Comparative tolerability of treatments for acute migraine: A network meta-analysis.

Introduction Migraine headache is a neurological disorder whose attacks are associated with nausea, vomiting, photophobia and phonophobia. Treatments for migraine aim to either prevent attacks before they have started or relieve attacks (abort) after onset of symptoms and range from complementary therapies to pharmacological interventions. A number of treatment-related adverse events such as somnolence, fatigue, and chest discomfort have previously been reported in association with triptans. The comparative tolerability of available agents for the abortive treatment of migraine attacks has not yet been systematically reviewed and quantified. Methods We performed a systematic literature review and Bayesian network meta-analysis for comparative tolerability of treatments for migraine. The literature search targeted all randomized controlled trials evaluating oral abortive treatments for acute migraine over a range of available doses in adults. The primary outcomes of interest were any adverse event, treatment-related adverse events, and serious adverse events. Secondary outcomes were fatigue, dizziness, chest discomfort, somnolence, nausea, and vomiting. Results Our search yielded 141 trials covering 15 distinct treatments. Of the triptans, sumatriptan, eletriptan, rizatriptan, zolmitriptan, and the combination treatment of sumatriptan and naproxen were associated with a statistically significant increase in odds of any adverse event or a treatment-related adverse event occurring compared with placebo. Of the non-triptans, only acetaminophen was associated with a statistically significant increase in odds of an adverse event occurring when compared with placebo. Overall, triptans were not associated with increased odds of serious adverse events occurring and the same was the case for non-triptans. For the secondary outcomes, with the exception of vomiting, all triptans except for almotriptan and frovatriptan were significantly associated with increased risk for all outcomes. Almotriptan was significantly associated with an increased risk of vomiting, whereas all other triptans yielded non-significant lower odds compared with placebo. Generally, the non-triptans were not associated with decreased tolerability for the secondary outcomes. Discussion In summary, triptans were associated with higher odds of any adverse event or a treatment-related adverse event occurring when compared to placebo and non-triptans. Non-significant results for non-triptans indicate that these treatments are comparable with one another and placebo regarding tolerability outcomes.

Risk of medication overuse headache across classes of treatments for acute migraine.

BACKGROUND: The most commonly prescribed medications used to treat migraine acutely are single analgesics, ergots, opioids, and triptans. Due to varying mechanisms of action across drug classes, there is reason to believe that some classes may be less likely than others to elicit Medication Overuse Headache (MOH) than others. We therefore aimed to determine whether certain classes of acute migraine drugs are more likely to elicit MOH than others. METHODS: A comprehensive systematic literature was conducted to identify studies of varying designs that reported on MOH within the considered treatment classes. Only studies that reported MOH according to the International Classification of Headache Disorders (ICHD) were considered. Since no causal comparative design studies were identified; data from prevalence studies and surveys were retrieved. Prevalence-based relative risks between treatment classes were calculated by integrating both medication overuse and medication use from published studies. For each pair wise comparison, pooled relative risks were calculated as the inverse variance weighted average. RESULTS: A total of 29 studies informed the relative risk between treatment classes, all of which reported country-specific data. Five studies reported country-specific medication use data. For triptans versus analgesics the study relative risks generally favored triptans. The pooled relative risk was 0.65 (i.e., relative risk reduction of 35 %). For ergots versus analgesics, a similar trend was observed in favor of ergots with a relative risk of 0.41. For triptans versus ergots, the direction of effect was mixed, and the pooled relative risk was 1.07. Both triptans and ergots appeared favorable when compared to opioids, with pooled relative risks of 0.35 and 0.76, respectively. However, the evidence was limited for these comparisons. Analgesics and opioids also appeared to yield similar risk of MOH (pooled relative risk 1.09). CONCLUSION: Our study suggests that in patients receiving acute migraine treatment, analgesics and opioids are associated with a higher risk of developing MOH compared with other treatments. These findings provide incentive for better monitoring of use of analgesics and opioids for treating acute migraine, and suggest possible clinical preference for use of so-called "migraine-specific" treatments, that is, triptans and ergots.

A review of the pharmacoeconomics of eletriptan for the acute treatment of migraine.

Migraine is a commonly occurring, chronic disorder that can cause significant disability. Eletriptan, a selective serotonin 5-hydroxytryptamine 1 receptor subtype B/D (5-HT1B/1D) agonist, is a clinically effective treatment for moderate to severe migraine. The objective of this literature review was to summarize the available data on the pharmacoeconomics of eletriptan relative to other triptans. Articles meeting the following three criteria were included in the review: 1) contained pharmacoeconomic data on a marketed dose of eletriptan; 2) included data on at least one other comparator triptan; and 3) was in English. A MEDLINE(®) search yielded a total of eight studies (from the European Union [n=5] and from the USA [n=3]) across multiple regions. Seven of the studies examined the pharmacoeconomics of eletriptan relative to other triptans, and a further study examined the health care costs of eletriptan 40 mg versus sumatriptan 100 mg. Eletriptan 40 mg was among a group of triptans, including rizatriptan 10 mg and almotriptan 12.5 mg, demonstrating the greatest cost-effectiveness. This result held across different definitions of efficacy (2 hours pain-free, sustained pain-free, and sustained pain-free with no adverse events) and also held when cost-effectiveness models accounted for second doses and use of rescue medication, management of adverse events, and productivity loss, in addition to drug acquisition costs. Only limited head-to-head comparator data were available. The majority of pharmacoeconomic studies utilized the same set of efficacy and/or tolerability data, and indirect costs were rarely included despite the fact that the majority of per capita migraine costs are attributable to indirect costs. In summary, although the market is now dominated by generics, eletriptan 40 mg is among the most clinically and cost-effective oral triptans available for the management of acute migraine. Increased effectiveness/efficacy of eletriptan may necessitate a lesser need for other migraine treatments and/or switching to other triptans.

Comparing the efficacy of eletriptan for migraine in women during menstrual and non-menstrual time periods: a pooled analysis of randomized controlled trials.

OBJECTIVE: To assess the efficacy and tolerability of eletriptan in treating migraine attacks occurring within the defined menstrual time period of 1 day before and 4 days after onset of menstruation (menses days -1 to +4) compared with attacks occurring during non-menstrual time periods (occurring outside of menses days -1 to +4). BACKGROUND: Migraine attacks during menses have been associated with longer duration, higher recurrence rates, greater treatment resistance, and greater functional disability than those not associated with menses. The efficacy of eletriptan in treating migraine attacks associated with menstruation vs those outside a defined menstrual period has not been evaluated. METHODS: Data were pooled from 5 similarly designed, double-blind, randomized, placebo-controlled trials of eletriptan 20 mg/40 mg/80 mg. Two groups were defined for this analysis: women with a single index migraine beginning during the menstrual (group 1) and non-menstrual (group 2) time periods. End points of interest were headache response at 2 hours, migraine recurrence and sustained responses for nausea, photo/phonophobia, and function. Logistic regression was used to compare group 1 vs group 2 and each eletriptan dose (20, 40, or 80 mg) vs. placebo. Adverse events were also assessed. RESULTS: Of 3217 subjects pooled from 5 studies, 2216 women were either in group 1 (n = 630) or group 2 (n = 1586). Rates of headache response at 2 hours were similar in group 1 vs. group 2 (odds ratio [OR] = 1.11 [95% confidence interval (CI) 0.91, 1.36]; P = .2944). The rate of headache recurrence was significantly higher in group 1 vs group 2 (26.8% vs. 18.6%; OR = 1.67 [95% CI 1.23, 2.26]; P < .001). The odds of achieving sustained nausea responses were significantly lower in group 1 than in group 2 (OR = 0.70 [95% CI 0.54, 0.92]; P = .0097). There was no significant difference between group 1 and group 2 in the odds of achieving a sustained photo/phonophobia and functional response (OR = 0.96 [95% CI 0.77, 1.20]; P = .7269 and OR = 1.14 [95% CI 0.87, 1.50]; P = .3425, respectively). Adverse events were comparable between group 1 and group 2. CONCLUSIONS: Two-hour headache outcome measures were similar in women treated with eletriptan both within and outside of the defined menstrual time period (menses days -1 to +4). The main treatment differences between the 2 groups occurred 2-24 hours post-treatment, with higher recurrence rates and lower sustained response rates for nausea in the group treated during the menstrual time period.

Outcome for headache and pain-free nonresponders to treatment of the first attack: a pooled post-hoc analysis of four randomized trials of eletriptan 40 mg.

OBJECTIVE: The objective of this article is to evaluate, in first attack eletriptan headache and pain-free nonresponders, the efficacy of treating a second and third attack with the same dose of eletriptan 40 mg (ELE-40). METHODS: Data were pooled from four randomized, double-blind, placebo-controlled, multiple attack studies of eletriptan in the treatment of migraine. The first-attack eletriptan headache (HNR) and pain-free (PFNR) nonresponder samples consisted of patients who did not achieve headache or pain-free responses at two hours, or sustained headache or pain-free responses at 24 hours. The efficacy of the same dose of eletriptan (vs placebo; PBO) in treating the second and third attacks was evaluated using a logistic regression model. RESULTS: Among Attack 1 eletriptan HNRs, treatment with ELE-40 (vs PBO) was associated with significantly higher two-hour headache response and pain-free rates, respectively, on both Attack 2 (48.8% vs 20.2%; 17.0% vs 3.9%; P < 0.0001 for both comparisons) and Attack 3 (37.4% vs 15.5%; 18.8% vs 3.2%; P < 0.0001 for both comparisons). Significantly higher sustained headache response and pain-free rates at 24 hours were also observed on both Attack 2 and Attack 3. CONCLUSIONS: The results of this pooled analysis suggest that patients who have HNR or PFNR to an initial dose of eletriptan may respond when a second and third attack is treated with the same dose.

Consistency of eletriptan in treating migraine: Results of a randomized, within-patient multiple-dose study.

OBJECTIVE: The current study evaluated the consistency of eletriptan response. METHODS: Using a within-patient crossover design, patients with migraine completed a three-attack, open-label, lead-in period, before being treated, double-blind for four attacks, with either eletriptan 40 mg (ELE-40; N = 539) or eletriptan 80 mg (ELE-80; N = 432); placebo was randomly substituted for the treatment of one attack. RESULTS: On an A PRIORI analysis of within-patient consistency, double-blind treatment was associated with similar 2 hour headache response rates using a ≥2/3 response criterion for ELE-40 (77%) and ELE-80 (73%), and using a 3/3 response criterion for ELE-40 (46%) and ELE-80 (47%). Within-patient consistency in achieving pain-free status at 2 hours using a ≥2/3 criterion was slightly higher on ELE-40 (42%) compared with ELE-80 (38%), and was similar using the 3/3 criterion (18% on ELE-40, 17% on ELE-80). On a repeated measures logistic regression analysis across all treated attacks, the probability of achieving a headache response at 2 hours ranged from 71% to 74% on ELE-40 vs. 17% to 28% on placebo ( P < 0.0001), and from 66% to 74% on ELE-80 vs. 21% to 27% on placebo ( P < 0.0001). The incidence, per attack, of adverse events was low for both ELE-40 and ELE-80. Few adverse events occurred with incidence ≥10% on ELE-40 (asthenia, 5.0%) or ELE-80 (asthenia, 10%; nausea, 5.8%). Discontinuations because of adverse events were 0.2% on ELE-40, and 1.6% on ELE-80 CONCLUSION: In this multiple attack study, eletriptan was well-tolerated and demonstrated consistent and significant efficacy in the treatment of migraine.

Comparative efficacy of triptans for the abortive treatment of migraine: a multiple treatment comparison meta-analysis.

BACKGROUND: Migraine is the most common neurological condition in developed countries. The abortive treatment of migraine attacks is important both for quality of life and costs associated with illness. Triptans, serotonin 5-HT1B/1D receptor agonists, effectively relieve the pain, disability, and associated symptoms of migraine while improving health-related quality of life. Although a number of direct head-to-head triptan comparisons have been made, data for all possible permutations are not available, and unlikely to ever be so, although in clinical practice such information would be useful. OBJECTIVE: We aimed to determine the relative efficacy of all available triptans to abort migraine headache among patients with previous adequate response to migraine treatments. METHODS: We included only double-blinded randomized clinical trials comparing triptans to either placebo or another triptan. Our primary outcomes were pain-free response at two hours and 24-hour sustained pain-free response, and our secondary outcomes were headache response at two hours and 24-hour sustained headache response. We used Bayesian multiple treatment comparison meta-analyses of seven triptans used in adult patients to abort migraine attacks. We applied a random-effects analysis with meta-regression adjusting for dose. Results are reported as odds ratios with 95% credible intervals. RESULTS: We included data from 74 randomized clinical trials. All triptans were significantly superior to placebo for all outcomes, with the exception of naratriptan for 24-hour sustained pain-free response. Eletriptan consistently yielded the highest treatment effect estimates. For the two-hour endpoints, eletriptan was statistically significantly superior to sumatriptan, almotriptan, naratriptan, and frovatriptan for at least one of the two outcomes. Rizatriptan yielded the second highest treatment effects followed by zolmitriptan. For the 24-hour endpoints, eletriptan was statistically significantly superior to sumatriptan, rizatriptan, almotriptan, and naratriptan for at least one of the two outcomes. Frovatriptan data were not available at that endpoint. Further, the probability that eletriptan is the most likely of all triptans to produce a favorable outcome was 68% for pain-free response at two hours, and 54% for 24-hour sustained pain-free response. CONCLUSION: Triptans appear to offer differing treatment effects. In the populations studied eletriptan was most likely to produce pain-free responses that were sustained.

Anticoagulant use in patients with cancer associated venous thromboembolism: a retrospective cohort study.

INTRODUCTION: Long term anticoagulant therapy is recommended for treatment and secondary prevention of venous thromboembolism in cancer patients. We assessed outpatient anticoagulants [warfarin, low molecular weight heparins (LMWHs), fondaparinux and unfractionated heparin (UFH)] use in adult, cancer patients, 20years of age or older, who incurred a venous thromboembolism (primary or secondary in-hospital diagnosis) in Quebec, Canada between 2007 and 2009. MATERIALS AND METHODS: Data were obtained from the Quebec Health Insurance Agency. Patients with an in-hospital cancer diagnosis between April 2007 and June 2009 and an in-hospital venous thromboembolism diagnosis either concurrently or consequently were eligible at the date of discharge (index date). Those patients registered with the provincial drug plan and discharged to the community were included in the study and followed for 6months. RESULTS: Among 2,070 study patients, 72.4% received anticoagulant therapy at index date, 60% of whom were persistent with therapy and received it for ≥80% of follow-up days. Outpatient anticoagulant use was more likely in those with primary versus secondary diagnosis of venous thromboembolism and less likely in patients with cerebrovascular disease, peptic ulcer disease or previous anticoagulant use. The small number of patients who used either UFH (n=11) or fondaparinux (n=5) at index date were included in the LMWH group. Warfarin use was less likely than LMWH use in corticosteroid users, previous anticoagulant users, patients with metastatic cancer and those with catheter or chemotherapy in the previous three months. Warfarin use was more likely than LMWH use in: older patients, those residing in rural areas, those with lower income and those suffering from ischemic heart disease, atrial fibrillation or chronic kidney disease. Patients with ischemic heart disease were more likely to have used a non-dalteparin LMWH versus dalteparin (currently, the only LMWH approved by health Canada for chronic treatment of VTE), while those residing in rural areas and those with catheter/chemotherapy were less likely to have used them. A primary (versus secondary) discharge diagnosis of venous thromboembolism [Odds Ratio 1.42; 95% confidence interval (1.14, 1.76)], and metastatic cancer 1.27 (1.00, 1.60) were associated with persistence on anticoagulant treatment. CONCLUSION: Guideline recommended outpatient use of anticoagulant in cancer patients hospitalized with venous thromboembolism was influenced by cancer status, old age and low income. Risk factors for bleeding prevented outpatient anticoagulant use in some patients.

An open-label trial of a sumatriptan auto-injector for migraine in patients currently treated with subcutaneous sumatriptan.

OBJECTIVE: To assess the ability of patients, during an acute migraine attack, to successfully self-inject a single dose of sumatriptan using a novel sumatriptan auto-injector (Alsuma(®)), and to evaluate the safety, tolerability, and effectiveness of this sumatriptan auto-injector during an acute migraine attack. BACKGROUND: This sumatriptan auto-injector is a single-use system for the rapid subcutaneous delivery of 6 mg of sumatriptan succinate in the acute management of migraine pain. This auto-injector was developed to address the clinical need for an easy-to-use and rapid-to-administer system that did not require any assembly during the time of an ongoing attack. METHODS: This was an open-label, phase 3 trial conducted at 10 sites in the USA. Male or female adults, ages 18-60 years old, were eligible for study entry if they met International Headache Society criteria for migraine with or without aura, with at least 2 attacks per month, and if they reported use of subcutaneous injectable sumatriptan on at least 2 occasions within the previous 2 months. During the onset of a migraine attack of moderate-to-severe intensity, patients were asked to administer a 6-mg subcutaneous dose of sumatriptan using the auto-injector. Patients returned to the study site within 72 hours of the migraine for the post-treatment assessment visit. RESULTS: A total of 63 patients met entry criteria and received a dose of study medication (the intent-to-treat sample). Sixty-one patients (96.8%) reported injection in the thigh, and 2 patients (3.2%) reported injection in the arm. On the patient questionnaire, 100% of patients (95% confidence interval [CI] 94.3-100%) "agreed" or "agreed strongly" that the written instructions for the auto-injector were clear and easy to follow (30.2% "agreed"; 69.8% "agreed strongly"); 95.2% of patients (95% CI 86.7-99.0%) found that the auto-injector was easy to use (36.5% "agreed"; 58.7% "agreed strongly"), and 65.1% of patients (95% CI 52.0-76.7%) stated that they preferred the new auto-injector to the traditional auto-injector that they were using prior to study entry (42.9% "agreed"; 22.2% "agreed strongly"). Headache response rate at 2 hours was 93.7% (95% CI 84.5-98.2%), and pain-free rate at 2 hours was 60.3% (95% CI 47.2-72.4%). Pain-free rates at 2 hours were similarly high (58.3%; 95% CI 36.6-77.9%) in the subgroup of patients reporting severe baseline headache pain. Only 1 patient reported use of rescue medication after use of the auto-injector, a single oral dose of sumatriptan 100 mg on the same day. The most frequent adverse event was injection site bruising, reported by 15.9% of patients, and rated in all instance as mild in intensity. The second most frequent adverse event was injection site pain, reported by 6.3% of patients, and rated as mild by all patients except 1, who rated it as moderate in intensity. CONCLUSION: The majority of injection-experienced patients reported the pre-assembled, single-use sumatriptan auto-injector to be an easy-to-use, preferred treatment for an acute migraine attack. The study found the auto-injector to be safe and well tolerated, with levels of injection site reactions that were mild and infrequent.

Use, tolerability and compliance of spironolactone in the treatment of heart failure.

BACKGROUND: Risk of morbidity and mortality in patients with severe heart failure (HF) is reduced by blockade of aldosterone receptors with spironolactone. However, benefits of spironolactone are potentially limited by treatment compliance and adverse events profile. The aim of this study was to estimate use of spironolactone by patients with HF, incidence of key adverse events, and patient compliance. METHODS: This study was performed using data from the Quebec provincial medical and drug plans (Régie de l'Assurance Maladie du Québec, RAMQ) for patients who had a diagnosis of HF. Relative incidence of gynecomastia and hyperkalemia was estimated for users and non-users of spironolactone. Treatment adherence was estimated for users of spironolactone and compared to adherence with angiotensin converting enzyme (ACE) inhibitors, beta-blockers (ß-blockers), and angiotensin receptor blockers (ARBs). RESULTS: RAMQ data were obtained for a total of 82,018 patients with a diagnosis of HF. Of these patients, 59.9% used an ACE inhibitor, 59.5% used a beta-blocker, 28.4% used an ARB, and 15.1% (n = 12,344) used spironolactone. Despite underestimation due to limitation of the database, the documented incidence of hyperkalemia (3.3% versus 1.4%) and gynecomastia (1.8% versus 0.7%) was significantly higher in spironolactone users than non-users (p < 0.001). Treatment compliance was significantly lower with spironolactone compared to ACE inhibitors, ß-blockers, and ARBs (45.6% versus 56.1%, 59.7%, and 57.0%, respectively; p < 0.001). Persistence to treatment over a one-year period was also lower with spironolactone compared to ACE inhibitors, ß-blockers, and ARBs (50.7% versus 64.5%, 70.4%, and 66.3%, respectively; p < 0.001). CONCLUSION: Use of spironolactone is associated with an incidence of adverse events, which may have an impact on treatment compliance.

Association between antidepressant use during pregnancy and infants born small for gestational age.

OBJECTIVE: To measure the association between the class of antidepressant (AD) used according to trimester of exposure during pregnancy and infants born small for gestational age (SGA). METHODS: A case-control study was performed using data from the Quebec Pregnancy Registry, which includes 152,107 pregnant women between January 1, 1998, and December 31, 2002. For this study, eligible women were aged 15 to 45 years on the first day of gestation, had drug plan coverage from the Régie de l'Assurance Maladie du Québec for 12 months or more prior to and during pregnancy, had at least 1 psychiatric disorder diagnosis before pregnancy, used ADs for at least 30 days in the year prior to pregnancy, and delivered a live singleton. AD exposure during pregnancy was defined according to trimester of use and class (selective serotonin reuptake inhibitors [SSRIs], tricyclic AD, or other ADs). SGA cases were defined as newborns with a birth weight of less than the 10th percentile according to Canadian charts. Relative risks, adjusted for potential confounders, were estimated using modified Poisson regression. RESULTS: Among the 938 eligible pregnancies, 128 (13.6%) infants were born SGA. Other ADs, mainly venlafaxine, used by women during the second trimester were associated with an increased risk of infants born SGA, compared with nonusers of ADs (adjusted relative risk = 2.41; 95% CI 1.07 to 5.43). Regardless of the trimester of use, no association was found between SSRIs or tricyclics and the risk of SGA. CONCLUSIONS: This study suggests that use of venlafaxine during the second trimester of pregnancy may increase the risk of infants born SGA.

Antidepressant therapy during pregnancy: an insight on its potential healthcare costs.

BACKGROUND: Information on healthcare costs associated with poorly treated psychiatric disorders during and after pregnancy is limited. OBJECTIVE: To compare the direct healthcare costs, during and after pregnancy, between women who continue their antidepressant therapy during the whole gestational period and those who discontinue their treatment during the first trimester. METHODS: Data from a 'Medications and Pregnancy' registry were used. Eligible women were 1) aged 15 - 45, 2) insured by the Quebec drug plan for > or =12 months prior to, during, and > or =3 months after pregnancy, 3) had > or =1 diagnoses of psychiatric disorders before pregnancy, 4) used antidepressants for . or =30 days in the year before pregnancy, and 5) had delivered. Women who continued their antidepressant therapy throughout pregnancy (Group 1) were compared to those who discontinued during the first trimester (Group 2). Healthcare costs, expressed as mean total costs and cost ratios, were determined during and after pregnancy. RESULTS: In total, 2822 women met inclusion criteria. Of these, 501 (17.8%) were in Group 1, and 676 (23.4%) in Group 2. The median number of days of antidepressant use before pregnancy was higher in Group 1 (260 days vs. 144 days, p<.01); the proportion of women visiting a psychiatrist was also higher in Group 1 (33.7% vs. 26.8%, p<.01). The mean total cost during pregnancy in Groups 1 and 2 were $2981.5 vs. $1842.9 (p<.01), respectively, and after pregnancy were $1761.2 vs. $1024.9 (p<.01), respectively. When prescription costs were excluded, these differences in costs were no longer significant. CONCLUSIONS: Women who use antidepressants during pregnancy are likely to have disorders of greater severity compared to those who discontinue during the first trimester. They incur significantly greater healthcare costs. However, this increased cost is attributable to higher prescription costs.

Duration of antidepressant use during pregnancy and risk of major congenital malformations.

BACKGROUND: Antidepressant use during the gestational period is a controversial topic. AIMS: To determine whether duration of antidepressant use during the first trimester increases the risk of major congenital malformations in offspring of women diagnosed with psychiatric disorders. METHOD: A case-control study was performed among women who had been pregnant between January 1998 and December 2002. Data were obtained from a Medication and Pregnancy registry, built by linking three databases from the province of Quebec, and a self-administered questionnaire. Women eligible for this study had to be 15-45 years old at the beginning of pregnancy, have at least one diagnosis of psychiatric disorder before pregnancy, have used antidepressants for > or =30 days in the year prior to pregnancy and have a pregnancy ending with a delivery. Cases were defined as any major congenital malformation diagnosed in the offspring's first year of life. Odds ratios, adjusted for relevant confounders, were estimated using logistic regression. RESULTS: Among the 2329 women meeting the inclusion criteria, 189 (8.1%) infants were born with a major congenital malformation. Duration of antidepressant use during the first trimester of pregnancy was not associated with an increased risk of major congenital malformations: 1-30 days v. 0 day, adjusted OR=1.23 (95% CI 0.77-1.98); 31-60 days v. 0 day, adjusted OR=1.03 (95% CI 0.63-1.69); > or =61 days v. 0 day, adjusted OR=0.92 (95% CI 0.50-1.69). CONCLUSIONS: These data do not support an association between duration of antidepressant use during the first trimester of pregnancy and major congenital malformations in the offspring of women with psychiatric disorders. These findings should help clinicians decide whether to continue antidepressant therapy during pregnancy.

[Antidepressants and pregnancy: risks and benefits for the mother and child]. / Antidépresseurs et grossesse: Risques et bénéfices pour la mère et l'enfant.

Depression, anxiety disorders, anorexia nervosa and bulimia, all indications for antidepressant use, are common disorders in women of childbearing age. Nevertheless, antidepressant use during the gestational period remains a controversial topic. Given that 50 % of pregnancies are unplanned, the safety of antidepressants during the first trimester of pregnancy, a critical period for foetal development, has become a major public health concern. Until now, most studies suggest that physicians may often under-prescribe or discontinue antidepressants at the time of conception and during pregnancy. This may be a consequence of the concern over the safety of these agents in pregnant women and the risks they may pose to the foetus. In fact, recent studies and warnings from Health Canada and the US Food and Drug Administration have reinforced this uncertainty regarding the adverse effects of antidepressant use on the foetus. On the other hand, discontinuation of antidepressant use during pregnancy was also recently associated with maternal relapse of depression and withdrawal symptoms, which is not optimal for the mother and her foetus. Consequently, women who wish to become pregnant and who suffer from psychiatric disorders are faced with the difficult task of deciding whether to continue or discontinue their antidepressant during pregnancy. At this time, it appears important to take into account all evidence-based data to evaluate the risks/benefits of using antidepressants during the gestational period in order to help mothers make the best choice for themselves, and their infants.

First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage.

BACKGROUND: Conflicting findings with regard to the teratogenic risks of first trimester use of paroxetine have prompted the FDA, Health Canada, and the manufacturer of the drug to issue warnings against its use during pregnancy. Given that untreated depression during pregnancy can lead to deleterious effect on the mother and her unborn fetus, data on the relationship between the dose and the range of malformations is warranted. This study attempts to quantify the association between first trimester exposure to paroxetine and congenital cardiac malformations, adjusting for possible confounders, and to quantify the dose-response relationship between paroxetine use and cardiac defects. METHODS: The Medication and Pregnancy registry was used. This population-based registry was built by linking three administrative databases (RAMQ, Med-Echo, and ISQ), and includes all pregnancies in Quebec between 01/01/1997 and 06/30/2003. Date of entry in the registry is the date of the first day of the last menstrual period. To be eligible for this study, women had to: 1) be 15-45 years of age at entry; 2) be covered by the RAMQ drug plan >or=12 months before and during pregnancy; 3) be using only one type of antidepressant during the first trimester; and 4) have a live birth. Two nested case-control studies were carried out comparing the prevalence of paroxetine use in the first trimester of pregnancy to the prevalence of other antidepressant exposures during the same time period. Cases were defined as: 1) any major malformations; or 2) any cardiac malformations diagnosed in the first year of life; controls were defined as no major or minor malformations. Multivariate logistic regression techniques were used to analyze data. RESULTS: Among the 1,403 women meeting inclusion criteria, 101 infants with major congenital malformations were identified; 24 had cardiac malformations. Adjusting for possible confounders, the use of paroxetine (odds ratio [OR] = 1.38, 95% confidence interval [CI] = 0.49-3.92), and the use of other SSRIs (OR = 0.89, 95% CI = 0.28-2.84) during the first trimester of pregnancy did not increase the risk of congenital cardiac malformations compared with the use of non-SSRI antidepressants. When considering the dose, however, a dose-response relationship was observed, thus women exposed to >25 mg/day of paroxetine during the first trimester of pregnancy were at increased risk of having an infant with major congenital malformations (adjusted [adj] OR = 2.23, 95% CI = 1.19, 4.17), or major cardiac malformations (adj OR = 3.07, 95% CI = 1.00, 9.42). CONCLUSIONS: Gestational exposure to paroxetine is associated with major congenital malformations and major cardiac malformations for only first trimester exposure above 25 mg/day.