Birth defects in a national cohort of pregnant women with HIV infection in Italy, 2001-2011.

OBJECTIVE: We used data from a national study of pregnant women with HIV to evaluate the prevalence of congenital abnormalities in newborns from women with HIV infection. DESIGN: Observational study. SETTING: University and hospital clinics. POPULATION: Pregnant women with HIV exposed to antiretroviral treatment at any time during pregnancy. METHODS: The total prevalence of birth defects was assessed on live births, stillbirths, and elective terminations for fetal anomaly. The associations between potentially predictive variables and the occurrence of birth defects were expressed as odds ratios (ORs) with 95% confidence intervals (95% CIs) for exposed versus unexposed cases, calculated in univariate and multivariate logistic regression analyses. MAIN OUTCOME MEASURES: Birth defects, defined according to the Antiretroviral Pregnancy Registry criteria. RESULTS: A total of 1257 pregnancies with exposure at any time to antiretroviral therapy were evaluated. Forty-two cases with major defects were observed. The total prevalence was 3.2% (95% CI 1.9-4.5) for exposure to any antiretroviral drug during the first trimester (23 cases with defects) and 3.4% (95% CI 1.9-4.9) for no antiretroviral exposure during the first trimester (19 cases). No associations were found between major birth defects and first-trimester exposure to any antiretroviral treatment (OR 0.94, 95% CI 0.51-1.75), main drug classes (nucleoside reverse transcriptase inhibitors, OR 0.95, 95% CI 0.51-1.76; non-nucleoside reverse transcriptase inhibitors, OR 1.20, 95% CI 0.56-2.55; protease inhibitors, OR 0.92, 95% CI 0.43-1.95), and individual drugs, including efavirenz (prevalence for efavirenz, 2.5%). CONCLUSIONS: This study adds further support to the assumption that first-trimester exposure to antiretroviral treatment does not increase the risk of congenital abnormalities.

Upper urinary tract biopsy: an old device for a new approach.

PURPOSE: The authors sought to evaluate the feasibility, diagnostic accuracy and safety of urological biopsy performed using a flexible alligator forceps. MATERIALS AND METHODS: Twenty-seven patients with suspected urothelial malignancy underwent retrograde biopsy using a 7-F biopsy forceps (Cordis, Miami, FL, USA). Mild sedation was guaranteed by an anaesthesiologist. The final diagnosis was confirmed by cytohistological data and subsequently by pathology findings at surgery. Lesions with benign histopathology were closely monitored for at least 12 months. RESULTS: The technical success rate was 92.6%. The high diagnostic accuracy was related to the positive correspondence between histological outcomes and surgical results or follow-up observations. As regards sample site, the procedure was less successful in calyceal lesions than in lesions located in the upper urinary tract, with a technical success of 71.43%. Twenty patients had asymptomatic haematuria in the early hours after the procedure; ten of them had mild dysuria. No one require medication, and no major complications occurred. CONCLUSIONS: Urological forceps biopsy is a safe and easy procedure. It provides a relatively high level of accuracy in the diagnosis of lesions of the upper urinary tract.

How many roads lead to stillbirth rate reduction? A 30-year analysis of risk factors in a Northern Italy University care center.

BACKGROUND: Stillbirths affect more than 2.5 million pregnancies worldwide every year and the progress in reducing stillbirth rates is slower than that required by World Health Organization. The aim of the present study was to investigate which factors were associated with stillbirths in a University Hospital in the North of Italy, over a time span of 30 years. The goal was to identify which factors are potentially modifiable to reduce stillbirth rate. METHODS: Retrospective case-control study (358 stillbirths, 716 livebirths) subdivided into two study periods (1987-2006 and 2007-2017). RESULTS: The prevalence of conception obtained by assisted reproductive technologies, pregnancy at advanced maternal age, and complications of pregnancy such as preeclampsia, fetal growth restriction (FGR), and other fetal diseases (abnormal fetal conditions including fetal anemia, fetal hydrops, TORCH infections) increased through the years of the study. Despite a rising prevalence, the last 10 years showed a significant reduction in stillbirths associated with preeclampsia and FGR. Similarly, the risk of stillbirth related to abnormal fetal conditions decreased in the second study period and a history of previous stillbirth becomes a nonsignificant risk factor. CONCLUSIONS: Altogether these results suggest that in pregnancies perceived as "high risk" (i.e. previous stillbirth, preeclampsia, FGR, abnormal fetal conditions) appropriate care and follow-up can indeed lower stillbirth rates. In conclusion, the road to stillbirth prevention passes inevitably through awareness and recognition of risk factors.

Promoting the well-being of mothers with multidisciplinary psychosocial interventions in the perinatal period.

BACKGROUND: Antenatal depressive and anxiety symptoms are common and may persist over time after delivery, with negative consequences on the mothers and their children. Evidence on the efficacy of psychological and pharmacological interventions during pregnancy aimed at preventing post-partum depression is controversial. METHODS: A consecutive sample of 318 women presenting for scheduled obstetric visits during pregnancy was screened for risk factors and anxiety or depressive symptoms. Based on the screening results, women were classified into three groups at increasing risk of post-partum depression (PPD) and were offered different interventions. RESULTS: Depressive or anxiety symptoms were found in 91 (28.6%) women, 89 (28.0%) had low risk of PPD and 138 (43.4%) had no risk of PPD. The multidisciplinary psychosocial interventions offered to women with clinical symptoms were well accepted, with an uptake of 76/91 (83.5%). Thirty-three women who did not improve with psychotherapy were offered sertraline or paroxetine as a second-line treatment: 7 accepted and 26 (78.8%) refused. Eleven women already on medication at baseline continued their treatment along with the MPI. The MPI interventions had some positive effects in terms of post-partum recovery, symptom reduction, and in preventing a new onset of depression. Among the 227 non-symptomatic during pregnancy, only 5 (2.2%) developed symptoms in the post-partum period. At 12 months post-partum, 84.6% of women who were symptomatic at 2 months post-partum recovered. LIMITATIONS: Our results should be interpreted in light of important limitations, including the lack of a control group that was not offered the MPI, the lack of information on the reasons for refusal and discontinuation and on the number of psychotherapy sessions attended. CONCLUSIONS: Our findings underscore the potential usefulness of MPI in recognizing early signs or symptoms during pregnancy and the advantage of building specific interventions for preventing post-natal depression. The MPI has positive effects on women with depressive or anxiety symptoms during pregnancy, that however did not exceed significantly those observed in women who refused the intervention. Thus, in the absence of a control group, our results are preliminary and warrant confirmation and testing in future randomized clinical trials.

Activation of Protein C in Human Trophoblasts in Culture and Downregulation of Trophoblast Endothelial Protein C Receptor by TNF-α.

In mice, trophoblasts are equipped with a potent anticoagulant mechanism, the protein C pathway. In human placenta, no functional studies of the protein C pathway are available. Human first-trimester trophoblasts (CK(++) HLA-G(+/-) Vim(-)) were isolated and kept in culture for a maximum of 48 hours. Activation of protein C on trophoblasts was at least as efficient as in endothelial cells (4.43 × 10 (-) (7) nmol/L/min/cell). Endothelial protein C receptor (EPCR) was expressed in syncytiotrophoblasts and extravillous trophoblasts. Downregulation of the messenger RNA of trophoblast EPCR occurred when trophoblasts were challenged with tumor necrosis factor α, and it could be prevented by unfractionated heparin but not by low-molecular-weight heparin at therapeutic doses. In conclusion, there is a functional protein C pathway on human first-trimester trophoblasts which can be modulated by inflammation. This finding has implications for the pathogenesis and prevention of placenta-mediated obstetric complications.

A study of the serum 3,5,3'-triiodothyronine sulfate concentration in normal and hypothyroid fetuses at various gestational stages.

We have studied T3 sulfate (T3S) levels, blindly, in coded plasma samples from 21 normal and 3 hypothyroid fetuses at different stages of gestation (19-42 weeks). Fetal plasma samples were obtained by cordocentesis. T3S was detectable in all samples studied, with values ranging from 50-294 (mean +/- SD, 130 +/- 62 pmol/L). Plasma T3S was low (< 45 pmol/L) in all 4 normal adult control subjects studied simultaneously; serum T3S ranged from less than 20 to 130 in another set of 18 control subjects (mean +/- SD, 63 +/- 32 pmol/L). Fetal T3S values were positively correlated with gestational age (r = 0.43; P < 0.05), but not with free T4 (FT4), FT3, or TSH values. In the 3 hypothyroid fetuses at 31, 38, and 40 weeks gestation, respectively, plasma TSH was elevated (26, 98, and 24 mU/L, respectively), FT4 was low (10, 6.7, and 7.5 pmol/L, respectively), and FT3 was normal or high (3.2, 8.2, and 2.2 pmol/L, respectively). However, T3S values in hypothyroid fetuses (88, 133, and 252 pmol/L, respectively) were similar to those in normal fetuses at corresponding gestational ages. We conclude that 1) T3S is detectable in fetal circulation from at least 19 weeks gestation, and its concentration increases with fetal-age; 2) plasma T3S concentrations in the fetus at 19-40 weeks gestation are at least comparable to but generally higher than those in the adult; and 3) plasma T3S levels in hypothyroid fetuses are similar to those in normal fetuses. Recent studies demonstrating the ability of some fetal rat tissues (e.g. cerebral cortex) to desulfate T3S to T3 have suggested a possible role of T3S as a source of T3. Normal T3S in fetal hypothyroidism suggests that T3S may contribute to attenuation of the effects of hypothyroidism during intrauterine life.

Placental transport of leucine, phenylalanine, glycine, and proline in intrauterine growth-restricted pregnancies.

L-[1-13C]Leucine, [1-13C]glycine, L-[1-13C]phenylalanine, and L-[1-13C]proline were infused as a bolus into the maternal circulation of seven appropriate for gestational age at 30.3 +/- 3.0 wk and 7 intrauterine growth-restricted pregnancies at 26.5 +/- 1.0 wk gestation to investigate placental transport in vivo. Umbilical venous samples were obtained at the time of in utero fetal blood sampling at 450 +/- 74 sec from the bolus injection. In normal pregnancies the fetal/maternal (F/M) enrichment ratios for leucine (0.76 +/- 0.06) and phenylalanine (0.77 +/- 0.06) were higher (P < 0.01) than the F/M ratios for glycine (0.18 +/- 0.04) and proline (0.22 +/- 0.02). This suggests that these two essential amino acids rapidly cross the placenta in vivo. Compared with the essentials, both glycine and proline had significantly lower F/M enrichment ratios, which were not different from each other. The results support the hypothesis that amino acids with high affinity for exchange transporters cross the placenta most rapidly. In intrauterine growth-restricted pregnancies, the F/M enrichment ratio was significantly lower (P < 0.01) for L-[1-13C]leucine (0.76 +/- 0.06 vs. 0.48 +/- 0.07) and for L-[1-13C]phenylalanine (0.77 +/- 0.06 vs. 0.46 +/- 0.07) compared with appropriate for gestational age pregnancies reflecting impaired transplacental flux. The F/M enrichment ratio did not differ for [1-13C]glycine (0.18 +/- 0.04 vs. 0.17 +/- 0.03), and L-[1-13C]proline (0.22 +/- 0.02 vs. 0.18 +/- 0.04).

Maturation of hypothalamic-pituitary-gonadal function in normal human fetuses: circulating levels of gonadotropins, their common alpha-subunit and free testosterone, and discrepancy between immunological and biological activities of circulating follicle-stimulating hormone.

The recent availability of both cordocentesis, a low risk and effective technique for fetal blood sampling, and ultrasensitive/highly specific two-site immunofluorometric assays (IFMA) for pituitary and chorionic glycoprotein hormone (I-LH, I-FSH, and I-CG) measurement prompted us to study the maturation of hypothalamic-pituitary-gonadal function in 114 normal human fetuses (49 females and 65 males) from 17-40 weeks gestation. The subjects were selected from 216 consecutive cordocenteses carried out for rapid karyotyping and diagnosis of fetal infection or hematological disorders. In addition, FSH bioactivity (B-FSH) was measured by rat Sertoli cell aromatase induction assay, glycoprotein hormone alpha-subunit (alpha-SU) by RIA, and circulating free testosterone (fT) by direct analog technique. No significant cross-reactions were recorded in the different measurement methods. In particular, alpha-SU did not interfere in any IFMA, and CG cross-reactivity in LH IFMA was 0.5%. Circulating I-LH, I-FSH, and B-FSH levels at 17-24 weeks gestation were significantly higher in female than in male fetuses (I-LH, 48 +/- 4 vs. 6.3 +/- 0.7 U/L; I-FSH, 35 +/- 2 vs. 0.7 +/- 0.1 U/L; B-FSH, 131 +/- 17 vs. 43.4 +/- 5.4 U/L). During the last weeks of gestation, a significant decrease in I-LH and I-FSH levels was seen in both female and male fetuses (I-LH, 0.24 +/- 0.05 and 1.0 +/- 0.3 U/L; I-FSH, 0.45 +/- 0.1 and 0.5 +/- 0.1 U/L), while serum B-FSH remained elevated, but the previously recorded difference between sexes disappeared (54.3 +/- 7.2 and 58.7 +/- 7.3 U/L). Circulating I-CG and alpha-SU levels at midgestation were elevated in both female and male fetuses (I-CG, 117 +/- 29 and 191 +/- 44 U/L; alpha-SU, 143 +/- 16 and 105 +/- 9 micrograms/L, respectively) and decreased thereafter (I-CG, 42 +/- 9 and 26 +/- 6 U/L; alpha-SU, 60 +/- 15 and 37 +/- 6 micrograms/L). Serum fT levels at midgestation were significantly lower in females than in males (4.3 +/- 0.9 vs. 10.0 +/- 0.8 pmol/L) and increased until term, when the difference between sexes disappeared (16.2 +/- 1.8 vs. 17.6 +/- 1.6 pmol/L).(ABSTRACT TRUNCATED AT 400 WORDS)

Characterization and sequence of a novel insertion sequence, IS1162, from Pseudomonas fluorescens.

We have determined the nucleotide sequence of IS1162, a new insertion sequence (IS) isolated from Pseudomonas fluorescens (Pf) strain ST. This IS element is present in two copies on the pEG plasmid harboured by Pf ST and in a single copy on the chromosome, adjacent to the styrene catabolic genes. IS1162 is 2634 bp in length with 12-bp terminal inverted repeats (IR), and could encode four proteins (ORFs), two for each strand. One strand, Pro1 (62,990 Da), showed a helix-turn-helix motif at the N-terminal region, and Pro2 (25,997 Da) was characterized by the presence of the A and B motives of the NTP (ATP/GTP)-binding site. Comparison of IS1162 of Pf with known IS showed a high homology with IS408 of Burkholderia cepacia [Byrne and Lessie, Plasmid 31 (1994) 138-147]. Pro1 and Pro2 were found to be homologous to the corresponding ORFs of IS408, IS21 [Reimmann et al., Mol. Gen. Genet. 215 (1989) 416-424], IS232 [Menou et al., J. Bacteriol. 172 (1990) 6689-6696] and IS5376 [Xu et al., Plasmid 29 (1993) 1-9]. IS1162 transposed at low frequency and no cointegrates were found among the transposition products. The target duplication sites, variable in length, showed the presence of homologous motives, suggesting a certain degree of specificity of the IS1162 insertion site.

A multiple infusion start time (MIST) protocol for stable isotope studies of fetal blood.

A new approach utilizing multiple infusion start times for two stable isotopes of leucine was applied to seven pregnancies in order to assess equilibration times for isotopic studies when a single fetal blood sample is available. Two infusates, one containing l -[1-(13)C]-leucine and the other l -[5,5,5-D3]-leucine, were given as a primed constant infusion in the maternal circulation at fetal blood sampling (FBS). In five patients l -[1-(13)C]-leucine infusion was started at time zero (T(0)) whereas l -[5,5,5-D3]-leucine infusion began 30 min later, and both were continued until the umbilical sample was obtained at 149.7+/-8.8 min. In order to assure non-steady state conditions, in two patients the first infusion started at T(0)and the second 17 and 6 min before FBS was performed at 115 and 154 min, respectively. The fetal/maternal ratio for l -[5,5,5-D3]-leucine over the fetal/maternal ratio for l -[1-(13)C]-leucine was 0.98+/-0.03, indicating steady state conditions for both infusions for the first six patients. In the last patient the ratio was 0.51, indicative of non-steady state conditions for the shortest infusion time. Our results show that a single fetal sample can provide data for fetal amino acid enrichments reflecting multiple time points. Leucine steady state is achieved 20 min after a primed continuous infusion both in the maternal and fetal circulations.

The relationship of maternal and fetal glucose concentrations in the human from midgestation until term.

The relationship between maternal and fetal glucose concentrations was investigated in pregnant women at different gestational ages. Maternal and fetal blood samples were obtained during 14 fetoscopies (17 to 21 weeks), four umbilical cord samples (32 to 36 weeks), nine elective cesarean sections with appropriate for gestational age (AGA) fetuses (35 to 39 weeks) and nine elective cesarean sections with small for gestational age (SGA) fetuses (34 to 37 weeks). A significant linear relationship between maternal and fetal glucose concentrations was demonstrated at midgestation (P less than .001) and at late gestation (P less than .001). At equal maternal concentrations there were no significant differences in fetal glucose concentration between the cord samples obtained in late gestation and those obtained at cesarean section. At midgestation fetal glucose concentration is independent of and may exceed maternal concentration at maternal glucose levels less than 4.44 mmol/L. Furthermore, the relationship between maternal and fetal concentrations at maternal glucose concentrations greater than 4.44 mmol/L is significantly different at midgestation from that at late gestation (P less than .01); at equal maternal concentrations there were higher glucose concentrations in the mid trimester fetus. In late gestation as the maternal glucose concentration increases there is an increase in the maternal arterial-umbilical arterial glucose concentration difference and the umbilical glucose/oxygen quotient (P less than .003) reflecting increased glucose utilization by the fetus. There were no significant differences between AGA and SGA babies with respect to these relationships.

An evaluation of fetal glucogenesis in intrauterine growth-retarded pregnancies.

The presence of fetal glucogenesis was evaluated in nine patients with pregnancies complicated by intrauterine growth retardation (IUGR) at the time of fetal blood sampling (FBS) between 29 and 35 weeks of pregnancy. Eight were singleton pregnancies and one was a twin pregnancy in which blood samples were obtained from both twins. A maternal primed-constant infusion of D(U-13C]glucose was performed, and the presence of fetal glucogenesis was assessed by a comparison of steady-state maternal and fetal glucose enrichments. No significant difference was present between maternal and fetal molar percent excess ([MPE] P = .97), and the mean fetal to maternal (F/M) MPE ratio (0.99 +/- 0.01) was not significantly different from 1 (P = .76). F/M MPE ratio was independent of the time of FBS and umbilical venous glucose and lactate concentrations. Thus fetal glucogenesis is not demonstrable in a group of fairly severe growth-retarded fetuses after an overnight fast with this relatively noninvasive approach.

The impact of gestational age and fetal growth on the maternal-fetal glucose concentration difference.

OBJECTIVE: To test whether the human fetus accommodates to the increasing glucose requirements of late pregnancy with an increased maternal-fetal glucose concentration gradient and whether there are differences in pregnancies with fetal growth restriction (FGR) according to clinical severity. METHODS: Umbilical venous glucose concentration was measured in 77 normal pregnancies (appropriate for gestational age [AGA]) and 42 pregnancies complicated by FGR at the time of fetal blood sampling. In 40 AGA and in all FGR cases, a maternal "arterialized" blood sample was collected simultaneously. Growth-restricted fetuses were subdivided into three groups according to fetal heart rate (FHR) recordings and Doppler measurements of the umbilical artery pulsatility index (PI): group 1 (normal FHR and PI; 12 cases), group 2 (normal FHR, abnormal PI; 17 cases) and group 3 (abnormal FHR and PI; 13 cases). RESULTS: In normal pregnancies with increasing gestational age, there was a significant decrease (P < .001) of umbilical venous glucose concentration and a significant increase of the maternal-fetal glucose concentration difference (P < .001). In addition, there was a significant relation between fetal and maternal glucose concentrations (P < .001). In FGR pregnancies, the maternal-fetal glucose concentration difference was significantly higher in fetuses of groups 2 and 3 compared with normal pregnancies and FGR pregnancies of group 1. CONCLUSION: In human pregnancy, the fetal glucose concentration is a function of both gestational age and the maternal glucose concentration. In FGR pregnancies, as an accommodation of the fetus to a restricted placental size and placental glucose transport capacity, the maternal-fetal glucose concentration difference is increased, and this increase is a function of the clinical severity.

Fetal amino acids in normal pregnancies and in pregnancies complicated by intrauterine growth retardation.

Plasma amino acid concentrations were measured in normal (AGA) and intrauterine growth retarded (IUGR) percutaneous umbilical blood sampling (PUBS) performed for prenatal diagnosis or at elective cesarean section. IUGR fetuses present significantly lower concentrations of most amino acids, with a significant reduction of the umbilical veno-arterial difference for total alpha-amino nitrogen. These findings are present early in growth retarded fetuses and may be potentially responsible for the growth retardation.

Undesired effects of steroids during pregnancy.

Antenatal corticosteroid administration for enhancing fetal lung maturity can be expected to induce negative maternal and fetal side-effects. Maternal short-term effects after multiple courses of corticosteroids are an increase of infections and a higher incidence of endometritis and chorionamnionitis in patients with premature rupture of membranes. A single dose of corticosteroid induces an increase in the count of maternal white blood cells and metabolic effects such as the augmentation of amino acid concentration and of fasting glucose levels in maternal plasma. Negative fetal effects of antenatal corticosteroids are a reduction of fetal body and breathing movements and a reduction of fetal heart rate variation, without any changes in Doppler waveform patterns of fetoplacental vessels. It has been suggested that a multiple course of corticosteroids antenatally might induce negative effects on fetal intrauterine growth and on neonatal birth weight. In addition, multiple courses are associated with an increased risk of early-onset neonatal sepsis.

Advanced tubal pregnancy associated with severe fetal growth restriction: a case report.

A case is described of advanced tubal pregnancy associated with severe fetal growth restriction delivered at 27 weeks. The placenta was implanted on the salpinx and on the uterotubal angle. Progressing tubal pregnancy and its placental histological characteristics could be a model of placental dysfunction typically associated with intrauterine growth restriction.

Pathophysiology of intrauterine growth retardation: role of the placenta.

The placenta is essential for normal fetal development. Failure of the placenta can result in many fetal conditions, for example, intrauterine growth retardation (IUGR). Placentas from pregnancies complicated by IUGR show vascular damage, which may lead to the onset of pregnancy-induced maternal hypertension. Accurate placental assessment may, therefore, indicate which fetuses are at risk of IUGR and so improve clinical evaluation and management of both the fetus and the mother. Placental development and function can be assessed by a number of methods, including measurement of placental weight at mid-gestation (placental growth in the second trimester correlates strongly with placental weight at birth), assessment of fetal and placental circulation (an association between perinatal morbidity and abnormal blood velocity profiles has been established) and assessment of placental metabolism and nutritional transfer (a reduction in transfer of nutrients may be an early indicator of IUGR.

[Anticholinergic treatment in the therapy of primary enuresis. Effectiveness of oxybutynin chloride in a controlled clinical study of 58 patients]. / II trattamento anticolinergico nella terapia della enuresi essenziale. Efficacia dell'ossibutinina cloruro in uno studio clinico controllato su 58 pazienti.

2 groups of enuretic children were respectively treated with anticholinergic drugs dicyclomine and oxybutynin chloride. The results of the trial clearly indicate oxybutynin as the most effective drug in the treatment of the disease.

Autophagy in term normal human placentas.

Autophagy is an inducible catabolic process that responds to environment and is essential for cell survival during stress, starvation and hypoxia. Its function in the human placenta it is not yet understood. We collected 14 placentas: 7 at vaginal delivery and 7 at elective caesarean section after uneventful term pregnancies. The presence of autophagy was assessed in different placental areas by immunoblotting, immunohistochemistry and electron microscopy. We found that autophagy is significantly higher in placentas obtained from cesarean section than in those from vaginal delivery. Moreover there is a significant inverse relationship between autophagy and umbilical arterial glucose concentration.