Association between maternal dupilumab exposure and pregnancy outcomes in patients with moderate-to-severe atopic dermatitis: A nationwide retrospective cohort study.

BACKGROUND: There is limited epidemiological evidence on outcomes associated with dupilumab exposure during pregnancy; monitoring pregnancy outcomes in large populations is required. OBJECTIVE: To investigate the potential association between exposure to dupilumab in pregnant women with atopic dermatitis and any adverse pregnancy, neonatal, congenital and post-partum outcomes. METHODS: We performed a multicentre retrospective cohort study across 19 Italian tertiary referral hospital. Childbearing women were eligible if aged 18-49 years and carried out the pregnancy between 1 October 2018 and 1 September 2022. RESULTS: We retrospectively screened records of 5062 patients receiving dupilumab regardless of age and gender, identifying 951 female atopic dermatitis patients of childbearing age, 29 of whom had been exposed to the drug during pregnancy (3%). The median duration of dupilumab treatment prior to conception was 22.5 weeks (range: 3-118). The median time of exposure to the drug during pregnancy was 6 weeks (range: 2-24). All the documented pregnancies were unplanned, and the drug was discontinued in all cases once pregnancy status was reported. The comparison of the study cohort and the control group found no significant drug-associated risk for adverse pregnancy, congenital, neonatal or post-partum outcomes. The absence of a statistically significant effect of exposure on the event was confirmed by bivariate analysis and multivariate analysis adjusted for other confounding factors. CONCLUSIONS: This cohort of pregnant patients exposed to dupilumab adds to the existing evidence concerning the safety of biologic agents in pregnancy. No safety issues were identified regarding the primary outcome assessed. In clinical practice, these data provide reassurance in case of dupilumab exposure during the first trimester. However, the continuous use of dupilumab throughout pregnancy warrants further research.

Immune Checkpoints in Recurrent Pregnancy Loss: New Insights into a Detrimental and Elusive Disorder.

Recurrent pregnancy loss (RPL) refers to two or more miscarriages before 20 weeks gestation. Its prevalence is 1-2%; its pathogenesis remains unexplained in more than 50% of cases, in which the cause is thought to be abnormal immune activity during placentation leading to a lack of pregnancy-induced immune tolerance. It is unknown whether immune activity is deranged in the endometrium of women with RPL. We studied the gene expression and the quantitative tissue protein levels of three immune checkpoints (CD276, which enhances cytotoxic T-cell activity, cytotoxic T-lymphocyte-associated antigen-4 [CTL-4], which reduces Th1 cytokine production, and lymphocyte activation gene-3 [LAG-3], which shows suppressive activity on Tregs and CD4+ T-cells) in endometrial samples from 27 women with unexplained RPL and in 29 women with dysfunctional uterine bleeding and previous uneventful pregnancies as controls. RNA isolation, real-time PCR, protein isolation, and ELISA were performed. CD276 gene expression and protein tissue levels were significantly lower in the endometrium of the RPL group than in the controls, whereas both CTL-4 and LAG-3 were significantly higher. This difference suggests defective endometrial immune regulation and overactivation of immune response in women with a history of RPL, at least in relation to controls with dysfunctional uterine bleeding and previous normal reproductive history.

Vulvar Paget's disease and stromal invasion: Clinico-pathological features and survival outcomes.

PURPOSE: To evaluate clinico-pathological features, treatments and survival outcomes of vulvar Paget's disease (VPD). METHODS: We retrospectively reviewed VPD diagnosed between 1983 and 2018 at the Department of Surgical Sciences, Sant'Anna Hospital, Turin. Clinico-pathological characteristics and surgical treatment outcomes were investigated according to the depth of invasion. RESULTS: A total of 122 patients were identified. Eighty-seven patients were diagnosed with intraepithelial VPD, 22 with microinvasive (<=1 mm) VPD and 16 with invasive VPD. The median follow-up was 94.6 months (interquartile range 25th-75th, 26-120). Most of patients 95/122 (77%) were treated by surgery. Local recurrence was observed in 69/95 (73%) patients without significant difference between the 3 groups (p = 0.33), however, total vulvectomy showed better local control in microinvasive and invasive VPD than in intraepithelial tumors. At 120 months the cancer-specific survival was 100% for intraepithelial and microinvasive VPD versus 31% for invasive VPD (log-rank p = <0.0001) Age ≥65 years (OR: 4.17 CI 1.12-15.5, p = 0.03) and VPD's area ≥15 cm2 (OR: 5.83 CI 1.75-19.3, p = 0.004) were associated with risk of invasiveness. CONCLUSION: Microinvasive VPD has an identical prognosis to intraepithelial VPD, suggesting the omission of lymphadenectomy or adjuvant treatments are safe in this subset of patients. We recommend caution to propose medical treatment in patients who are ≥65 years old and with wide tumor area, as they are at the greatest risk of invasiveness.

Controlled ovarian stimulation and progesterone supplementation affect vaginal and endometrial microbiota in IVF cycles: a pilot study.

PURPOSE: Does controlled ovarian stimulation (COS) and progesterone (P) luteal supplementation modify the vaginal and endometrial microbiota of women undergoing in vitro fertilization? METHODS: Fifteen women underwent microbiota analysis at two time points: during a mock transfer performed in the luteal phase of the cycle preceding COS, and at the time of fresh embryo transfer (ET). A vaginal swab and the distal extremity of the ET catheter tip were analyzed using next-generation 16SrRNA gene sequencing. Heterogeneity of the bacterial microbiota was assessed according to both the Bray-Curtis similarity index and the Shannon diversity index. RESULTS: Lactobacillus was the most prevalent genus in the vaginal samples, although its relative proportion was reduced by COS plus P supplementation (71.5 ± 40.6% vs. 61.1 ± 44.2%). In the vagina, an increase in pathogenic species was observed, involving Prevotella (3.5 ± 8.9% vs. 12.0 ± 19.4%), and Escherichia coli-Shigella spp. (1.4 ± 5.6% vs. 2.0 ± 7.8%). In the endometrium, the proportion of Lactobacilli slightly decreased (27.4 ± 34.5% vs. 25.0 ± 29.9%); differently, both Prevotella and Atopobium increased (3.4 ± 9.5% vs. 4.7 ± 7.4% and 0.7 ± 1.5% vs. 5.8 ± 12.0%). In both sites, biodiversity was greater after COS (p < 0.05), particularly in the endometrial microbiota, as confirmed by Bray-Curtis analysis of the phylogenetic distance among bacteria genera. Bray-Curtis analysis confirmed significant differences also for the paired endometrium-vagina samples at each time point. CONCLUSIONS: Our findings suggest that COS and P supplementation significantly change the composition of vaginal and endometrial microbiota. The greater instability could affect both endometrial receptivity and placentation. If our findings are confirmed, they may provide a further reason to encourage the freeze-all strategy.

Human Endogenous Retroviruses Are Preferentially Expressed in Mononuclear Cells From Cord Blood Than From Maternal Blood and in the Fetal Part of Placenta.

Background: Placenta shows high transcription levels of human endogenous retroviruses (HERVs) that are overexpressed during embryonic and fetal development. Methods: In order to gather further information on the degree of HERV activation in maternal and fetal tissues we assessed the transcription levels of pol genes of HERV-H, -K, and -W in PBMCs of newborns and their mothers as well as in chorion (fetal part) and decidua basalis (maternal part) of the placenta using a real time PCR assay. Results: Transcripts of pol genes of the three HERV families were significantly higher in mononuclear cells from cord blood than from maternal blood and in the fetal part than in the maternal part of the placenta. Conclusions: The HERV over-expressions in cells and tissues of the offspring are further clues that they play pivotal physiologic roles during early life events and suggest that HERV-driven abnormalities of pregnancy and fetal development may derive mostly from the conceptus, not from the mother.

Maternal age over 40 years and pregnancy outcome: a hospital-based survey.

OBJECTIVE: Increased risk for adverse pregnancy outcomes with advancing maternal age has been described but the strength of association remains debated, particularly in presence of confounding factors such as parity, twin pregnancy and pregnancy from assisted reproductive technologies. The aim of this study was to evaluate pregnancy outcomes in a large cohort of women aged over 40 years. The hypothesis was that advanced maternal age may be an independent risk factor for adverse pregnancy outcome. STUDY DESIGN: We reviewed the clinical records of 56,211 women who delivered at Sant'Anna University Hospital, Turin, Italy, in the period between 2009 and 2015. Of these, 3798 women aged over 40 years were divided into two age groups (40 - 44 years and ≥45 years). Women of any parity, with singleton or twin pregnancies, or with assisted reproductive technology pregnancies were included. Women aged less than 40 years were considered as controls. Primary outcome measures were maternal and perinatal complications. Comparisons were performed using Chi-square test and Fisher's exact test. Univariate analysis and logistic regression analysis were performed to test the possible independent role of maternal age as a risk factor for adverse pregnancy outcome. RESULTS: Maternal age was an independent risk factor for gestational diabetes (age 40-44 years: odds ratios (OR) 2.10, 95% CI 1.80-2.45; age ≥45 years: OR 2.83, 95% CI 1.79-4.46) and early-onset preeclampsia (age 40-44 years: OR 2.10, 95% CI 1.63-2.70; age ≥45 years: OR 3.16, 95% CI 1.68-5.94). The risk for placenta praevia was higher in the women aged 40-44 years (OR 1.87, 95% CI 1.36-2.57). Neonatal outcomes were similar among groups, except for the rate of birth weight less than 2500 g, which was higher in women aged 40-44 years (OR 1.27, 95% CI 1.12-1.42). However, older women showed an overall higher incidence of preterm birth. CONCLUSIONS: Maternal age over 40 years is an independent risk factor for adverse pregnancy outcomes, particularly for the mother. Pregnancies in women over 40 years should be considered at risk and carefully monitored with individualized care protocols.

Arterial stiffness in normal pregnancy at 11-13 weeks of gestation and risk of late-onset hypertensive disorders of pregnancy.

OBJECTIVE: We evaluated the possible correlation between pulse wave analysis (PWA) parameters measured during the first trimester of pregnancy in normotensive, low-risk women, and the development of hypertensive disorders later in pregnancy. Our hypothesis was that a still asymptomatic increase in arterial stiffness may potentially precede the onset of overt hypertension in pregnancy and that PWA could detect it. METHODS: The study population (n = 1648) was recruited at the time of prenatal screening for chromosomal abnormalities (11-12 weeks of gestation). The radial pressure waveform was obtained with an applanation tonometer (Sphygmocor, Atcor Medical, West Ryde, Australia) on pregnant women in recumbent position. Arterial stiffness was evaluated using arterial PWA. The aortic systolic pressure (aSp), aortic diastolic pressure, and aortic mean pressure, the aortic pulse pressure, the augmentation pressure, and the augmentation index were calculated. The main outcome measure was the development of hypertensive disorders later in pregnancy. RESULTS: The values of aSp (P < 0.0001), aortic diastolic pressure (P < 0.0001), aortic mean pressure (P < 0.0001), aortic pulse pressure (P = 0.0140), and augmentation index-75 (P < 0.0001) measured in the first trimester of pregnancy were significantly higher in the women who later developed hypertensive disorders of pregnancy than in those who remained normotensive. The aSp (sensitivity 72.6%; specificity 59.6%) was found to be the best predictor for the later development of hypertension. CONCLUSION: In normotensive, low-risk pregnant women, PWA may be useful for the early detection of risk for the development of hypertensive disorders of pregnancy.

What European gynaecologists need to master: Consensus on medical expertise outcomes of pan-European postgraduate training in obstetrics & gynaecology.

OBJECTIVE: European harmonisation of training standards in postgraduate medical education in Obstetrics and Gynaecology is needed because of the increasing mobility of medical specialists. Harmonisation of training will provide quality assurance of training and promote high quality care throughout Europe. Pan-European training standards should describe medical expertise outcomes that are required from the European gynaecologist. This paper reports on consensus development on the medical expertise outcomes of pan-European training in Obstetrics and Gynaecology. STUDY DESIGN: A Delphi procedure was performed amongst European gynaecologists and trainees in Obstetrics & Gynaecology, to develop consensus on outcomes of training. The consensus procedure consisted of two questionnaire rounds, followed by a consensus meeting. To ensure reasonability and feasibility for implementation of the training standards in Europe, implications of the outcomes were considered in a working group thereafter. We invited 142 gynaecologists and trainees in Obstetrics & Gynaecology for participation representing a wide range of European countries. They were selected through the European Board & College of Obstetrics and Gynaecology and the European Network of Trainees in Obstetrics & Gynaecology. RESULTS: Sixty people participated in round 1 and 2 of the consensus procedure, 38 (63.3%) of whom were gynaecologists and 22 (36.7%) were trainees in Obstetrics & Gynaecology. Twenty-eight European countries were represented in this response. Round 3 of the consensus procedure was performed in a consensus meeting with six experts. Implications of the training outcomes were discussed in a working group meeting, to ensure reasonability and feasibility of the material for implementation in Europe. The entire consensus procedure resulted in a core content of training standards of 188 outcomes, categorised in ten topics. CONCLUSION: European consensus was developed regarding the medical expertise outcomes of pan-European training in Obstetrics and Gynaecology. The outcomes will be described in core trainings standards, aimed at harmonising training in Obstetrics and Gynaecology in Europe to promote high quality care.

Role of the 12q24.12 locus in the onset of preeclampsia: an Italian case-control study.

OBJECTIVE: The 12q24.12 locus has been reported to be involved in the control of many traits and also in severe diseases such as cardiovascular disease, hypertension and some immune-related disease. To our knowledge, no study has been published so far investigating the role of this locus in the pathogenesis of preeclampsia (PE). METHODS: We genotyped four single nucleotide polymorphisms (SNPs) in 12q24.12 locus in 198 preeclamptic, 224 chronic hypertensive and 265 normotensive women from Italy, to test the contribution polymorphisms/haplotypes on the onset of preeclampsia and their association with chronic hypertension. RESULTS: No association was observed for any single SNP, while a common haplotype CGTG (21% in normotensive women) revealed a possible protective effect (OR 0.64, 95% CI 0.42-0.97) against preeclampsia. CONCLUSIONS: Our data suggest that a common haplotype within 12q24.12 locus may be associated with a protective effect against preeclampsia. This observation may be linked with the potential role of this region in the control of microcirculation. To the best of our knowledge, our study is the first one that links the 12q24.12 locus with this life-threatening perinatal complication of unknown etiology. Further physiological and functional studies are needed to clarify the molecular mechanisms and pathways of preeclampsia.

Biochemistry of HELLP syndrome.

The HELLP syndrome is a serious complication of pregnancy characterized by hemolysis (H), elevated liver (EL) enzymes, and low platelet (LP) count that occurs in 0.2-0.6% of all pregnancies and in 10-20% of cases with severe preeclampsia and frequently leads to adverse maternal and perinatal outcome. The exact pathobiology of HELLP syndrome has not been clearly defined. As it is considered a form or a complication of severe preeclampsia, it likely has its origin in aberrant placental development and function resulting in ischemia-producing oxidative stress. However, there is still a debate on whether HELLP must be considered a severe form of preeclampsia or a separate disease entity. It can be described as a placenta-induced disease, as is preeclampsia itself, but with a more acute and predominant inflammatory process typically targeting the liver and with a greater activation of the coagulation system. This occurs during a disordered immunologic process and may be due to a genetic predisposition. In this review, we discuss the main biochemical characteristics of HELLP syndrome, particularly focusing on molecular aspects of placental involvement and maternal systemic responses.

The combined immunodetection of AP-2alpha and YY1 transcription factors is associated with ERBB2 gene overexpression in primary breast tumors.

INTRODUCTION: Overexpression of the ERBB2 oncogene is observed in about 20% of human breast tumors and is the consequence of increased transcription rates frequently associated with gene amplification. Several studies have shown a link between activator protein 2 (AP-2) transcription factors and ERBB2 gene expression in breast cancer cell lines. Moreover, the Yin Yang 1 (YY1) transcription factor has been shown to stimulate AP-2 transcriptional activity on the ERBB2 promoter in vitro. In this report, we examined the relationships between ERBB2, AP-2alpha, and YY1 both in breast cancer tissue specimens and in a mammary cancer cell line. METHODS: ERBB2, AP-2alpha, and YY1 protein levels were analyzed by immunohistochemistry in a panel of 55 primary breast tumors. ERBB2 gene amplification status was determined by fluorescent in situ hybridization. Correlations were evaluated by a chi2 test at a p value of less than 0.05. The functional role of AP-2alpha and YY1 on ERBB2 gene expression was analyzed by small interfering RNA (siRNA) transfection in the BT-474 mammary cancer cell line followed by real-time reverse transcription-polymerase chain reaction and Western blotting. RESULTS: We observed a statistically significant correlation between ERBB2 and AP-2alpha levels in the tumors (p < 0.01). Moreover, associations were found between ERBB2 protein level and the combined high expression of AP-2alpha and YY1 (p < 0.02) as well as between the expression of AP-2alpha and YY1 (p < 0.001). Furthermore, the levels of both AP-2alpha and YY1 proteins were inversely correlated to ERBB2 gene amplification status in the tumors (p < 0.01). Transfection of siRNAs targeting AP-2alpha and AP-2gamma mRNAs in the BT-474 breast cancer cell line repressed the expression of the endogenous ERBB2 gene at both the mRNA and protein levels. Moreover, the additional transfection of an siRNA directed against the YY1 transcript further reduced the ERBB2 protein level, suggesting that AP-2 and YY1 transcription factors cooperate to stimulate the transcription of the ERBB2 gene. CONCLUSION: This study highlights the role of both AP-2alpha and YY1 transcription factors in ERBB2 oncogene overexpression in breast tumors. Our results also suggest that high ERBB2 expression may result either from gene amplification or from increased transcription factor levels.

Analysis of the discriminant ability of shorter versions of the French ADAM questionnaire.

OBJECTIVE: To investigate whether shorter versions of the ADAM test, a screening questionnaire for andropause, provide better diagnostic value than the original tool. METHODS: Five thousand and twenty-eight volunteer men aged 50-70 years attending a screening campaign for andropause, provided a fasting blood sample and completed the French ADAM test. Logistic regression analysis identified items that best predict andropause defined as serum free testosterone level below 70 ng/l. ROC curves assessed the diagnostic value of modified versions of the ADAM test, obtained by elimination of the less relevant predictors of andropause. RESULTS: Only four items of the ADAM questionnaire may account for the diagnosis of andropause. These items concerned loss of height, decrease in libido and in enjoyment of life and deterioration in work performance. Item 9 was borderline significant. The area under the ROC curve for the short versions varied slightly from 0.555 to 0.560. As expected, model 6 has a greater specificity (56.02%) than the original tool while the efficiency increased slightly (54.85%). CONCLUSION: The modified versions of the ADAM test do not provide better diagnostic value than the original tool.

No major month to month variation in free testosterone levels in aging males. Minor impact on the biological diagnosis of 'andropause'.

BACKGROUND: The measurement of bioavailable testosterone (BT) or free testosterone (FT) levels is currently considered the gold standard for the diagnosis of androgen deficiency in elderly men. While the impact of age on circulating testosterone levels (total, bioavailable and free) has been strongly documented, the existence of seasonal variations in testosterone levels remains debated. OBJECTIVE: We investigated whether seasonal variations in serum calculated free testosterone (cFT) levels may translate into variations in the prevalence of low testosterone levels. Diagnosis was on the basis of biochemical determinations and was cross-checked with the prevalence of clinical signs and symptoms of 'andropause', as assessed by the Androgen Deficiency in Aging Males (ADAM) questionnaire. METHODS: The study recruited 5028 men aged 50 years and over from September 2000 to January 2003. Their serum FT levels were assessed and they completed the French ADAM test. Men were considered eugonadal when cFT was > or =70 ng/l. The ADAM test was scored as described originally. The prevalence of 'andropause', diagnosed by the two methods, was compared throughout the year, on a month by month basis. RESULTS: The percentage of subjects with cFT levels below 70 ng/l increased significantly with age (P<0.001). Serum cFT levels (mean [SD]) varied significantly with the month of sampling (P<0.0001), the highest (88.1 [30.2] ng/l) and lowest (76.9 [28.0] ng/l) mean values occurring in April and in October, respectively. Conversely, the prevalence of testosterone deficiency (cFT<70 ng/l) reached a peak in October (45.7%) and a nadir in April (29.7%). Although the prevalence of 'andropause', based on the ADAM questionnaire, increased significantly with age (P<0.0001), no influence of the month of the year was noticed. CONCLUSIONS: Our results confirm a progressive age-related decline in FT levels. The monthly variations in serum FT values, observed throughout the year, do not show a major seasonal rhythm in elderly community-dwelling males, since the magnitude of the variations (<15%) remains marginal. This slight variation may, however, have an impact on the number of elderly men diagnosed with Partial Androgen Deficiency in Aging Males (PADAM).

Interest of the androgen deficiency in aging males (ADAM) questionnaire for the identification of hypogonadism in elderly community-dwelling male volunteers.

OBJECTIVE: To date, serum free testosterone measurement is considered to be the gold standard for the diagnosis of hypogonadism in elderly males but it is not available to all subjects suspected of a decrease in testicular function. Therefore, we evaluated whether the Androgen Deficiency in Aging Males (ADAM) questionnaire, in its original or in a modified 'quantitative' version (qADAM), could be used as a surrogate to biochemical determinations for the identification of hypogonadism in elderly males. METHODS: 5028 men, aged 50-70 years, spontaneously consulting for the assessment of their gonadal function were studied. ADAM and qADAM, allocating a value of 1 point for any positive answer to each of the 10 questions of the ADAM test, were assessed for their ability to discriminate between males with free testosterone levels below or above 70 ng/l. RESULTS: The sensitivity and specificity of the ADAM score were 81% and 21.6% respectively. The use of ADAM resulted in an appropriate classification of our population in normal or hypogonadal subjects in 44.5% of the cases. The area under the receiver operating characteristics (ROC) curve for the qADAM (0.529) revealed a highly marginal interest of this quantitative approach compared with the original scoring system. CONCLUSIONS: The ADAM test has a high sensitivity to identify aging males with low free testosterone levels. However, due to its lack of specificity, this test cannot be used as a surrogate to serum free testosterone testing for the identification of androgen deficiency in elderly, community-dwelling males.

Do utility values and willingness to pay suitably reflect health outcome in hip and knee osteoarthritis? A comparative analysis with the WOMAC Index.

OBJECTIVE: To establish whether health utility (time trade-off, TTO) and willingness to pay (WTP) values reflect clinical health outcome as evaluated by the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) in hip and knee osteoarthritis (OA). METHODS: One hundred twenty-eight patients with OA attending a specialized arthritis clinic were interviewed about their socioeconomic characteristics and administered the TTO technique and the WOMAC. Their WTP for 2 hypothetical anti-osteoarthritic drugs was also investigated: the first drug was said to provide a significant improvement in WOMAC dimensions and the second a complete cure of the disease. WTP was elicited by both discrete-choice and bidding game methods. Results. Answer rates were 89.1% for TTO, 98.4% for discrete-choice WTP for both scenarios, and 89.8% and 85.2% for bidding game WTP in the relief and the cure scenario, respectively. The mean TTO utility value was 0.84 (standard deviation 0.20). In discrete-choice, those accepting the bid had higher monthly income (EURO 1536.5 vs EURO 1060.1, p < 0.001, for the relief scenario and EURO 1449.3 vs EURO 1071.6, p < 0.001, for the cure scenario). With the bidding game format, WTP was positively correlated with income in both scenarios (r = 0.56, r = 0.55, p < 0.001). WTP measures differed equally between education and socioeconomic groups with those in favored groups consistently reporting higher WTP (Kruskal-Wallis tests statistics ranging from p < 0.01 to p < 0.001). Except for stiffness, WOMAC dimensions were correlated in the expected direction with TTO values (r = -0.27, p < 0.01 for pain and r = -0.36, r = -0.34, p < 0.001 for physical function and total score, respectively). CONCLUSION: Whereas they showed good feasibility, WTP measures poorly reflected clinical condition and were mainly related to economic status and ability to pay. TTO was correlated with the WOMAC dimensions and may be considered closer to clinical situations than WTP. However, concern arises regarding the homogeneity of the study sample in terms of clinical severity, which may have precluded the identification of a relationship between WTP and clinical status.