Subfertility versus ART: unraveling the origins of fetal cardiac programming.

STUDY QUESTION: Do spontaneously conceived (SC) fetuses from subfertile couples show the same signs of cardiac remodeling as those observed after IVF treatments? SUMMARY ANSWER: As opposed to fetuses from IVF, SC fetuses from subfertile couples do not show cardiac remodeling and present a similar cardiac structure and function to those of SC fetuses from fertile couples. WHAT IS KNOWN ALREADY: Subjects conceived by IVF present signs of cardiac remodeling and suboptimal function in utero and during childhood, including larger atria, more globular and thicker ventricles, reduced longitudinal motion, and impaired relaxation as compared to SC individuals from fertile couples. There are no previous publications investigating the independent cardiac programming effects of infertility in SC fetuses from subfertile couples (with time-to-pregnancy (TTP) over 12 months). STUDY DESIGN, SIZE, DURATION: A prospective cohort study of 289 singleton pregnancies exposed and not exposed to subfertility recruited from 2019 to 2021, including 96 SC pregnancies from fertile couples (TTP under 12 months), 97 SC from subfertile couples (TTP over 12 months), and 96 from IVF after fresh embryo transfer. Fetal echocardiography was performed in all pregnancies. Epidemiological data and perinatal outcomes were collected in all pregnancies. The overall attrition rate was 15.7%. PARTICIPANTS/MATERIALS, SETTING, METHODS: SC from subfertile couples and IVF pregnancies were identified as eligible at pregnancy diagnosis, and eligible SC pregnancies from fertile couples who attended our maternal-fetal unit were invited to participate at third trimester, being matched to the other groups by maternal age. Fetal echocardiography was performed at 29-34 weeks of pregnancy to assess cardiac structure and function, and results were adjusted by parental age, maternal smoking status, child's birth order, birthweight centile, gestational age, and estimated fetal weight at scan. MAIN RESULTS AND THE ROLE OF CHANCE: Parental age, ethnicity, BMI, and smoking exposure, median gestational age and estimated fetal weight were similar in all study groups. There were no significant differences in infertility duration or etiology between the subfertile and the IVF populations (TTP: subfertile median 35 months (interquartile range 20-48) versus IVF: 47 (25-61); P-value = 0.051). While both fertile and subfertile SC groups presented similar fetal cardiac results, IVF fetuses showed larger atria (right atria-to-heart ratio: IVF mean 18.9% (SD 3.4) versus subfertile 17.8% (3.5) versus fertile 17.6% (3.3); adjusted P-value < 0.001), more globular ventricles (right ventricular sphericity index: IVF 1.56 (0.25) versus subfertile 1.72 (0.26) versus fertile 1.72 (0.26); <0.001), and thicker myocardial walls (relative wall thickness: IVF 0.86 (0.22) versus subfertile 0.64 (0.13) versus fertile 0.64 (0.18); <0.001). Whereas SC fetuses from fertile and subfertile couples had preserved cardiac function, IVF fetuses showed signs of suboptimal systolic and diastolic function, with reduced tricuspid ring displacement (IVF 7.26 mm (1.07) versus subfertile 8.04 mm (1.18) versus fertile 7.89 mm (1.51); <0.001) and increased left myocardial performance index (IVF 0.49 (0.08) versus subfertile 0.45 (0.09) versus fertile 0.45 (0.10); <0.001). A sub-analysis including only unexplained infertility cases in subfertile SC and IVF groups showed similar results. LIMITATIONS, REASONS FOR CAUTION: The fetal cardiac changes reported here are subclinical, and most of the cardiovascular parameters were within normal ranges. Although echocardiographic changes are recognized as potential cardiovascular risk factors, their association with long-term cardiovascular disease remains to be demonstrated. WIDER IMPLICATIONS OF THE FINDINGS: Subfertility per se does not seem to be associated to fetal cardiac remodeling, which has been previously described in IVF fetuses. Future studies are warranted to further investigate other factors related to the observed fetal cardiac changes associated with ART. STUDY FUNDING/COMPETING INTEREST(S): This project has been partially funded with support from the Erasmus + Programme of the European Union (Framework Agreement number: 2013-0040). This publication reflects the views only of the author, and the Commission cannot be held responsible for any use, which may be made of the information contained therein. Additionally, the research leading to these results has received funding from 'la Caixa' Foundation under grant agreement LCF/PR/GN18/10310003, the Instituto de Salud Carlos III (PI15/00130, PI16/00861, PI17/00675, PI18/00073, INT21/00027)-co-funded by the European Union, Cerebra Foundation for the Brain Injured Child (Carmarthen, Wales, UK) and AGAUR 2017 SGR grant no 1531. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Fetal neurosonography and infant neurobehavior following conception by assisted reproductive technology with fresh or frozen embryo transfer.

OBJECTIVE: We aimed to explore fetal cortical brain development by neurosonography in fetuses conceived by assisted reproductive technology (ART), including frozen and fresh embryo transfer (ET), compared with those conceived spontaneously (SC), and to investigate its association with infant neurobehavior at 12 months of age. METHODS: This was a prospective cohort study of 210 singleton pregnancies, including 70 SC pregnancies, 70 conceived by in-vitro fertilization (IVF) following frozen ET and 70 conceived by IVF after fresh ET. Fetal neurosonography was performed at 32 ± 2 gestational weeks to assess cortical development. Sulci depths were measured offline and normalized by biparietal diameter (BPD). Ages and Stages Questionnaires (ASQ) were completed postnatally, at 12 ± 1 months of corrected age. Neurosonographic findings were adjusted by regression analysis for maternal age, ethnicity, parity, fetal sex and fetal-weight centile and gestational age at scan, and ASQ scores were adjusted for maternal age, ethnicity, parity, educational level and employment status, gestational age at birth, breastfeeding, infant sex and infant age at the ASQ evaluation. RESULTS: Overall, in comparison to the SC fetuses, fetuses conceived by ART showed statistically significant differences in cortical development, with reduced parieto-occipital sulci depth adjusted for BPD (mean ± SD: fresh ET, 12.5 ± 2.5 vs frozen ET, 13.4 ± 2.6 vs SC, 13.4 ± 2.6, P < 0.001), cingulate sulci depth adjusted for BPD (median (interquartile range (IQR)): fresh ET, 5.8 (4.2-7.4) vs frozen ET, 5.8 (4.1-7.5) vs SC, 6.5 (4.8-7.8), P = 0.001) and calcarine sulci depth adjusted for BPD (median (IQR): fresh ET, 13.5 (10.1-16.1) vs frozen ET, 14.5 (12.1-15.8) vs SC, 16.4 (14.3-17.9), P < 0.001), together with lower Sylvian fissure grading score. Changes in cortical development were more pronounced in the fresh ET than in the frozen ET group. ART infants showed lower ASQ scores as compared to SC infants, particularly in the fresh ET group (mean ± SD global ASQ Z-score: fresh ET, -0.3 ± 0.4 vs frozen ET, -0.2 ± 0.4 vs SC, 0 ± 0.4, P < 0.001). CONCLUSIONS: Fetuses conceived by ART show a distinctive pattern of cortical development and suboptimal infant neurodevelopment, with more pronounced changes in those conceived following fresh ET. These findings support the existence of in-utero brain reorganization associated with ART and warrant follow-up studies to assess its long-term persistence. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Cardiac remodeling in fetuses conceived by ARTs: fresh versus frozen embryo transfer.

STUDY QUESTION: Do fetuses from frozen embryo transfer (FET) present signs of cardiac remodeling and suboptimal function similar to those observed in fetuses from fresh embryo transfer (ET)? SUMMARY ANSWER: Fetuses from both fresh ET and FET present signs of fetal cardiac remodeling and suboptimal function, with more pronounced changes after fresh ET as compared to FET. WHAT IS KNOWN ALREADY: Our group and others have previously demonstrated that fetuses and children conceived by ARTs present cardiac remodeling and suboptimal function. These fetuses show dilated atria, more globular and thicker ventricles, reduced longitudinal motion, and impaired relaxation. Cardiac changes were already present in utero and persisted after birth. Most of the ART fetuses included in previous publications were from fresh ET. However, singletons from FET have different perinatal outcomes compared to those from fresh ET. There are no previous studies comparing cardiac morphology and function between fetuses following fresh and FET. STUDY DESIGN, SIZE, DURATION: This is a prospective cohort study of 300 singleton pregnancies recruited from 2017 to 2020, including 100 spontaneously conceived (SC) pregnancies, 100 fetuses conceived by IVF with FET, and 100 fetuses conceived by IVF with fresh ET. Fetal structural and functional echocardiography was performed in all pregnancies. PARTICIPANTS/MATERIALS, SETTING, METHODS: Pregnancies conceived by IVF were recruited from a single assisted reproduction center, ensuring homogeneity in IVF stimulation protocols, endometrial preparation for FET, laboratory procedures, and embryo culture conditions. SC pregnancies from fertile couples were selected from the general population and matched to IVF pregnancies by maternal age. Epidemiological and perinatal outcomes were collected in all cases. Fetal echocardiography was performed at 28-33 weeks of pregnancy to assess cardiac structure and function in all pregnancies. All echocardiographic comparisons were adjusted by maternal age, nulliparity, birthweight centile, preeclampsia, and prematurity. MAIN RESULTS AND THE ROLE OF CHANCE: Parental age, ethnicity, body mass index and smoking were similar among the study groups. Median gestational age at echocardiography and estimated fetal weight were similar in all study groups. Both fresh ET and FET groups showed similar fetal echocardiographic changes, with more pronounced features in the fresh ET as compared to FET pregnancies. Fetuses conceived by IVF showed larger atria (right atria-to-heart ratio: fresh ET mean 18.1% (SD 3.2) vs FET 18.0% (3.9) vs SC 17.3% (3.2); linear tendency P-value <0.001), more globular ventricles (right ventricular sphericity index: fresh ET 1.62 (0.29) vs FET 1.61 (0.25) vs SC 1.68 (0.26); <0.001) and thicker myocardial walls (relative wall thickness: fresh ET 0.79 (0.21) vs FET 0.74 (0.22) vs SC 0.65 (0.25); <0.001) as compared to SC pregnancies. Both fresh ET and FET groups also had signs of suboptimal systolic and diastolic function, with reduced tricuspid annular systolic peak velocity (fresh ET 7.17 cm/s (1.22) vs FET 7.41 cm/s (1.19) vs SC 7.58 cm/s (1.32); <0.001) and increased left myocardial performance index (fresh ET 0.53 (0.08) vs FET 0.53 (0.08) vs SC 0.50 (0.09); <0.001) as compared to SC pregnancies. LIMITATIONS, REASONS FOR CAUTION: The cardiac changes reported here are subclinical, with most cardiovascular indexes lying within normal ranges. Although echocardiographic changes are recognized as potential cardiovascular risk factors, their association with the long-term cardiovascular disease remains to be proven. The observed milder fetal cardiac features in FET fetuses cannot condition the choice of this technique and must be considered together with the global perinatal results related to these gestations. WIDER IMPLICATIONS OF THE FINDINGS: The identification of cardiac remodeling in fetuses conceived by IVF with fresh ET and FET represents an opportunity for early detection. Future studies are warranted to study the potential long-term consequences of these findings. STUDY FUNDING/COMPETING INTEREST(S): This project has been partially funded with support from the Erasmus + Programme of the European Union (Framework Agreement number: 2013-0040). This publication reflects the views only of the author, and the Commission cannot be held responsible for any use, which may be made of the information contained therein. Additionally, the research leading to these results has received funding from 'la Caixa' Foundation under grant agreement LCF/PR/GN18/10310003, the Instituto de Salud Carlos III (PI15/00130, PI17/00675, PI18/00073) integrated into the Plan Nacional de I + D+I and cofinanced by ISCIII-Subdirección General de Evaluación and Fondo Europeo de Desarrollo Regional (FEDER) 'Una manera de hacer Europa', Cerebra Foundation for the Brain Injured Child (Carmarthen, Wales, UK) and AGAUR 2017 SGR grant n° 1531. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Postnatal persistence of fetal cardiovascular remodelling associated with assisted reproductive technologies: a cohort study.

OBJECTIVE: To assess the postnatal persistence of fetal cardiovascular remodelling associated with assisted reproductive technologies (ART) in children at 3 years of age. DESIGN: A cohort study of children conceived by ART. SETTING: Maternal-Fetal Medicine Unit, Hospital Clinic Barcelona, Spain. POPULATION SAMPLE: Eighty singleton pregnancies conceived by ART and 80 spontaneously conceived (controls) followed from fetal life up to childhood. METHODS: Cardiovascular evaluation was performed at 3 years of corrected age, including echocardiography, carotid intima-media (cIMT) by ultrasound, and blood pressure. MAIN OUTCOME MEASURES: Postnatal persistence of cardiovascular changes in children conceived by ART. RESULTS: Compared with controls, children conceived by ART showed larger atria (right atrial area: control 4.9 cm2 (0.9) versus ART 5.5 cm2 (0.9), P < 0.001), more globular ventricles (right ventricular sphericity index: control mean 1.8 (SD 0.5) versus ART 1.6 (0.2), P < 0.001), and signs of systolic (tricuspid annular plane systolic excursion: control 18 mm (2) versus ART 16 mm (3), P < 0.001) and diastolic dysfunction (isovolumic relaxation time: control 68 ms (12) versus ART 79 ms (12), P < 0.001). ART children also presented increased systolic blood pressure (control 90 mmHg (6) versus ART 94 mmHg (5), P < 0.003) and cIMT (control 0.52 µm (0.14) versus ART 0.60 µm (0.16), P < 0.001) as compared with those spontaneously conceived. CONCLUSIONS: Cardiovascular changes previously reported in ART fetuses persist postnatally at 3 years of age. These results underscore the importance of future studies for assessing the long-term cardiovascular health associated with ART. TWEETABLE ABSTRACT: Cardiovascular changes described in fetuses conceived by ART, persist in children at 3 years of age.

Early in vitro development of daptomycin non-susceptibility in high-level aminoglycoside-resistant Enterococcus faecalis predicts the efficacy of the combination of high-dose daptomycin plus ampicillin in an in vivo model of experimental endocarditis.

Background: Previous studies showed development of daptomycin non-susceptibility (DNS: MIC >4 mg/L) in Enterococcus faecalis infections. However, no studies have assessed the efficacy of the combination of daptomycin/ampicillin against E. faecalis strains developing DNS in the experimental endocarditis (EE) model. Objectives: To assess the in vitro and in vivo efficacy of daptomycin at 10 mg/kg/day, daptomycin/ampicillin and ampicillin/ceftriaxone against two high-level aminoglycoside-resistant E. faecalis strains, one developing DNS after in vitro exposure to daptomycin and another that did not (DS). Methods: Subculture of 82 E. faecalis strains from patients with endocarditis with daptomycin MICs, time-kill and in vivo experiments using the EE model. Results: 33% of the strains (27 of 82) displayed DNS after subculture with daptomycin. Daptomycin MIC rose from 0.5-2 to 8-16 mg/L. In time-kill experiments, when using a high inoculum (10 8 cfu/mL), daptomycin/ampicillin was synergistic for one-third of DS strains and none of DNS strains, while ampicillin/ceftriaxone retained synergy in all cases. In the EE model, daptomycin did not significantly reduce cfu/g from vegetations compared with control against either strain, while daptomycin/ampicillin reduced significantly more cfu/g than daptomycin against the DS strain, but not against the DNS strain [2.9 (2.0-4.1) versus 6.1 (4.5-8.0); P = 0.002]. Ampicillin/ceftriaxone was synergistic and bactericidal against both strains, displaying the same activity as daptomycin/ampicillin against the DS strain. Conclusions: Performance of an Etest for daptomycin MIC after subculture with daptomycin inhibitory doses on strains of high-level aminoglycoside-resistant E. faecalis endocarditis may be an easy test to predict the in vivo efficacy of daptomycin/ampicillin.

Early non-invasive selection of patients at high risk of severe hepatitis C recurrence after liver transplantation.

BACKGROUND: The early identification of patients at high risk of severe post liver transplant hepatitis C recurrence is relevant, as these patients may be treated using interferon (IFN)-free regimens. METHODS: In a retrospective study with prospectively collected data, we investigated whether the use of several non-invasive methods (fibrosis 4 index [FIB-4], AST-to-platelets ratio index [APRI], enhanced liver fibrosis test [ELF], IFN-γ-inducible protein 10 [IP-10], and transient elastography by Fibroscan) and their combinations 6 months after transplantation could identify those recipients at higher risk of severe recurrence, defined by the presence of significant fibrosis (F ≥2) and/or portal hypertension (hepatic venous pressure gradient ≥6 mmHg) 12 months after transplant. Seventy-two hepatitis C virus (HCV)-infected liver transplant patients and 10 recipients in whom HCV was eradicated before transplantation were included in the study. RESULTS: The levels of all biomarkers were significantly higher in HCV-infected recipients than in controls. Among HCV recipients, levels of biomarkers were significantly higher in patients with severe recurrence. Although there were no statistically significant differences between biomarkers, APRI, ELF, and FIB-4 obtained the highest area under the ROC curve values. The combination of serum biomarkers with Fibroscan increased the negative and positive predictive values, although diagnostic accuracy of individual tests was not significantly improved. CONCLUSIONS: Patients at higher risk of severe HCV recurrence can be identified early, 6 months after transplantation, using readily available non-invasive methods.

Accuracy of immunoassay and mass spectrometry urinary free cortisol in the diagnosis of Cushing's syndrome.

PURPOSE: Urinary free cortisol (UFC) determination by highly specific methods as mass spectrometry instead of commercially available antibody-based immunoassays is increasingly recommended. However, clinical comparisons of both analytical approaches in the screening of Cushing's syndrome (CS) are not available. The aim of this study was to evaluate the diagnostic value of mass spectrometry versus immunoassay measurements of 24 h-UFC in the screening of CS. METHODS: Cross-sectional study of 33 histologically confirmed CS patients: 25 Cushing's disease, 5 adrenal CS and 3 ectopic CS; 92 non-CS patients; and 35 healthy controls. UFC by immunoassay (UFCxIA) and mass spectrometry (UFCxMS), urinary free cortisone (UFCo) and UFC:UFCo ratio were measured, together with creatinine-corrected values. Sensitivity, specificity, AUC and Landis and Koch concordance index were determined. RESULTS: AUC for UFCxIA and UFCxMS were 0.77 (CI 0.68-0.87) and 0.77 (CI 0.67-0.87) respectively, with a kappa coefficient 0.60 and strong Landis and Koch concordance index. The best calculated cutoff values were 359 nmol/24 h for UFCxIA (78 % sensitivity, 62 % specificity) and 258.1 nmol/24 h for UCFxMS (53 % sensitivity, 86 % specificity). The upper limit of UFCxIA and UCFxMS reference ranges were 344.7 and 169.5 nmol/24 h respectively. Sensitivity and specificity for CS diagnosis at these cutpoints were 84 and 56 % for UFCxIA and 81 and 54 % for UFCxMS. CONCLUSIONS: According to our data, both methods present a very similar diagnostic value. However, results suggest that lower cutoff points for mass spectrometry may be necessary in order to improve clinical sensitivity.

Long-term remission and recurrence rate in a cohort of Cushing's disease: the need for long-term follow-up.

OBJECTIVE: Transsphenoidal surgery is the procedure of choice in Cushing disease (CD), with immediate post-operative remission rates ranging between 59 and 94% and recurrence rates between 3 and 46%, both depending upon the definition criteria and the duration of the follow-up. Our aim was to assess the rate of remission, recurrence and persistence of the disease after the first treatment and to identify predictors of remission in the CD population of our center. METHODS: Retrospective cohort study of the patients diagnosed of CD and with follow-up in our center between 1974 and 2011. We analyzed 41 patients (35 women and 6 men) with a mean age at diagnosis of 34 ± 13 years. The mean follow-up was 14 ± 10 years (range 1-37 years) and the median of follow-up period was 6.68 years. RESULTS: Thirty-five (85.4%) patients underwent transsphenoidal surgery as first treatment option. Histopathological evidence of a pituitary adenoma was registered in 17 (48.5%) patients. Thirty-two (78%) patients achieved disease remission after the first treatment, 21 (65.6%) of them presented disease recurrence. Persistent disease was observed in 9 (22%) patients. Twelve (29.3%) subjects developed post-surgical adrenal insufficiency, 7 of which (70%) achieved stable remission. Two parameters were found to be significant predictors of remission after the first treatment: age at disease diagnosis and the development of adrenal insufficiency (cortisol <3 µg/dl) in the immediate post-operative state. CONCLUSIONS: We report a high recurrence rate, at least partially attributable to the long follow-up time. Early post-surgery adrenal insufficiency predicts remission. Hypopituitarism was also very prevalent, and strongly associated with radiotherapy. These results lead us to the conclusion that CD needs a life-long strict follow-up.

Adenoviral dominant-negative soluble PDGFRß improves hepatic collagen, systemic hemodynamics, and portal pressure in fibrotic rats.

BACKGROUND & AIMS: Platelet-derived growth factor (PDGF) is the most potent stimulus for proliferation and migration of stellate cells. PDGF receptor ß (PDGFRß) expression is an important phenotypic change in myofibroblastic cells that mediates proliferation and chemotaxis. Here we analyzed the relationship between PDGFRß expression, hemodynamic deterioration, and fibrosis in CCl(4)-treated rats. Thereafter, we investigated the effects produced by an adenovirus encoding a dominant-negative soluble PDGFRß (sPDGFRß) on hemodynamic parameters, PDGFRß signaling pathway, and fibrosis. METHODS: Mean arterial pressure, portal pressure, PDGFRß mRNA expression, and hepatic collagen were assessed in 6 controls and 21 rats induced to hepatic fibrosis/cirrhosis. Next, 30 fibrotic rats were randomized into three groups receiving iv saline and an adenovirus encoding for sPDGFRß or ß-galactosidase. After 7days, mean arterial pressure, portal pressure, serum sPDGFRß, and hepatic collagen were measured. RESULTS: CCl(4)-treated animals for 18weeks showed a significantly higher increase in PDGFRß mRNA compared to those treated for 13weeks and control rats. In CCl(4)-treated rats, the fibrous tissue area ranged from moderate to severe fibrosis. A direct relationship between the degree of fibrosis, hemodynamic changes, and PDGFRß expression was observed. Fibrotic rats transduced with the adenovirus encoding sPDGFRß showed increased mean arterial pressure, decreased portal pressure, lower activation of the PDGFRß signaling pathway, and reduced hepatic collagen than fibrotic rats receiving ß-galactosidase or saline. CONCLUSIONS: PDGFRß activation closely correlates with hemodynamic disorders and increased fibrosis in CCl(4)-treated rats. Adenoviral dominant negative soluble PDGFRß improved fibrosis. As a result, the hemodynamic abnormalities were ameliorated.

Inactivation of extrahepatic vascular Akt improves systemic hemodynamics and sodium excretion in cirrhotic rats.

BACKGROUND & AIMS: Increased activity of the vascular Akt/eNOS signaling pathway is involved in the hemodynamic and renal complications developed by patients and rats with cirrhosis and ascites. This occurs in the setting of impaired Akt/eNOS activity within the cirrhotic liver. Here we assessed the feasibility of selectively inhibiting vascular eNOS without further impairing the intrahepatic activity of this enzyme. Ultimately, we sought to determine whether endothelial transduction of a constitutively inactive mutant of Akt (AA-Akt) improves circulatory function and sodium excretion in cirrhotic rats with ascites. METHODS: First, we administered recombinant adenoviruses that encode the ß-galactosidase gene (ß-gal) to 5 control rats and 5 cirrhotic rats with ascites and analyzed their tissue distribution by chemiluminescence. Next, urine samples were obtained from 18 cirrhotic rats with ascites and then the animal randomly received saline or adenoviruses containing the ß-gal or the AA-Akt genes. Following a 24-h urine collection period, hemodynamic studies were performed and tissue samples were obtained to analyze Akt and eNOS expressions. RESULTS: No ß-gal activity was detected in the liver of cirrhotic rats compared to that of controls. This was paralleled by increased ß-gal activity in other territories such as the thoracic aorta. AA-Akt transduction improved systemic hemodynamics, splanchnic perfusion pressure and renal excretory function in comparison with cirrhotic rats transduced with ß-gal adenoviruses or receiving saline. Moreover, the AA-Akt transgene did not modify portal pressure. CONCLUSIONS: Inactivation of extrahepatic vascular Akt and the concomitant decrease in nitric oxide expression ameliorate systemic hemodynamics and renal excretory function in experimental cirrhosis.

Risk factors associated with high linezolid trough plasma concentrations.

AIM: The major concern of linezolid is the adverse events. High linezolid trough serum concentration (Cmin) has been associated with toxicity. The aim of this study was to analyze factors associated with high Cmin. METHODS: Main clinical characteristics of 104 patients treated with 600 mg/12 hours of linezolid were retrospectively reviewed. Samples were obtained just before the next dose after at least three doses and within the first 8 days of treatment. High Cmin was considered when it was >8 mg/L. Univariate and multivariate analysis were performed. RESULTS: 34.6% patients had a Cmin >8 mg/L, and they were older and had more frequently an estimated glomerular filtration by MDRD <40 mL/min. There were more patients co-treated with rifampin in the group with low Cmin. The only factor independently associated with Cmin >8 was the renal function. Patients with an eGF < 40 mL/min had significantly higher Cmin than those with eGF > 80 mL/min (OR: 4.273) and there was a trend towards a high Cmin in patients with eGF between 40-80 mL/min (OR: 2.109). CONCLUSIONS: High Cmin were frequent, especially in patients with MDRD <40 mL/min. Therapeutic drug monitoring could be useful to avoid toxicity in patients with renal dysfunction.