Emilia-Romagna Study on Pregnancy and Exposure to Antiepileptic drugs (ESPEA): a population-based study on prescription patterns, pregnancy outcomes and fetal health.

OBJECTIVES: To assess the prevalence of antiepileptic drug (AED) exposure in pregnant women and the comparative risk of terminations of pregnancy (TOPs), spontaneous abortions, stillbirths, major birth defects (MBDs), neonatal distress and small for gestational age (SGA) infants following intrauterine AED exposure in the Emilia Romagna region, Italy (4 459 246 inhabitants on 31 December 2011). METHODS: We identified all deliveries and hospitalised abortions in Emilia Romagna in the period 2009-2011 from the certificate of delivery assistance registry (Certificato di Assistenza al Parto- CedAP) and the hospital discharge card registry, exposure to AEDs from the reimbursed drug prescription registries, MBDs from the regional registry of congenital malformations, and Apgar scores and cases of SGA from the CedAP. Records from different registries were linked. RESULTS: We identified 145 243 pregnancies: 111 284 deliveries, 16 408 spontaneous abortions and 17 551 TOPs. Six hundred and eleven pregnancies (0.42%; 95% Cl 0.39 to 0.46) were exposed to AEDs. In the AED-exposed group 21% of pregnancies ended in TOPs vs 12% in the non-exposed women (OR: 2.24; 95% CI 1.41 to 3.56). Rates of spontaneous abortions, stillbirths, neonatal distress and SGA were comparable. Three hundred and fifty-three babies (0.31%; 95% CI 0.28 to 0.35) were exposed to AEDs during the first trimester. MBD rates were 2.3% in the exposed vs 2.0% in the non-exposed pregnancies (OR: 1.12, 95% CI 0.55 to 2.55). CONCLUSION: The Emilia Romagna prevalence of AED exposure in pregnancy was 0.42%, comparable with previous European studies. Rates of spontaneous abortions, stillbirths, neonatal distress, SGA and MBDs following AED exposure were not significantly increased. The rate of TOPs was significantly higher in the AED-exposed women.

Perinatal Outcomes of Non-Primary Maternal Cytomegalovirus Infection: A 15-Year Experience.

OBJECTIVE: To evaluate perinatal outcomes in case of non-primary maternal cytomegalovirus (CMV) infection. METHODS: We performed a retrospective cohort study of pregnant women with active CMV infection referred to our unit over a 15-year period (January 2000 to December 2014). Non-primary infection was diagnosed on the basis of the results of confirmatory serological and virological tests (avidity test, immunoblotting, real-time PCR-DNA). The vertical transmission rate and the percentage of symptomatic congenital infection were determined in this group of patients. RESULTS: A total of 205 pregnant women were enrolled. Congenital infection occurred in 7 (3.4%) fetuses/neonates. Symptomatic disease was present at birth in 3 of the 7 congenitally infected neonates (1.5%). Two out of 3 symptomatic newborns presented a pathologic second-trimester ultrasound scan. CONCLUSION: Maternal immunity offers substantial protection against intrauterine transmission of CMV infection, but not against disease once the fetus is infected.

First-line dose-dense chemotherapy with docetaxel, cisplatin, folinic acid and 5-fluorouracil (DCF) plus panitumumab in patients with locally advanced or metastatic cancer of the stomach or gastroesophageal junction: final results and biomarker analysis from an Italian oncology group for clinical research (GOIRC) phase II study.

BACKGROUND: Survival for patients with advanced gastroesophageal cancer (AGC) using standard treatment regimens is poor. EGFR overexpression is common in AGC and associated with poor prognosis. We hypothesized that increasing the dose intensity of chemotherapy and adding panitumumab could improve efficacy. METHODS: HER2 negative, PS 0-1 patients, received up to 4 cycles of panitumumab 6 mg/kg d 1, docetaxel 60 mg/m2 d 1, cisplatin 50 mg/m2 d 1, l-folinic acid 100 mg/m2 d 1-2, followed by 5-FU 400 mg/m2 bolus d 1-2, and then 600 mg/m2 as a 22 h c.i. on d 1-2, q15 d, plus pegfilgrastim 6 mg on d 3. Patients with disease control after 4 cycles received panitumumab until progression. RESULTS: From 05/2010 to 01/2014, 52 patients (75% male; median age 64.5 y; metastatic 90%, locally advanced 10%; 96% adenocarcinoma; 25% GEJ) were recruited. Three CR, 29 PR, 10 SD and 8 PD were observed, for an ORR by ITT (primary endpoint) of 62% (95% CI, 48%-75%) and a DCR of 81%. Median TTP was 4.9 months (95% CI, 4.2-7.0) and mOS 10 months (95% CI, 8.2- 13.5). Most frequent G3-4 toxicities: leucopenia (29%), asthenia (27%), skin rash (25%), neutropenia (19%), anorexia (17%), febrile neutropenia (13%), and diarrhea (15%). EGFR expression tested both with dd-PCR and FISH was not associated with any significant clinical benefit from treatment. CONCLUSIONS: Dose-dense DCF plus panitumumab is an active regimen. However, the toxicity profile of this limits further development. Further research on predictive biomarkers for treatment efficacy in AGC is required.Clinical trial information: 2009-016962-10.

Safety and efficacy of dose-dense chemotherapy with TCF regimen in elderly patients with locally advanced or metastatic gastric cancer.

PURPOSE: To evaluate the efficacy and safety of dose-dense TCF in elderly (≥65 years) compared to younger patients. METHODS: Safety and efficacy data relative to 119 consecutive patients with locally advanced or metastatic gastric cancer treated at our institution and enrolled in different phase II trials were retrospectively collected. All patients were treatment-naive and received docetaxel 70 mg/m2 day 1, cisplatin 60 mg/m2 day 1, l-folinic acid 100 mg/m2 days 1-2, followed by 5-fluorouracil 400 mg/m2 bolus days 1-2, and then 600 mg/m2 as a 22-hour continuous infusion days 1-2, every 14 days, plus pegfilgrastim 6 mg on day 3. Sixty patients (50%) aged ≥65 years received the same schedule with a dose reduction by 30%. RESULTS: A total of 86% of patients were evaluable for response and all for toxicity. In patients aged ≥65 years, we observed an overall response rate of 51%. Median overall survival was 11.2 (95% confidence interval [CI] 7.3-15.1) and 11.8 months (95% CI 9.2-16.2) in elderly and younger patients, respectively. In the elderly patients, the most frequent grade 3-4 toxicities were neutropenia (13%), leukopenia (7%), thrombocytopenia (18%), anemia (3%), and febrile neutropenia (8%); in the younger patients, neutropenia (56%), leucopenia (31%), thrombocytopenia (22%), anemia (15%), and febrile neutropenia (15%). CONCLUSIONS: Elderly patients can be safely treated with a dose-dense TCF regimen with a 30% dose reduction achieving similar efficacy results as younger patients with lesser toxicity.

Maternal plasma mRNA species in fetal heart defects: a potential for molecular screening.

OBJECTIVE: To verify the hypothesis that aberrant placental mRNA genes related to cardiogenesis can be detected in maternal plasma at the second trimester of pregnancy. METHODS: NanoString technology was used to identify aberrant genes, comparing 39 women carrying a fetus with a congenital heart defect (CHD) to 31 controls at 19-24 weeks of gestation. The genes with differential expression were subsequently tested using real time polymerase chain reaction. Linear discriminant analysis (LDA) was used to combine all the mRNA species with discriminant ability for CHD. A multivariable receiver operating characteristic (ROC) curve having the estimated discriminant score as an explanatory variable was generated. RESULTS: Six genes with differential expression, namely FALZ, PAPP-A, PRKACB, SAV1, STK4 and TNXB2, were found. The ROC curve yielded a detection rate of 66.7% at a false positive rate of 10%. A higher discriminant score (>75(th) centile) was reached for 14 CHD cases (82.4%) and only 1 control (5.8%). Two cases (11.8%) of heart rhythm disorders also yielded a discriminant score value >75(th) centile. CONCLUSION: These data represent a step forward in the screening of CHDs. Additional studies are needed to detect more mRNAs with discriminant ability and to move the first trimester screening.

Performance of Circulating Placental Growth Factor as A Screening Marker for Diagnosis of Ovarian Endometriosis: A Pilot Study.

BACKGROUND: The aim of this study is to compare the circulating placental growth factor (PlGF) concentration in women with and without endometrioma to verify the performance of this marker to diagnose the disease. MATERIALS AND METHODS: In this case-control study, thirteen women with histological diagnosis of ovarian endometriosis were compared with women without endometriosis disease. PlGF plasma levels of endometriotic patients and controls were investigated using a fluorescence immunoassay technique. RESULTS: PlGF showed a direct correlation with body mass index (BMI) only in the control group (P=0.013). After adjustment for BMI values, PlGF median value in endometriosis group (14.7 pg/mL) resulted higher than in control group (13.8 pg/ mL, P=0.004). CONCLUSION: PlGF is a promising peripheral blood marker that can discriminate between patients with and without ovarian endometriosis.

Fetal cerebellar damage in fetuses with severe anemia undergoing intrauterine transfusions.

OBJECTIVE: To evaluate radiologic findings and outcomes of cerebellar injuries in fetuses with severe anemia due to RhD alloimmunization undergoing intrauterine transfusions. METHODS: Imaging of multiplanar neurosonography and magnetic resonance imaging (MRI) were reviewed. Pregnancy outcomes were recorded. RESULTS: Cerebellar injuries were identified after the first intravascular transfusion in four fetuses. Two of these cases were previously reported. The median hemoglobin concentration was 2.1 g/dL. Prenatal neurosonography identified an echogenic collection involving the cerebellum suggestive for hemorrhage in three cases. A progressive hypoplasia of a hemisphere was demonstrated at follow-up examination in one of these cases. Hypoplasia of a cerebellar hemisphere was seen in the fourth fetus. Ultrasound diagnosis was confirmed by prenatal MRI in two cases. In the third case, the postnatal MRI showed as additional finding vermian involvement. One pregnancy was terminated and autopsy confirmed the presence of infratentorial hemorrhage. The remaining infants were delivered alive. At time of writing, a truncal ataxia was diagnosed in the child with vermian hypoplasia, while the other children have met all age-appropriate milestones. CONCLUSIONS: A severe anemia seems to put the fetus at risk of cerebellar damage, despite successful intravascular transfusion.

Cervical lacerations in planned versus labor cerclage removal: a systematic review.

OBJECTIVE: The aim of this study was to evaluate the incidence of cervical lacerations with cerclage removal planned before labor compared to after the onset of labor by a systematic review of published studies. STUDY DESIGN: Searches were performed in electronic databases from inception of each database to November 2014. We identified all studies reporting the rate of cervical lacerations and the timing of cerclage removal (either before or after the onset of labor). The primary outcome was the incidence of spontaneous and clinically significant intrapartum cervical lacerations (i.e. lacerations requiring suturing). RESULTS: Six studies, which met the inclusion criteria, were included in the analysis. The overall incidence of cervical lacerations was 8.9% (32/359). There were 23/280 (6.4%) cervical lacerations in the planned removal group, and 9/79 (11.4%) in the removal after labor group (odds ratio 0.70, 95% confidence interval 0.31-1.57). CONCLUSIONS: In summary, planned removal of cerclage before labor was not shown to be associated with statistically significant reduction in the incidence of cervical lacerations. However, since that our data probably did not reach statistical significance because of a type II error, further studies are needed.

Serum and Urinary Neutrophil Gelatinase-associated Lipocalin Monitoring in Normal Pregnancy Versus Pregnancies Complicated by Pre-eclampsia.

AIM: Pre-eclampsia is a syndrome characterized by endothelium dysfunction, systemic inflammation, and kidney injury that could be associated with increased levels of neutrophil gelatinase-associated lipocalin (NGAL). We investigated whether serum and urinary NGAL may have a clinical value in defining the severity of pre-eclampsia. PATIENTS AND METHODS: This cross-sectional case-control study enrolled 18 women with pre-eclampsia matched for gestational age with 22 uncomplicated pregnancies. We evaluated the correlation between NGAL levels and blood pressure and 24-hour proteinuria values by linear regression. RESULTS: Linear regression disclosed a positive and significant correlation between urinary NGAL and 24-hour proteinuria. Serum NGAL appeared to be higher, but not significantly different, in severe pre-eclampsia. CONCLUSION: These preliminary data indicate that NGAL may correlate with an inflammatory renal involvement in severe pre-eclampsia. Further studies would be useful to better estimate the clinical value of an NGAL increase for evaluating the possibility of delivery induction.

Circulating mRNA for the PLAC1 gene as a second trimester marker (14-18 weeks' gestation) in the screening for late preeclampsia.

OBJECTIVE: To develop a model for prediction of late preeclampsia (PE; which develops at or after 34 weeks' gestation) based on maternal history and characteristics, mean arterial pressure (MAP), and circulating levels of mRNA for the placenta-specific 1 (PLAC1) gene in maternal plasma at 14-18 weeks' gestation. METHOD: This was a screening study of singleton pregnancies at 14-18 weeks' gestation including 43 women that subsequently developed PE and 200 that were unaffected by PE. A Gaussian model was fitted to the log distribution of the multiple of the median (log MoM) PLAC1 mRNA in the PE group and in the unaffected group. Likelihood ratios for log MoM of circulating levels of mRNA for the PLAC1 gene were used to combine the a priori risk from maternal characteristics with MAP to produce patient-specific risks for each case. RESULTS: Screening by maternal characteristics (including BMI, woman's mother's history of PE, previous PE, and parity) (a priori risk) and MAP detected 46.8% of all cases of late PE at a fixed false-positive rate (FPR) of 10%. The addition of PLAC1 yielded a detection rate (DR) of 62.8% at the same level of FPR. PLAC1 alone yielded a DR of 30.2%. CONCLUSION: In late PE, molecular markers can be used to improve the DR of screening and can be a valid option for the biochemical approach.

Congenital cytomegalovirus infection and small for gestational age infants.

OBJECTIVE: To evaluate the incidence of infants with birth weight less than the 10(th) centile for small for gestational age (SGA) in primary maternal cytomegalovirus (CMV) infection and to determine whether SGA predicts poor neurodevelopmental outcome. METHODS: A retrospective cohort study, which included singleton live-born infants from pregnancies complicated by primary maternal CMV infection. Infants were classified as uninfected or infected based on viral virus isolation and real-time PCR in urine at birth. SGA neonates rate and long-term sequelae were evaluated. RESULTS: Between 2000 and 2012, 848 women with primary CMV infection were referred to our center with 588 infants assessed at birth. Congenital CMV infection was diagnosed in 119 cases (20%), of which 8 were SGA (6.7%) compared with 27 out of the 469 uninfected infants (5.7%) (p-value = 0.69). Among the 119 infected babies, 14 infants were symptomatic at birth or at postnatal follow-up (12%), of whom two were SGA compared with six out of the 105 asymptomatic neonates (5.7% versus 15%, respectively, p-value = 0.22). CONCLUSION: Congenital CMV infection does not seem to be associated with a higher incidence of SGA, and long-term outcomes do not seem to be affected by isolated impaired fetal growth.

Symptomatic cerebral cavernomas in pregnancy: a series of 6 cases and review of the literature.

OBJECTIVE: To present our experience of symptomatic cerebral cavernous malformations (CCMs) in pregnancy and to review the literature on the topic. METHODS: We retrospectively collected a case series of symptomatic CCMs during pregnancy or the puerperium. A literature search was performed to identify all similar reports. RESULTS: We collected 16 cases of symptomatic CCMs. Haemorrhage occurred in 10 patients. Two patients opted for termination of pregnancy. Delivery occurred preterm in four cases, in only one case due to neurological symptoms at 30 weeks' gestation. Caesarean section was performed in 9 cases; concern over CCM was the indication for delivery in eight of these cases. Four out of 16 patients underwent neurosurgery, three during pregnancy. CONCLUSION: Symptomatic CCMs seldom require neurosurgery either during or after pregnancy and are not associated with preterm delivery.

Efficacy and tolerability of chemotherapy with modified dose-dense TCF regimen (TCF-dd) in locally advanced or metastatic gastric cancer: final results of a phase II trial.

BACKGROUND: We previously studied a dose-dense TCF (TCF-dd) regimen demonstrating its feasibility and an activity comparable to epirubicin-based chemotherapy and TCF q3w in terms of overall survival and time to progression (TTP). We report here the final results of a phase II study of chemotherapy with a modified TCF-dd regimen in locally advanced or metastatic gastric cancer (MGC). METHODS AND STUDY DESIGN: Patients with histologically confirmed measurable MGC, not previously treated for advanced disease, received docetaxel 70 mg/m(2) day 1, cisplatin 60 mg/m(2) day 1, l-folinic acid 100 mg/m(2) days 1 and 2, followed by 5-fluorouracil (5-FU) 400 mg/m(2) bolus days 1 and 2, and then 600 mg/m(2) as a 22-h continuous infusion days 1 and 2, every 14 days, plus pegfilgrastim 6 mg on day 3. Patients aged ≥65 years received the same schedule with a dose reduction of 30 %. RESULTS: Study duration: December 2007-November 2010. Forty-six consecutive patients were enrolled (78 % male, 22 % female; median age, 66 years, range, 38-76 years; ECOG PS: 0, 48 %, 1, 46 %). Primary endpoint was overall response rate (ORR). A median of four cycles (range, one to six) was administered. Forty-three patients were evaluated for response (93.5 %) and all for toxicity: 3 complete response (CR), 25 partial response (PR), 10 stable disease (SD), and 5 progressive disease (PD) were observed, for an ORR by intention to treat (ITT) of 61 % (95 % CI 47-75). Median overall survival (OS) was 17.63 months (95 % CI, 13.67-20.67); median progression-free survival was 8.9 months (95 % CI, 6.5-13.4). Twenty-one patients (46.0 %) were treated at full doses without any delay, thus respecting the dose-dense criterion. Most frequent grade 3-4 toxicities were neutropenia (20 %), leukopenia (4 %), thrombocytopenia (2 %), anemia (2 %), febrile neutropenia (6 %), asthenia (22 %), diarrhea (4 %), nausea/vomiting (11 %), and hypokalemia (6 %). Overall, TCF-dd was shown to be safe. CONCLUSIONS: The TCF-dd regimen in locally advanced or MGC is confirmed to be feasible and very active and needs to be further tested in randomized studies.

Multivariable evaluation of term birth weight: a comparison between ultrasound biometry and symphysis-fundal height.

OBJECTIVE: To derive a birth weight predictive equation and to compare its diagnostic value with that of ultrasound. METHODS: A longitudinal observational cohort study, including singleton pregnancies at term, was performed at St. Orsola-Malpighi Hospital, University of Bologna (Italy). A birth weight prediction formula, including symphysis-fundal height (SFH), BMI, maternal abdominal circumference (mAC) and parity was derived from a general linear model (GLM) (retrospective study). Moreover, on a new series of patients, the fetal weight was estimated by using both GLM and ultrasound using Hadlock formula (prospective study). The residual analysis and the intraclass correlation coefficient (ICC) were used to test the accuracy of methods in predicting birth weight. RESULTS: Between January and November 2012, 1034 patients were included in the retrospective study and 44 in the prospective one. The following GLM was derived: estimated birth weight (g) = 1485.61 + (SFH (cm) × 23.37) + (11.62 (cm) × mAC) + [BMI × (-6.81)] + (parity (0 = nulliparous, 1 = multiparous) × 72.25). When prospectively applied, the GLM and ultrasound provided a percentage of prediction within ±10% of the actual weight of 73% and 84%, respectively. Ultrasound estimation, as opposite of GLM one, was significantly associated with neonatal weight (R(2 )= 0.388, F = 26.607, p value <0.001, ICC = 0.767). CONCLUSIONS: Although ultrasound biometry has provided the best values in fetal weight estimation, the predictive performance of both methods is limited.

Cervical length and risk of antepartum hemorrhage in presence of low-lying placenta.

OBJECTIVES: To evaluate whether transvaginal ultrasound cervical length (TVU CL) can predict antepartum bleeding (APB) in women with low-lying placenta. STUDY DESIGN: A retrospective study was performed including pregnancies with low-lying placenta for which third trimester TVU CL was available. Multiple pregnancies were excluded. Short cervix was defined as TVU CL ≤25 mm. Outcomes of interest were compared with respect to the TVU CL. RESULTS: Forty three cases of singleton pregnancies complicated by low-lying placenta in third trimester were identified. Short cervix was reported in 8 cases (19%). APB (75% vs. 31 %, p = 0.02), blood transfusions (25% vs. 3%, p = 0.02), lower birth weight (2246 vs. 2985 g, p = 0.02), and neonatal intensive care unit (NICU) admissions (50% vs. 17%, p = 0.04) were more frequent in the women with short cervix. Rate of unplanned cesarean delivery for APB was similar between both the groups (25% vs. 28%, p = 0.83). CONCLUSIONS: In women with low-lying placenta persisting into third trimester, short cervical length can be used as a predictor for APB.

Exam-indicated cerclage in patients with fetal membranes at or beyond external os: a retrospective evaluation.

AIM: To evaluate pregnancy outcome in women with fetal membranes at or beyond external os who underwent exam-indicated cerclage or conservative management. MATERIAL AND METHODS: Retrospective cohort study including 52 patients with fetal membranes at or beyond external os between 17 and 27 weeks of gestation, treated in two third-level hospitals, between January 2001 and April 2009. The outcomes of interest of the study, prolongation of pregnancy and neonatal survival rate, were stratified according to type of management, parity, clinical conditions and blood tests at admission and calculated using the Kaplan-Meier algorithm. RESULTS: Of 52 women, 37 received exam-indicated cerclage and 15 were managed conservatively. The rate of patients still pregnant beyond 180 days within the cerclage group differed significantly from those of the conservative management group (80% vs 0%, respectively) (P-value<0.001). No difference has been found according to neonatal survival (82% versus 53%, respectively). CONCLUSION: Exam-indicated cerclage appears to prolong gestation compared to expectant management.

Association of killer cell immunoglobulin-like receptors and human leukocyte antigen-C genotypes in South Brazilian with type 1 diabetes.

Type 1 diabetes mellitus (T1D) is a multifactorial and chronic autoimmune disease caused by the deficiency of insulin synthesis and or by its secretion or action defects. Genetic and environmental factors are known to be involved in its pathogenesis. The human leukocyte antigen complex (human leukocyte antigen (HLA)) constitutes the most relevant region contributing with 50% of the inherited risk for T1D. Natural killer cells (NK) are part of the innate immune system recognizing class I HLA molecules on target cells through their membrane receptors, called killer immunoglobulin-like receptors (KIR). The aim of our study is to evaluate the association between the KIR genes and HLA alleles in patients with T1D and healthy controls. Two hundred forty-eight T1D patients and 250 healthy controls were typed for HLA and KIR genes by PCR-SSP. Our results showed an increase of C2 in controls (p = 0.002). The genotype 2DL1/C2+ was also more common in controls (p = 0.001), as well as haplotype association KIR2DL2/DR3/DR4+ and the combination with only DR3+ (p < 0.001; p < 0.001). The maximum protection was seen when KIR2DL2/DR3-were absent when the combination of KIR2DL1/C2+ were present (p < 0.001) and the maximum risk was observed when KIR2DL2/DR3/DR4+ were present in the absence of KIR2DL1/C2- (p = 0.005). Our results confirmed the association of the KIR2DL2/DR3 increasing risk for T1D and suggest a protective role of KIR2DL1/C2.