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Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy. We did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors. Between June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to one of the eight antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10·3%) of 1381 pregnancies for valproate, 19 (6·5%) of 294 for phenobarbital, eight (6·4%) of 125 for phenytoin, 107 (5·5%) of 1957 for carbamazepine, six (3·9%) of 152 for topiramate, ten (3·0%) of 333 for oxcarbazepine, 74 (2·9%) of 2514 for lamotrigine, and 17 (2·8%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (p=0·0140), lamotrigine (p=0·0145), phenobarbital (p=0·0390), and valproate (p<0·0001). After adjustment, multivariable analysis showed that the prevalence of major congenital malformations was significantly higher for all doses of carbamazepine and valproate as well as for phenobarbital at doses of more than 80 mg/day than for lamotrigine at doses of 325 mg/day or less. Valproate at doses of 650 mg/day or less was also associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250–4000 mg/day (odds ratio [OR] 2·43, 95% CI 1·30–4·55; p=0·0069). Carbamazepine at doses of more than 700 mg/day was associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250–4000 mg/day (OR 2·41, 95% CI 1·33–4·38; p=0·0055) and oxcarbazepine at doses of 75–4500 mg/day (2·37, 1·17–4·80; p=0·0169). Different antiepileptic drugs and dosages have different teratogenic risks. Risks of major congenital malformation associated with lamotrigine, levetiracetam, and oxcarbazepine were within the range reported in the literature for offspring unexposed to antiepileptic drugs. These findings facilitate rational selection of these drugs, taking into account comparative risks associated with treatment alternatives. Data for topiramate and phenytoin should be interpreted cautiously because of the small number of exposures in this study. Bial, Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, the Netherlands Epilepsy Foundation, and Stockholm County Council.

Background Small pneumothoraxes (PTXs) may not impart an immediate threat to trauma patients after chest injuries. However, the amount of pleural air may increase and become a concern for patients who require positive pressure ventilation or air ambulance transport. Lung ultrasonography (US) is a reliable tool in finding intrapleural air, but the performance characteristics regarding the detection of small PTXs need to be defined. The study aimed to define the volume threshold of intrapleural air when PTXs are accurately diagnosed with US and compare this volume with that for chest x-ray (CXR). Methods Air was insufflated into a unilateral pleural catheter in seven incremental steps (10, 25, 50, 100, 200, 350 and 500 mL) in 20 intubated porcine models, followed by a diagnostic evaluation with US and a supine anteroposterior CXR. The sonographers continued the US scanning until the PTXs could be ruled in, based on the pathognomonic US “lung point” sign. The corresponding threshold volume was noted. A senior radiologist interpreted the CXR images. Results The mean threshold volume to confirm the diagnosis of PTX using US was 18 mL (standard deviation of 13 mL). Sixty-five percent of the PTXs were already diagnosed at 10 mL of intrapleural air; 25%, at 25 mL; and the last 10%, at 50 mL. At an air volume of 50 mL, the radiologist only identified four out of 20 PTXs in the CXR pictures; i.e., a sensitivity of 20% (95% CI: 7%, 44%). The sensitivity of CXR increased as a function of volume but leveled off at 67%, leaving one-third (1/3) of the PTXs unidentified after 500 mL of insufflated air. Conclusion Lung US is very accurate in diagnosing even small amounts of intrapleural air and should be performed by clinicians treating chest trauma patients when PTX is among the differential diagnoses.

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