Ellen Lu

Disease-modifying drugs for multiple sclerosis in pregnancy A systematic review

Objective: To systematically review the literature regarding safety of disease-modifying drug (DMD) use during pregnancy on perinatal and developmental outcomes in offspring of patients with multiple sclerosis (MS). Methods: A PubMed and EMBASE search up to February 2012 was conducted with a manual search of references from relevant articles. Selected studies were evaluated using internationally accepted criteria. Results: Fifteen studies identified 761 interferon β-, 97 glatiramer acetate-, and 35 natalizumab-exposed pregnancies. Study quality ranged from poor to good; no study was rated excellent. Small sample sizes limited most studies. Compared with data for unexposed pregnancies, fair- to good-quality prospective cohort studies reported that interferon β exposure was associated with lower mean birth weight, shorter mean birth length, and preterm birth (<37 weeks), but not low birth weight (<2,500 g), cesarean delivery, congenital anomaly (including malformation), or spontaneous abortion. Fewer studies of fair quality were available for glatiramer acetate and natalizumab. Glatiramer acetate exposure was not associated with lower mean birth weight, congenital anomaly, preterm birth, or spontaneous abortion. Natalizumab exposure did not appear to be associated with shorter mean birth length, lower mean birth weight, or lower mean gestational age. No studies examined mitoxantrone or fingolimod exposure. One study of paternal DMD use during conception found no effect on gestational age or birth weight. Few studies examined longer-term developmental outcomes. Conclusion: Further studies are needed to determine the potential risks associated with preconceptional and in utero DMD exposure in patients with MS. Discontinuation of DMDs before conception is still recommended.

Management of multiple sclerosis during pregnancy and the reproductive years: a systematic review.

OBJECTIVE: To examine the evidence guiding management of multiple sclerosis (MS) in reproductive-aged women. DATA SOURCES: We conducted an electronic literature search using PubMed, ClinicalTrials.gov, and other available resources. The following keywords were used: “multiple sclerosis” and “pregnancy.” We manually searched the reference lists of identified studies. METHODS OF STUDY SELECTION: Two reviewers categorized all studies identified in the search by management topic, including effect of pregnancy on MS course, fetal risks associated with disease-modifying treatments during pregnancy, and management of patients off disease-modifying treatment. We categorized studies by strength of evidence and included prior meta-analyses and systematic studies. These studies were then summarized and discussed by an expert multidisciplinary team. TABULATION, INTEGRATION, AND RESULTS: The risk of MS relapses is decreased during pregnancy and increased postpartum. Data are lacking regarding the risks of disease-modifying treatments during pregnancy. There may be an increased risk of MS relapses after use of assisted reproductive techniques. There does not appear to be a major increase in adverse outcomes in newborns of mothers with MS. CONCLUSION: Although there are many unmet research needs, the reviewed data support the conclusion that in the majority of cases, women with MS can safely choose to become pregnant, give birth, and breastfeed children. Clinical management should be individualized to optimize both the mothers reproductive outcomes and MS course.

Perinatal outcomes in women with multiple sclerosis exposed to disease-modifying drugs

Background: The incidence of disease-modifying drug (DMD) exposure during pregnancy in multiple sclerosis (MS) is unknown and limited data exists regarding the potential harm of DMD exposure during pregnancy. Objective: To investigate the incidence and effect of in utero DMD exposure on perinatal outcomes. Methods: We conducted a retrospective analysis by linking two provincial, population-based databases, the British Columbia (BC) MS database with the BC Perinatal Database Registry. Delivery (duration of the second stage of labor, assisted vaginal delivery and Cesarean section) and neonatal (birth weight, gestational age, 5-minute Apgar score and congenital anomalies) outcomes were compared between women exposed and unexposed to a DMD within 1 month prior to conception and/or during pregnancy. Findings were reported as odds ratios (ORs) with 95% confidence intervals (CIs). Results: In all, 311 women with relapsing–remitting MS delivered 418 singleton babies between April 1998 and March 2009. 21/101 (21%) of births to MS women treated with DMD prior to pregnancy were exposed to a DMD. In all cases, exposure was documented as unintentional and DMD treatment was stopped within 2 months of gestation. The overall incidence of exposure was 21/418 (5%). DMD exposure was associated with a trend towards a greater risk of assisted vaginal delivery compared to the DMD naïve groups (OR = 3.0; 95% CI: 1.0–9.2). All other comparisons of perinatal outcomes were unremarkable. Conclusion: The incidence of DMD exposure was relatively low and no cases were intentional. Further studies are needed to ascertain the safety of DMD exposure during pregnancy in MS.

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

When contemplating a pregnancy, women treated for multiple sclerosis (MS) with a disease-modifying drug must decide to discontinue their medication before conception or risk exposing their unborn child to potential drug toxicity. Few studies exist as reference for patients and physicians, and of those available, the majority are less than ideal due to real-world constraints, ethical issues and methodological shortcomings. The authors provide a brief summary of existing animal and human data with current recommendations regarding the safety of IFN-β, glatiramer acetate, natalizumab, mitoxantrone, fingolimod and teriflunomide during pregnancy and lactation in women with MS. We also assess the quality, strengths and limitations of the existing studies including challenges with study design. The investigation of outcomes such as spontaneous abortion and congenital anomalies are highlighted with potential methodological improvements for future studies on drug safety in pregnancy suggested. The authors explore the pharmacokinetics and pharmacodynamics of the MS disease-modifying drugs for their possible mechanistic role in fetal harm and discuss the potential role of clinical trials. Future pharmacovigilance studies should continue to pursue multicenter collaboration with an emphasis on appropriate study design.

Multiple pathologies are common in Alzheimer patients in clinical trials.

OBJECTIVE To determine the frequency of multiple pathology [Alzheimer Disease (AD) plus Vascular Dementia and/or Dementia with Lewy Bodies] in patients enrolled in clinical trials of AD therapy, and to compare the cognitive and functional assessments between patients with pure AD and AD with multiple pathology. METHODS We conducted a retrospective analysis of patients with a clinical diagnosis of AD who were enrolled in AD therapy clinical trials and subsequently received an autopsy for confirmation of their diagnosis from 2000 to 2009. Performance on cognitive screening tests, namely Modified Mini Mental state (3MS) exam, Mini Mental state Exam (MMSE) and Functional Rating Scale (FRS) were compared between patients with pure AD and multiple pathology. RESULTS Autopsy reports were available for 16/47 (34%) of deceased patients. Of these 16 patients, 5 (31%) had pure AD pathology, 10 (63%) had AD with other pathology, and 1 (6%) had non-AD pathology. Compared to patients with pure AD, patients with AD mixed with other pathology had poorer baseline FRS in problem-solving (p<0.01) and community affairs (p<0.02). CONCLUSION While the strict enrollment criteria for clinical trials identified the presence of AD pathology in the majority of cases (15/16), multiple pathology was more common than pure AD in our series of autopsied patients. Premortem biomarkers that can distinguish between pure AD and AD with multiple pathology will be beneficial in future clinical trials and dementia patient management.

Birth hospitalization in mothers with multiple sclerosis and their newborns

Objective: To compare the duration of birth hospitalization in mothers with multiple sclerosis (MS) and their newborns relative to the general population and to investigate the impact of MS-related clinical factors on the length of birth hospitalization stays. Methods: Data from the British Columbia Perinatal Database Registry and the British Columbia MS database were linked in this retrospective cohort study. The duration of birth hospitalization in mothers with MS and their newborns (n = 432) were compared with a frequency-matched sample of the general population (n = 2,975) from 1998 to 2009. Clinical factors investigated included disease duration and disability, as measured by the Expanded Disability Status Scale. A multivariable model (generalized estimating equations) was used to analyze the association between MS and duration of birth hospitalization, adjusting for factors such as maternal age, diabetes, hypertension, and consecutive births to the same mother. Additional analyses included propensity score matching to further balance cohort characteristics. Results: Compared with the general population, the duration of birth hospitalization was not statistically or clinically different for mothers with MS or their newborns (median differences = +1.5 and +2.1 hours, respectively; adjusted p > 0.4). Lengths of birth hospitalization were not significantly associated with disease duration (adjusted p > 0.7) or level of disability (adjusted p > 0.5). Findings remained virtually unchanged after propensity score matching. Conclusions: Birth hospitalization has been understudied in women with MS. Contrary to existing studies, we found that MS was not associated with a longer birth hospitalization. This study provides assurance to expectant mothers with MS, their families, and health care providers.

A Review of Safety-Related Pregnancy Data Surrounding the Oral Disease-Modifying Drugs for Multiple Sclerosis

The recent approval of several oral disease-modifying drugs (DMDs) for multiple sclerosis (MS) brings promise of improved clinical effectiveness as well as greater drug compliance compared to the existing non-oral DMDs, and substantially increases patient choice and therapeutic options in the effective management of MS. However, for men and women with MS of childbearing age, concerns about the effect of oral DMDs on pregnancy and the fetus may arise. Some limited data from animal reproductive studies of oral DMDs suggest a potential increased risk of early pregnancy loss, impaired growth and birth defects. Although active surveillance mechanisms exist, there is limited data to inform clinical practice. Using existing information from published clinical trials and drug monographs, as well as recent conference proceedings, this review summarizes the mechanism of action (in relation to embryogenesis and pregnancy) and existing animal or human pregnancy-related data for approved (fingolimod, teriflunomide and dimethyl fumarate) and investigational (laquinimod and firategrast) oral DMDs for MS.

Birth outcomes of pregnancies fathered by men with multiple sclerosis.

We linked several population-based clinical and health administrative databases in British Columbia, Canada. We identified and compared birth outcomes of pregnancies fathered by men with multiple sclerosis (MS) (n=202) and men from a frequency-matched general population cohort (n=981) between 1996 and 2010. Using multivariate models, we analyzed the association of paternal MS, disease duration at conception and disability (as measured by the Expanded Disability Status Scale) with birth weight and gestational age. Paternal MS and MS-related clinical factors were not significantly associated with birth outcomes (p>0.05). This study provides assurance to expecting fathers with MS and their families.

Labor induction and augmentation in women with multiple sclerosis

Background: Fatigue and pelvic organ dysfunction are common among women with multiple sclerosis (MS), which may prolong labor and increase the risk of labor induction and/or augmentation. Objective: We set out to investigate the association between MS and related clinical factors (disease duration and the Expanded Disability Status Scale, EDSS) with labor induction/augmentation. Methods: Data from the British Columbia (BC) MS database were linked with the BC Perinatal Database Registry. Multivariable models were used to compare the likelihood of labor induction and augmentation between attempted vaginal deliveries (1998–2009) in women with MS (n=381) and the general population (n=2615). Results: In the MS cohort, 94/381 deliveries (25%) required labor induction and 147/381 deliveries (39%) required labor augmentation. Having MS was not associated with labor induction (adjusted odds ratio (OR)=0.91; 95% confidence interval (CI)=0.68–1.22, p=0.54) or augmentation (adjusted OR=0.91; 95% CI=0.72–1.15, p=0.43), but was associated with multiple methods of labor induction (OR=1.94; 95% CI=1.23–3.06, p=0.004). A higher EDSS score was associated with an increased risk of labor induction (adjusted p=0.04), but not labor augmentation (adjusted p > 0.5). Disease duration was not associated with either outcome (adjusted p > 0.2). Conclusions: Greater intervention may be required to initiate labor for women with a higher degree of disability due to MS.

Disease-modifying drugs for multiple sclerosis in pregnancy: A systematic reviewAuthor Response

Based on fair quality Level 3 evidence, Lu et al.1 note that glatiramer acetate (GA) exposure was not associated with lower mean birthweight, lower mean gestational age, preterm birth (37 weeks), congenital anomaly, or spontaneous abortion. However, GA was given an indeterminate recommendation because further research is needed. The results are not compelling: 3 of the 4 existing human studies of GA were small case series.1