Pregnancy outcomes in patients treated with leflunomide, the parent compound of the multiple sclerosis drug teriflunomide.

Leflunomide is contraindicated in pregnant women, yet human data from leflunomide-exposed pregnancies do not indicate an embryofetal toxicity signal. The objective of the present analysis was to report pregnancy outcomes for leflunomide-exposed pregnancies in clinical trials and in the post-marketing setting. Pregnancy outcomes are summarized from leflunomide clinical trials and the post-marketing setting. The data cut-off was 31 December 2017. Of 1167 pregnancies reported in female patients exposed to leflunomide, 587 had a known outcome. Of these, 337 (57.4%) were reported prospectively and 250 (42.6%) were reported retrospectively. Of the 587 pregnancies with a known outcome (which involved 15 sets of twins), there were 333 (56.7%) live births, with 285 (48.6%) full-term births and 48 (8.2%) pre-term births. Birth defects were reported in 44 babies/fetuses/embryos from 587 pregnancies, with 2 reporting at least 3 minor defects and 20 reporting major defects. Major defects were reported in 3 of 337 (0.9%) prospectively-reported pregnancies; 1 major birth defect occurred in a live birth, and 2 were electively terminated due to a detected fetal anomaly. Two of the babies/fetuses/embryos, a live birth and an electively aborted baby/fetus/embryo, from 206 prospectively-reported pregnancies exposed to leflunomide during the first trimester experienced major defects. Birth defects showed no specific patterns and were distributed evenly across organ systems. Outcomes were consistent with the general population. These findings do not suggest an embryofetal toxicity signal for leflunomide, which is consistent with previous findings from leflunomide-exposed pregnancies.

Automatic atrial threshold measurement and adjustment in pediatric patients.

BACKGROUND: Automatic threshold measurement and output adjustment are used as default settings in modern pacemakers. The purpose of the study was to assess Atrial Capture Management (ACM) of Medtronic pacemakers in pediatric patients. METHODS: Forty children were enrolled in two centers. Median age was 9.8 years (range 0.8-17.5 years). Half had undergone surgery for congenital heart defects; 45% of patients had an epicardial atrial lead. The pacing indication was atrioventricular block in 82% of patients and sinus node disease in 18%. Manually determined atrial thresholds and ACM measurements were compared. RESULTS: ACM measurements were within the expected variation in 37/40 (93%) of the patients. In one patient the threshold was 0.625-V lower manually than with ACM. One patient had too high an intrinsic atrial rate for ACM to be able to measure threshold. The mean threshold at 0.4 ms was 0.69 +/- 0.32 V manually and 0.68 +/- 0.35 V with ACM (two-tailed paired t-test, P = 0.52) in all patients. The mean difference was 0.012 V (95% confidence interval: -0.027, 0.053). The mean endocardial threshold was 0.70 +/- 0.36 V manually and 0.69 +/- 0.38 V with ACM; epicardial threshold was 0.67 +/- 0.27 V manually and 0.68 +/- 0.32 V with ACM. The difference between the measurements was 0.012 V for endocardial and 0.014 V for epicardial leads. No atrial arrhythmias due to ACM measurements were observed. CONCLUSIONS: ACM measures atrial thresholds reliably in pediatric patients with both endocardial and epicardial leads, allowing its use in both. Constant high intrinsic atrial rate may prevent automatic threshold measurement in young children.

Fluctuation of left ventricular thresholds and required safety margin for left ventricular pacing with cardiac resynchronization therapy.

AIMS: Fluctuations in left ventricular (LV) thresholds with cardiac resynchronization therapy (CRT) are unknown. The LV capture management (LVCM) algorithm automatically measures LV thresholds on a daily basis and offers the opportunity to analyse threshold fluctuations. METHODS AND RESULTS: A total of 282 patients implanted with a Medtronic Concerto CRT-D device were prospectively studied. Device data were collected at periodic visits, including daily thresholds from the preceding 14 days and weekly threshold ranges since implantation, acquired by the LVCM algorithm up to 12 months' follow-up. Overall, LV thresholds remained relatively stable, with 189/208 (91%) patients having a maximum increase in threshold of < or = 1.0 V at any time between their 1 and 6 month visits and 127/135 (94%) between the 6 and 12 month visits. However, increase in threshold was significantly affected by LV threshold amplitude. Of the 170 patients with a 1 month threshold of < or = 2.0 V, 159 (94%) had increases of <1.0 V up to their 6 month visit, whereas 8/38 (21%) patients with >2.0 V threshold had increases of >1.0 V (P = 0.01). There were no significant changes in LV threshold amplitude and fluctuation over the 12 month follow-up. CONCLUSION: For patients with low (< or = 2.0 V) LV thresholds, a safety margin of 1.0 V is sufficient to ensure LV capture if phrenic nerve stimulation is an issue, and may be even lower in devices with auto-adaptive capture management algorithms. However, the margin should be greater in patients with higher thresholds because of larger fluctuations. Left ventricular capture management may be particularly useful in these patients to ensure LV capture without sacrificing device longevity.

Automated left ventricular capture management.

BACKGROUND: The stimulation thresholds of left ventricular (LV) leads tend to be less reliable than conventional leads. Cardiac resynchronization therapy (CRT) requires continuous capture of both ventricles. OBJECTIVE: The purpose of this study is to evaluate a novel algorithm for the automatic measurement of the stimulation threshold of LV leads in cardiac resynchronization systems. METHODS: We enrolled 134 patients from 18 centers who had existing CRT-D systems. Software capable of automatically executing LV threshold measurements was downloaded into the random access memory (RAM) of the device. The threshold was measured by pacing in the left ventricle and analyzing the interventricular conduction sensed in the right ventricle. Automatic LV threshold measurements were collected and compared with manual LV threshold tests at each follow-up visit and using a Holter monitor system that recorded both the surface electrocardiograph (ECG) and continuous telemetry from the device. RESULTS: The proportion of Left Ventricular Capture Management (LVCM) in-office threshold tests within one programming step of the manual threshold test was 99.7% (306/307) with a two-sided 95% confidence interval of (98.2%, 100.0%). The algorithm measured the threshold successfully in 96% and 97% of patients after 1 and 3 months respectively. Holter monitor analysis in a subset of patients revealed accurate performance of the algorithm. CONCLUSION: This study demonstrated that the LVCM algorithm is safe, accurate, and highly reliable. LVCM worked with different types of leads and different lead locations. LVCM was demonstrated to be clinically equivalent to the manual LV threshold test. LVCM offers automatic measurement, output adaptation, and trends of the LV threshold and should result in improved ability to maintain LV capture without sacrificing device longevity.