Bove R, Alwan S, Friedman JM, Hellwig K, Houtchens M, Koren G, et al. Management of multiple sclerosis during pregnancy and the reproductive years: a systematic review.
Obstet Gynecol 2014;124.
The authors provided this information as a supplement to their article.
© Copyright 2014 American College of Obstetricians and Gynecologists. Page 1 of 7
Definition of DMT Exposure (n of Women Exposed)
(n)
Beta interferons Boskovic et al.
(2005)(1)
Prospective cohort
First trimester (n=23)
Disease matched unexposed –
discontinued IFNβ or GA at least 1 month before conception (n=21). Healthy controls (n=20)
IFNβ associated with lower birth weight (p=
0.002), miscarriages and stillbirths (p= 0.03).
Patti et al.
(2008)(2)
Retrospective cohort
While becoming pregnant (n=14)
Discontinued IFNβ at least 1 month before conception (n=7).
Unexposed to IFNβ (n=17)
No differences in rates of adverse outcomes, including birth defects, between exposed and unexposed.
Hellwig et al.
(2012) (3) Prospective
cohort During early pregnancy (mean=
8.8 gestational weeks) (n=78)
Non-DMT exposed
pregnancies (n=216) No increased rates of low birth weight, length, gestational age or birth defects in exposed compared with unexposed.
Weber- Schoendorfer et al. (2009)(4)
Prospective cohort
Median duration:
8.8 weeks during pregnancy (n=69)
No exposure to IFNβ or GA (n=64). Healthy controls (n=1556)
Rate of spontaneous abortions significantly increased in a subgroup of IFNβ-1b exposed pregnancies compared with non-MS controls (28%, p=0.02). Adjusted mean birth weight was significantly lower for term newborns in exposed compared with MS controls and non-MS controls (P< 0.001). No increased rates of birth defects.
Bove R, Alwan S, Friedman JM, Hellwig K, Houtchens M, Koren G, et al. Management of multiple sclerosis during pregnancy and the reproductive years: a systematic review.
Obstet Gynecol 2014;124.
The authors provided this information as a supplement to their article.
© Copyright 2014 American College of Obstetricians and Gynecologists. Page 2 of 7
Study (year) Study Design Timing or Definition of DMT
Exposure (n of Women Exposed)
Comparison Groups (n)
Findings
Amato et al.
(2010) (5)
Prospective cohort
Discontinued IFNβ
<4 weeks from conception (n=88)
Discontinued IFNβ ≥ 4 weeks before
conception or never used DMTs (n=318)
No association of IFNβ with increased risk of spontaneous abortions, malformations or developmental abnormalities. Association with lower birth weight and length (p< 0.0001 for each) and preterm delivery (adjusted OR: 2.11, CI: 1.18-3.78)
Sandberg- Wollheim et al.
(2011) (6)
Prospective
case-series During pregnancy
(n=425) None Rates of spontaneous abortions and major
congenital anomalies similar to those observed in the general population.
Coyle et al.
(2014) (7) Pregnancy registry findings
Anytime from two weeks before conception and during pregnancy (n=96)
Population based external comparator groups for spontaneous abortions and birth defects.
The birth defect rate estimated for exposed pregnancies (5.8%, 95% CI: 1.9%-13%) was not significantly different than population rate (2.78%, p=0.092). No increased rates for spontaneous abortions or other adverse pregnancy outcomes.
Glatiramer acetate Weber-
Schoendorfer et al. (2009)(4)
Prospective
cohort (TIS) Median duration:
6.9 weeks during pregnancy (n=31)
No exposure to IFNβ or GA (n=64). Healthy controls (n=1556)
No significant differences in the rate of spontaneous abortions or preterm birth in GA exposed versus unexposed pregnancies Fragoso et al.
(2010) (8) Prospective
case-series ≥7 months during
pregnancy (n=11) None All pregnancies resulted in livebirths (1 pregnancy with twins delivered at 31 weeks), with no cases of malformations.
Salminen et al.
(2010) (9) Prospective
case-series Throughout (n=9) or during but not throughout pregnancy (n=5)
None 13 livebirths (1 twin pregnancy) and 2 spontaneous abortions. No birth defects were identified amongst the 13 babies born.
Hellwig et al. Prospective During early Non DMT exposed No increased rates of low birth weight, length,
Bove R, Alwan S, Friedman JM, Hellwig K, Houtchens M, Koren G, et al. Management of multiple sclerosis during pregnancy and the reproductive years: a systematic review.
Obstet Gynecol 2014;124.
The authors provided this information as a supplement to their article.
© Copyright 2014 American College of Obstetricians and Gynecologists. Page 3 of 7
(2012) (3) cohort pregnancy (mean=
8.8 gestational weeks) (n=41)
pregnancies (n=216) gestational age or birth defects in exposed compared with unexposed.
Giannini et al.
(2012) (10)
Prospective cohort
Four weeks from conception; mean duration exposure:
4.9 weeks (n=17)
Discontinued DMT ≥4 weeks from conception (n=318)
No increased associations of maternal GA exposure with spontaneous abortions, preterm delivery or low birth weight and length.
Malformations were not reported in GA exposed infants.
Natalizumab Hellwig et al.
(2011) (11) Prospective
cohort Very early
pregnancy (n=35) MS patients with no DMT exposure in pregnancy (n=23)
No significant differences in rates of adverse outcomes, including birth defects, between exposed and unexposed groups
Ebrahimi et al,
(2014) Prospective
cohort Before or during
pregnancy (n=101) Unexposed disease matched group (n=78) and healthy controls (n=97)
No increase in the risk of major malformations or other adverse perinatal outcomes as compared to disease-matched and healthy controls.
Haghikia et al,
(2014) (12) Prospective
case-series Third trimester of
pregnancy (n=12) None Mild to moderate hematologic alterations in 10 of 13 infants including thrombocytopenia and anemia
Fingolimod Karlsson et al.
(2014)(13)
Pregnancy registry findings
During pregnancy (n=66)
None 5 cases with first trimester exposure (7.6%; 95%
CI: 3%-17%) had abnormal fetal development.
Two infants with congenital anomalies
(unilateral posteromedial bowing of the tibia and acrania) were described among 28 livebirths, and one infant with tetralogy of Fallot in an elective
Bove R, Alwan S, Friedman JM, Hellwig K, Houtchens M, Koren G, et al. Management of multiple sclerosis during pregnancy and the reproductive years: a systematic review.
Obstet Gynecol 2014;124.
The authors provided this information as a supplement to their article.
© Copyright 2014 American College of Obstetricians and Gynecologists. Page 4 of 7
Study (year) Study Design Timing or Definition of DMT
Exposure (n of Women Exposed)
Comparison Groups (n)
Findings
abortion was reported.
More than one DMT class considered de las Heras et
al. (2007)(14) Retrospective
cohort At time of
conception (n=34) Unexposed to DMT ≤ before conception (n=54)
No difference in rates of spontaneous abortions or malformations between exposed and
unexposed.
Fernandez Liguori et al.
(2009)(15)
Retrospective cohort
<15 days before conception (n=23)
Unexposed to DMT (n=88)
Association of DMT exposure with increased rate of any birth defect (OR: 10.8, 95% CI: 1.6- 71.0). Limitations: some women may not have been exposed during the critical period of embryogenesis, and any problem or disorder occurring at birth was defined as a “birth defect”.
Lu et al. (2012) (16)
Retrospective cohort
Either IFNβ (n=15) or GA (n=6) 1 month prior to conception or/and during pregnancy
Discontinued DMTs at least 1 month before conception (n=80) or never used DMTs (n=317)
Increase in risk of assisted vaginal delivery between exposed pregnancies compared to never exposed to DMTs pregnancies (OR: 3.0, 95% CI:
1.0-9.2)
Bove R, Alwan S, Friedman JM, Hellwig K, Houtchens M, Koren G, et al. Management of multiple sclerosis during pregnancy and the reproductive years: a systematic review. Obstet Gynecol 2014;124.
The authors provided this information as a supplement to their article.
© Copyright 2014 American College of Obstetricians and Gynecologists. Page 5 of 7
Drug Experience in Pregnancy
Azathioprine The risk of maternal treatment on the developing embryo or fetus (hereafter referred to collectively as fetus) appeared to be increased when women with inflammatory bowel disease were compared to healthy women, but no clear pattern of malformation has been reported and numbers are small. (17, 18)
Cyclophosphamide A characteristic embryopathy has been reported among children whose mothers were treated with
cyclophosphamide during the first trimester of pregnancy; the frequency with which this occurs is unknown.(19, 20)
Methotrexate A methotrexate embryopathy has been described after maternal treatment early in pregnancy.(21, 22) The frequency of fetal malformations with maternal first trimester methotrexate treatment appears to be moderately high and is probably dose-related.
Mitoxantrone There is very little human experience with
mitoxantrone in pregnancy,(23) and the associated teratogenic risk is largely unknown but suspected to be significant.(24)
Mycophenolate mofetil Maternal mycophenolate mofetil treatment during early pregnancy has also been associated with a moderately high risk of embryopathy.(25)
Bove R, Alwan S, Friedman JM, Hellwig K, Houtchens M, Koren G, et al. Management of multiple sclerosis during pregnancy and the reproductive years: a systematic review. Obstet Gynecol 2014;124.
The authors provided this information as a supplement to their article.
© Copyright 2014 American College of Obstetricians and Gynecologists. Page 6 of 7
REFERENCES FOR APPENDIXES
1. Boskovic R, Wide R, Wolpin J, Bauer D, Koren G. The reproductive effects of beta interferon therapy in pregnancy: a longitudinal cohort. Neurology 2005;65(6):807-11.
2. Patti F, Cavallaro T, Lo Fermo S, Nicoletti A, Cimino V, Vecchio R, et al. Is in utero early-exposure to interferon beta a risk factor for pregnancy outcomes in multiple sclerosis? J Neurol 2008 Aug;255(8):1250-3.
3. Hellwig K, Haghikia A, Rockhoff M, Gold R. Multiple sclerosis and pregnancy:
experience from a nationwide database in Germany. Ther Adv Neurol Disord 2012 Sep;5(5):247-53.
4. Weber-Schoendorfer C, Schaefer C. Multiple sclerosis, immunomodulators, and pregnancy outcome: a prospective observational study. Mult Scler 2009 Sep;
2009;15(9):1037-42.
5. Amato MP, Portaccio E, Ghezzi A, Hakiki B, Zipoli V, Martinelli V, et al. Pregnancy and fetal outcomes after interferon-beta exposure in multiple sclerosis. Neurology 2010 Nov 16;75(20):1794-802.
6. Sandberg-Wollheim M, Alteri E, Moraga MS, Kornmann G. Pregnancy outcomes in multiple sclerosis following subcutaneous interferon beta-1a therapy. Mult Scler 2011 Apr;17(4):423-30.
7. Coyle PK, Sinclair SM, Scheuerle AE, Thorp JM, Jr., Albano JD, Rametta MJ. Final results from the Betaseron (interferon beta-1b) Pregnancy Registry: a prospective observational study of birth defects and pregnancy-related adverse events. BMJ Open 2014;4(5):e004536.
8. Fragoso YD, Finkelsztejn A, Kaimen-Maciel DR, Grzesiuk AK, Gallina AS, Lopes J, et al. Long-term use of glatiramer acetate by 11 pregnant women with multiple sclerosis:
a retrospective, multicentre case series. CNS Drugs 2010 Nov;24(11):969-76.
9. Salminen HJ, Leggett H, Boggild M. Glatiramer acetate exposure in pregnancy:
preliminary safety and birth outcomes. J Neurol 2010 Dec;257(12):2020-3.
10. Giannini M, Portaccio E, Ghezzi A, Hakiki B, Pasto L, Razzolini L, et al. Pregnancy and fetal outcomes after Glatiramer Acetate exposure in patients with multiple sclerosis:
a prospective observational multicentric study. BMC Neurol 2012;12:124.
11. Hellwig K, Haghikia A, Gold R. Pregnancy and natalizumab: results of an observational study in 35 accidental pregnancies during natalizumab treatment. Mult Scler 2011 Aug;17(8):958-63.
12. Haghikia A, Langer-Gould A, Rellensmann G, Schneider H, Tenenbaum T, Elias- Hamp B, et al. Natalizumab Use During the Third Trimester of Pregnancy. JAMA Neurol 2014 May 12.
13. Karlsson G, Francis G, Koren G, Heining P, Zhang X, Cohen JA, et al. Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis.
Neurology 2014 Jan 24.
14. De Las Heras V, De Andres C, Tellez N, Tintore M. Pregnancy in multiple sclerosis patients treated with immunomodulators prior to or during part of the pregnancy: a descriptive study in the Spanish population. Mult Scler 2007 Sep;13(8):981-4.
Bove R, Alwan S, Friedman JM, Hellwig K, Houtchens M, Koren G, et al. Management of multiple sclerosis during pregnancy and the reproductive years: a systematic review. Obstet Gynecol 2014;124.
The authors provided this information as a supplement to their article.
© Copyright 2014 American College of Obstetricians and Gynecologists. Page 7 of 7
16. Lu E, Dahlgren L, Sadovnick A, Sayao A, Synnes A, Tremlett H. Perinatal outcomes in women with multiple sclerosis exposed to disease-modifying drugs. Mult Scler 2012 Apr;18(4):460-7.
17. Hutson JR, Matlow JN, Moretti ME, Koren G. The fetal safety of thiopurines for the treatment of inflammatory bowel disease in pregnancy. J Obstet Gynaecol 2013
Jan;33(1):1-8.
18. Cleary BJ, Kallen B. Early pregnancy azathioprine use and pregnancy outcomes.
Birth Defects Res A Clin Mol Teratol 2009 Jul;85(7):647-54.
19. Enns GM, Roeder E, Chan RT, Ali-Khan Catts Z, Cox VA, Golabi M. Apparent cyclophosphamide (cytoxan) embryopathy: a distinct phenotype? Am J Med Genet 1999 Sep 17;86(3):237-41.
20. Ozolins TR. Cyclophosphamide and the Teratology Society: an awkward marriage.
Birth Defects Res B Dev Reprod Toxicol 2010 Aug;89(4):289-99.
21. Lloyd ME, Carr M, McElhatton P, Hall GM, Hughes RA. The effects of methotrexate on pregnancy, fertility and lactation. Qjm 1999 Oct;92(10):551-63.
22. Donnenfeld AE, Pastuszak A, Noah JS, Schick B, Rose NC, Koren G. Methotrexate exposure prior to and during pregnancy. Teratology 1994 Feb;49(2):79-81.
23. 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 2011 Aug 15;307(1-2):164-5.
24. De Santis M, Straface G, Cavaliere AF, Rosati P, Batocchi AP, Caruso A. The first case of mitoxantrone exposure in early pregnancy. Neurotoxicology 2007
May;28(3):696-7.
25. Hoeltzenbein M, Elefant E, Vial T, Finkel-Pekarsky V, Stephens S, Clementi M, et al.
Teratogenicity of mycophenolate confirmed in a prospective study of the European Network of Teratology Information Services. Am J Med Genet A 2012
Mar;158A(3):588-96.
26. Tomassini V, Onesti E, Mainero C, Giugni E, Paolillo A, Salvetti M, et al. Sex hormones modulate brain damage in multiple sclerosis: MRI evidence. J Neurol Neurosurg Psychiatry 2005 Feb;76(2):272-5.
27. Safarinejad MR. Evaluation of endocrine profile, hypothalamic-pituitary-testis axis and semen quality in multiple sclerosis. J Neuroendocrinol 2008 Dec;20(12):1368-75.
