Discussion
To date the information on pregnancy and fetal outcomes after in-utero exposure to GA in patients with MS is limited. The main data on the safety of GA is from the manufacturer’s post-marketing surveillance, that suggests no increased risk in terms of spontaneous abortion and other outcomes. Indeed the reported miscarriage rate (17%) is similar to that observed in the general population [
7].
With regard the experience of Italian centers routine practice was to discontinue DMDs before a pregnancy program and to advise preventing pregnancy while on therapy. However, in a previous multicentric, prospective study that was focused on the issue of IFNB exposure, we observed 115 unplanned pregnancies occurred during DMD treatment (88 exposed to IFNB, 17 to GA). As for GA, in the present study we found no significant association between drug exposure and increased risk of spontaneous abortion, after an average exposure of approximately 4 weeks. Moreover, the risk of spontaneous abortion was comparable to that of the general population.
Similar findings were reported by Weber-Schoendorfer et al., in a prospective observational cohort study [
6], assessing the outcomes of 69 pregnancies exposed to IFNB and 31 exposed to GA (the latter with a median duration of exposure of 6.9 weeks).
As for other pregnancy and fetal outcomes, in our study GA exposure was associated with neither a higher risk of preterm and caesarean delivery nor a lower weight and length of the babies. It has to be noted that lower birth-weight and –lenght resulted to be related with the exposure to IFNB. This difference was observed also by Weber-Schoendorfer and co-workers. This result may be due, at least in part, by the different mechanism of action of the drugs. Although IFNBs are macromolecules that do not easily pass the placenta, it is known that cytokine imbalance may affect pregnancy outcomes [
13‐
15].
Furthermore no fetal complication was observed in pregnancies exposed to GA and , in a median follow-up period of 2.1 years, we did not observe developmental abnormalities in the GA exposed group. Probably a low risk of GA teratogenicity may be due to its mechanism of action [
16].
In interpreting the study results, a few possible limitations should be taken into account. The sample size of GA-exposed pregnancies is small. Moreover, we cannot exclude the occurrence of recall bias, even if women were prospectively followed up and the interview was performed soon after the delivery.
Our study focused on the effects of GA after an average exposure of approximately 4 weeks, and the consequences of longer duration of exposure cannot be assessed. However, two smaller uncontrolled studies and a another recent study performed on a larger population of patients reported the safety of continuous exposure of GA for at least eight weeks of gestation [
4,
9,
10]. Neither drug-related obstetric/neonatal complications nor malformations were observed in the pregnancies exposed to GA.
Despite these limitations, taken as a whole our findings point to the safety of GA utero exposure in terms of the risk of spontaneous abortion and the main maternal and fetal outcomes. With respect to what observed after IFNB exposure, GA exposure did not affect gestational age, birth-weight and –length, possibly resulting in a better safety profile. Our study can assist the neurologist facing the issue of pregnancy planning in MS patients. In particular, in subjects with high disease activity and high risk of post-partum relapses, prosecution of GA treatment may be considered.
Disclosures
Dr. Giannini has received compensation from Biogen Idec.
Dr. Portaccio serves on a scientific advisory board for Biogen Idec and receives research support from Merck Serono, Biogen Idec, Bayer Schering Pharma, and sanofi-aventis.
Dr. Ghezzi serves on scientific advisory boards for Merck Serono and Teva Pharmaceutical Industries Ltd.; has received speaker honoraria from Merck Serono, Biogen Idec, Bayer Schering Pharma, and Novartis; serves as a consultant for Novartis; and receives research support from
Sanofi-aventis, Biogen Idec, and Merck Serono.
Dr. Hakiki receives research support from Novartis and Merck Serono; received funding for travel from Biogen, Sanofi, Novartis, Bayer, Merck Serono.
Dr. Pastò has received compensation from Biogen Idec.
Dr. Razzolini has received funding for travel and research support from Novartis.
Dr. Piscolla has nothing to disclose.
Dr. Pozzilli serves on scientific advisory boards for and has received speaker honoraria from Novartis, Merck Serono, Biogen Idec, Bayer Schering Pharma, and sanofi-aventis.
Dr. De Giglio reports no disclosures.
Dr. Paolicelli serves as a consultant for Merck Serono and Bayer Schering Pharma.
Dr. Trojano has received speaker honoraria from Merck Serono, Bayer Schering Pharma, sanofi-aventis, and Biogen Idec; and has received research support from Biogen Idec and Merck Serono.
Dr. Marrosu serves on scientific advisory boards for Merck Serono, Biogen Idec, and Bayer Schering Pharma; has received funding for travel from Biogen Idec, Merck Serono, Bayer Schering Pharma, and sanofi-aventis; serves on the editorial board of Neurological Sciences; has received speaker honoraria from Biogen Idec and Merck Serono; and has received research support from
Merck Serono, Biogen Idec, and Fondazione Banco di Sardegna.
Dr. Patti has served on scientific advisory boards for Merck Serono, Bayer Schering Pharma, Novartis, and Biogen Idec; has received speaker honoraria from Biogen Idec, Bayer Schering Pharma, sanofi-aventis, and Novartis; and has received research support from the University of Catania and FISM
Dr. La Mantia has received funding for travel from Biogen Idec and Bayer Schering Pharma
Dr. Mancardi has received funding for travel from Biogen Idec, Merck Serono, and Bayer Schering Pharma; serves on the editorial board of Neurological Sciences; and has received speaker honoraria from Biogen Idec and Bayer Schering Pharma.
Dr. Solaro reports no disclosures.
Dr. Totaro has received honoraria for consultancy or speaking from sanofi-aventis, Biogen Idec, Bayer Schering Pharma, and Merck Serono.
Dr. Tola has served on scientific advisory boards for and received speaker honoraria from Biogen Idec, sanofi-aventis, Merck Serono, and Novartis; and has received research support fromsanofi-aventis.
Dr. Di Tommaso reports no disclosures.
Dr. Lugaresi has served on scientific advisory boards for Biogen Idec, Merck Serono, and Bayer Schering Pharma; has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Sanofi Aventis, and Teva Pharmaceutical Industries Ltd.; serves as a consultant for Fondazione "Cesare Serono"; and has received research support from Fondazione Italiana Sclerosi Multipla, Bayer Schering Pharma, Biogen Idec, Merck Serono, Sanofi Aventis, Novartis, and AISM (Associazione Italiana Sclerosi Multipla).
Dr. Moiola reports no disclosures.
Dr. Martinelli has received funding for travel and speaker honoraria from Biogen Idec, Merck Serono, Bayer Schering Pharma, Novartis, and sanofi-aventis; and has served as a consultant to Bayer Schering Pharma, sanofi-aventis, and Teva Pharmaceutical Industries Ltd.
Dr. Comi serves on scientific advisory boards for Bayer Schering Pharma, Merck Serono, Teva Pharmaceutical Industries Ltd., sanofi-aventis, Novartis, and Biogen Idec; and has received speaker honoraria from Teva Pharmaceutical Industries Ltd., sanofi-aventis, Serono Symposia International Foundation, Biogen Idec, Merck Serono, Novartis, and Bayer Schering Pharma.
Dr. Amato serves on scientific advisory boards for and has received speaker honoraria and research support from Biogen Idec, Merck Serono, Bayer Schering Pharma, and sanofi-aventis; and serves on the editorial board of BMC Neurology.
Authors’ contributions
MG, Drafting/revising the manuscript Study concept or design Analysis or interpretation of dataAcquisition of data EP, Drafting/revising the manuscript Study concept or design Analysis or interpretation of data Acquisition of data Statistical analysis Study supervision AG, Drafting/revising the manuscript Study concept or design Acquisition of data BH, Study concept or design Acquisition of data LP, Study concept or design Acquisition of data LR, Study concept or design Acquisition of data EP, Acquisition of data LDG, Analysis or interpretation of data Acquisition of data CP, Drafting/revising the manuscript Study supervision DP, Analysis or interpretation of data Acquisition of data MT, Drafting/revising the manuscript Study concept or design Acquisition of data MGM, Drafting/revising the manuscript Acquisition of data FP, Drafting/revising the manuscript Study concept or design Analysis or interpretation of data Acquisition of data LLM, Drafting/revising the manuscript Acquisition of data GM, Study concept or design Acquisition of data CS, Analysis or interpretation of data Study supervision RT, Drafting/revising the manuscript Acquisition of data MRT, Drafting/revising the manuscript Study concept or designAcquisition of dataDT, Analysis or interpretation of data Acquisition of data AL, Drafting/revising the manuscript Analysis or interpretation of data Acquisition of data LM, Analysis or interpretation of data Acquisition of data VM, Drafting/revising the manuscript Analysis or interpretation of data Acquisition of data GC, Drafting/revising the manuscript Study supervision MPA, Drafting/revising the manuscript Study concept or design Analysis or interpretation of data Study supervision. All authors read and approved the final manuscript.