Safety of disease-modifying drugs for multiple sclerosis in pregnancy: current challenges and future considerations for effective pharmacovigilance

Figures & data

Figure 1. A conceptual timeline of pharmacokinetic and pharmacodynamic effects of drugs on pregnancy and potential methodological improvements to study design.

‘All or none’ refers to the time from conception until implantation when insults to the embryo are likely to result in either death or intact survival of the embryo. The ‘critical period’ refers to early organogenesis, during which all the major organ systems of the body are being formed; drug exposure during this period can result in significant congenital anomalies (although exposure at any time during pregnancy has the potential for adverse effects).

DMD: Disease-modifying drug; MS: Multiple sclerosis.

Table 1. Disease-modifying drugs for multiple sclerosis during pregnancy and breastfeeding: summary of current evidence and recommendations.

Drug	Animal studies	Human studies	Breastfeeding	Current recommendations
IFN-β	Pregnancy loss observed in monkeys with 100× human dose of IFN-β1a [101] and 2.8–40× human dose of IFN-β1b [102] Decreased fetal growth: unknown Teratogenicity not observed in monkeys with 100× human dose of IFN-β-1a [101] or 2.8–40× human dose of IFN-β1b [102] Decreased newborn survival: unknown	Pregnancy loss: conflicting findings (observed in n = 23 [25] and n = 69 [IFN-β1b only [13]], but not in n = 88 [12]) Decreased fetal growth: conflicting findings (observed in n = 88 [12] and n = 69 [13], but not in n = 78 [59]) Teratogenicity not observed (n = 88 [12], n = 78 [59] and n = 69 [13]) Impaired development of newborn not observed (n = 88 [12])	Minimal excretion of IFN-β1a in human milk, even at the highest recommended human dose [58] Excretion of IFN-β1b in human milk: unknown [102]	Pregnancy category C (risk shown in animal studies [101,102]) Women should be cautioned about the abortifacient potential of IFN-β1b [102] Recommend discontinuation prior to conception or once pregnancy is known [7,8] with some suggesting a washout period of at least 1 month prior to conception [60] for women with mild MS Recommend continuation until conception or through pregnancy [6] for women with severe or highly active MSUse not recommended in breastfeeding [6,8,10]
Glatiramer acetate	Pregnancy loss: unknown Decreased fetal growth not observed in rats with 18–36× human dose [110] Teratogenicity not observed in rats or rabbits with 18–36× human dose [110] Decreased newborn survival: unknown	Pregnancy loss not observed (n = 31 [13], n = 46 [61] and n = 17 [62]) Decreased fetal growth not observed (n = 31 [13] and n = 17 [62]) Teratogenicity not observed (n = 31 [13], n = 46 [61] and n = 17 [62]) Impaired development of the newborn not observed (n = 11 [16])	Excretion in human milk: unknown [110] Breastfeeding not observed to harm newborn (n = 10 [16])	Pregnancy category B (no risk shown in animal studies; no adequate human studies [110]) Recommend discontinuation prior to conception or once pregnancy is known [7,8] with some suggesting a washout period of at least 1 month prior to conception [60] for women with mild MS Use until conception or into pregnancy may be recommended for women with severe or highly active MS [6] Use not recommended in breastfeeding [6]
Natalizumab	Pregnancy loss: unknown Decreased fetal growth: unknown Teratogenicity: unknownDecreased newborn survival observed in guinea pig with 7× human dose [106]	Pregnancy loss: unknown Decreased fetal growth not observed (n = 35 [17]) Teratogenicity not observed (n = 35 [17]) Impaired development of newborn: unknown Preliminary data of the Tysabri Pregnancy Exposure Registry (expected study end date: June 2016) suggests no increased risk of pregnancy loss or teratogenicity (n = 277 [63,103])	Detected excretion in human milk [106] Breastfeeding: unknown effect on newborn [106]	Pregnancy category C (risk shown in animal studies; no adequate human studies [106]) Contraception required for women with childbearing potential; recommend discontinuation at least 3 months prior to conception [6] Use not recommended in breastfeeding [6,11]
Mitoxantrone	Pregnancy loss: unknown Decreased fetal growth observed in rats and rabbits with <0.01× human dose [107] Teratogenicity not observed in rats or rabbits with <0.01× human dose [107] Decreased newborn survival: unknown	Restricted fetal growth in one case report [64] Fetal malformation in one case report [65])	Detected excretion in human milk at significant concentrations (18 ng/ml [107])	Pregnancy category D (positive evidence of human fetal risk [107]) Negative pregnancy test prior to each dose required in women with childbearing potential [107] Use NOT recommended in breastfeeding [11,60]
Fingolimod	Pregnancy loss observed in rats with <1× and rabbits with >20× human dose [108] Decreased fetal growth observed in rabbits with >20× human dose [108] Teratogenicity observed in rats with <1× human dose [108] Decreased newborn survival observed in rats with <1× human dose [108]	Preliminary data from the Multi-National Gilenya Pregnancy Exposure Registry in Multiple Sclerosis (expected registry completion date: August 2017) suggests no increased risk of teratogenicity [66,104]	Detected excretion in rat milk, but unknown for human milk [108]	Pregnancy category C (risk shown in animal studies; no adequate human studies [108]) Contraception required for women with childbearing potential; 2 months contraception recommended after discontinuation [6] Use not recommended in breastfeeding [11]
Teriflunomide	Pregnancy loss observed in rats and rabbits with <1× human dose [109] Decreased fetal growth observed in rats with <1× human dose [109] Teratogenicity observed in rats and rabbits with <1× human dose [109] Decreased newborn survival observed in rats with <1× human dose [109]	A clinical trial database revealed no increased risk spontaneous abortion, lower birthweight, lower gestational age or congenital malformation (n = 43 [67]) Detected in semen [109]	Detected excretion in rat milk, but unknown for human milk [109]	Pregnancy category X (fetal malformation reported in animal studies [109]) Negative pregnancy test and contraception required for use in women with childbearing potential [109] Accelerated elimination procedure recommended for discontinuation of therapy in men wishing to father a child [109]

MS: Multiple sclerosis.

Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

	1	2	3	4	5
1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
4. The activity was presented objectively and free of commercial bias.

Biogen Idec. Avonex® (interferon β-1a). www.accessdata.fda.gov/drugsatfda_docs/label/2007/103628s5115lbl.pdf (Accessed 10 June 2012)

 Google Scholar

Bayer HealthCare. Betaseron® (interferon β-1b). http://berlex.bayerhealthcare.com/html/products/pi/Betaseron_PI.pdf (Accessed 10 June 2012)

 Google Scholar

Boskovic R, Wide R, Wolpin J, Bauer DJ, Koren G. The reproductive effects of β interferon therapy in pregnancy: a longitudinal cohort. Neurology 65(6), 807–811 (2005).

 PubMed Web of Science ®Google Scholar

Weber-Schoendorfer C, Schaefer C. Multiple sclerosis, immunomodulators, and pregnancy outcome: a prospective observational study. Mult. Scler. 15(9), 1037–1042 (2009).

 PubMed Web of Science ®Google Scholar

Amato MP, Portaccio E, Ghezzi A et al.; MS Study Group of the Italian Neurological Society. Pregnancy and fetal outcomes after interferon-b exposure in multiple sclerosis. Neurology 75(20), 1794–1802 (2010).

 PubMed Web of Science ®Google Scholar

Hellwig K, Haghikia A, Rockhoff M, Gold R. Multiple sclerosis and pregnancy: experience from a nationwide database in Germany. Ther. Adv. Neurol. Disord. 5(5), 247–253 (2012).

 PubMed Web of Science ®Google Scholar

Hale TW, Siddiqui AA, Baker TE. Transfer of interferon b-1a into human breastmilk. Breastfeed. Med. 7(2), 123–125 (2012).

 PubMed Web of Science ®Google Scholar

Stuart M, Bergstrom L. Pregnancy and multiple sclerosis. J. Midwifery Womens Health 56(1), 41–47 (2011).

 Google Scholar

Tsui A, Lee MA. Multiple sclerosis and pregnancy. Curr. Opin. Obstet. Gynecol. 23(6), 435–439 (2011).

 Google Scholar

Teva Pharmaceuticals. Copaxone® (glatiramer acetate). www.copaxone.com/pdf/prescribinginformation.pdf (Accessed 10 June 2012)

 Google Scholar

Miller AE, Rustgi S, Farrell C. Use of glatiramer acetate during pregnancy: offering women a choice. Mult. Scler. 18(Suppl. 4), P733 (2012).

 Google Scholar

Giannini M, Portaccio E, Ghezzi A et al. Pregnancy and fetal outcomes after glatiramer acetate exposure in patients with multiple sclerosis: a prospective observational multicentric study. BMC Neurol. 12, 124 (2012).

 PubMed Web of Science ®Google Scholar

Fragoso YD, Finkelsztejn A, Kaimen-Maciel DR et al. Long-term use of glatiramer acetate by 11 pregnant women with multiple sclerosis: a retrospective, multicentre case series. CNS Drugs 24(11), 969–976 (2010).

 PubMed Web of Science ®Google Scholar

Biogen Idec/Elan Pharmaceuticals I. Tysabri® (natalizumab). www.accessdata.fda.gov/drugsatfda_docs/label/2006/125104s015lbl.pdf (Accessed 10 June 2012)

 Google Scholar

Hellwig K, Haghikia A, Gold R. Pregnancy and natalizumab: results of an observational study in 35 accidental pregnancies during natalizumab treatment. Mult. Scler. 17(8), 958–963 (2011).

 PubMed Web of Science ®Google Scholar

EMD Serono I/C. Novantrone® (mitoxantrone). www.accessdata.fda.gov/drugsatfda_docs/label/2009/019297s030s031lbl.pdf (Accessed 14 September 2012)

 Google Scholar

De Santis M, Straface G, Cavaliere AF, Rosati P, Batocchi AP, Caruso A. The first case of mitoxantrone exposure in early pregnancy. Neurotoxicology 28(3), 696–697 (2007).

 PubMedGoogle Scholar

Hellwig K, Schimrigk S, Chan A, Epplen J, Gold R. A newborn with Pierre Robin sequence after preconceptional mitoxantrone exposure of a female with multiple sclerosis. J. Neurol. Sci. 307(1–2), 164–165 (2011).

 PubMed Web of Science ®Google Scholar

Novartis Pharmaceuticals Corp. Gilenya™ (fingolimod). www.accessdata.fda.gov/drugsatfda_docs/label/2010/022527s000lbl.pdf (Accessed 10 June 2012)

 Google Scholar

Houtchens MK, Kolb CM. Multiple sclerosis and pregnancy: therapeutic considerations. J. Neurol. doi:10.1007/s00415-012-6653-9 (2012) (Epub ahead of print).

 Google Scholar

Sanofi Aventis US. Aubagio® (teriflunomide).www.accessdata.fda.gov/drugsatfda_docs/label/2012/202992s000lbl.pdf (Accessed 30 December 2012).

 Google Scholar

Kieseier B, Benamor M, Benzerdjeb H, Stuve O. Pregnancy outcomes from the teriflunomide clinical development programme: retrospective analysis of the teriflunomide clinical trial database. Mult. Scler. 18(Suppl. 4), P737 (2012).

 Google Scholar