Efficacy, tolerability, and safety of eptinezumab in patients with a dual diagnosis of chronic migraine and medication-overuse headache: Subgroup analysis of PROMISE-2.

OBJECTIVE: To evaluate the efficacy, tolerability, and safety of eptinezumab 100 and 300 mg compared with placebo in patients with the dual diagnosis of chronic migraine (CM) and medication-overuse headache (MOH). BACKGROUND: Eptinezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide, may be effective for treating patients with a dual diagnosis of CM and MOH. METHODS: PROMISE-2 (NCT02974153) was a double-blind, randomized, placebo-controlled, phase 3 study that comprised a screening visit, a 28-day pretreatment period, and a 32-week study duration. Patients in this exploratory analysis of a prespecified subgroup had confirmed diagnoses of both CM and MOH at screening. Patients were randomly assigned to receive intravenous eptinezumab 100, 300 mg, or placebo every 12 weeks. Efficacy outcomes included mean changes from baseline in monthly migraine days (MMDs) during weeks 1-12, migraine responder rates at week 12, and percentages of patients below International Classification of Headache Disorders thresholds for CM and MOH over weeks 1-24. RESULTS: There were 431 patients who were diagnosed with CM and MOH as specified in the protocol and received eptinezumab 100 mg (n = 139), 300 mg (n = 147), or placebo (n = 145). During the baseline period, these patients experienced an average of 16.7 migraine days across treatment arms. Over weeks 1-12, eptinezumab-treated patients experienced greater reductions from baseline in MMDs than placebo patients (100 mg, change from baseline = -8.4, difference from placebo [95% confidence interval (CI)] = -3.0 [-4.56, -1.52], p < 0.0001 vs. placebo; 300 mg, change from baseline = -8.6, difference from placebo [95% CI] = -3.2 [-4.66, -1.78], p < 0.0001 vs. placebo; placebo, -5.4). Compared with placebo, more eptinezumab-treated patients were ≥50% migraine responders (100 mg, 84/139 [60.4%]; 300 mg, 91/147 [61.9%]; placebo, 50/145 [34.5%]) or ≥75% responders (100 mg, 38/139 [27.3%]; 300 mg, 44/147 [29.9%]; placebo, 21/145 [14.5%]) over weeks 1-12. Therapeutic benefits with eptinezumab were observed from day 1 after dosing, and improvements were sustained with an additional dose. For the full 24-week treatment period, 71/139 (51.1%), 80/147 (54.4%), and 47/145 (32.4%) of 100, 300 mg, and placebo-treated patients, respectively, were below CM thresholds, and of the patients who provided sufficient acute medication data, 47/93 (50.5%), 53/107 (49.5%), and 26/96 (27.1%), respectively, were below medication-overuse thresholds. CONCLUSIONS: In patients diagnosed with both CM and MOH, eptinezumab treatment resulted in greater reductions in MMDs, higher responder rates, and fewer patients meeting CM and MOH criteria, thus demonstrating the efficacy and clinical utility of eptinezumab in this patient population.

Preventive migraine treatment with eptinezumab reduced acute headache medication and headache frequency to below diagnostic thresholds in patients with chronic migraine and medication-overuse headache.

OBJECTIVE: This post hoc analysis in patients medically diagnosed with chronic migraine (CM) and medication-overuse headache (MOH) evaluated reductions in the use of acute headache medication (AHM) and sustained changes in the diagnostic status of CM and MOH following eptinezumab treatment in the PROMISE-2 study. BACKGROUND: Eptinezumab, a monoclonal antibody that inhibits calcitonin gene-related peptide, is approved in the United States for the preventive treatment of migraine. A previous analysis showed that eptinezumab reduced monthly migraine days and was well tolerated in the subgroup of PROMISE-2 patients diagnosed with both CM and MOH. METHODS: The phase 3, double-blind, placebo-controlled PROMISE-2 study (NCT02974153) randomized adults with CM to eptinezumab 100 mg, 300 mg, or placebo (administered intravenously every 12 weeks for up to two doses). MOH was prospectively diagnosed at screening by trained physicians based on 3 months of medication history and International Classification of Headache Disorders-3ß criteria. This post hoc analysis evaluated changes in total and class-specific days of AHM usage, the percentage of patients using AHM at or above MOH diagnostic thresholds, and the percentage of patients experiencing monthly headache and migraine day frequency below diagnostic thresholds for MOH and/or CM. RESULTS: In PROMISE-2, 431/1072 (40.2%) patients with CM were diagnosed with MOH (eptinezumab 100 mg, n = 139; 300 mg, n = 147; placebo, n = 145) and were included in this analysis. Total monthly AHM use decreased from 20.6 days/month at baseline to 10.6 days/month over 24 weeks of treatment (49% decrease) with eptinezumab 100 mg, from 20.7 to 10.5 days/month (49% decrease) with eptinezumab 300 mg, and from 19.8 to 14.0 days/month (29% decrease) with placebo. Numerically greater decreases from baseline with eptinezumab were also observed for individual drug classes. In each study month, the percentages of patients who were below MOH thresholds were numerically higher for both eptinezumab doses compared with placebo, as were the percentages of patients experiencing headache and migraine frequency below CM thresholds. Of patients with available data across the entire treatment period, 29.0% (58/200) of patients treated with eptinezumab stopped meeting and remained below diagnostic thresholds for both CM and MOH during Weeks 1-24, as well as 6.3% (6/96) of patients who received placebo. CONCLUSIONS: Across 24 weeks of treatment, eptinezumab reduced AHM use in patients diagnosed with CM and MOH. More than one-fourth (29%) of patients treated with eptinezumab did not meet the diagnostic thresholds for either CM or MOH for the entire treatment period.

Sumatriptan-naproxen sodium for menstrual migraine and dysmenorrhea: satisfaction, productivity, and functional disability outcomes.

OBJECTIVE: To evaluate the impact of a sumatriptan/naproxen sodium combination tablet on patient satisfaction, productivity, and functional disability in menstrual migraine treated during the mild pain phase of a single menstrual migraine attack associated with dysmenorrhea. BACKGROUND: Menstrual migraineurs with dysmenorrhea represent a unique patient population not previously studied. When health outcomes end points are analyzed alongside traditional efficacy end points in migraine studies, a more comprehensive and robust understanding of the many factors that may influence patients' choice of and adherence to pharmacological treatments for migraine is observed. METHODS: In 2 replicate, multicenter, randomized, double-blind, placebo-controlled trials, participants with menstrual migraine and dysmenorrhea treated a single menstrual migraine attack with a single fixed-dose tablet of sumatriptan 85 mg formulated with RT Technology™ and naproxen sodium 500 mg (sumatriptan-naproxen sodium) or placebo. RESULTS: Participants randomized to sumatriptan-naproxen sodium were significantly more satisfied than those randomized to placebo at 24 hours post dose, as demonstrated by higher satisfaction subscale scores for efficacy (P < .001 for both studies), functionality (P = .003 for study 1; P < .001 for study 2), and ease of use (P = .027 for study 1; P = .011 for study 2). There was little bothersomeness of side effects associated with either treatment. Use of sumatriptan-naproxen sodium was also associated with lower reported "lost-time equivalents" in work and leisure time (pooled analysis, P = .003) and lower rates of functional disability (P = .05, study 1; P < .001, study 2) compared with placebo. CONCLUSION: A fixed-dose combination tablet containing sumatriptan and naproxen sodium significantly improved patient satisfaction, productivity, and restoration of normal functioning in menstrual migraineurs with dysmenorrhea.

Combination treatment for menstrual migraine and dysmenorrhea using sumatriptan-naproxen: two randomized controlled trials.

OBJECTIVE: To evaluate the efficacy and tolerability of sumatriptan-naproxen during the mild pain phase of a single menstrual migraine attack associated with dysmenorrhea. METHODS: Two replicate randomized, multicenter, double-blind, placebo-controlled, trials of adults with menstrual migraine and dysmenorrhea were conducted. Participants treated their menstrual migraine attack during the mild pain phase (within 1 hour of onset) with sumatriptan 85 mg and naproxen sodium 500 mg in a single fixed-dose formulation (sumatriptan-naproxen) or placebo. The primary endpoint was 2-hour pain-free response. RESULTS: Sumatriptan-naproxen was statistically superior to placebo in both studies (n=311, Study 1; n=310, Study 2) for 2-hour and, 2- to 24-hour sustained pain-free response, use of headache and menstrual rescue medications, and several nonpain menstrual symptom categories. Two-hour pain-free rates were Study 1, 42% compared with 23%, and Study 2, 52% compared with 22%, P<.001. Two- to 24-hour sustained pain-free rates were Study 1, 29% compared with 18%, P=.022; Study 2, 38% compared with 10%, P<.001. Headache and menstrual medication rates were Study 1, 37% compared with 53%, P=.005; Study 2, 31% compared with 69%, P<.001. Women treated with sumatriptan-naproxen continued to be pain free through 48 hours compared with placebo: Study 1, 26% compared with 17%, P=.040; Study 2, 28% compared with 8%, P<.001. No serious adverse events were reported in either study; nausea and dizziness were the most frequently reported adverse events. CONCLUSION: Sumatriptan-naproxen provided an effective pain-free response at 2 hours, which was maintained up to 48 hours in menstrual migraineurs with dysmenorrhea. Sumatriptan-naproxen was well-tolerated and resulted in decreased rescue medication use and relief of nonpainful menstrual symptoms. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00329459 and NCT00329355 LEVEL OF EVIDENCE: I.

Migraine during pregnancy: options for therapy.

Migraine is common during pregnancy, but fortunately this combination of conditions obviously exists for only a finite period. The greatest frequency of migraine attacks occurs during the first trimester. Accurate diagnosis is a sine qua non in this setting as in any headache patient. It is in the first trimester that the fetus is at greatest risk from abortifacient and teratogenic drugs, and when very early pregnancy may be undiagnosed. Ergot alkaloids (including methysergide) should be avoided during pregnancy because of their teratogenicity, and most other drug classes should be used only when unavoidable. The use of prophylactic agents during pregnancy should be the exception, not the rule, and preferably only during the second and third trimesters; propranolol is probably safest in this situation. De novo headache during pregnancy usually requires expert review of the patient. Treatment tactics for uncomplicated migraine in pregnancy depend on the concurrent clinical situation. Paracetamol (acetaminophen) is the mainstay for the patient whose typical attacks continue into the first trimester. If paracetamol is insufficient, then partial agonist opioids may be used if typical migraine attacks persist in the second and third trimesters (which is uncommon). 'Chronic migraine' in pregnancy, i.e. >or=15 headache days per month, is rare, and is the greatest therapeutic challenge. Co-morbidities such as depression or epilepsy require specialised approaches. The complexities associated with these tactics are discussed in this article, and it is emphasised that none has the specific approval of regulatory authorities. Heightened pharmacovigilance will better inform the future pregnant migraineur. However, this type of information is less likely to be available for novel classes of neuropharmacological agents than for existing ones.

Advances in migraine treatment.

Migraine is a common, incapacitating disorder that is underdiagnosed in clinical practice. Early and correct diagnosis of migraine is essential and can lead to significant improvements in a patient's quality of life. In the clinical practice setting, a screening tool can be used that can help differentiate migraine from other headache disorders. New research into the development of central sensitization and cutaneous allodynia in chronic migraine sufferers has led to an early treatment approach with triptans and other agents for acute migraine episodes. This approach results in greater 2-hour headache pain-free results. The use of botulinum toxin type A in the prophylaxis of migraine and mixed-headache types offers an alternative treatment in patients who may not have responded to other currently available migraine prophylactic agents.

The role of concomitant headache types and non-headache co-morbidities in the underdiagnosis of migraine.

That migraine is significantly underdiagnosed in the United States and other countries is well established. New data from a follow-up survey to the American Migraine Study II reveal that the presence of concomitant headache types and co-morbid conditions significantly affects the ability to detect and diagnose migraine. This article describes these data and explores the contribution of concomitant headache types and co-morbidities to the problem of underdiagnosis of migraine. Migraine continues to be underdiagnosed because of failure to recognize it (missed diagnosis) and because of misdiagnosis of migraine as another headache type. First, a diagnosis of migraine may be missed in the presence of other headache types that occur proportionally more frequently than migraine and thereby overshadow migraine. Second, migraine may be misdiagnosed when health-care providers inappropriately interpret specific symptoms and co-morbid conditions as indicators of the presence of a non-migraine headache type such as sinus or tension. By becoming aware of these diagnostic pitfalls and being more judicious and deliberate in diagnosing migraine and other headache types, health-care providers can improve the diagnosis of migraine and help patients to receive appropriate therapy.

Characteristics of migraine attacks and responses to almotriptan treatment: a comparison of menstrually related and nonmenstrually related migraines.

OBJECTIVES: To compare the clinical characteristics of menstrually related migraines (MRMs) and nonmenstrually related migraines (nonMRMs) and to investigate the efficacy of almotriptan in the treatment of these migraine subtypes. DESIGN/METHODS: These are post hoc analyses of data from the AXERT Early miGraine Intervention Study (AEGIS), a multicenter, double-blind, parallel-group trial that evaluated adults with IHS-defined migraine with and without aura. Patients were randomized 1:1 to treat 3 consecutive headaches with almotriptan 12.5 mg or matching placebo at the first sign of headache typical of their usual migraine, at any level of pain intensity but within 1 hour of onset. MRMs were defined as those occurring +/-2 days of the first day of menstrual flow. Post hoc analyses to describe headache characteristics pooled all migraine attacks experienced by patients who reported > or = 1 menses during the study regardless of assigned treatment group. The post hoc efficacy analyses included outcomes of almotriptan treatment compared with placebo treatment for all migraines in patients with a menstrual record. RESULTS: Of the 275 women in the AEGIS intent-to-treat population, 190 (69.1%; 97 almotriptan, 93 placebo; aged 18-54 years) reported > or = 1 menses during the trial. Of the 506 migraines reported by these patients, 95 (18.8%) occurred +/-2 days of the first day of menstrual flow and were defined as MRM. Aura was associated with 11.7% of MRM and 15.0% of nonMRM. Allodynia-associated symptoms were present with 62.8% of MRM and 57.0% of nonMRM. Prior to treatment, 19.1% of MRM were associated with normal functional ability, 68.1% with disturbed functional ability, and 12.8% required bed rest compared with 18.9%, 68.8%, and 12.3%, respectively, of nonMRM. Pretreatment pain intensity was mild in 40.0%, moderate in 47.4%, and severe in 12.6% of MRM compared with 43.6%, 47.2%, and 9.2%, respectively, of nonMRM. Almotriptan treatment efficacy outcomes for MRM vs nonMRM, respectively, were: 2-hour pain relief, 77.4% vs 68.3%; 2-hour pain free, 35.4% vs 35.9%; and sustained pain free, 22.9% vs 23.8%. Almotriptan was similarly effective in relieving migraine-associated symptoms and improving functional disability associated with both MRM and nonMRM. CONCLUSIONS: Prior to treatment, the presence of migraine-associated characteristics including aura, allodynia-associated symptoms, photophobia, phonophobia, and nausea were similar for both MRM and nonMRM attacks. The pretreatment levels of pain intensity and functional disability were likewise similar across the migraine subtypes. Almotriptan was equally effective in the treatment of both MRM and nonMRM attacks and was associated with an adverse event profile that was similar to placebo treatment.

Effect of pain intensity and time to administration on responsiveness to almotriptan: results from AXERT 12.5 mg Time Versus Intensity Migraine Study (AIMS).

OBJECTIVE: To determine whether time-based early treatment, independent of pain intensity, is superior to a pain intensity-based treatment, where patients are asked to treat at least moderate intensity headaches, resulting in a reduction of overall migraine headache duration. BACKGROUND: Retrospective and prospective trials have reported improved outcomes when triptans were used early or to treat mild migraine headache pain. However, tolerability as well as efficacy may be 2 of several key issues that have prevented this new treatment paradigm from becoming universally accepted. METHODS: In this multicenter, open-label, cluster-randomized study, patients with IHS-defined migraine were instructed to treat 2 sequential migraine headaches with almotriptan 12.5 mg using either Early Treatment (ET, ie, treat at earliest onset of headache pain, within 1 hour) or Standard Treatment (ST, ie, treat when headache pain intensity is moderate or severe). The novel trial design uses total migraine headache pain duration as the primary endpoint. RESULTS: Results are presented for the first headache and include an ITT population of 757 ET and 693 ST patients. Median headache duration (time from onset of headache pain until no pain) was significantly shorter in ET patients compared to ST patients (3.18 vs 5.53 hours, P < .001). An analysis of the ET subgroup treating headache pain within 1 hour of onset revealed pain intensity, ie, treating mild or moderate versus severe pain, was significantly correlated with treatment outcomes defined by total headache duration, 2-hour pain free, sustained pain free, and use of rescue medication. Multivariate analyses comparing ST subgroups that treated within 1 hour versus greater than 1 hour after headache onset, demonstrate that both pain intensity, ie, treating moderate versus severe headache pain, and treating early versus late, were significantly correlated with total headache duration, 2-hour pain free, sustained pain free, and use of rescue medication. The overall incidence of adverse events was low; nausea and dizziness were the only adverse events with an incidence > or =1% in either treatment group (nausea: 2.5% and 1.7% and dizziness 1.1% and 0.7%, in the ET and ST groups, respectively). CONCLUSION: Total headache duration was significantly shorter in the early treatment group compared to the standard treatment group. Considering time to treatment within a relatively early range of 1 hour or less, efficacy results when treating mild versus moderate pain were similar and both were associated with better outcomes than treatment of severe pain. When considering the prognostic variables of time to treatment and headache pain intensity (limited to moderate vs severe), both were independent predictors, with time to treatment a better predictor of headache duration and rescue medication use, and pain intensity a better predictor of 2-hour pain free and sustained pain free.

Optimizing migraine therapy: evidence-based and patient-centered care.

Migraine is a chronic, intermittently debilitating neurovascular condition that affects the physical, mental and social aspects of health-related quality of life. Primary care provider interactions with migraine sufferers are common, highlighting the need for clinicians to provide optimal therapy. A comprehensive therapy plan should encompass the whole patient, via a patient-physician partnership where goals and strategies are mutually established. Key treatments include nondrug approaches, such as education and lifestyle modifications, to reduce the occurrence of attacks, as well as acute medications to address the immediate need for relief during an attack. Routine assessment and adjustment of therapy based on data recorded by patient diaries is paramount. Clinical trials support the use of triptans and dihydroergotamine for moderate-to-severe migraine and nonsteroidal anti-inflammatory drugs (alone or in combination with antiemetics or caffeine) for mild-to-moderate migraine, as the treatments of choice to reduce pain and disability time in a cost-effective manner. Published evidence also endorses stratified care, where medication selection is geared towards disease severity, instead of step care, where nonspecific mediations are given to all patients. Thus, patients with significant migraine-induced debilitation, as assessed by tools, such as the Migraine Disability Assessment Scale or the Headache Impact Test, are prescribed migraine-specific agents from the onset of therapy, thereby avoiding the inherent failures of step care. For individuals experiencing a high frequency of attacks or routine debilitation, preventive medications are warranted.

Migraine therapy: a survey of pharmacists' knowledge, attitudes, and practice patterns.

OBJECTIVE: Study pharmacists' knowledge, attitudes, and practice patterns with regard to migraine therapy. BACKGROUND: Pharmacists interact with headache sufferers at least 53,000 times daily, thus are well positioned to improve the less than optimal medication management of these disorders. Methods.-Two hundred self-administered surveys, distributed at a migraine symposium, assessing pharmacists' demographic characteristics and level of agreement or disagreement with treatment approaches were conducted. RESULTS: A total of 171 useable surveys (86%) were received. Of the sample, 35% were community pharmacists, 29% were hospital pharmacists, and the remainder were from other work environments. Exclusively among community pharmacists, 80% feel that headache is an important part of their practice, 85% make between one and five over-the-counter (OTC) headache product suggestions per day, and 12% make six or more daily OTC recommendations. Among all the sample's pharmacists, more than half feel migraine patients should try OTC drugs prior to prescription medications, only half ask patients about headache-related morbidity, and one-third feel migraine-specific medications should be reserved only for patients who initially fail nonspecific drugs. Few pharmacists utilize published migraine treatment guidelines. Approximately two-thirds of pharmacists do not feel migraine is a neurobiological illness. The majority is comfortable with their ability to identify people needing a physician referral. CONCLUSIONS: Our results show pharmacists, particularly those in community pharmacies, interact with headache sufferers multiple times daily. Most pharmacists were neither familiar with nor practice migraine therapies endorsed by evidence-based guidelines. Further training of pharmacists is warranted.

Emergency Room Treatment of Migraine Headache.

Headache is the chief complaint in the emergency room in between 0.36% and 2.5% of patients. It is essential that the headache diagnosis be established to rule-out a potentially morbid disorder, as well as facilitate selection of appropriate interventions. Referral with follow-up care is essential to patients with frequent headaches in order to prevent repeat emergency room visits and possible narcotic dependency. Two stages define emergency room treatment of any form of headache--initial stabilization and treatment (which may be started in the emergency room). Despite the introduction of migraine-specific therapy in 1993, only a minority of migraine headache patients are prescribed this treatment.

Recognition and intervention in patients with migraine.

Migraine is a disabling headache that affects patients for a long time before they seek treatment. For many physicians, such patients are difficult to treat because they can require lengthy questioning to elicit critical information during exams. Careful history taking and physical examination can solve this problem and aid physicians in diagnosis and treatment of patients with migraine. No laboratory tests are available to establish a diagnosis, but tests can rule out other conditions that may cause headaches. Although imaging is not necessary to establish the diagnosis of migraine, MRI and CT may be used in selected situations.

Effectiveness of eletriptan in acute migraine: primary care for Excedrin nonresponders.

OBJECTIVE: To evaluate the effectiveness of eletriptan as a treatment for acute migraine in patients who were poor responders to Excedrin and had not yet been exposed to a triptan. BACKGROUND: Self-medication with over-the-counter drugs, such as Excedrin, is the most common treatment for migraine. Guidelines, however, recommend that triptans be used as first-line treatment of moderate to severe migraine--the severity affecting approximately 80% of migraineurs. Since over-the-counter medications, such as Excedrin, continue to be used in many patients, it is important that clinicians have information on the efficacy of triptans as first-line treatment and on treatment of migraineurs who have shown poor response to over-the-counter medications. METHODS: One hundred ten patients meeting criteria for migraine who were poor responders to Excedrin received open-label treatment with a 40-mg dose of eletriptan for one migraine attack. Efficacy assessments were made at 1, 2, 4, and 24 hours postdose and consisted of headache and pain-free response rates, absence of associated symptoms, and functional response. RESULTS: At 1 hour, the headache response rate was 44%; at 2 hours, 81%. The pain-free response rate at 1 hour was 14% and at 2 hours, 48%. At 2 hours, relief of baseline-associated symptoms ranged from 74% to 80%. Functional response was achieved by 82% of patients by 2 hours, and 68% of patients achieved relief of migraine that was sustained across 24 hours with no need for a second dose of eletriptan or for rescue medication. Eletriptan was well tolerated with adverse events being transient and mild to moderate in intensity. CONCLUSION: Previous studies have established the efficacy of eletriptan as a first-line treatment for migraine. The results of this open-label trial demonstrate that the 40-mg dose of eletriptan had a high degree of efficacy and tolerability among patients who were poor responders to Excedrin.

Evidence-based assessment of pregnancy outcome after sumatriptan exposure.

OBJECTIVE: Assessment of best available evidence for tolerability of sumatriptan after inadvertent exposure during pregnancy. BACKGROUND: Migraine's demography suggests that inadvertent exposure to acute therapies is likely during the earliest undiagnosed stages of pregnancy. The tolerability of such therapies under these conditions is not amenable to clinical trial for ethical reasons. In the United States, sumatriptan is currently labeled pregnancy category C (ie, not recommended for use during pregnancy unless the potential benefit justifies the potential risk to the fetus). METHODS: Three types of adverse events were studied: spontaneous abortion, fetal abnormality, and obstetric complications. Traditional evidence-based criteria were used to assess a search-protocol product of four clinical studies and two case reports. RESULTS: The single positive finding ("preterm delivery" without low birth weight) was in the smallest study; this study was retrospective and the finding was externally inconsistent with the other three larger studies, all of which were prospective. No study followed children for more than 4 years, which is the period needed to identify the maximum number of congenital anomalies. Rigorous teratological technique was generally not employed. Post hoc power calculations were used to provide parameters of the hazard detectable by these studies in aggregate. CONCLUSIONS: Pregnancy categories B and C both seem feasible for sumatriptan. Within the limits of the examined studies, there is no evidence for any specific effect of sumatriptan on pregnancy outcome. Patients inadvertently exposed to sumatriptan during an early stage of pregnancy should be reassured by these data.