title: Delayed-Release Dimethyl Fumarate and Pregnancy: Preclinical Studies and Pregnancy Outcomes from Clinical Trials and Postmarketing Experience.
abstract: BACKGROUND
  Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) is an oral agent for the treatment of relapsing forms of multiple sclerosis (MS). No formal studies of DMF were conducted in pregnant women, although pregnancies have occurred during clinical trials and in the postmarketing setting.
  
  
  METHODS
  Preclinical developmental and reproductive toxicology studies were performed with DMF in rats and rabbits. As of March 26, 2014, the DMF clinical development program included a total of 4132 subjects consisting of 2898 patients with MS, 320 psoriasis patients, 101 rheumatoid arthritis patients, and 813 healthy volunteers. Subjects were required to use reliable contraception and immediately discontinue treatment in the event of pregnancy.
  
  
  RESULTS
  Animal studies showed no evidence of impaired fertility or teratogenicity with DMF. Overall as of June 30, 2014, 63 pregnancies were reported in clinical trials. Outcomes are known for 39 of 42 subjects receiving DMF and include 26 live births (67%), three spontaneous abortions (8%), and 10 elective terminations (26%); follow-up is ongoing in 2 cases and one patient was lost to follow-up. The incidence of spontaneous abortion in subjects exposed to DMF was consistent with the expected rate of early pregnancy loss in the general population (12-22%). A total of 135 pregnancies were reported in the postmarketing setting (spontaneous and solicited reports). Outcomes are known for 30 cases and include 10 live births, 13 spontaneous abortions, and 5 elective terminations; follow-up is ongoing in 103 cases and 2 patients have been lost to follow-up.
  
  
  CONCLUSIONS
  Although data are limited and all known exposures have occurred in the first trimester, no increased risk of fetal abnormalities or adverse pregnancy outcomes associated with gestational exposure to DMF has been observed.
  
  
  BACKGROUND
  Biogen, Inc.
authors.affiliation: St. Josef Hospital, Ruhr University, Bochum, Germany. ralf.gold@ruhr-uni-bochum.de.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
authors.affiliation: Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, USA.
authors.forename: J Theodore
authors.initials: JT
authors.lastname: Phillips
authors.affiliation: Charles University, Prague, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Havrdova
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
authors.forename: Amit
authors.initials: A
authors.lastname: Bar-Or
authors.affiliation: University Hospital, Basel Neurology, Basel, Switzerland.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
authors.affiliation: Biogen, Inc., Cambridge, MA, USA.
authors.forename: Norman
authors.initials: N
authors.lastname: Kim
authors.affiliation: Biogen, Inc., Cambridge, MA, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Thullen
authors.affiliation: Biogen, Inc., Cambridge, MA, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Valencia
authors.affiliation: Biogen, Inc., Cambridge, MA, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Oliva
authors.affiliation: Biogen, Inc., Cambridge, MA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Novas
authors.affiliation: Biogen, Inc., Cambridge, MA, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Biogen, Inc., Cambridge, MA, USA.|Alnylam Pharmaceuticals, Inc., Cambridge, MA, USA.
authors.forename: Marianne T
authors.initials: MT
authors.lastname: Sweetser
authors.affiliation: Biogen, Inc., Cambridge, MA, USA.
authors.forename: Nuwan
authors.initials: N
authors.lastname: Kurukulasuriya
authors.affiliation: Biogen, Inc., Cambridge, MA, USA.
authors.forename: Vissia
authors.initials: V
authors.lastname: Viglietta
authors.affiliation: Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fox
keywords: Clinical trial; Delayed-release dimethyl fumarate; Multiple sclerosis; Postmarketing; Preclinical; Pregnancy; Safety; Women