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Introduction
Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system that is usually diagnosed in a patient's 20s or 30s and is more common in women than in men.1 Given this typical patient profile, many patients with MS are women in their reproductive years. None of the currently approved disease-modifying therapies (DMTs) for patients with MS are recommended for use during pregnancy. Furthermore, all of these medications have been given a pregnancy category B, C, D or X by the US Food and Drug Administration, indicating that in the best case (category B), animal studies have failed to identify potential harmful effects of the medication but long-term safety data in humans are not available or, in the worst case (category X), studies in human patients or animals have identified risks of negative birth outcomes associated with exposure during pregnancy and the medication should not be used by patients who are or may become pregnant.1
Patients should be informed of the potential hazards of medication use during pregnancy, and discontinuation should be considered if patients become pregnant during treatment. However there are few recommendations about when to stop medication before becoming pregnant. Thus, some patients may be taking a DMT when they become pregnant, thereby leading to fetal exposure. In addition, unplanned pregnancies can occur during treatment with DMTs, increasing the chance of accidental exposure to the fetus. Given these potential challenges, counselling patients about the possible risks of DMT use during pregnancy is an important part of disease management for patients with MS.
Reliable data on the effects of DMTs on pregnancy outcomes are difficult to obtain. Randomised, controlled trials of the potential teratogenic effects of DMT exposure during pregnancy are unlikely to be conducted given the ethical concerns of such a trial. In addition, prospective observational studies or registries require many years to reach a sample size that affords the statistical power to detect a difference in the relevant risk compared with the general population or untreated patients. Consequently, an analysis of prospective cases from existing pharmacovigilance databases may be an appropriate alternative to help guide decision-making in this population.
Methods
The objective of the present analysis was to review pregnancy outcomes in patients who were exposed to interferon beta-1b (Betaferon/Betaseron; Bayer HealthCare Pharmaceuticals) during pregnancy. Worldwide pregnancy cases reported to Bayer HealthCare's global pharmacovigilance database were retrieved and assessed for teratogenicity. To avoid reporting bias, only prospective cases (those who were pregnant at the time of reporting) were included in this analysis. Pregnancies reported spontaneously, during clinical trials, in registries or by patient support programmes were included. Outcomes and follow-up information were collected from patients and their healthcare providers.
Results
As of July 2013, the cumulative postmarketing exposure since interferon beta-1b became available in 1993 was estimated to be 1 367 697 patient-years. As of April 2013, 1045 prospective pregnancies with exposure to interferon beta-1b were retrieved. A total of 423 pregnancies had documented outcomes, with 113 reporting an abnormal outcome. The majority of the cases with abnormal outcomes were reported in the USA (73); with 15 in Brazil; 3 each in Canada, Germany and Turkey; 2 each in Belgium, Italy, Poland, Portugal and Russia; and 1 each in Australia, Hungary, Ireland, Serbia, Spain and the UK. Maternal age data were available from 105 of the cases reporting an abnormal outcome. Median age at exposure was 30 years (range 10–48 years, mean 31.2 years).
The majority of outcomes were normal live births (308 of 423 (72.8%)). Spontaneous abortions occurred in 61 (14.4%) of the 423 prospective pregnancy cases. This rate is consistent with the rate reported in the general population (12–15%)2 and specifically in the population of the USA (15–16%).3 Induced abortions were reported in 3 (<1%) cases. In addition, there were 2 (<1%) ectopic pregnancies and 11 (3%) cases of fetal death, 1 of which was possibly accompanied by unspecified malformations. Thirty cases (7%) reported other outcomes, including preterm delivery (n=10), premature labour and delivery (n=2), infant large for gestational age (n=3), infant small for gestational age (n=1), transient problems during delivery (n=4), caesarean section (n=8), lethargy (n=1) and hypotonia at 4 months of age (n=1). Cumulatively, major and minor birth defects were observed in 8 of 423 pregnancy outcomes (1.9%), similar to the 3% rate reported in the USA4 and the 2% rate reported in the European Union.5 There was no specific pattern of birth defects (table 1) and no pattern with maternal age at exposure could be identified.
Birth defects reported in pharmacovigilance database
Discussion
This cohort represents the largest number of interferon beta-1b-exposed pregnancies to be reported to date. Importantly, the rates of spontaneous abortions and birth defects did not differ from available population estimates. In addition, no pattern of specific birth defects was observed. Other studies that examined pregnancies exposed to interferon beta have found, evidence of low birth weight or prematurity in infants born after exposure to interferon beta.1 However, these studies contained much smaller sample sizes (N=16–88 with interferon beta exposure) and often did not distinguish between interferon beta-1b and beta-1a exposure.
Despite the relative size of the population in this analysis, the number of cases is still too small to make a final assessment of the safety of interferon beta-1b during pregnancy. Rather, these data are meant to provide a descriptive overview of the safety profile of interferon beta-1b during pregnancy.
Acknowledgments
Authors are extremely thankful to the patients and healthcare providers who reported the data used in this analysis. Additionally, they thank Robert C Ristuccia, PhD (Precept Medical Communications), for assistance with preparation of the manuscript.
Footnotes
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Contributors RSR contributed to the design of the study, reviewed the data, drafted the manuscript and provided final approval for submission. CL contributed to the design of the study, reviewed the data, performed the statistical analysis, drafted the manuscript and provided final approval for submission. J-PB contributed to the design of the study, reviewed the data, drafted the manuscript and provided final approval for submission.
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Funding This study was funded by Bayer HealthCare Pharmaceuticals.
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Competing interests RSR has received financial compensation for serving as a consultant or advisor for Bayer HealthCare, Biogen Idec, Novartis Pharmaceuticals, Serono, and Teva Pharmaceuticals, and has received fellowship support from the National Multiple Sclerosis Society and Teva Pharmaceuticals. CL and J-PB are salaried employees of Bayer HealthCare Pharmaceuticals.
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Provenance and peer review Not commissioned; externally peer reviewed.
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Open Access This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/