Pregnancy and Natalizumab

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I provide details of the paper for those that may be interested. If you are considering starting a family, speak to your nurse/neurologist and plan this

Pregnancy outcomes amongst multiple sclerosis females with third trimester natalizumab use. Triplett JD, Vijayan S, Rajanayagam S, Tuch P, Kermode AG.Mult Scler Relat Disord. 2020 Jan 30;40:101961. doi: 10.1016/j.msard.2020.101961. [Epub ahead of print].

BACKGROUND:Natalizumab, a monoclonal antibody directed against alpha-4-integrin, is an efficacious treatment used in Multiple Sclerosis (MS). Use in early pregnancy is safe but information in the third trimester is limited. Ceasing natalizumab is often associated with an increased risk in MS relapse and in some instances natalizumab continuation during pregnancy may be required. However natalizumab crosses the placenta in late pregnancy and has been associated with hematological abnormalities. We present clinical and haematological outcome data of newborns from a series of MS patients who received natalizumab during their second and third pregnancy trimesters. We describe possible methods to mitigate risks to the foetus.

METHODS: Retrospective chart review of 15 births from mothers receiving natalizumab throughout pregnancy.

RESULTS: Thirteen mothers with third-trimester exposure to natalizumab were identified. Median age at conception was 34 years (26-40) and median disease duration was 53.5 months (11-204). The 13 mothers gave birth to 15 newborns (2 mothers each with 2 individual births), median (SD) birth weight was 2778 gs (2100 – 3790). Congenital or laboratory abnormalities were identified in 5, which included anemia (low red blood cells. n = 2) and thrombocytopenia (n = 3. Low platelet counts).

CONCLUSIONS: Complications following natalizumab administration during the second and third trimester of pregnancy occurred in 33% of newborns. However, did not result in mortality or morbidity. Dose alterations during the third trimester, pre-delivery umbilical cord sampling and IVIG administration may reduce haematological effects on newborns. Prospective studies with larger numbers of patients are required to provide further evidence regarding the safety of Natalizumab use in pregnancy.

PURPOSE OF REVIEW:

This article provides practical guidance on successful management of women with multiple sclerosis (MS) through pregnancy and the postpartum period.

RECENT FINDINGS:

Recent studies indicate that most women diagnosed with MS today can have children, breast-feed, and resume beta interferons or glatiramer acetate per their preferences without incurring an increased risk of relapses during the postpartum period. More than 40% of women with mild MS do not require any treatment before conception or in the postpartum period. Women with highly active MS can now become well-controlled before, throughout, and after pregnancy via highly effective treatments. Unfortunately, pregnancy does not protect against relapses following the cessation of fingolimod or natalizumab, and some women experience severe rebound relapses during pregnancy. Accidental first-trimester exposure to teriflunomide or fingolimod increases the risk of foetal harm.

You asked for more information.

Langer-Gould AM Pregnancy and Family Planning in Multiple Sclerosis. Continuum (Minneap Minn). 2019 ;25(3):773-792. 

Most women with MS can have normal pregnancies and breast-feed without incurring harm. Clinicians should avoid prescribing medications with known teratogenic potential (teriflunomide, fingolimod), known risk of severe rebound relapses (fingolimod, natalizumab), or unclear but plausible risks (dimethyl fumarate, alemtuzumab) to women of childbearing age who desire pregnancy or are not on reliable birth control. If a treatment needs to be resumed during breast-feeding, clinicians should opt for glatiramer acetate, interferon beta, natalizumab, or rituximab/ocrelizumab, as biologically plausible risks to the infant are exceedingly low.

Severe rebound disease activity after fingolimod withdrawal in a pregnant woman with multiple sclerosis managed with rituximab: A case study.

Canibaño B, Ali M, Mesraoua B, Melikyan G, Al Hail H, Ibrahim F, Hanssens Y, Deleu D. Case Rep Womens Health. 2019;25:e00162. 

Severe rebound disease activity after fingolimod withdrawal in a pregnant woman with multiple sclerosis managed with rituximab: A case study.Although pregnancy is potentially protective against relapses of multiple sclerosis, severe rebound of disease activity after withdrawal of fingolimod may occur. We report a woman with multiple sclerosis who discontinued fingolimod in the first month of her pregnancy. She developed severe disease rebound which responded poorly to steroids. She was started on rituximab, which was continued during the rest of her pregnancy and beyond. Rituximab appeared safe and well tolerated by both mother and infant, and could be considered in pregnancy for those patients with multiple sclerosis who are at high risk of gestational and postpartum relapse.

ECTRIMS 2019

P411 – Effect of Fingolimod on Pregnancy Outcomes in Patients with Multiple SclerosisS. Lopez Leon1, Y. Geissbuehler2, A. Moore2, A. Saxena3, A. Bhatt3, M. Guennec4, S. Vukusic5,6,7, H. Butzkueven8, H. Tilson9, T. M. MacDonald10, K. Hellwig11Background: Understanding the impact of fingolimod on pregnancy outcomes is important for management of MS during pregnancy or for women who plan to conceive.
Objective: To report the updated information on pregnancy outcomes in women exposed to fingolimod during pregnancy or for up to 8 weeks before the last menstrual period.
Method: Cumulative pregnancy outcome data from the Multinational Gilenya® Pregnancy Exposure Registry (prospective) and prospective cases from the Novartis Safety database (NSDB), including the PRegnancy outcomes Intensive Monitoring (PRIM) programme are reported. For the Registry, cases were considered prospective if, at the time of enrolment, no prenatal testing had been performed and the pregnancy outcome was unknown. For the NSDB and PRIM, prospective cases included those for which the pregnancy outcome was unknown and for which no prenatal testing was performed or, if prenatal testing was performed, the results were either normal or not known. The prevalence (95% confidence interval) of major congenital malformations in live births and proportion of spontaneous abortions among all pregnancies in the NSDB, PRIM, and the Registry was estimated.
Results: By 28th February 2019, 1586 prospective cases of maternal fingolimod exposure during pregnancy were documented in the NSDB, including 1030 cases from PRIM and 155 cases from the Registry. Of 967 cases with known outcomes in the NSDB there were 678 (70.1%) live births (PRIM: 393 live births in 557 cases with known outcome; Registry: 112 live births in 134 cases with known outcome). The mean age at the last menstrual period was comparable among the data sources (NSDB: 31.0, PRIM: 31.0, Registry: 31.6 years). Estimated prevalence of major congenital malformations among live births in the NSDB, PRIM, and the Registry was 3.69% (2.40; 5.40), 2.04% (0.88; 3.97), and 5.3% (2.0; 11.2), respectively. No discernible pattern of specific malformation was observed. Corresponding prevalence estimates range from 2.04-4.5% in the general population. The overall proportions of spontaneous abortions for the NSDB (8.1%), PRIM (13.1%), and Registry (7.4%) were within the expected range observed in the general population (7-20%).
Conclusion: Cumulative data indicate that prevalence of major congenital malformations among live births is consistent with the general population; the prevalence in the Registry suggests an increase when compared with EUROCAT, however, methodological differences should be considered .

P412 – Anti CD20 therapies and pregnancy in neuroimmunological disorders – a case series from Germany T. Kümpfel, S. Thiel, I. Meinl, A. Bayas, A. Ciplea, F. Hoffmann, U. Hofstadt-van Oy, M. Hoshi, A. Neubert, M. Ringelstein, O. Aktas, M. Stoppe, F. Then Bergh, B. Tackenberg, A. Walter, M. Weber, J. Kluge, R. Gold, K. Hellwig

Introduction: Information on disease activity during pregnancy after anti-CD 20 treatment such as rituximab (RTX) or ocrelizumab (OCR) in women with neuroimmunological diseases is scarce. Data on pregnancy outcomes in exposed pregnancies are also lacking.
Objectives and Aims: To assess disease activity and pregnancy outcomes after RTX or OCR treatment in neuroimmunological disorders.
Methods: 48 pregnancies of 44 women from Germany were recorded. We included women with multiple sclerosis (MS; n=32), neuromyelitis optica spectrum disorders (NMOSD; n=8), myasthenia (n=1) and other inflammatory diseases of the central nervous system (n=3). Information on disease course were assessed and pregnancy outcomes were collected.
Results: We collected 32 pregnancies after treatment with RTX and 16 after OCR. Mean age at conception was 30.4±5.1 years. In 37 pregnancies last therapy with RTX/OCR was performed ≤6 months before last menstrual period (LMP; range 163-3 days); in four pregnancies RTX/OCR was given >6 months prior to LMP (range 231-183 days) and in a patient exact data is not available yet. Three women received RTX and three OCR during pregnancy (range 9-148 days).So far 27 (87.1%) live births of healthy newborns without any major malformations were reported. Three spontaneous (9.7 %) and one elective abortion were recorded. Mean birthweight was 3,275g ± 606g. 17 pregnancies are ongoing.All women with MS or NMOSD and anti-CD20 treatment before pregnancy were relapse free during pregnancy. Two women received RTX/OCR during pregnancy due to a severe relapse. Of 31 women with a mean postpartum follow up of 24.9±32.1 month, two women with MS and two with NMO experienced at least one relapse during the postpartum period. Three women relapsed during the first 6 month postpartum (range 10-147 days), one woman within one year. Updated information on this cohort will be presented at the time of the meeting,
Conclusions: Women treated with anti-CD20 therapies experienced good control of disease activity. Thus RTX/OCR might be an interesting option for women with neuroimmunological diseases who plan a pregnancy. As sample size is still small, more information on pregnancy outcomes and best treatment strategies postpartum is needed.

P413 – Rituximab, Multiple Sclerosis and PregnancyK. Fink, A. Gorczyca, J. Smith, F. Piehl, A. Langer-Gould

Background: Women with highly active multiple sclerosis (MS) who desire pregnancy have limited safe and effective treatment options. Fingolimod (FNG) is a weak teratogen and natalizumab (NAT) use during pregnancy can result in neonatal cytopenias. However, stopping FNG or NAT can result in rebound relapses during pregnancy. Due to long lasting immunomodulatory effects extending beyond drug elimination, rituximab (RTX) is an attractive treatment for women with MS planning pregnancy.
Objective: To describe the efficacy and safety of RTX in women with MS who became pregnant.
Methods: We conducted a retrospective cohort study of women treated with RTX prior to or during pregnancy identified from 2 population-based settings: Sweden (2011-2016) and Kaiser Permanente Southern California (KPSC; 2012-3/2019). MS characteristics were obtained from the Swedish MS Register and complete electronic health records (EHR, KPSC). Pregnancy and infant outcomes were obtained from the Swedish Medical Birth Register (22 weeks gestation and beyond) and KPSC’s EHR (entire pregnancy and beyond).
Results: We identified 104 pregnancies (74 Sweden) exposed to RTX prior to delivery; 47 (45%) were switched from FNG or NAT to RTX; 59 (57%) pregnancies were exposed to RTX within six months prior to conception and 6 during pregnancy. Among the 106 babies, 93 (87.7%) were normal full-term babies. Adverse outcomes were as follows: 2 major malformations, 1 stillbirth, 1 neonatal death (preterm twin); 8 preterm (including 2 sets of twins); 2 small for gestational age (SGA), and two with other adverse events in the post-natal period. Only 11 women experienced relapses during pregnancy (n=3, 2.9%) or the postpartum period (n=8, 7.7%). Of 50 pregnancies in KPSC, 10 resulted in spontaneous first trimester abortions.
Conclusions: This represents the largest cohort of RTX-exposed MS pregnancies. We provide high quality and complete data on pregnancy and maternal outcomes. Most women were exposed to RTX prior to but not during pregnancy. We observed no increase in adverse pregnancy outcomes compared to expected national incidence rates. MS relapses observed during pregnancy and postpartum period are lower than expected compared to population-based cohort and far lower than in natalizumab-treated cohorts. Our findings indicate that RTX may be a safer and more effective alternative than FNG or NAT in women with highly active MS who desire pregnancy.

P780 – Pregnancy outcomes in patients treated with ocrelizumab C. Oreja-Guevara, S. Wray, R. Buffels, D. Zecevic, S. Vukusic

Background: Ocrelizumab (OCR) is a humanised anti-CD20+ monoclonal antibody approved for the treatment of relapsing and primary progressive forms of multiple sclerosis (MS) and has also been studied in clinical trials for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). As many patients with MS are women of reproductive age, pregnancy outcomes in OCR-exposed patients are important. B-cell levels in neonates exposed to OCR in utero have not been studied in trials, and the effect of OCR on the immune system of the newborn is unknown.
Objective: To report an update on pregnancy outcomes in women receiving OCR in clinical trials and the post-marketing setting up to 31/03/2019.
Methods: Analysis includes pregnancies in women treated with OCR in clinical trials/post-marketing sources up to 31/03/2019. In the EU, women of childbearing potential are recommended to use contraception while receiving and for 12 months after the last OCR infusion; use of two contraceptive methods until 48 weeks after the last OCR infusion/until B-cell repletion (whichever longer) was required in trials. A foetus was considered to have in utero OCR exposure if the last infusion occurred within 3 months of conception or during pregnancy or if the date was unknown.
Results: As of 31/03/2019, a total of 362 pregnancies exposed to OCR (MS, N=267; RA or SLE, N=33; no reported indication, N=62) have been reported. Of these, 267 were MS patients (trials, N=78; post-marketing, N=189); 118 were considered to have foetal OCR exposure (N=47 with no foetal exposure; N=102 foetal exposure unknown). Preliminary outcomes of the 267 pregnancies in women with MS exposed to OCR at cut-off include 62 live births, 86 ongoing pregnancies, 25 elective abortions, 10 spontaneous abortions, 1 stillbirth, 3 ectopic pregnancies, 22 lost to follow-up and 58 unknown or not reported outcomes.
Conclusions: Reviewed cases to date do not suggest an increased risk of adverse pregnancy outcomes, including spontaneous abortions or malformations, with OCR treatment. The current update remains in line with previous reports. Data will continue to be collected and assessed as part of post-authorisation commitments.

P1146 – Pregnancy outcomes in female partners of male patients treated with teriflunomide or leflunomide (an in vivo precursor of teriflunomide)S. Vukusic K. Hellwig, P. Truffinet, M. Benamor, S. Strattman, S. Afsar, A. Purvis, E.M. Poole, P.K. Coyle

Introduction: Teriflunomide is an approved treatment for relapsing forms of multiple sclerosis (MS) or relapsing remitting MS, depending on the local label, and leflunomide (an in vivo precursor of teriflunomide) for rheumatoid arthritis. Both drugs are contraindicated in pregnant women because of the potential for foetal harm. Teriflunomide is known to be present in semen at very low levels in men receiving teriflunomide. Risk of male-mediated embryo-foetal toxicity is considered low. Evidence from preclinical data indicates no effect of teriflunomide on male fertility or damage to DNA.
Objective: To evaluate outcomes of pregnancies in female partners of male patients treated with teriflunomide or leflunomide.
Methods: Pregnancy outcomes were analysed using prospective and retrospective data from clinical trials and the post-marketing setting. Measures included primary pregnancy outcomes, adverse pregnancy and development outcomes, and birth defects using the European Surveillance of Congenital Anomalies (EUROCAT) and Metropolitan Atlanta Congenital Defects Program (MACDP) classifications.
Results: A total of 88 and 144 pregnancies were reported in female partners of male patients treated with teriflunomide and leflunomide, of which 48 (54.5%) and 57 (39.6%), respectively, had known outcomes. Among the pregnancies in female partners of male patients treated with teriflunomide, there were 37 (77.1%) live births, 3 (6.3%) stillbirths, 6 (12.5%) spontaneous abortions, and 2 (4.2%) elective abortions. There were 2 foetal anomaly cases reported: congenital pes planus (outcome not reported) and congenital hip dysplasia (family had a history of congenital hip dysplasia; Pavlik Harness was used to correct). Among the pregnancies in female partners of male patients treated with leflunomide, there were 37 (64.9%) live births, of which 3 (5.3%) were pre-term [< 37 weeks], 2 (3.5%) still births, 9 (15.8%) spontaneous abortions, 8 (14.0%) elective abortions, and 1 (1.8%) ectopic pregnancy. There was 1 foetal anomaly case reported: bilateral renal agenesis (elective abortion).
Conclusions: No detectable teratogenic signal was observed in female partners of male patients receiving teriflunomide or leflunomide. To minimize any possible risk, men not wishing to father a child and their female partners should use reliable contraception, and men wishing to father a child should discontinue treatment and undergo an accelerated elimination procedure.

Any drug that interferes with DNA will carry risks to the unborn.

Coi: Not relevant, except I’m not a neuro

About the author

MouseDoctor

14 comments

  • Thank you for providing this information.
    I, however, wonder if you can provide information on Pregnancy outcomes amongst multiple sclerosis females with RITUXIMAB use. Perhaps there is a scientific articles or already established opinion among doctors/neuros on how to make the pregnancy more secure both for the mother and fetus. PLEASE. THANK YOU !

    • Remember rituximab is is not currently licenced for MS. These is a literature on rituximab as it is widely used in MS and elsewhere.
      I believe there are ongoing studies with ocrleizumab in relation to pregnancy.

      If you look at my posts of ocrelizumab this week, it talks about extended dosing and orelizumab. These studies need to be done to determine if you can have a drug free pregnancy. If you are taking IgG1 antibody, this can cross the placenta and rituximab and ocrelizumab and alemtuzumab can enter the foetus and deplete any B cell (& T cell with alemtuzumab)

      • Thanks. I, unfortunately, have not received that post where it talks about extended dosing and ocrelizumab. I, therefore, would appreciate haveing a link to copied here, perhaps ? thanks in advance.

        Other than that, I know that Rituximab enters placenta only on the 3rd month of the pregnancy, and therefore doctors used to recommend getting pregnant after 3 to 6 months of Rituximab injection. It is thought that the medicine will affect the fetus in limited terms. Howeber the fetus when born might (or will?) have low level of B-cells?! How dangerous that situation is for the newborn? I mean babies when born, do not have any immunity and mother’s immune cells will cover up for that. In my case being on Rituximab, my B cells are already depleted. I wonder about the possible dangers and complications that you might know and share with. Any knowledge on that aspect in a bit detailed manner (ie. opinions, links ) will be much appreciated. thank you ever so much. My email address can be used to share more info on this subject if you wish so (usahc7@yahoo.com ).

        • https://multiple-sclerosis-research.org/2020/02/the-case-for-more-trials-with-ocrelizumab-can-we-use-reduced-dosing-of-ocrelizumab-part-i/

          B cells dont form until 12 weeks of age. However remember the antibody may still be around three months and ocrelizumab maybe closer to 6 months hence uS recomendation for a 6 months wait, in EU it is 12 months.

          B cell depletion of the unborn new born is inpart tolerated as immunity is provided for by the mothers milk. Rituximab does not quickly drop immunoglobulin so you get maternal transfer. I know of some labs where cd20 depletion during pregnancy is more common.

          • Thank you for replay. I wonder why then it is recommended to get pregnant after 12 weeks? Is not that too soon? I mean if antybodies are still around even for 6 months, then would not they potentially harm the fetus in 3 months?

          • Always changing 🙂

            14- to 23-week-old fetuses

            Konnikova and her colleagues applied advanced cellular and genomic analyses to study the makeup of the immune system in gut tissues from 14- to 23-week-old fetuses and infants undergoing surgery to correct gut defects.

            “We were surprised to find that almost complete immune capacity in the gut had developed as early as 14 weeks, and it remained mostly stable through infancy,” said Konnikova. The fetal gut had cells from both the innate and adaptive immune

            Konnikova and her colleagues also found abundant amounts of B cells and T cells in the fetal gut, which are part of the adaptive immune system

            Gut immunity more developed before birth than previously thought

            https://medicalxpress.com/news/2019-10-gut-immunity-birth-previously-thought.html

            Obrigado

      • Anti CD20 therapies and pregnancy in neuroimmunological disorders – a case series from Germany

        Results: We collected 32 pregnancies after treatment with RTX and 16 after OCR. Mean age at conception was 30.4±5.1 years. In 37 pregnancies last therapy with RTX/OCR was performed ≤6 months before last menstrual period (LMP; range 163-3 days); in four pregnancies RTX/OCR was given >6 months prior to LMP (range 231-183 days) and in a patient exact data is not available yet. Three women received RTX and three OCR during pregnancy (range 9-148 days).
        So far 27 (87.1%) live births of healthy newborns without any major malformations were reported. Three spontaneous (9.7 %) and one elective abortion were recorded. Mean birthweight was 3,275g ± 606g. 17 pregnancies are ongoing.
        All women with MS or NMOSD and anti-CD20 treatment before pregnancy were relapse free during pregnancy. Two women received RTX/OCR during pregnancy due to a severe relapse. Of 31 women with a mean postpartum follow up of 24.9±32.1 month, two women with MS and two with NMO experienced at least one relapse during the postpartum period. Three women relapsed during the first 6 month postpartum (range 10-147 days), one woman within one year. Updated information on this cohort will be presented at the time of the meeting,
        Conclusions: Women treated with anti-CD20 therapies experienced good control of disease activity. Thus RTX/OCR might be an interesting option for women with neuroimmunological diseases who plan a pregnancy. As sample size is still small, more information on pregnancy outcomes and best treatment strategies postpartum is needed.

        https://www.professionalabstracts.com/ectrims2019/iplanner/#/presentation/416

  • Pregnancy Outcome in Multiple SclerosisPatients Exposed to Disease
    ModifyingTherapies.

    http://indexsmart.mirasmart.com/AAN2019/PDFfiles/AAN2019-002849.pdf

    Pregnancy Outcomes in Alemtuzumab-treated Patients With RRMS in the Phase 2 and 3 Clinical Development Program Over 16 Years

    https://cmsc.confex.com/cmsc/2019/meetingapp.cgi/Paper/6331

    Rituximab for Treatment of Aggressive Multiple Sclerosis During Pregnancy: A Case
    Series

    http://indexsmart.mirasmart.com/AAN2019/PDFfiles/AAN2019-000752.pdf

    The use natalizumab in multiple sclerosis
    patients during pregnancy is safe and
    prevents disease reactivation

    http://indexsmart.mirasmart.com/AAN2019/PDFfiles/AAN2019-003004.pdf

    What is the best time to stop natalizumab in patients with active RRMS planning pregnancy?

    https://www.professionalabstracts.com/ectrims2019/iplanner/#/presentation/786

        • Please talk to your health care professional. The recommendations about pregnancy are generally part of the label and these can be found for any drug type in the drug name and INN or EPAR and then you will get the summary of product characterisitics = the label and look for advce on pregnancy but I believe the recomemndation is that you wait for 6-12 months before trying to get pregnant

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