxyvitamin D, which increase late in pregnancy, then rapidly drop off postpartum. This has led to the evaluation of sex hormone therapy for MS.
The impact of other pregnancy factors on MS disease activity remains unknown. One is microchimerism, a maternal-fetal exchange of cells and DNA. “These cells can last for a long time; you can find them in the blood, as well as in the [central nervous system],” Dr. Coyle said. “It’s been reported that fetal microchimerism may be increased in immune-mediated diseases like MS, but we really don’t have a lot of good data.”
Also of unknown impact are exosomes, which are small lipid-bound vesicles that are increased in the sera during pregnancy. “They appear to be involved in modulating the immune system. They’ve been studied in [experimental autoimmune encephalomyelitis], where they’ve been reported to have a potent effect. We don’t know if exosomes play a role in MS or not.”
Researchers also are studying the impact of changes in the gut microbiota that occur during pregnancy. “Could this be a potential target for MS therapy?” Dr. Coyle asked. “This is in its infancy.”
She went on to share counseling tips for MS patients of childbearing age, including the fact that some studies report slightly smaller babies born to mothers with MS, while others have not found that association. “This is a question mark, but it doesn’t seem to be a major issue,” she said. One thing you can tell patients for certain is that MS is not inherited. “There are well over 230 genes linked to MS, so there’s a genetic enrichment that can make somebody vulnerable to MS, but there’s no gene that passes on MS,” Dr. Coyle said. “The risk is slightly higher for a first-degree relative, so when a parent has MS, the risk for the child is in the range of 2% to 2.5%, compared with the expected 0.13% in the general population. But there’s a slightly higher risk when you’re a sibling than when you’re a parent – 2.7% – which is speaking to environmental factors having an important impact on genes.”
Controversial data exist as to whether a maternal deficiency in vitamin D poses a risk of MS in the offspring. Dr. Coyle makes it a point to “normalize” vitamin D levels in pregnant MS patients, particularly in white patients. “You’d want to have them on prenatal vitamins and folic acid and tell them not to smoke, to limit their alcohol use, and advise them to have good sleep hygiene.”
Dr. Coyle, vice chair of clinical affairs at Stony Brook University Medical Center, said that up until the 1950s, physicians advised women with MS against having children. “They were told not to get pregnant or to have an abortion, because it was thought to make MS worse,” she said. “It turns out that was fiction. That was completely wrong. Pregnancy has no negative effect on long-term MS prognosis. It may have long-term benefits for relapsing MS, but there are not enough data to comment on its impact on progressive MS. Pregnancy makes it less likely that someone will develop a clinically isolated syndrome, but it may increase the radiologically isolated syndrome risk for clinical attack. That’s based on 7 pregnant patients out of a cohort of 60, so we need further data to explain that.”
When it comes to washouts of disease-modifying therapies (DMTs), no one-size-fits-all approach exists. Interferon betas and glatiramer acetate have more than 1,000 pregnancy exposures that yield no evidence for teratogenicity or negative fetal impact. No washout is needed prior to pregnancy. “These agents can be used during pregnancy and breastfeeding,” she said.
The other DMTs paint a somewhat different picture. “There is insufficient pregnancy exposure to the three available oral DMTs to comment definitively on their safety, but there is no clear human teratogenicity to date,” Dr. Coyle said. The conventional washout for fingolimod is 8 weeks. In Dr. Coyle’s opinion, no washout is required with dimethyl fumarate. “The half-life is 40 minutes. There are no good signs of issues. For teriflunomide, it can hang around in individuals for 18-24 months. You should go through an accelerated elimination procedure with oral cholestyramine 8 mg three times a day for 11 days until blood level of the agent is less than 0.02 mcg/mL. Avoid all the orals with breastfeeding.”
Monoclonal antibodies – another form of DMTs – lack sufficient pregnancy exposures to merit comment on safety, but they should not be used during breastfeeding. Natalizumab is a humanized IgG4 antibody that crosses the placenta. “This has been used in several dozen pregnancies because the patients got so bad when they were taken off that it required reinstituting natalizumab even though they were pregnant,” Dr. Coyle said. “Human pregnancy exposures have been associated with transient hematologic issues in the newborn, including anemia, thrombocytopenia, and pancytopenia.” Data indicate that the rate of spontaneous abortion among pregnant women treated with natalizumab was 9%, the rate of major birth defects was 5.05%, and no malformation pattern was observed. The drug is detected in human breast milk and has a half-life of 11 days.
Alemtuzumab is a humanized IgG1 monoclonal antibody that crosses the placenta. The half-life elimination is about 14 days. In transgenic mice, giving alemtuzumab during organogenesis was found to be embryolethal. In human pregnancy, hypothyroidism is a concern. “The recommendation has been to wait 4 months after the last treatment before you try to become pregnant. Alemtuzumab is considered a two-cycle treatment. You don’t get the maximum benefit after the first cycle of 5 days. The complete treatment is the second cycle 3 days.”
Daclizumab, another humanized IgG1 monoclonal antibody, also crosses the placenta. Monkey exposure during gestation led to embryofetal death and decreased fetal growth, “but this was at greater than 30 times the human dose,” she said. “It was found to be excreted in monkey breast milk and the half-life is 21 days.” In humans, there have been 36 exposed women who had 38 pregnancies and 20 live births. The rate of spontaneous abortions/miscarriages was 11%, there were eight elective terminations, two ectopic pregnancies, and one congenital heart defect. “This is very limited data, but nothing that would raise the level of concern,” Dr. Coyle said.
Ocrelizumab, another humanized IgG1 monoclonal antibody, was approved by the Food and Drug Administration in March 2017. Prior studies of anti-CD20 antibodies in human pregnancy noted transient lymphocytopenia and peripheral B cell depletion in the newborns. In studies of pregnant monkeys that used 2 and 10 times human doses during organogenesis, it was associated with B cell depletion in spleen/lymph nodes, Dr. Coyle said. “During organogenesis and throughout the neonatal period, treatment could be associated with perinatal death, some associated with bacterial infection; glomerulonephropathy with inflammation; a decrease in circulating B cells, a decrease in testicular weight, and bone marrow lymphoid follicle formation.” Ocrelizumab is excreted in monkey breast milk and the prescription label suggests a 6-month delay in pregnancy. The drug’s half-life is 26 days.
Dr. Coyle reported that she has served as a consultant for Accordant, Acorda, Bayer, Biogen, Celgene, Genentech/Roche, Genzyme/Sanofi, Novartis, Serono, and Teva. She has also received research support from Actelion, Alkermes, Genentech/Roche, MedDay, the National Institute of Neurological Disorders and Stroke, and Novartis.