B-cell-activating factor (BAFF) and platelet-activating factor (PAF) in pregnancies complicated by maternal obesity and diabetes: a preliminary study.

OBJECTIVE: In pregnancies complicated by maternal obesity and diabetes, a disruption in inflammatory mediators occurs, resulting in endothelial microvascular dysfunction, oxidative stress, tissue damage, and maternal and feto-neonatal complications. To outline this proinflammatory status, an innovative approach is represented by the measurement of proinflammatory cytokines. Among these biomarkers, B-cell-activating factor (BAFF) and platelet-activating factor (PAF) play a key role in metabolic regulation, immune response to infections, tissue homeostasis, and "food-related inflammation." The aim of the present study is to investigate the blood expression of BAFF and PAF in a cohort of pregnant women affected by obesity and diabetes compared with a control group of healthy pregnant women. METHODS: A prospective longitudinal cohort study has been conducted on pregnant women referred to Fondazione Policlinico Universitario Gemelli IRCCS in Rome. For each pregnant woman, a capillary sample was collected with a swab in three different consecutive evaluations carried out in the three trimesters of pregnancy. RESULTS: A total of 77 pregnant women have been enrolled. No significant differences in BAFF and PAF levels were longitudinally observed between groups. Focusing on the exposed group, in the third trimester of pregnancy, both PAF and BAFF levels were lower than the basal time. Among the selected group of patients who developed Gestational Diabetes, only PAF values were longitudinally lower when compared to other groups. The multivariate analysis showed that BAFF levels were positively correlated with thyroid-stimulating hormone levels. No macrosomia, no shoulder dystocia, no major perineal lacerations at birth, and no intrauterine growth restriction were observed in the whole population. CONCLUSIONS: This study supports the involvement of metabolic and proinflammatory biomarkers in the mechanisms related to pregnancy complications. Improving a good metabolic environment for obese and diabetic pregnant women could break the vicious cycle connecting inflammation, oxidative stress, and metabolic disorders.

Maternal position during the second stage of labor and maternal-neonatal outcomes in nulliparous women: a retrospective cohort study.

BACKGROUND: The existing evidence is insufficient to draw conclusions about the association between maternal position in labor and obstetrical outcomes. OBJECTIVE: This study aimed to evaluate the effects of different maternal positions during the second stage of labor among women with and those without epidural analgesia on important obstetrical outcomes including perineal damage. STUDY DESIGN: In this retrospective cohort study, we collected data of women who delivered vaginally over a 2-year period. The associations between maternal and gestational characteristics and several obstetrical outcomes were analyzed. We considered perineal damage as the primary outcome. Secondary outcomes were the incidence of operative vaginal births, duration of fetal descent, intrapartum blood loss, and 1-minute and 5-minutes Apgar scores. RESULTS: A total of 2240 nulliparous, at-term pregnancies were included. Of those, 76.9% gave birth in a supine position and 23.1% gave birth in alternative positions. The results showed that regardless of the use of epidural analgesia, nonsupine positions in the second stage of labor are associated with a significant reduction in the risk of both episiotomy and perineal damage to any degree (P<.0001) and to a reduction in the duration of fetal descent (Spearman rho, 9.17; confidence interval, 3.07-15.32; P=.003). No statistically significant differences were found in the 1-minute and 5-minutes Apgar score between the 2 groups. CONCLUSION: Our results show that nonsupine positions in the second stage of labor and at the time of birth are associated with a significant increase in having an intact perineum and a reduction in any perineal trauma and in the need for an episiotomy regardless of the use of epidural analgesia.

Multiple Pregnancy and the Risk of Postpartum Hemorrhage: Retrospective Analysis in a Tertiary Level Center of Care.

The aim of our study was to identify characteristics associated with postpartum hemorrhage (PPH defined as blood loss >1000 mL) in twin pregnancies in order to select patients at higher risk to be treated. This retrospective study includes multiple pregnancies between 2015 and 2020. The possible association between pregnancy characteristics and the primary endpoint (occurrence of PPH) was conducted using chi-square or Fisher exact test and Wilcoxon test. Then, univariate logistic models were performed considering as outcome the PPH, and the odds ratios with 95% CI were estimated. Finally, a multivariate logistic model was implemented, including all significant covariates. Seven hundred seven twin pregnancies giving birth beyond 32 weeks were included and of those, 120 (16.97%) had a PPH. The univariate analysis showed that factors significantly associated with PPH were: Preterm delivery, episiotomy, neonatal weight, and mode of delivery. The multivariate analysis showed that the most important factors were episiotomy and neonatal weight. The results show that the performance of episiotomy and the neonatal weight are the factors that most impact the risk of PPH in twin pregnancies. The correct identification of factors associated with PPH in twins could ideally allow to modify the clinical management and positively affect the rate of complications.

Impact of maternal obesity on the risk of preterm delivery: insights into pathogenic mechanisms.

PURPOSE: Preterm delivery (PTD) represents the leading cause of neonatal death and disability. Among risk factors for PTD, maternal obesity (MO) is becoming an ever more relevant condition in developed countries, although the mechanisms relating this condition to higher risk of PTD is not clear. Aim of this narrative review is to summarize evidences from clinical and translational research showing how MO might negatively impact on pregnancy and neonatal outcomes, particularly, by increasing the risk of PTD. METHODS: We performed comprehensive review of the literature in PubMed and Google Scholar databases for studies from 1998 to 2018 linking MO to PTD and inflammation. RESULTS: Chronic inflammatory status associated to increased synthesis of adipokines and cytokines from fat tissue has been shown in obesity. Obese women have a higher risk of both spontaneous and medically induced PTD. In about 50% of cases of spontaneous PTD, an infection-induced chorion amnionitis can be detected while in the remaining 50% a sterile inflammatory response has been described. Activation of uterine innate immunity system in intra-amniotic cavity and in chorioamniotic membranes might represent the missing link between MO and the pathogenesis of PTD. CONCLUSION: Tissue inflammation might represent the pathogenic link between MO and increased occurrence of PTD. The achievement of pre-pregnancy normal maternal weight and body mass index is a fundamental aim of public health to reduce the incidence of PTD and get optimal reproductive outcomes.

Microbiome and Gestational Diabetes: Interactions with Pregnancy Outcome and Long-Term Infant Health.

Microbiota composition is progressively being connected to different physiologic effects, such as glucose metabolism, and also to different pathologies, such as gestational diabetes mellitus (GDM). GDM is a public health concern that affects an important percentage of pregnancies and is correlated with many adverse maternal and neonatal outcomes. An increasing number of studies are showing some connections between specific microbial composition of the gut microbiota and development of GDM and adverse outcomes in mothers and neonates. The aim of this review is to analyze the available data on microbial changes that characterize healthy pregnancies and pregnancies complicated by GDM and to understand the correlation of these changes with adverse maternal outcomes; this review will also discuss the consequences of these maternal gut microbiome alterations on neonatal microbiota composition and neonatal long-term outcomes.

Circulating Placental Vesicles Carry HLA-DR in Pre-Eclampsia: A New Potential Marker of the Syndrome.

Background: Pre-eclampsia (PE) is a common disorder of pregnancy that usually presents with hypertension and proteinuria. The clinical presentation arises from soluble factors released into the maternal circulation from the placenta owing to the stress of syncytiotrophoblast, consequence of defective placentation occurring in the first half of pregnancy. Reduced tolerance of the semiallogeneic fetus by the maternal immune system has been proposed as first trigger leading to poor placentation. We previously observed aberrant expression of human leukocyte antigen (HLA)-DR molecules in the syncytiotrophoblast of a subset of women with PE. Aim of this study was to investigate abnormal expression of circulating HLA-DR in syncytiotrophoblast-derived extracellular vesicles (STBEVs) in women with PE compared to normal pregnant women. Methods: peripheral venous blood was collected from 22 women with PE and 22 normal pregnant women. Circulating STBEVs were collected by ultra-centrifugation (120000 g) and analyzed for the expression of HLA-DR and placental alkaline phosphatase (PLAP), a specific marker of the placenta, by Western blot analysis and flow cytometry. Results: circulating STBEVs positive for HLA-DR were observed in 64% of PE women while no HLA-DR positivity was detected in any of the controls (P<0.01). Conclusions: Aberrant expression of HLA-DR in circulating STBEVs is specifically associated to PE. Further studies are required: a) to define the role of aberrant placental expression of HLA-DR molecules in the pathogenesis of PE; b) evaluate a possible application of detecting circulating HLA-DR positive STBEVs in the diagnosis and prediction of PE in the first and second trimester of pregnancy.

Role of Human Leukocyte Antigens at the Feto-Maternal Interface in Normal and Pathological Pregnancy: An Update.

The successful maternal tolerance of the semi-allogeneic fetus provides an apparent immunologic paradox. Indeed, deep invasion of placental trophoblast cells into maternal uterine tissue and the following growth of the fetus have to be tolerated by a pregnant woman's immune system. Among the various possible protective mechanisms that may be involved in human pregnancy, the expression of a non-classical pattern of human leukocyte antigen (HLA) class I molecules and the complete lack of expression of HLA class II molecules in placental tissues seem to be the most relevant mechanisms of fetal escape from maternal immune recognition. The importance of HLA molecules in fetal toleration by the maternal immune system is highlighted by pregnancy complications occurring in cases of abnormal HLA molecule expression at the maternal-fetal interface. In this review, we summarize evidences about the role of placental HLA molecules in normal and pathological pregnancies.

Vaginal birth after caesarean section: a multicentre study on prognostic factors and feasibility.

PURPOSE: Vaginal birth after caesarean (VBAC) is an option to avoid major abdominal surgery and many consequences related to repeated caesarean delivery. In the last years, many efforts have been made to increase the number of patients attempting trial of labour after caesarean (TOLAC). The aim of our study was to identify the most important factors associated with the success of VBAC. METHODS: A retrospective study was conducted in two Italian referral centres. Subjects included were singleton and morphologically normal pregnancy with previous C-section. Subjects with an inter-pregnancy interval shorter than 18 months, a large for gestational age baby, a pregnancy complicated with gestational diabetes and a previous unclassified uterine scar were excluded. The characteristics of the subjects were compared and a logistic regression was performed to evaluate variables associated with successful VBAC. RESULTS: Of the 300 patients included, 224 (74.7%) achieved VBAC while 76 (25.3%) underwent C-section after failed TOLAC. The number of previous C-sections was not significantly associated with the success of TOLAC. Factors positively associated with achievement of VBAC were previous vaginal delivery (OR of 6.88 for one and 9.68 for more than one) and oxytocin implementation (OR 3.32). No maternal and neonatal adverse events occurred. CONCLUSION: Our results show that attempting VBAC is a feasible option in referral centres after adequate evaluation of the potential factors affecting the probability of success. A careful record of obstetrical history and management of labour can provide clinicians useful information to counsel women before and during labour.

Fetal Doppler Parameters at Term in Pregnancies Affected by Gestational Diabetes: Role in the Prediction of Perinatal Outcomes.

OBJECTIVE: The timing of delivery for women affected by gestational diabetes (GDM) is still controversial. Good clinical practice often suggests offering induction of labor at term in order to reduce the complications associated with this condition, while recent evidence supports expectant management. Fetal Doppler parameters represent a validated tool for testing fetal well-being at term and can select pregnancies that need increased surveillance. The aim of the present study was to evaluate the role of fetal Doppler parameters at term for the prediction of pregnancy outcomes in patients affected by GDM. METHODS: Prospective cohort study in a single center. Evaluation of umbilical artery (UA) PI, middle cerebral artery (MCA) PI, cerebroplacental ratio (CPR) and umbilical-to-cerebral ratio (UCR) at > 37 weeks of gestation in singleton, morphologically normal pregnancies affected by GDM, was performed in order to estimate the association between ultrasound measurements at term and perinatal outcome. Regression linear analysis was used to estimate the association between fetal Doppler parameters and neonatal pH, neonatal Apgar score, neonatal weight and a composite adverse outcome. The receiver operating characteristic (ROC) curve was used to estimate the possible predictive value of the above association. RESULTS: Our results on 130 women showed MCA PI to be the best predictor of perinatal outcomes in terms of low Apgar score at the 1st minute (p = 0.00), pH (p = 0.02) and composite adverse outcome (p = 0.05). UCR showed a significant correlation with neonatal pH (p = 0.02). No significant correlations for UA PI and CPR MoMs have been demonstrated in our population. However, the small sample size is a limitation of the study. CONCLUSION: Evaluation of MCA Doppler and eventually UCR at term can be a useful tool to discriminate pregnancies affected by GDM that can benefit from IOL before 41 weeks in order to reduce complications related to this condition.

Managing fertile women under lithium treatment: the challenge of a Teratology Information Service.

BACKGROUND: The objective of the present study is to review the literature regarding the management of fertile patients under lithium treatment for bipolar disorder and to report the experience of our Teratology Information Service over the past thirteen years in managing women treated with lithium during preconception, pregnancy and breastfeeding. METHODS: This research focuses on a selective review of the literature and a retrospective survey has been carried out on fertile women under lithium treatment who called our service at A. Gemelli University Hospital in Rome from May 2002 to December 2015. RESULTS: A total of 140 women under lithium treatment called our TIS. A complete follow-up has been performed on 34 patients: 29 called during pregnancy and 5 called during preconception. None of the patients called during breastfeeding, while half of the patients were taking concomitant drugs during pregnancy. One major cardiac malformation (hypoplastic left heart syndrome) has been reported. No minor malformations have been detected. Twenty-one patients delivered a living child, with one premature neonate. Two patients underwent voluntary interruption of pregnancy and six patients had early spontaneous abortion. In one patient, intrauterine growth retardation occurred, but with no adverse neonatal outcomes. Four neonates experienced transient respiratory distress at birth. Two children developed mild to severe language delay, but normal motor development. CONCLUSIONS: Lithium treatment in fertile women is a very delicate topic, where risks and benefits of discontinuing therapy when women plan to become pregnant should be accurately evaluated. Thorough peri-conceptional counselling is crucial for the outcome of pregnancy and for maternal health status during preconception, gestation and breastfeeding.

Oral misoprostol versus intravaginal dinoprostone for labor induction: a comparison study.

BACKGROUND: Induction of labor (IOL) is one of the most common procedures performed in obstetrics, accounting for about the 20% of deliveries in the developed countries and it still represents a challenge to obstetricians. The aim of this study is the comparison between two techniques for IOL: oral misoprostol and Propess®. METHODS: A retrospective study has been carried out in a single tertiary referral center. Clinical maternal, fetal and neonatal information was recorded. RESULTS: A total of 863 women were included. the vaginal delivery (VD) rate was significantly higher in the misoprostol group. The cesarean section rate was comparable between groups. Adverse events and neonatal outcomes were comparable between groups. CONCLUSIONS: Misoprostol shows a higher VD rate with fewer patients needing a second type of induction and a shorter time to the onset of active labor and to VD.

Chronic exposure to high doses of selenium in the first trimester of pregnancy: Case report and brief literature review.

BACKGROUND: Obstetricians usually prescribe supplements during pregnancy without actual indication. The use of selenium during pregnancy has increased, due to its function in several antioxidant mechanisms. CASE: A pregnant woman received 200,000 micrograms (µg) per day of a selenium galenic formulation, since gestational week (g.w.) 7 to 12, due to a prescription error. The patient experienced nausea, vomiting, hand and foot paresthesia, followed by fatigue, loss of fingernails and hair. The woman was referred to our Fetal and Maternal Medicine Unit for surveillance. The mother's blood selenium levels went back to normal 13 weeks after arrest and the baby was born at term, without complications. Clinical evaluation and imaging studies were normal at one month of age. CONCLUSION: This is the first case of severe chronic selenium intoxication during the first trimester of pregnancy. In the present case, no consequences of congenital defects or pregnancy complications occurred. However, since vitamins, minerals, and food supplements may be harmful and prescription errors occur, obstetricians should avoid prescribing supplements in the absence of maternal deficiency.

Glaucoma Drug Therapy in Pregnancy: Literature Review and Teratology Information Service (TIS) Case Series.

BACKGROUND: There are many contradictions about pregnancy and fetal/neonatal outcomes after topical use of timolol alone or timolol in combination with other antiglaucoma medications. METHODS: Seventy-five pregnant women exposed to antiglaucoma medications were followed prospectively by phone interviews. 27 women used timolol as monotherapy, 48 women used timolol as a part of multidrug therapy. We selected a control group of 187 healthy pregnant women. RESULTS: Topical use of timolol alone or timolol in combination with other antiglaucoma medications does not influence pregnancy or fetal/neonatal outcomes. CONCLUSION: Beta-blocker is the first choice treatment for glaucoma in pregnancy but, when necessary, multidrug therapy should not to be excluded.

Males are from Mars, and females are from Venus: sex-specific fetal brain gene expression signatures in a mouse model of maternal diet-induced obesity.

BACKGROUND: Maternal obesity is associated with adverse neurodevelopmental outcomes in children, including autism spectrum disorders, developmental delay, and attention-deficit hyperactivity disorder. The underlying mechanisms remain unclear. We previously identified second-trimester amniotic fluid and term cord blood gene expression patterns suggesting dysregulated brain development in fetuses of obese compared with lean women. OBJECTIVE: We sought to investigate the biological significance of these findings in a mouse model of maternal diet-induced obesity. We evaluated sex-specific differences in fetal growth, brain gene expression signatures, and associated pathways. STUDY DESIGN: Female C57BL/6J mice were fed a 60% high-fat diet or 10% fat control diet for 12-14 weeks prior to mating. During pregnancy, obese dams continued on the high-fat diet or transitioned to the control diet. Lean dams stayed on the control diet. On embryonic day 17.5, embryos were weighed and fetal brains were snap frozen. RNA was extracted from male and female forebrains (10 per diet group per sex) and hybridized to whole-genome expression arrays. Significantly differentially expressed genes were identified using a Welch's t test with the Benjamini-Hochberg correction. Functional analyses were performed using ingenuity pathways analysis and gene set enrichment analysis. RESULTS: Embryos of dams on the high-fat diet were significantly smaller than controls, with males more severely affected than females (P = .01). Maternal obesity and maternal obesity with dietary change in pregnancy resulted in significantly more dysregulated genes in male vs female fetal brains (386 vs 66, P < .001). Maternal obesity with and without dietary change in pregnancy was associated with unique brain gene expression signatures for each sex, with an overlap of only 1 gene. Changing obese dams to a control diet in pregnancy resulted in more differentially expressed genes in the fetal brain than maternal obesity alone. Functional analyses identified common dysregulated pathways in both sexes, but maternal obesity and maternal dietary change affected different aspects of brain development in males compared with females. CONCLUSION: Maternal obesity is associated with sex-specific differences in fetal size and fetal brain gene expression signatures. Male fetal growth and brain gene expression may be more sensitive to environmental influences during pregnancy. Maternal diet during pregnancy has a significant impact on the embryonic brain transcriptome. It is important to consider both fetal sex and maternal diet when evaluating the effects of maternal obesity on fetal neurodevelopment.

Effects of Maternal Obesity on Fetal Programming: Molecular Approaches.

Maternal obesity has become a worldwide epidemic. Obesity and a high-fat diet have been shown to have deleterious effects on fetal programming, predisposing offspring to adverse cardiometabolic and neurodevelopmental outcomes. Although large epidemiological studies have shown an association between maternal obesity and adverse outcomes for offspring, the underlying mechanisms remain unclear. Molecular approaches have played a key role in elucidating the mechanistic underpinnings of fetal malprogramming in the setting of maternal obesity. These approaches include, among others, characterization of epigenetic modifications, microRNA expression, the gut microbiome, the transcriptome, and evaluation of specific mRNA expression via quantitative reverse transcription polmerase chain reaction (RT-qPCR) in fetuses and offspring of obese females. This work will review the data from animal models and human fluids/cells regarding the effects of maternal obesity on fetal and offspring neurodevelopment and cardiometabolic outcomes, with a particular focus on molecular approaches.

The FG syndrome from a pathological perspective.

We report on a case of FG syndrome in an almost 6-year-old boy, diagnosed post-mortem. The description of the intellectual and behavior phenotype provided by the mother, together with the evidence gathered at autopsy, were sufficient to reach a clinical diagnosis. The mother had mild manifestations, including a symptomatic tethered cord, which established her as a carrier of the putative mutation causing the syndrome in the son. The propositus' phenotype did not suggest involvement of the MED12 gene.

Unexpected finding of a paternal premutation of the fragile X FMR1 gene in a female fetus of a premutation carrier mother.

We report on the fortuitous finding of a paternal premutation of the FMR1 gene during prenatal diagnosis in a female fetus whose mother was known to be a premutation carrier. Analysis of the DNA, extracted from cultured cells obtained by chorionic villus sampling, demonstrated the presence in the fetus of two FMR1 alleles of 23 and 71 CGG repeats, respectively. Chromosome analysis confirmed a normal female karyotype. The mother was known to be carrier of a normal allele of 23 repeats and a premutation of 79 repeats. Because the 23-CGG repeat allele is uncommon, we wanted to confirm its presence in the father, also given that a reduction in size from 79 to 71 repeats of the putative maternal allele is an unlikely event. Analysis of the father's DNA did in fact show that he is a carrier of a 69-CGG premutated allele. Therefore, the fetus inherited the normal 23-CGG allele from the mother and the 71-CGG allele from the father. Although a parental couple composed of two premutation carriers is rare, this case illustrates the importance of characterizing both parental genotypes when the results of prenatal diagnosis suggest an unusual segregation of the mutant and/or normal allele.

Morphology and immunophenotyping of a monolateral ovotestis in a 46,XderY/45,X mosaic individual with ambiguous genitalia.

Disorders of sexual development represent a pathologic and clinical challenge. Many different clinical syndromes exist, and several classifications have been proposed in relation to different risks for malignant degeneration. The morphology, cytogenetics, and immunophenotype of a monolateral ovotestis in a 3-month-old individual with ambiguous genitalia and right inguinal mass are reported. The inguinal mass consisted of a tiny female genital tract with a hermaphroditic gonad with focal placental-like alkaline phosphatase-stained gonocytes; chromosome analysis disclosed a mosaic constitution: 46,XderY/45,X with a rearranged Y chromosome. A sharp morphologic distinction between true hermaphroditism and mixed gonadal dysgenesis probably does not exist, and cytogenetic characterization is mandatory. The presence of placental-like alkaline phosphatase-stained gonocytes indicates a high risk of malignant transformation, and justifies the surgical removal of the dysgenetic gonad. Fertility is unlikely.