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).
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.
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.
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.
To evaluate the safety and tolerability of natalizumab when added to glatiramer acetate (GA) in patients with relapsing multiple sclerosis. The primary outcome assessed whether this combination would increase the rate of development of new active lesions on cranial MRI scans vs GA alone.
This phase 2, randomized, double-blind, placebo-controlled study included patients aged 19 to 55 years who were treated with GA for at least 1 year before randomization and experienced at least one relapse during the previous year. Patients received IV natalizumab 300 mg (n = 55) or placebo (n = 55) once every 4 weeks plus GA 20 mg subcutaneously once daily for ≤20 weeks.
The mean rate of development of new active lesions was 0.03 with combination therapy vs 0.11 with GA alone (p = 0.031). Combination therapy resulted in lower mean numbers of new gadolinium-enhancing lesions (0.6 vs 2.3 for GA alone, p = 0.020) and new/newly enlarging T2-hyperintense lesions (0.5 vs 1.3, p = 0.029). The incidence of infection and infusion reactions was similar in both groups; no hypersensitivity reactions were observed. One serious adverse event occurred with combination therapy (elective hip surgery). With the exception of an increase in anti-natalizumab antibodies with combination therapy, laboratory data were consistent with previous clinical studies of natalizumab alone.
The combination of natalizumab and glatiramer acetate seemed safe and well tolerated during 6 months of therapy.
= adverse event;
= Consolidated Standards of Reporting Trials;
= Expanded Disability Status Scale;
= glatiramer acetate;
= Glatiramer Acetate and Natalizumab Combination Evaluation;
= interferon β;
= multiple sclerosis;
= progressive multifocal leukoencephalopathy.
The objective of this study was to evaluate exposure to disease-modifying therapies (DMTs) during pregnancy in 335 pregnancies of multiple sclerosis (MS) patients and to further determine whether exclusive breastfeeding of MS mothers has any relevant influence on postpartum relapse rate.
Only limited data are available on whether DMT exposure during pregnancy affects relapse rate during pregnancy or after birth. Currently, findings on beneficial effect of exclusive breastfeeding on MS disease course are controversially discussed.
We enrolled pregnant women with MS who contacted us directly or via their treating physicians to be included in our nationwide MS and pregnancy database.
We identified 78 pregnancies under interferon-beta (IFNβ) preparations, 41 under glatiramer acetate (GLAT), and 216 pregnancies without DMT exposure during pregnancy. As expected, annualized relapse rate (ARR) decreased continuously during pregnancy in nonexposed mothers (p < 0.001) to then increase after birth. In IFNβ- or GLAT-exposed women this typical pattern was not as obvious. Congenital anomalies were within normal ranges in exposed pregnancies. In total, 170 women were identified who exclusively breastfed (EBF). Significantly reduced postpartum relapse rate during the first 3 months after birth were registered in the EBF group as compared with nonexclusively breastfeeding (NEBF) or nonbreastfeeding women (NBF) women with MS (p < 0.0001). Relapse rate (RR) in the year before pregnancy had been similar throughout all groups. We did not observe any significant differences in RR of NEBF and NBF women.
Exclusive breastfeeding showed some beneficial effects on postpartum relapse rate in our cohort. Our data support that IFNβ and GLAT do not seem to represent a major teratogenic risk in pregnancy.
breastfeeding; disease-modifying therapy (DMT); relapse rate
QUESTION My patient is taking a medication for a chronic condition and has just found out that she is 6 weeks pregnant. The US Food and Drug Administration (FDA) has assigned this medication to pregnancy risk category D, and the Compendium of Pharmaceuticals and Specialties provides no additional data. How should I interpret this information, and how does the Motherisk Program evaluate the safety or risks of drug use in pregnancy?
ANSWER Pregnancy safety data provided by the FDA pregnancy risk categories and the Compendium of Pharmaceuticals and Specialties are insufficient to guide clinical decisions on how to proceed with a pregnancy following exposure to a category D medication. The Motherisk Program creates peer-reviewed statements derived from the primary literature, and we examine fetal outcomes as well as the risk-benefit profile of maternal treatment when evaluating the safety of medication use in pregnancy. The FDA announced in May 2008 that it is dropping its pregnancy risk categories and adopting a method similar to the one we use at Motherisk.
We examined the effect of glatiramer acetate, a random copolymer of alanine, lysine, glutamic acid, and tyrosine, on antigen-specific T-cell responses in patients with multiple sclerosis (MS). Glatiramer acetate (Copaxone) functioned as a universal antigen, inducing proliferation, independent of any prior exposure to the polymer, in T-cell lines prepared from MS or healthy subjects. However, for most patients, daily injections of glatiramer acetate abolished this T-cell response and promoted the secretion of IL-5 and IL-13, which are characteristic of Th2 cells. The surviving glatiramer acetate–reactive T cells exhibited a greater degree of degeneracy as measured by cross-reactive responses to combinatorial peptide libraries. Thus, it appears that, in some individuals, in vivo administration of glatiramer acetate induces highly cross-reactive T cells that secrete Th2 cytokines. To our knowledge, glatiramer acetate is the first agent that suppresses human autoimmune disease and alters immune function by engaging the T-cell receptor. This compound may be useful in a variety of autoimmune disorders in which immune deviation to a Th2 type of response is desirable.
Background and Aims
Q fever is a bacterial zoonosis caused by infection with Coxiella burnetii. It is well established that Q fever causes fetal loss in small ruminants. The suspicion has been raised that pregnant women may also experience adverse pregnancy outcome when the infection is acquired or reactivated during pregnancy. The purpose of this study was to assess the potential association between serologic markers of infection with C.burnetii and spontaneous abortion.
A nested case-control study within the Danish National Birth Cohort, a cohort of 100,418 pregnancies recruited from 1996–2002. Women were recruited in first trimester of pregnancy and followed prospectively. Median gestational age at enrolment was 8 weeks (25 and 75 percentiles: 7 weeks; 10 weeks). During pregnancy, a blood sample was collected at gestational week 6–12 and stored in a bio bank. For this study, a case sample of 218 pregnancies was drawn randomly among the pregnancies in the cohort which ended with a miscarriage before 22 gestational weeks, and a reference group of 482 pregnancies was selected in a random fashion among all pregnancies in the cohort. From these pregnancies, serum samples were screened for antibodies against C. burnetii in a commercial enzyme-linked immunosorbent assay (ELISA). Samples that proved IgG or IgM antibody positive were subsequently confirmatory tested by an immunofluorescence (IFA) test.
Among cases, 11 (5%) were C. burnetii positive in ELISA of which one was confirmed in the IFA assay compared to 29 (6%) ELISA positive and 3 IFA confirmed in the random sample.
We found no evidence of a higher prevalence of C.burnetii antibodies in serum samples from women who later miscarried and the present study does not indicate a major association between Q fever infection and spontaneous abortion in humans. Very early first trimester abortions were, however, not included in the study.
An understanding of the risks, benefits, and relative value of glatiramer acetate (GA) in multiple sclerosis (MS) has been evolving based on recently completed head-to-head studies: REGARD (REbif vs Glatiramer Acetate in Relapsing MS Disease); BEYOND (Betaseron Efficacy Yielding Outcomes of a New Dose); and BECOME (BEtaseron vs COpaxone in Multiple Sclerosis with Triple-Dose Gadolinium and 3-Tesla MRI Endpoints). Outcomes in the primary endpoints of these trials showed no significant differences between GA and high-dose beta-interferons (IFNβs). Results of the PreCISe (Early GA Treatment in Delaying Conversion to Clinically Definite Multiple Sclerosis [CDMS] in Subjects Presenting With a Clinically Isolated Syndrome [CIS]) trial led to the US Food and Drug Administration approval of GA in patients with a CIS. Furthermore, the ongoing follow-up study to the original pivotal GA trial, now extending beyond 15 years, continues to support the safety of GA. Currently, GA and IFNβs are no longer the only immunomodulators available for MS. Introduction of the monoclonal antibody, natalizumab (Tysabri®; Biogen Idec, Inc., Cambridge, MA, USA) provides an alternative immunomodulator for MS and has changed the therapeutic landscape dramatically. However, the rare but serious cases of progressive multifocal leukoencephalopathy that have occurred with natalizumab have raised concerns among clinicians and patients about using this agent and some of the emerging agents. The potential risks and benefits of the emerging therapies (cladribine, alemtuzumab, rituximab, fingolimod, laquinimod, teriflunomide, and dimethyl fumarate) based on phase II/III trials, as well as their use for indications other than MS, will be presented. This review provides available data on GA, natalizumab, and the emerging agents to support new developments in our understanding of GA and how its long-standing role as a first-line therapy in MS will evolve within the increasingly complex MS therapeutic landscape.
annual relapse rate; alemtuzumab; cladribine; rituximab; fingolimod; teriflunomide; dimethyl fumarate; laquinimod; interferon
Psoriasis affects a considerable proportion of women in their reproductive years. Limited published data exist about the possible negative impact of the disease itself in the prognosis of pregnancy. On this background, the emergence of newer biologic agents for psoriasis treatment – such as ustekinumab – raises safety issues concerning the exposure to the drug during pregnancy. To our knowledge this is the first report in the literature describing a pregnancy outcome under ustekinumab treatment.
We report a 35-year-old female psoriasis patient who was under treatment with ustekinumab for a year when she inadvertedly became pregnant. The drug was discontinued immediately and the patient did not opt for termination. During the 12th week of gestation she experienced a spontaneous abortion.
Although the patient’s profile fulfilled 2 general risk factors for spontaneous abortion – she was a smoker and this was her third pregnancy – one could not underestimate the possible role of the drug and of psoriasis per se in this adverse pregnancy outcome. Pregnancy registries and large prospective studies are needed in order to determine whether poorer pregnancies outcomes in psoriatic women are due to the disease itself, associated comorbidities or side-effects of new therapies such as ustekinumab.
abortion; biologic agents; pregnancy outcomes; psoriasis; ustekinumab
Treatment of multiple sclerosis patients with glatiramer acetate has been demonstrated a beneficial effect on disease activity. The objective of this prospective naturalistic study was to evaluate the impact of glatiramer acetate on fatigue and work absenteeism.
291 treatment-naïve patients with relapsing remitting multiple sclerosis were included and treated with glatiramer acetate for twelve months. Relapse rates, disability, fatigue symptoms, days of absence from work and adverse events were monitored. Fatigue was measured with the MFIS scale and with a visual analogue scale.
Total MFIS scores decreased by 7.6 ± 16.4 from 34.6 to 27.0 (p ≤ 0.001). Significant reductions were observed on all three subscales of the MFIS. Fatigue symptoms, assessed using a visual analogue scale, decreased by 1.04 ± 2.88 cm from 4.47 cm to 3.43 cm (p ≤ 0.001). The proportion of patients absent from work at least once was reduced by a factor of two from 65.1% to 30.1% (p ≤ 0.001). Tolerance to treatment was rated as very good or good in 78.3% of patients. Adverse effects, most frequently local injection site reactions, were reported in 15.1% of patients.
Treatment with glatiramer acetate was associated with a significant improvement in fatigue symptoms and a marked reduction in absence from work. Treatment was well-tolerated. Such benefits are of relevance to overall patient well-being.
Investigators often employ a single cross-sectional measure of in utero exposure when evaluating associations between organochlorine pesticides/ metabolites (OCs) and adverse reproductive outcomes. Few data are available on the stability of exposures to OCs over critical windows of human reproduction and development inclusive of the periconception window. Our objective was to measures changes in OC concentrations prior to conception and throughout pregnancy or after 12 unsuccessful months attempting pregnancy. Seventy-nine women planning pregnancy were prospectively enrolled and followed for up to 12 menstrual cycles. Blood specimens were obtained for toxicologic analysis of seven OCs from participating women at baseline (preconception, n=79), at the first prenatal visit following a positive pregnancy test leading to a live birth (n=54) or after pregnancy loss (n=10), at approximately 6 weeks post-partum (n=53), and after 12 unsuccessful cycles (n=9). Overall and daily rate of change in OCs concentration (ng/g serum) were estimated adjusting for serum lipids and baseline concentration. Significant (P<0.05) decreases in the overall and daily rate of change in OCs concentrations (ng/mL serum) were observed from baseline to pregnancy for HCB (−0.032, −0.001, respectively) and trans-nonachlor (−0.050, −0.002, respectively) while oxychlordane demonstrated an increase during this critical window (0.029, 0.001, respectively). Significant decreases in aldrin (−0.002, −1.47 × 10−4, respectively), HCB (−0.069, −0.003, respectively), and trans-nonachlor (−0.045, −0.002 respectively), and an overall increase for oxychlordane (0.015) were seen for women with pregnancy losses. Significant decreases also were observed among infertile women for aldrin (−0.003, −3.52 × 10−6, respectively), DDE (−0.210, −4.29 × 10−4, respectively), and HCB (−0.096, −2.03 × 10−4, respectively), along with an increase for trans-nonachlor (0.034, 7.59 × 10−5, respectively). These data, though limited by sample size and the possibility of laboratory measurement error, suggest that OC concentrations may change over critical windows. This underscores the importance of timing biospecimen collection to critical windows for development in the assessment of reproductive and/or developmental effects.
critical windows; organochlorine pesticides; persistent organic pollutants; pregnancy; pregnancy loss
Previous studies have described stabilization of aggressive multiple sclerosis (MS) with one-time induction therapy with high-dose cyclophosphamide (HiCy). The long-term benefit of this stabilization followed by conventional therapy has not been explored.
The objective of this study was to evaluate the safety and clinical outcomes following treatment of relapsing–remitting MS with HiCy induction therapy followed by glatiramer acetate maintenance.
A retrospective review of a closely followed population of thirty two MS patients treated with HiCy (200mg/kg intravenous infusion over 4 days) followed by maintenance with glatiramer acetate was performed.
Annualized relapse rate was reduced from 1.37 in the 2 years prior to treatment to 0.27 over a mean post-treatment follow-up period of 14 months (range 0.5–33.8). The projected probability of relapse-free survival at 2 years was 0.64 (95% CI 0.37–0.82). The projected probability of Expanded Disability Status Scale (EDSS) progression-free survival at 2 years was 0.77 (95% CI 0.43–0.92). The mean number of gadolinium-enhanced lesions was reduced from 0.86 (SD 1.6) at baseline to 0 at 12 months and 0.08 (SD 0.28) at 15–24 months. A total of 55% of patients had no evidence of disease activity in follow-up. Infectious complications occurred in 47% with no long-term morbidity and no deaths.
Induction therapy with HiCy followed by long-term maintenance with glatiramer acetate is well tolerated in patients with MS, and appears to be efficacious in reducing the risk of relapse, disability progression, and new MRI lesions.
cyclophosphamide; glatiramer acetate; immunosuppression; multiple sclerosis
The participation of neurologists and patients in studies on the effectiveness and safety of newly authorized drugs in multiple sclerosis (MS) is insufficient. Monthly online self-assessments using patient-reported outcomes may help in short-term monitoring of neurological changes and side effects.
Investigate in relapsing-remitting (RR) MS patients the adherence to monthly online self-assessments after the start of disease modifying treatment.
Observational study in 39 neurological departments in The Netherlands. Patients starting glatiramer acetate treatment were instructed to complete online the Modified Fatigue Impact Scale 5-item version and the 8-item Leeds Multiple Sclerosis Quality of Life scale every month during 1 year (T0 toT12).
Sixty-three investigators included 163 analyzable patients. At T3, 148 (90.8%) patients had completed all questionnaires; at T6, 142 (87.1%); at T9, 133 (81.6%); and at T12, 123 (75.5%). Eight (4.9%) patients did not complete any questionnaire. Median values for inter-assessment intervals ranged from 32 to 34 days (first quartile [Q1] 30 days, third quartile [Q3] 41 days), and the final assessment was at 417 days (median: Q1 385 days, Q3 480 days). Forty-three (26.3%) patients completed the questionnaires at all time points (completion adherent) with their final assessment within 30 days after the scheduled T12 (interval adherent). Eighty (49.1%) patients were completion adherent, but not interval adherent. Forty (24.5%) patients were not completion adherent, as they discontinued assessments prematurely. Men were more interval adherent than women (47.5% vs 20.0%; P = 0.001).
The observation that three out of four (75.5%) RRMS patients completed two short questionnaires at all monthly time points during 1 year after the start of disease modifying treatment suggests that intensive online monitoring in this patient group is feasible. As only one in five (19.6%) patients adhered to the time intervals between self-assessments, measures are needed that improve the timely completion of questionnaires.
effectiveness; glatiramer acetate; fatigue; health-related quality of life; MFIS-5; LMSQoL
Interleukin 12 (IL-12), a cytokine that promotes generation of helper T cells subtype 1, is increased in multiple sclerosis. Albuterol sulfate, a β2-adrenergic agonist, reduces IL-12 expression, so we tested the effect of albuterol as an add-on treatment to glatiramer acetate therapy.
To investigate the clinical and immunologic effects of albuterol treatment as an add-on therapy in patients starting glatiramer acetate treatment.
Single-center double-masked clinical trial.
Subjects with relapsing-remitting multiple sclerosis.
Main Outcome Measures
In this single-center double-masked clinical trial, subjects with relapsing-remitting multiple sclerosis were randomized to receive a subcutaneous injection of glatiramer acetate (20 mg) plus an oral dose of placebo daily for 2 years or a subcutaneous injection of glatiramer acetate (20 mg) plus an oral dose of albuterol daily for 2 years. The primary clinical efficacy measurement was the change in Multiple Sclerosis Functional Composite at 2 years, and the primary immunologic end point was the change in expression of IL-13 and interferon γ at each study time point. The classification level of evidence from this trial is C for each question, as this is the first class II clinical trial addressing the efficacy of glatiramer acetate plus albuterol.
Forty-four subjects were randomized to receive glatiramer acetate plus albuterol or glatiramer acetate plus placebo, and 39 subjects contributed to the analysis. Improvement in the Multiple Sclerosis Functional Composite was observed in the glatiramer acetate plus albuterol group at the 6-month (P = .005) and 12-month (P = .04) time points but not at the 24-month time point. A delay in the time to first relapse was also observed in the glatiramer acetate plus albuterol group (P = .03). Immunologically, IL-13 and interferon-γ production decreased in both treatment groups, and a treatment effect on IL-13 production was observed at the 12-month time point (P < .05). Adverse events were generally mild, and only 3 moderate or severe events were considered related to the treatment.
Treatment with glatiramer acetate plus albuterol is well tolerated and improves clinical outcomes in patients with multiple sclerosis.
Objective To generate evidence on the longer term cost effectiveness of disease modifying treatments in patients with relapsing-remitting multiple sclerosis.
Design Prospective cohort study with historical comparator.
Setting Specialist multiple sclerosis clinics in 70 centres in the United Kingdom.
Participants Patients with relapsing-remitting multiple sclerosis who started treatment from May 2002 to April 2005 under the UK risk sharing scheme.
Interventions Treatment with interferon beta or glatiramer acetate in accordance with guidelines of the UK Association of British Neurologists.
Main outcome measures Observed utility weighted progression in disability at two years’ follow-up assessed on the expanded disability status scale (EDSS) compared with that expected by applying the progression rates in a comparator dataset, modified for patients receiving treatment by multiplying by the hazard ratio derived separately for each disease modifying treatment from the randomised trials.
Results In the primary per protocol analysis, progression in disability was worse than that predicted and worse than that in the untreated comparator dataset (“deviation score” of 113%; excess in mean disability status scale 0.28). In sensitivity analyses, however, the deviation score varied from −72% (using raw baseline disability status scale scores, rather than applying a “no improvement” algorithm) to 156% (imputing missing data for year two from progression rates for year one).
Conclusions It is too early to reach any conclusion about the cost effectiveness of disease modifying treatments from this first interim analysis. Important methodological issues, including the need for additional comparator datasets, the potential bias from missing data, and the impact of the “no improvement” rule, will need to be addressed and long term follow-up of all patients is essential to secure meaningful results. Future analyses of the cohort are likely to be more informative, not least because they will be less sensitive to short term fluctuations in disability.
Decreased relapse rate and slower disease progression have been reported with long-term use of immunomodulatory treatments (IMTs, interferon beta or glatiramer acetate) in relapsing–remitting multiple sclerosis. There are, however, patients who do not respond to such treatments, and they can be potential candidates for alternative therapeutic approaches.
To identify clinical factors as possible predictors of poor long-term response.
A 9-year prospective, continuous follow-up at a single center in Hungary to assess clinical efficacy of IMT.
In a patient group of 81 subjects with mean IMT duration of 54 ± 33 months, treatment efficacy expressed as annual relapse rate and change in clinical severity from baseline did not depend on the specific IMT (any of the interferon betas or glatiramer acetate), and on mono- or multifocal features of the initial appearance of the disease. Responders had shorter disease duration and milder clinical signs at the initiation of treatment. Relapse-rate reduction in the initial 2 years of treatment predicted clinical efficacy in subsequent years.
Based on these observations, we suggest that a 2-year trial period is sufficient to decide on the efficacy of a specific IMT. For those with insufficient relapse reduction in the first 2 years of treatment, a different IMT or other therapeutic approaches should be recommended.
multiple sclerosis; immunomodulatory; EDSS; relapse; response
Few studies have systematically addressed the role of epidural analgesia and caesarean delivery in predicting the post-partum disease activity in women with Multiple Sclerosis (MS).
The objective of this study was to assess the impact of epidural analgesia (EA) and caesarean delivery (CD) on the risk of post-partum relapses and disability in women with MS.
In the context of an Italian prospective study on the safety of immunomodulators in pregnancy, we included pregnancies occurred between 2002 and 2008 in women with MS regularly followed-up in 21 Italian MS centers. Data were gathered through a standardized, semi-structured interview, dealing with pregnancy outcomes, breastfeeding, type of delivery (vaginal or caesarean) and EA. The risk of post-partum relapses and disability progression (1 point on the Expanded Disability Status Sclae, EDSS, point, confirmed after six months) was assessed through a logistic multivariate regression analysis.
We collected data on 423 pregnancies in 415 women. Among these, 349 pregnancies resulted in full term deliveries, with a post-partum follow-up of at least one year (mean follow-up period 5.5±3.1 years). One hundred and fifty-five patients (44.4%) underwent CD and 65 (18.5%) EA. In the multivariate analysis neither CD, nor EA were associated with a higher risk of post-partum relapses. Post-partum relapses were related to a higher EDSS score at conception (OR=1.42; 95% CI 1.11-1.82; p=0.005), a higher number of relapses in the year before pregnancy (OR=1.62; 95% CI 1.15-2.29; p=0.006) and during pregnancy (OR=3.07; 95% CI 1.40-6.72; p=0.005). Likewise, CD and EA were not associated with disability progression on the EDSS after delivery. The only significant predictor of disability progression was the occurrence of relapses in the year after delivery (disability progression in the year after delivery: OR= 4.00; 95% CI 2.0-8.2; p<0.001; disability progression over the whole follow-up period: OR= 2.0; 95% CI 1.2-3.3; p=0.005).
Our findings, show no correlation between EA, CD and postpartum relapses and disability. Therefore these procedures can safely be applied in MS patients. On the other hand, post-partum relapses are significantly associated with increased disability, which calls for the need of preventive therapies after delivery.
Epidural analgesia; Caesarean delivery; Multiple sclerosis; Pregnancy
Concerns regarding the teratogenicity of fluoroquinolones have resulted in their restricted use during gestation. This is despite an increasing need for their use due to emerging bacterial resistance. The objectives of the present investigation were to evaluate pregnancy and fetal outcomes following maternal exposure to fluoroquinolones and to examine whether in utero exposure to quinolones is associated with clinically significant musculoskeletal dysfunctions. We prospectively enrolled and followed up 200 women exposed to fluoroquinolones (norfloxacin, ciprofloxacin, ofloxacin) during gestation. Pregnancy outcome was compared with that for 200 controls matched for age and for smoking and alcohol consumption habits. Controls were exposed to nonteratogenic, nonembryotoxic antimicrobial agents matched by indication, duration of therapy (±3 days), and trimester of exposure. Rates of major congenital malformations did not differ between the group exposed to quinolones in the first trimester (2.2%) and the control group (2.6%) (relative risk, 0.85; 95% confidence interval, 0.21 to 3.49). Women treated with quinolones had a tendency for an increased rate of therapeutic abortions compared with the rate among women exposed to nonteratogens (relative risk, 4.50; 95% confidence interval, 0.98 to 20.57), resulting in lower live-birth rates (86 versus 94%; P = 0.02). The rates of spontaneous abortions, fetal distress, and prematurity and the birth weight did not differ between the groups. Gross motor developmental milestone achievements did not differ between the children of the mothers in the two groups. We concluded that the use of fluoroquinolones during embryogenesis is not associated with an increased risk of major malformations. There were no clinically significant musculoskeletal dysfunctions in children exposed to fluoroquinolones in utero. The higher rate of therapeutic abortions observed in quinolone-exposed women compared to that for their controls may be secondary to the misperception of a major risk related to quinolone use during pregnancy.
Systemic lupus erythematosus (SLE) is an autoimmune disease that predominantly affects women of reproductive age. Pregnancy and its outcome is a major concern to most SLE patients. Queries regarding the risk of disease flares during pregnancy, chance of fetal loss, and the safety of various drugs are often raised. With the improvement in the understanding of the pathogenesis of SLE and the judicious use of immunosuppressive drugs, better disease control can now be achieved and SLE patients should not be deprived of the opportunity for bearing children. Prepregnancy counselling and close collaboration with other specialists such as the obstetricians and the perinatologists is essential in optimising the maternal and fetal outcome in lupus pregnancies. In this review, important issues regarding the fertility rate, optimal timing of conception, risk of disease flares during lupus pregnancy, pregnancy course, fetal outcome, safety of various drugs used for disease control during pregnancy and lactation, and contraceptive advice are discussed.
Keywords: systemic lupus erythematosus; pregnancy; flare; hormone
Risk sharing schemes represent an innovative and important approach to the problems of rationing and achieving cost-effectiveness in high cost or controversial health interventions. This study aimed to assess the feasibility of risk sharing schemes, looking at long term clinical outcomes, to determine the price at which high cost treatments would be acceptable to the NHS.
This case study of the first NHS risk sharing scheme, a long term prospective cohort study of beta interferon and glatiramer acetate in multiple sclerosis (MS) patients in 71 specialist MS centres in UK NHS hospitals, recruited adults with relapsing forms of MS, meeting Association of British Neurologists (ABN) criteria for disease modifying therapy. Outcome measures were: success of recruitment and follow up over the first three years, analysis of baseline and initial follow up data and the prospect of estimating the long term cost-effectiveness of these treatments.
Centres consented 5560 patients. Of the 4240 patients who had been in the study for a least one year, annual review data were available for 3730 (88.0%). Of the patients who had been in the study for at least two years and three years, subsequent annual review data were available for 2055 (78.5%) and 265 (71.8%) patients respectively. Baseline characteristics and a small but statistically significant progression of disease were similar to those reported in previous pivotal studies.
Successful recruitment, follow up and early data analysis suggest that risk sharing schemes should be able to deliver their objectives. However, important issues of analysis, and political and commercial conflicts of interest still need to be addressed.
Results regarding potential adverse effects of antiretroviral drugs during pregnancy are discrepant and few studies, most from Europe, have provided information about pregnancy outcomes of those already on treatment at conception. The aim of this study was to investigate the impact of antiretrovirals on pregnancy outcome according to the timing of treatment initiation in relation to pregnancy in a cohort of Brazilian HIV infected pregnant women.
A prospective cohort of 696 pregnancies followed-up in one single center between 1996 and 2006 was studied. Patients in receipt of antiretrovirals before pregnancy were compared with those treated after the first trimester. The outcomes evaluated were preterm delivery (PTD): < 37 weeks; severe PTD (< 34 weeks); low birth weight (LBW): < 2500 g; very LBW: < 1500 g.
Patients on pre-conception use of ARV had higher rates of LBW (33.3% vs. 16.5%; p = 0.0002), and a similar trend for PTD (26.3% % vs. 17.7%; p = 0.09). Stratification by type of therapy (dual vs. HAART) according to timing of initiation of ARV showed that patients in use of pre-conception HAART have a higher rate of PTD (20.2% vs. 10.2%, p = 0.03) and LBW (24.2% vs. 10.2%, p = 0.002). After adjusting for several factors, pre-conception HAART was associated with an increased risk for PTD (AOR: 5.0; 95% CI: 1.5 – 17.0, p = 0.009) and LBW (OR: 3.6; 95% CI: 1.7 – 7.7, p = 0.001).
We identified an increased risk for LBW and PTD in patients in receipt of HAART prior to pregnancy.
pregnancy; outcome; HIV; antiretroviral
Pregnancy outcomes following in utero exposure to antiepileptic drugs (AEDs) are uncertain, limiting an evidenced-based approach.
To determine if fetal outcomes vary as a function of different in utero AED exposures.
This ongoing prospective observational study across 25 epilepsy centers in the USA and UK enrolled pregnant women with epilepsy from October 1999 to February 2004 to determine if differential long-term cognitive and behavioral neurodevelopmental effects exist across the four most commonly used AEDs. This initial report focuses on the incidence of serious adverse outcomes including major congenital malformations (which could be attributable to AEDs) or fetal death. A total of 333 mother/child pairs were analyzed for monotherapy exposures: carbamazepine (n = 110), lamotrigine (n = 98), phenytoin (n = 56), and valproate (n = 69).
Response frequencies of pregnancies resulting in serious adverse outcomes for each AED were as follows: carbamazepine 8.2%, lamotrigine 1.0%, phenytoin 10.7%, and valproate 20.3%. Distribution of serious adverse outcomes differed significantly across AEDs and was not explained by factors other than in utero AED exposure. Valproate exhibited a dose-dependent effect.
More adverse outcomes were observed in pregnancies with in utero valproate exposure vs the other antiepileptic drugs (AEDs). These results combined with several recent studies provide strong evidence that valproate poses the highest risk to the fetus. For women who fail other AEDs and require valproate, the dose should be limited if possible.
To estimate the association between over-the-counter nonsteroidal anti-inflammatory drug (NSAID) exposure during the early first-trimester and risk for spontaneous abortion (gestation prior to 20 weeks) in a prospective cohort.
Women were enrolled in the Right from the Start study (2004–2010). Exposure data regarding over-the-counter NSAID use from the last menstrual period through the 6th week of pregnancy were obtained from intake and first-trimester interviews. Pregnancy outcomes were self-reported and verified by medical records. Gestational age was determined from last menstrual period. Stage of development prior to loss was determined from study ultrasound. Cox proportional hazards regression models were used to estimate the association between NSAID exposure and pregnancy outcome, taking into account candidate confounders.
Among 2,780 pregnancies, 367 women (13%) experienced an spontaneous abortion. NSAID exposure was reported by 1,185 (43%) women. NSAID exposure was not associated with spontaneous abortion risk in unadjusted models (hazard ratio [HR] = 1.01, 95% confidence interval [CI] 0.82, 1.24) or models adjusted for maternal age (adjusted [aHR] = 1.00, 95% CI 0.81, 1.23).
Our findings suggest that use of non-prescription over-the-counter NSAIDs in early pregnancy does not put women at increased risk of spontaneous abortion.
Multiple sclerosis is a chronic disease characterized by demyelination and neurodegeneration of the central nervous system. Immunomodulatory treatment is possible at an early stage of the disease, and consists of injections of either beta-interferon or glatiramer acetate. The drugs are not curative, and the need for frequent injections may give rise to a serious problem regarding adherence to treatment. The present study analyzed the database of all Brazilian patients using glatiramer acetate between June 2003 and December 2006 who had enrolled in the patient program run by the pharmaceutical company commercializing the drug. The rate of treatment discontinuation was 10% over this period, and the main reason for suspending the drug was medical decisions (47% of all discontinuations), rather than side effects or the patient’s choice. The present work did not take into consideration the regularity of injections and the main objective was to assess discontinuation. It was concluded that adequate healthcare, education, and a specific program for patients were the factors responsible for this 90% adherence to glatiramer acetate treatment in Brazil.
multiple sclerosis; glatiramer acetate; adherence
Multiple sclerosis (MS) in children and adolescents accounts for 3–10% of the whole MS population, and is characterized by a relapsing course in almost all cases. The frequency of relapses is higher than in adult onset MS, at least in the first years of evolution. The objective of treatment is to speed the recovery after a relapse, to prevent the occurrence of relapses, and to prevent disease progression and neurodegeneration. The use of drugs for MS in children and adolescents has not been studied in clinical trials, so their use is mainly based on results from trials in adults and from observational studies. There is a consensus to treat acute relapses with intravenous high-dose corticosteroids. The possibility of preventing relapses and disease progression is based on the use of immunomodulatory agents. Interferon-beta (IFNB) and glatiramer acetate (GA) have been demonstrated to be safe and well tolerated in pediatric MS patients, and also to reduce relapse rate and disease progression. Cyclophosphamide and natalizumab could be offered as second-line treatment in patients with a poor response to IFNB or GA. New oral and injectable drugs will be available in the near future: if safe and well tolerated in the long-term follow up of adults with MS, they could be tested in the pediatric MS population.
adolescence; childhood; cyclophosphamide; glatiramer acetate; interferon beta; intravenous immunoglobulin; intravenous methylprednisolone; mitoxantrone; multiple sclerosis; natalizumab
Pregnant women who travel to malarious areas and their clinicians need data on the safety of malaria chemoprophylaxis. The drug safety database analysis of mefloquine exposure in pregnancy showed that the birth defect prevalence and fetal loss in maternal, prospectively-monitored cases were comparable to background rates.
Background. Pregnant women who travel to malarious areas and their clinicians need data on the safety of malaria chemoprophylaxis.
Methods. The effect of exposure to mefloquine on pregnancy and offspring outcomes was evaluated using the F. Hoffmann–La Roche global drug safety database for the time frame 31 January 1986 through 26 October 2010. We investigated pregnancy and fetal outcomes in maternal, paternal, and both-parent exposure cases with a focus on congenital malformations and fetal loss. The main outcome measures were birth defect prevalence and types of malformations.
Results. A total of 2506 cases of mefloquine exposure during pregnancy or in the pre- and periconception period were evaluated. Most cases were maternal prospective (outcome of the pregnancy unknown at the time of reporting; n = 2246 [89.6%]) followed by maternal retrospective cases (outcome of the pregnancy known at the time of reporting; n = 227 [9.0%]), with small numbers of paternal and both-parent exposure cases. Of the total 2246 mefloquine maternal prospective exposures (95.2%), 2139 occurred before conception and/or during the first trimester. Of 1383 maternal prospective cases with known outcome, 978 (70.7%) resulted in delivery, 405 (29.3%) resulted in abortion (112 spontaneous, 293 therapeutic), and 43 resulted in birth defects, corresponding to a birth defect prevalence of 4.39% (43 of 978). Prospective cases overall showed no specific pattern of birth malformations.
Conclusions. The drug safety database analysis of mefloquine exposure in pregnancy showed that the birth defect prevalence and fetal loss in maternal, prospectively monitored cases were comparable to background rates.