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The need for a disease-specific prospective pregnancy registry for multiple sclerosis (MS)
Multiple Sclerosis and Related Disorders
Multiple sclerosis (MS) is the most commonly acquired neurological disorder affecting young adults of reproductive age with an approximately 3:1 female to male ratio. Although pregnancy is not contraindicated in MS, data are limited regarding pregnancy outcome among MS patients, and the safety or risk to the fetus associated with most maternal MS treatments, such as disease modifying therapies (DMTs), during pregnancy is unknown. We review available epidemiological and registry data on MS and pregnancy and discuss the need to initiate a North American Multiple Sclerosis Pregnancy Registry that will prospectively identify pregnancies in women with MS, obtain information on the disease, and its treatment during gestation and lactation and follow the children to determine their health status.
- Epidemiological studies are scarce regarding pregnancy outcome among patients with multiple sclerosis (MS).
- Current pregnancy registries conducted by the manufactures of disease modifying therapies (DMTs) are limited by many factors.
- Only one disease-specific MS pregnancy registry exists in Germany.
- A general framework to initiate a North American Multiple Sclerosis Prospective Pregnancy Registry is proposed.
Keywords: Multiple sclerosis, Pregnancy, Reproduction, Birth outcome, Pregnancy registry.
Reproduction among individuals who have MS has long been a topic of interest for health care professionals. In the past, with a long lag time from clinical onset to diagnosis, women often had pregnancies while unaware of their diagnosis. The advent and progression of MRI and the resultant updating of MS diagnostic criteria (McDonald et al, 2001, Polman et al, 2005, and Polman et al, 2011) have resulted in patients being younger and healthier at the time of diagnosis. Thus, reproductive options are increasingly important to this population, especially with the current increase in use and access to a variety of disease modifying therapies for relapsing/remitting MS.
Since the advent of formal clinical drug trials in MS (The IFNB Multiple Sclerosis Study Group, 1993 and The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group, 1995) (as with most other therapeutic trials), pregnancy has been an exclusion criteria for trial entry. In most early trials, women were regularly screened for pregnancy. If an unexpected pregnancy occurred, the trial participation was ended (patient blinded to drug or placebo) and possible teratogenic implications (often based on animal studies but not in humans) were discussed with the women. In some cases, the pregnancy was terminated. If the pregnancy continued, outcome (healthy livebirth, late miscarriage, stillbirth, minor or major birth defects) was recorded by the trial site and reported to the study sponsor.
Several studies have been reported on pregnancy and MS, but the data remain limited in some aspects, such as the effect of MS therapy on birth outcome. Although reproductive issues are also relevant to men with MS who father pregnancies as well as individuals with the diagnosis of Clinically Isolated Syndrome (CIS) ( Karussis, 2014 ) and Radiologically Isolated Syndrome (RIS) ( Karussis, 2014 ), as well as patients with Neuromyelitis Optica (NMO) ( Karussis, 2014 ) who are often seen by MS specialists, the current paper will focus on women with a clinical diagnosis of MS according to recognized criteria.
The MotherToBaby Pregnancy Study conducted by the non-profit Organization of Teratology Information Specialists (OTIS) began researching the possible effects of MS and its related treatments in 2012 as part of the ongoing OTIS Autoimmune Diseases in Pregnancy Project. The OTIS Research Group is a North American collaboration of researchers, established in 1998, whose objective is to conduct multicenter controlled prospective cohort studies evaluating the effect of medications or vaccines on a spectrum of adverse pregnancy outcomes, in some cases with dysmorphological assessment of live infants (Scialli, 1999 and Chambers et al, 2001).
A virtualMultipleSclerosisCentre ofExcellence onReproduction andChildHealth (MS-CERCH) is an international collaborative multidisciplinary research consortium established in February 2013 to study and improve the reproductive experience and outcomes of people with MS Bove et al. (in press) . The review described here is based on one of the major recommendations of the MS-CERCH Advisory Board, i.e. that a disease specific pregnancy registry is needed to properly assess the impact of disease modifying therapies (DMTs) and the MS disease itself on pregnancy outcome. A woman׳s therapy can vary with time, disease progression, response to therapy and different modes of therapeutic administration (e.g. weekly, monthly, injection, infusion, etc.) thus focusing on a specific DMT is not the optimal approach. In addition, new therapies are increasingly being developed and tested so that a resource to include all MS women who have pregnancies will stand the test of time.
Here, we introduce a general framework for a planned collaboration between OTIS and MS-CERCH to initiate a North American Multiple Sclerosis Pregnancy Registry. This will be a prospective, comprehensive, longitudinal and sustainable registry that will prospectively identify pregnancies in women with MS to obtain information on the disease and its treatment during conception, gestation and lactation.
2. Epidemiology of MS and reproduction
MS itself does not appear to increase adverse pregnancy outcomes (e.g. spontaneous abortions, stillbirth, Cesarean delivery, premature birth, birth defects, etc.) compared to women who did not have MS at the time of conception and pregnancy (Worthington et al, 1994, Orvieto et al, 1999, Sadovnick et al, 1994, Mueller et al, 2002, Poser and Poser, 1983, Roullet et al, 1993, van der Kop et al, 2011, Kelly et al, 2009, Finkelsztejn et al, 2011, and Jalkanen et al, 2010). Some studies report that mothers with MS are more likely to have infants with low birth weight for gestational age (Kelly et al, 2009, Chen et al, 2009, Dahl et al, 2005, and Hellwig et al, 2008), or be born prematurely ( Chen et al., 2009 ), compared to healthy mothers. For example, in one Norwegian study, birth outcomes for pregnant women were compared among those who delivered prior to the clinical onset of their MS (Pre MS), during the lag time from MS clinical onset and diagnosis (early MS) and after the diagnosis of MS (manifest MS). A significantly lower mean birth weight of 75 g was associated with the manifest MS compared to the pre MS group ( Dahl et al., 2008 ). Moreover, it is virtually impossible to distinguish the effect of treatment from the effect of disease itself and from other potential contributing risk factors (e.g. maternal age, ethnicity, previous pregnancy history, family history, etc.) in most, if not all, of these studies.
2.1. Disease Modifying Therapies (DMTs)
There are currently 10 approved DMTs in the US and Canada available for the treatment of RRMS, of which three belong to a class of medications called beta interferons (IFNβ): Intramuscular interferon beta-1a (IFNβ-1a) (Avonex®), subcutaneous IFNβ-1a (Rebif®) and interferon beta-1b (IFNβ-1b) (Betaseron®). Other approved DMTs are glatiramer acetate (Copaxone®), natalizumab (Tysabri®), mitoxantrone (Novantrone®), fingolimod (Gylenia®), teriflunomide (Aubagio®), dimethyl fumarate (Tecfidera®) and alemtuzumab (Lemtrada®).
DMTs are a biologically and chemically diverse group of agents and human data is lacking on their impact, if any, on a developing fetus. In addition, each DMT must be studied independently. To date, most analytical studies have examined the risk of maternal exposure during conception/pregnancy to DMTs as a group. Although the results of these studies have generally been reassuring, this may be misleading because grouping several treatments with different risks together is likely to make it more difficult to identify associations that actually may exist with one of the treatments. To date, there has been no teratogenic “phenotype” associated with MS mothers or any specific therapy as, for example, is recognized for many of the anticonvulsant medications used in women with epilepsy ( Holmes et al., 2011 ).
Current data provide no strong evidence that either beta interferons (IFNβ), glatiramer acetate, or natalizumab are likely to pose a substantial teratogenic risk, but the data remain insufficient to state absolute safety and to confirm the absence of later onset problems ( Lu et al., 2012 ) ( Table 1 ). Nevertheless, the US Food and Drug Administration (FDA) and the National Multiple Sclerosis Society (NMSS) consensus guidelines suggest that women discontinue IFNβ therapy when trying to conceive, throughout gestation and while breastfeeding based on expert opinion ( National Clinical Advisory Board of the National Multiple Sclerosis Society, 2007) . However, in the absence of controlled data and limited studies with contradicting results, it remains inconclusive whether or not their contraindication is actually warranted.
|DMT||Study (year)||Country||Study design||Timing of DMT exposure ( n )||Comparison groups ( n )||Findings|
|Beta interferons||Boskovic et al. (2005)||Canada||Prospective cohort (TIS) a||Exposed to IFNβ during first trimester (23)||Disease matched unexposed – discontinued IFNβ or Copaxone at least 1 month before conception (21)||Association of IFNβ with lower birth weight (p=0.002), miscarriages and stillbirths (p=0.03).|
|Healthy controls (20)||Limitations: Small sample size. Possibility for selection bias (common in TIS studies).|
|Patti et al. (2008)||Italy||Retrospective cohort||Exposed to IFNβ during pregnancy (14)||Discontinued IFNβ at least 1 month before conception (7)||No differences in rates of adverse outcomes between exposed and unexposed.|
|Unexposed to IFNβ (17)||Limitations: Small sample size.|
|Hellwig et al. (2012)||Germany||Prospective cohort||Exposed to IFNβ during early pregnancy (mean=8.8 gestational weeks) (78)||Non DMT exposed pregnancies (216)||No increased rates of low birth weight, length, gestational age or birth defects in exposed compared to unexposed pregnancies.|
|Limitations: Largest reported study on MS patients in pregnancy, but selection bias cannot be excluded. Documentation of family history and race/ethnicity as well as other potential contributing factors is not standardized in the registry.|
|Weber-Schoendorfer and Schaefer (2009)||Germany||Prospective cohort (TIS)||Exposed to IFNβ (69); median duration: 8.8 weeks||No exposure to IFNβ or GA (64)||IFNβ: Rate of spontaneous abortions significantly increased in exposed pregnancies compared to non-MS controls (28%, p=0.02). Adjusted mean birth weight was significantly lower for term newborns in exposed compared to MS controls and non-MS controls (p<0.001)|
|Healthy controls (1556)||Limitations: Small sample size. Possibility for selection bias.|
|Amato et al. (2010)||Italy||Prospective cohort||Discontinued IFNβ <4 weeks from conception (88)||Discontinued IFNβ ≥4 weeks from conception or never used DMTs (318)||No association of IFNβ with increased risk of spontaneous abortions, malformations or developmental abnormalities. Association with low birth weight (p<0.0001), low birth length (p<0.0001) and preterm delivery (AOR: 2.11, CI: 1.18–3.78)|
|Limitations: Lacked control for confounders or longitudinal data on live births. Some pregnancies in the exposed group may not actually have been exposed after implantation.|
|Sandberg-Wollheim et al. (2011)||Merck Serono S.A. clinical trials||Prospective case-series||Exposed to IFNβ-1a in pregnancy (425)||None||No increased rates of spontaneous abortions or major congenital anomalies compared to those observed in the general population.|
|Limitations: No control group. Women studied were from clinical trials (subjects tend to be exceptionally well-screened) and are not representative of the general population. Lack of adjustment to potential confounders.|
|Coyle et al. (2014)||Pregnancy Registry Findings||Anytime from two weeks before conception and during pregnancy (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.|
|Limitations: No control group; comparisons made to general population data. Uncertain ascertainment of birth defects, and variable quality and completeness of the information on the abnormal outcomes.|
|Glatiramer acetate||Weber-Schoendorfer and Schaefer (2009)||Germany||Prospective cohort (TIS)||Exposed to GA (31); median duration: 6.9 weeks||No exposure to IFNβ or GA (64)||No significant differences in the rate of spontaneous abortions or preterm birth in GA exposed versus unexposed pregnancies.|
|Healthy controls (1556)||Limitations: Small sample size. Possibility for selection bias.|
|Fragoso et al. (2010)||Brazil||Prospective case-series||Exposed to GA ≥7 months during pregnancy (11)||None||No increased rates of adverse outcomes|
|Limitations: Small sample size. No comparison group.|
|Salminen et al. (2010)||UK||Prospective case-series||Exposed to GA throughout pregnancy (14)||None||No increased rates of adverse outcomes|
|Limitations: Small sample size. No comparison group.|
|Hellwig et al. (2012)||Germany||Prospective cohort||Exposed to GA during early pregnancy (mean=8.8 gestational weeks) (41)||Non DMT exposed pregnancies (216)||No increased rates of low birth weight, length, gestational age or birth defects in exposed compared to unexposed.|
|Limitations: Largest reported study on MS patients in pregnancy, but selection bias cannot be excluded. Documentation of family history and race/ethnicity as well as other potential contributing factors is not standardized in the registry.|
|Giannini et al. (2012)||Italy||Prospective cohort||Exposed to GA , 4 weeks from conception (17) (Mean duration exposure: 4.9 weeks)||Discontinued DMT ≥4 weeks from conception (318)||No increased associations of maternal GA exposure with spontaneous abortions, preterm delivery or low birth weight and length. Congenital malformations were not reported in GA exposed infants.|
|Limitations: Small sample size.|
|Natalizumab||Hellwig et al. (2011b)||Germany||Prospective cohort||Accidental exposure to natalizumab in very early pregnancy (35)||MS patients with no DMT exposure in pregnancy (23)||No significant differences in rates of adverse outcomes between exposed and unexposed groups|
|Limitations: Small sample size.|
|Ebrahimi et al. (2014)||Prospective cohort||Before or during pregnancy (101)||Unexposed disease matched group (78) and healthy controls (97)||No increase in the risk of major malformations or other adverse perinatal outcomes as compared to disease-matched and healthy controls.|
|Limitations: Largest controlled reported study reporting on fetal outcome of natalizumab in early pregnancy. However, exposure may have occurred a few weeks before conception.|
|Haghikia et al. (2014)||Prospective case-series||Third trimester of pregnancy (12)||None||Mild to moderate hematologic alterations in 10 of 13 infants including thrombocytopenia and anemia|
|Limitations: No control group|
|Fingolimod||Karlsson et al. (2014)||Pregnancy registry findings||Exposed to fingolimod in utero (66)||None||5 cases with first trimester exposure (7.6%, 95% CI: 3–17%) were found to have abnormal fetal development.|
|Limitations: No control group.|
|All DMTs||De Las Heras et al. (2007)||Spain||Retrospective cohort||Exposed to DMT at time of conception (34)||Unexposed to DMT ≤before conception (54)||No difference in rates of spontaneous abortions or malformations between exposed and unexposed.|
|Limitations: Small sample size.|
|Fernandez Liguori et al. (2009)||Argentina||Retrospective cohort||Exposed to DMT <15 days before conception (23)||Unexposed to DMT (88)||Association of DMT exposure with increased rate of any birth defect (OR: 10.8, 95% CI: 1.6–71.0).|
|Limitations: Retrospective collection of data through surveys, limited size and lack of family and previous pregnancy history data. Some pregnancies in the exposed group may not actually have been exposed after implantation.|
|Lu et al. (2012)||Canada||Retrospective cohort||Exposed to DMTs 1 month prior to conception or/and during pregnancy (21)||Discontinued DMTs at least 1 month from conception (80) or never used DMTs (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).|
|Limitations: Small sample size. Lack of adjustment to potential confounders.|
a TIS: Teratogen Information Service studies; typically identify pregnant women when they call to request counseling about the teratogenic potential of medications or other products and then follow the women to determine pregnancy outcome.
Mitoxantrone is a DMT and an immunosuppressive agent that is prescribed for worsening Relapsing Remitting MS (RRMS). It is contraindicated in pregnancy and considered a potential human teratogen based on its mechanism of action, animal reproductive toxicology studies ( James et al., 1983 ) and two case reports (De Santis et al, 2007 and Hellwig et al, 2011a). No epidemiological studies on the reproductive outcomes among infants born to women who were treated with fingolimod, teriflunomide, dimethyl fumarate or alemtuzumab during pregnancy have been reported yet, but some pregnancy registry reports have been published for fingolimod ( Karlsson et al., 2014 ).
2.2. Immunosuppressive therapies
MS is an inflammatory, B cell and T cell-mediated autoimmune disease affecting the central nervous system (CNS) so immunosuppressive agents have been used over the past 30 years before DMTs were approved. In contrast to DMTs, which tend to be specific to MS treatment, immunosuppressive agents have long been in use. Thus, animal and human data on their use in pregnancy is known, at least to some extent. Most are contraindicated at conception and during pregnancy because of their likely teratogenic potential. These include cyclophosphamide (Cytoxan®) (Enns et al, 1999, Ozolins, 2010, and Sanders et al, 1996), methotrexate (Lloyd et al, 1999 and Donnenfeld et al, 1994), mycophenlate mofetil (Anderka et al, 2009 and Carey et al, 2009) and azathioprine (Polifka and Friedman, 2002, Cleary and Kallen, 2009, and Langagergaard et al, 2007).
2.3. Symptom specific therapies
In addition to DMTs and immunosuppressive therapies, MS patients require symptom-specific treatment during the course of their disease. Corticosteroids are regarded generally safe when used in later pregnancy, but a slightly increased risk for orofacial clefts has been reported to be associated with first trimester corticosteroid exposure (Rodriguez-Pinilla and Martinez-Frias, 1998, Carmichael and Shaw, 1999, and Pradat et al, 2003). Use of corticosteroids in the postpartum period has been shown to have a slight beneficial effect on decreasing postpartum relapses ( de Seze et al., 2004 ). For MS patients with acute relapses who cannot tolerate steroids, intravenous immunoglobulin (IVIg) therapy is usually offered off label as an alternative ( Giesser, 2011 ). It appears that IVIg therapy is generally safe in pregnancy and well tolerated. No associations with severe adverse reproductive outcomes, including malformations, have been reported ( Achiron et al., 2004 ). Moreover, monthly IVIg use has been reported to reduce the risk of relapses during pregnancy and postpartum, with no clear adverse consequences for the fetus, but the data are limited (Achiron et al, 2004, Haas and Hommes, 2007, and Hellwig et al, 2009).
There are several symptoms that women with MS may experience in general (e.g. urinary urgency and frequency, fatigue, lower extremities paresthesias and gait problems), and they can get worse during pregnancy. However, most of the medications that are used to treat these symptoms are either contraindicated during pregnancy, such as some anticonvulsants (benzodiazepines and phenytoin) or have a minimal or undetermined adverse effect on the fetus, such as some anti-anxiety medications (diazepam), muscle relaxers (baclofen), antiviral medications (amantadine) and anti-fatigue medications (modafinil) ( Voskuhl and Giesser, 2011 ).
3. Pregnancy registries
A prospective pregnancy registry is an observational study specifically designed to collect information on an exposure of interest and/or disease status at pregnancy, before outcome is known. Participants are voluntarily enrolled at conception or during early gestation until the end of pregnancy, or for a defined period afterwards. Information is then collected on the outcomes and their frequency evaluated relative to an unexposed comparison group or to a valid reference population(s) ( Agency for Health Research and Quality, 2014 ). An exposure pregnancy registry is a form of a post-marketing surveillance study that aims to detect signals for the teratogenic potential of specific marketed drugs in humans. In contrast, disease-specific pregnancy registries aim to evaluate the potential for teratogenic risks associated with the disease and its associated therapies. Adopting a prospective pregnancy registry approach appears to be a very efficient method to assess clinical teratogenic potentials of neurological diseases and their medications, independently and interactively. To date, a prospective, population-based MS specific pregnancy registry does not exist.
3.1. Therapy-specific exposure pregnancy registries for MS
Several registries have been developed by manufacturers of IFNβ to monitor the outcomes of pregnancies in women with MS who were treated shortly before or during pregnancy. The main limitations of these registries are the absence of comparable control data, i.e., a comparison group of women with MS who have not taken IFNβ in or shortly before pregnancy, uncertain ascertainment of birth defects, and variable quality and completeness of the information on the abnormal outcomes as well as minimal or no information on race/ethnicity, previous pregnancy history or family history. Outcomes are compared to general population data, such as the Metropolitan Atlanta Congenital Defects Program and the National Center for Health Statistics. These data are based on active case-finding and rigorous validation and classification of birth defect outcomes. Therefore, an increased rate of any reported adverse outcome does not necessarily indicate an increased risk of that specific outcome.
Interim results have been reported from the Avonex (intramuscular IFNβ-1a) ( Richman et al., 2012 ), Betaseron (IFNβ-1b) ( Coyle et al., 2014 ), Rebif (subcutaneous IFNβ-1a) registries ( Sandberg-Wollheim et al., 2011 ). The rates of birth defects reported from these registries might be expected to be similar but are, in fact, rather different: 27 (10.3%) of 261 infants whose mothers had been treated with intramuscular IFNβ-1a, ( Richman et al., 2012 ) 5 (5.8%) of 86 infants whose mothers had been treated with subcutaneous IFNβ-1b ( Coyle et al., 2014 ), and 0 (0.0%) of 30 infants whose mothers had been treated with subcutaneous IFNβ-1a ( Rebif Pregnancy Registry, 2013 ).
In a review of the outcomes of pregnancies identified prospectively from a manufacturer׳s global drug safety database for subcutaneous and intramuscular IFNβ-1a ( Sandberg-Wollheim et al., 2011 ), the observed rate of spontaneous abortions (49/425; 11.5%) was similar to that expected in the general population. However these “background” population rates were not collected in the same way as the data in the drug safety database and may not be an appropriate comparator. A similar concern exists for data collected through voluntary pregnancy exposure registries set up by the manufacturers of intramuscular IFNβ-1a (30 [10%] spontaneous abortions in 298 pregnancies), ( Richman et al., 2012 ) subcutaneous IFNβ-1b (11 [11%] spontaneous abortions in 96 pregnancies), ( Coyle et al., 2013 ) and subcutaneous IFNβ-1a (2 [2%] spontaneous abortions in 96 pregnancies) ( Rebif Pregnancy Registry, 2013 ). In each instance, the rate of miscarriage observed was similar to “background” rates, but no control data were collected. It is uncertain what rate of spontaneous abortion should be expected in voluntary manufacture-sponsored pregnancy exposure registries of this kind.
The manufacturer of Copaxone׳s post-marketing surveillance data showed 215 live births amongst 277 known outcomes, the majority of which were reported to be exposed to glatiramer acetate in the first trimester ( Coyle et al., 2003 ). Their data showed a 17% spontaneous abortion rate, which approximates the rate observed in the general population, and six (3.1%) of 193 liveborn infants had congenital anomalies, which were different specific defects in each case. No information on comorbidities, concomitant exposures or the timing of exposures was available and the lack of a control group was also a limitation.
Biogen Idec and Elan Pharmaceuticals have implemented the Tysabri®Pregnancy Exposure Registry, which is an ongoing registry following up on pregnant women with MS or Crohn׳s disease who are exposed to natalizumab within 3 months prior to conception or anytime during gestation ( Cristiano et al., 2011 ). The registry reports to date 314 livebirths, including 8 twin pregnancies, 13 elective terminations, 34 spontaneous abortions and 1 stillbirth. Major and/or minor congenital malformations were observed in 28 pregnancy outcomes. Although the rate of spontaneous abortions was consistent with background rates, it is hard to draw any conclusions on birth defects because there were no details reported on the nature of the birth defects observed, and the expected rates of congenital anomalies in these post-marketing surveillance data are unknown ( Cristiano et al., 2011 ).
The Multinational Gilenya®Pregnancy Exposure Registry in MS has been established to monitor fetal outcomes of pregnant women exposed to fingolimod. Among 66 pregnancies reported in the registry that had in utero exposure to fingolimod, 5 cases with first trimester exposure (7.6%; 95% confidence interval 3–17%) were found to have abnormal fetal development ( Karlsson et al., 2014 ). Two infants with congenital anomalies (unilateral posteromedial bowing of the tibia and acrania) were described among 28 livebirths, and one infant with tetraology of Fallot in an elective abortion was reported.
Preliminary data to date from a teriflunomide׳s clinical trial database reported 12 healthy infants born to women who became pregnant while on terflunomide treatment in clinical trials ( Kieseier et al., 2012 ).
Teratogen Information Service (TIS) studies typically identify pregnant women when they call to request counseling about the teratogenic potential of medications or other products and then follow the women to determine pregnancy outcome. Two such controlled prospective cohort studies of IFNβ treatment have been reported, one performed through the Motherisk Program in Toronto ( Boskovic et al., 2005 ) and the other through the Berlin TIS ( Weber-Schoendorfer and Schaefer, 2009 ). Both studies compared pregnancy outcomes in women with MS who were treated with IFNβ, women with MS who were untreated during pregnancy, and non-MS healthy control women. An increased risk for spontaneous abortions and lower birth weight was shown in both studies in the treated groups compared to the treatment naïve or healthy control groups. However, their relatively small size and design limited these studies to detect only very strong teratogenic effects. Also, in an exposure cohort study, women who call a teratogen information service tend to be from higher socioeconomic groups who are at a lower risk of having babies with many birth defects, making it more difficult to extrapolate the study findings to the MS population as a whole.
3.2. Disease-specific pregnancy registries
Large multi-centered disease-specific pregnancy registries are rare despite increasing recognition of their importance. The prototypic disease specific registry is the North American AED (Antiepileptic Drug) Pregnancy Registry originated by Dr. Lewis B. Holmes at the Massachusetts General Hospital in Boston, Massachusetts. This is a prospective registry that systematically monitors pregnancy outcomes in women with epilepsy. The registry has been running since 1997 enrolling U.S. and Canadian pregnant women on antiepileptic drugs ( Holmes et al., 2004 ). The main objective is to determine the safety of AEDs by collecting information on the frequency of major malformations among infants whose mothers had taken one or more AEDs for epilepsy or another condition. The Registry is monitored by an independent Scientific Advisory Committee and a Steering Committee that incorporates representatives of the pharmaceutical companies that manufacture the products and provide financial support the Registry. As of April 2012, 8500 pregnant women have been enrolled into the AED Registry ( The North American Antiepileptic Drug Pregnancy Registry, 2012 ). Several analytical studies have been published so far using its data with regard to risk of congenital malformations in relation to prenatal use of antiepileptic drugs (Holmes et al, 2008, Holmes et al, 2011, Hernandez-Diaz et al, 2012, and Wyszynski et al, 2005).
The National Transplantation Pregnancy Registry (NTPR), overseen by Dr. Vincent T. Armenti, was established in 1991 at Thomas Jefferson University, Philadelphia, PA and is now conducted at Gift of Life Institute with the support of manufacturers of immunosuppressive medications. The NTPR studies the safety of pregnancies in both transplant recipients who become pregnant and those who father pregnancies (Coscia et al, 2010 and Armenti et al, 2008). The NTPR is an ongoing active study that continuously collects data from transplant recipients and their healthcare providers. Recipients who are pregnant, have had a pregnancy or fathered a pregnancy are eligible to enroll in the NTPR. Referrals are obtained from healthcare providers or recipients may self-enroll. Data are confirmed through medical records review. The NTPR has enrolled more than 2100 solid organ recipients with over 3400 pregnancies, and also provides information to any patient who takes immunosuppressive medications and is considering parenthood, as well as to the healthcare providers who counsel them. All pregnancy outcomes are analyzed (live births, spontaneous abortions, therapeutic abortions, stillbirths and ectopic pregnancies) and long-term follow-up of the recipients׳ graft status and of their offspring is conducted. Collaborators include obstetricians, pediatricians, teratologists, transplant nurses, physicians, and surgeons, as well as statisticians. The NTPR has published several reports on the incidence of birth defects in relation to immunosuppressive agents, including a paper that was instrumental in identifying a potential risk of taking mycophenolic acid products during pregnancy (Coscia et al, 2010, Armenti et al, 2008, and Sifontis et al, 2006). More recent publications include information about pregnancy in the comparatively high risk lung transplant group and the growing number of transplant mothers who are breastfeeding while on immunosuppression (Shaner et al, 2012 and Thiagarajan et al, 2013).
The OTIS Autoimmune Diseases in Pregnancy Project is an ongoing prospective cohort study whereby pregnant women, who do or do not have the autoimmune disease of interest and who may or may not be taking a medication to treat their disease, are enrolled. Comprehensive data on their maternal characteristics, pregnancy exposures and pregnancy outcome information are collected in a standardized fashion through maternal telephone interviews (conducted on up to three occasions during pregnancy). Medical records reviews and their infants are followed up for at least 1 year postpartum. Eligible enrollees are pregnant women residing in the U.S. or Canada, who agree to enroll no later than 20 completed weeks from the last menstrual period and who have not had prenatal diagnosis in the current pregnancy of any major birth defect prior to enrollment. Currently, autoimmune diseases covered in the project include rheumatoid arthritis (RA), psoriasis/psoriatic arthritis, ankylosing spondylitis, Crohn׳s disease and MS (added in 2012) and over 2300 women have been enrolled.
3.3. MS-specific pregnancy registry
The only existing disease-specific pregnancy registry on MS is the German MS pregnancy database run by Dr. Kerstin Hellwig from the Ruhr University Bochum, Germany ( Hellwig et al., 2012 ). This is an independent database, which similar to TIS studies, is contacted by neurologists and MS patients who seek advice for any reproductive question concerning MS and especially MS therapies. It prospectively and systematically follows up on MS pregnancies via standardized and structured telephone or in-person interviews conducted every pregnancy trimester until six months post delivery. Throughout the interviews, information is obtained on obstetrical/breastfeeding and neurologic MS history and characteristics of the newborns by an MS specialized consultant neurologist. Analytical studies reporting the effect of MS medications on pregnancy outcome using data from this registry have been published and the details described in Table 1 (Hellwig et al, 2011b and Hellwig et al, 2012).
While the German registry is acknowledged as an important start, there are limitations. The study is led solely by one neurologist with no input from a dysmorphologist who could confirm or examine pregnancy outcomes. It relies mainly on patient information. Documentation of family history and race/ethnicity as well as other potential contributing factors is not standardized. Furthermore, the population base is small and the follow-up period is short, missing later onset issues.
There is a real need for a prospective well-designed disease-specific pregnancy registry in MS using detailed information collected by standard procedures such as family history, ethnicity, pregnancy history, drug and environmental exposures and mother׳s health status with respect to MS and other illnesses. Existing MS pregnancy registries and adverse event databases, as discussed above, are incomplete as data are not collected in a standardized manner. The registry will collect and measure data on MS disease-related maternal factors including DMT exposures during pregnancy and lactation, other medications used, disease history, activity, progression, type and severity of disability, as well the prevalence of other MS-related comorbidities such as hypertension, psychiatric disorders, chronic pain, bladder/urinary problems and lifestyle factors such as alcohol and tobacco use. Pregnancies will be ascertained prospectively (i.e., before the status of the outcome is known). The pregnancies will be followed, the outcome determined, and the children followed up primarily up to one year after delivery (and extended to 6 years postpartum). Main outcome measures will include spontaneous and induced abortions, live births without malformations, major congenital anomalies, other adverse reproductive outcomes (e.g., low birth weight, premature delivery), developmental or learning disabilities (e.g., developmental delay, abnormal speech/language development), designated behavioral and cognitive disorders (e.g. ADHD, autism), and signs of immunological dysfunction (e.g., frequent infections, asthma).
The need for an MS pregnancy registry was discussed and agreed upon in February 2013 by a group of academic and clinical investigators who met at the MS-CERCH official meeting in Vancouver, BC. As a result of the MS-CERCH recommendations, the “MotherToBaby Pregnancy Study” conducted by OTIS was contacted for potential collaboration in the creation of a disease-based MS pregnancy registry. The advisory committee for OTIS has approved this initiative and funding is being applied for.
The purpose of this paper is to provide neurologists and health care providers who regularly see MS patients with information about the usefulness and limitations of current registries on pregnancy in women with MS. The overall aim is to encourage these individuals and their patients to enroll in this planned registry. The knowledge translation (KT) component that will be available from this Endeavor will be critical for informed reproductive and therapy decisions in MS.
Conflict of interest
We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
Dr. Sadovnick is a consultant for Novartis and receives travel funds and consulting fees but has no company shares. She receives travel funds, honoraria and unrestricted educational funds from Novartis, Biogen Idec, Teva Neuroscience, and Merck Serono.
Dr. Chambers receives grant funding from Genzyme/Sanofi, AbbVie, Amgen, Pfizer, Bristol Myers Squibb, Novartis, Roche Genentech, GSK, CSL, Teva, Sandoz, and UCB.
We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.
We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property.
The meeting that launched MS-CERCH was funded by the Canadian Institutes of Health Research (CIHR), Teva Neurosciences and Biogen Idec.
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a Department of Medical Genetics, University of British Columbia, Vancouver, Canada
b School of Medicine, University of California, San Diego, La Jolla, CA, USA
c National Transplantation Pregnancy Registry, Gift of Life Institute, Philadelphia, PA, USA
d University of Central Florida College of Medicine, Orlando, FL, USA
e Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, Canada
Correspondence to: The University of British Columbia, Vancouver Coastal Health Authority – UBC Hospital, S113-2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2B5. Tel.: +1 604 827 3111; fax: +1 604 827 5740.
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