Comparison between trans-vaginal and trans-abdominal ultrasound examination of the cervix in the second trimester of pregnancy: a prospective study.

OBJECTIVES: To compare transvaginal (TV) and trans-abdominal (TA) ultrasound assessment of cervical length (CL) at the time of the second-trimester scan for fetal anomalies. METHODS: This was a prospective study including consecutive pregnant women attending the low-risk ultrasound clinic of two fetal medicine centres in Italy. The inclusion criteria were women between 19 + 0 and 22 + 0 weeks of gestation, attending the prenatal ultrasound clinic for the routine second trimester screening for fetal anomalies. The primary outcome was to compare the CL measurement obtained at TV compared to TA ultrasound; the secondary outcome was to report the inter and intra-observer variability of CL measured with the two different approaches. All women underwent TV and TA assessment of the cervix performed by two experienced certified operators, blinded to each other. Intra-class correlation coefficients (ICC) and Bland-Altman analyses were used to analyse the data. RESULTS: Two hundred and fifty women were included in the analysis. All women had anteverted uterus. The mean gestational age at ultrasound was 20.7 ± 0.7 weeks; 1.2 % (3/250) scans were performed at 19 weeks, 49.2 % (123/250) at 20 weeks, 44.8 % (112/250) at 21 weeks and 4.8 % (12/250) at 22 weeks of gestations. Identification of the major landmarks of CL at TA ultrasound was achieved in all the included cases. There was good reliability between CL measured at TA (ICC 0.95, 95 % CI 0.93-0.97 for observer 1 and 0.92 %, 95 % CI 0.89-0.94 for observer 2) and TV ultrasound 0.97, 95 % CI 0.96-0.98 for observer 1 and 0.96, 95 % CI 0.95-0.97 for observer 2). There was also good reliability between the two observers for both the TA and TV assessment of the CL. Mean TA CL was 41.4 ± 5.5 for observer 1 and 40.5 ± 4.8 for observer 2 with no significant differences between the two measurements (mean difference 0.92 mm, 95 % CI -9.7 to 11.2). Likewise, there was no difference between the CL measured at TV ultrasound between the two observers (mean difference -0.83 mm, 95 % CI -5.97 to 4.30). Finally, there was no difference in the mean CL measured at TA compared to TV, either considering the overall population of women (mean difference: -0.43, 955 CI -8.65 to 7.79), or when stratifying the analysis according to the parity status and the operator. CONCLUSIONS: Among experienced operators, there was no difference between TV and TA ultrasound assessment of the CL at the time of the routine anomaly scan for fetal anomaly.

Prevalence and burden of nausea and vomiting in pregnant women: Interim analysis of the PURITY survey.

OBJECTIVES: Nausea and vomiting in pregnancy is a common and invalidating condition in early pregnancy. However, no data are available on its prevalence in Italy. This survey aims to evaluate the prevalence and impact of nausea and vomiting during pregnancy on the quality of life of Italian women. STUDY DESIGN: The survey was performed in three Italian public University Hospitals in two distinct periods: a first interview took place between the 18th and 22nd week of pregnancy, using the Questionnaire for Pregnancy Period (14 questions regarding demographic data and 30 questions about nausea and vomiting in pregnancy, including Pregnancy-Unique Quantification of Emesis questionnaire), and a follow-up interview, by telephone call, took place immediately after giving birth and in any case within 14 days of delivery, using the Questionnaire for Post-Pregnancy (9 questions). Included women were Caucasian, in physiological pregnancy and between the 18th and 22nd week (time of morphological ultrasound), able to communicate adequately with the interviewer, understand the questionnaires and able to provide valid informed consent. Twin pregnancies and women who recurred to medically assisted procreation were excluded. This is an interim report on data collected from 232 of the planned 600 women. RESULTS: Mean age of the recruited subjects was 32.6 ± 4.6 years, with approximately 60% primiparous. The prevalence of nausea and vomiting in pregnancy in the sample examined was 65.5% overall (152 out of 232 subjects). Of these 152 women, 63 (41.4%) experienced only nausea, 6 (3.9%) only vomiting, and 83 (54.6%) reported both. Symptoms were reported to begin at 7.2 ± 2.7 weeks, lasted 10.2 ± 5.6 weeks, and persisted at the time of the interview in 32.2% of cases. Overall, over 50% of the women interviewed experienced a negative impact of nausea and vomiting in pregnancy on social relationships and work activity. CONCLUSIONS: A high prevalence of nausea and vomiting in pregnancy, 65.5% overall, was found in this interim analysis. These symptoms appeared capable of negatively influencing women quality of life. Screening procedures should be offered during pregnancy and measures that address nausea and vomiting in pregnancy impact warranted.

Extracellular vesicles during the three trimesters of pregnancy.

OBJECTIVES: Extracellular vesicles (EVs) are cell-derived particles released during different pathophysiological processes and emerging as relevant players in inter-cellular crosstalk. Previous studies have highlighted the role of EVs as potential biomarkers for several pregnancy complications, including miscarriage, pre-eclampsia and gestational diabetes. Despite that, the actual distribution of EVs through gestation has not been reported yet. The aim of this study was to report the concentration of different sub-types of EVs in the first, second and third trimester of pregnancy and to correlate them with different pregnancy and ultrasound characteristics. STUDY DESIGNS: Prospective observational study including uncomplicated pregnancies in the first, second and third trimester of pregnancy. The first aim of the study was to report the concentration of the EVs derived from endothelial, epithelial, platelet and leukocyte cells of maternal peripheral blood samples in the first, second and third trimester pregnancy using polychromatic flow cytometry. The secondary aim was to correlate EVs with neonatal birthweight and fetal Dopplers, including uterine and umbilical arteries. Un and multivariate analyses were used to compute the data. RESULTS: 64 women (20 in the first, 22 in the second and 22 in the third trimester of pregnancies) were included in the analysis. There was no difference in the median concentration of either platelet, leukocyte and endothelial EVs between the first, second and third trimester of pregnancy. The concentration of epithelial derived EVs was higher in the third compared to first and second trimester of pregnancy. When analyzing the percentage of EV vesicles through gestation, there was no difference in the percentage of either leukocyte or endothelial EVs through gestation. Conversely, the median percentage of platelet derived vesicles was higher in the first (48.7 %, IQR 34.1-58.5) compared to second (34.0 %, IQR 22.7-44.9) and third (9.13 %, IQR 5.01-12.1) trimester of pregnancy, while the median percentage of third trimester (6.01, IQR 2.42-7.34) epithelial derived vesicles was higher than that of the second (1.53 %, IQR 0.65-2.98), but not of the first (4.45 %, IQR 1.44-6.07) trimester. Finally, we found no association between the median concentration or percentage of endothelial, epithelial, leukocyte vesicles, neonatal birthweight and fetal or maternal Dopplers. CONCLUSIONS: Distribution of EVs examined does not change during the three trimesters of pregnancy and is not influenced by neonatal birthweight or maternal and fetal Dopplers. The findings from this study allows a more objective interpretation of studies comparing EVs in pregnancies with compared to those without obstetric complication. EVs in future can be used for "liquid biopsy" for the early diagnosis of pathological pregnancies up to the development of possible screening protocols.

Whole exome sequencing in fetuses with isolated increased nuchal translucency: a systematic review and meta-analysis.

OBJECTIVE: To estimate the incremental yield of detecting pathogenic or likely pathogenic diagnostic genetic variants (DGV) by whole exome sequencing (WES) over standard karyotype and chromosomal microarray (CMA) analyses in fetuses with isolated increased nuchal translucency (NT) and normal fetal anatomy at the time of 11-14 weeks scan. MATERIALS AND METHODS: Medline and Embase databases were searched. Inclusion criteria were fetuses with NT >95th percentile, normal karyotype and CMA and no associated structural anomalies at the time of the 11-14 weeks scan. The primary outcome was to estimate the incremental yield of detecting pathogenic or likely pathogenic genetic variants by WES over standard karyotype and CMA analyses in fetuses with isolated increased nuchal translucency. The secondary outcomes were the detection of a genetic variant of unknown significance. Sub-analysis according to different NT cutoffs (between 3.0 and 5.5 mm and > 5.5 mm) and considering fetuses with isolated NT in which fetal anatomy was confirmed to be normal at the anomaly scan were also performed. Random effects model meta-analyses of proportion were used to analyze the data. RESULTS: Eight articles (324 fetuses) were included in the systematic review. Of the fetuses with negative standard karyotype and CMA analysis, the 8.07% (95% CI 5.4-11.3) had pathogenic or likely pathogenic genetic variants detected exclusively by WES. When stratifying the analysis according to NT cutoffs, genetic anomalies detected exclusively at WES analysis were found in 44.70% (95% CI 26.8-63.4) of fetuses with NT between 3.0 mm and 5.5 mm and 55.3% (95% CI 36.6-73.2) in those fetuses with NT >5.5 mm and positive WES results. The 7.84% (95% CI 1.6-18.2) had variants of unknown significance identified by WES. When considering fetuses with isolated increased NT and normal fetal anatomy at the anomaly scan, the rate of pathogenic or likely pathogenic genetic variants detected by WES was 3.87% (95% CI 1.6-7.1), while variants of unknown significance were detected in 4.27% (95% CI 2.2-7.0) of cases. CONCLUSIONS: Pathogenic and likely pathogenic genetic variants detected by WES are present in a significant proportion of fetuses with increased NT but normal standard karyotype and CMA analysis, also when no anomalies are detected at the anomaly scan. Further large studies sharing objective protocols of imaging assessment are needed to confirm these findings and to elucidate which gene panels should be assessed in fetuses with isolated increased NT to rule out associated genetic anomalies, which may potentially impact post-natal outcomes.

A systematic review and critical evaluation of quality of clinical practice guidelines on fetal growth restriction.

INTRODUCTION: To systematically identify and critically assess the quality of clinical practice guidelines (CPGs) on management fetal growth restriction (FGR). CONTENT: Medline, Embase, Google Scholar, Scopus and ISI Web of Science databases were searched to identify all relevant CPGs on FGR. SUMMARY: Diagnostic criteria of FGR, recommended growth charts, recommendation for detailed anatomical assessment and invasive testing, frequency of fetal growth scans, fetal monitoring, hospital admission, drugs administrations, timing at delivery, induction of labor, postnatal assessment and placental histopathological were assessed. Quality assessment was evaluated by AGREE II tool. Twelve CPGs were included. Twenty-five percent (3/12) of CPS adopted the recently published Delphi consensus, 58.3% (7/12) an estimated fetal weight (EFW)/abdominal circumference (AC) EFW/AC <10th percentile, 8.3% (1/12) an EFW/AC <5th percentile while one CPG defined FGR as an arrest of growth or a shift in its rate measured longitudinally. Fifty percent (6/12) of CPGs recommended the use of customized growth charts to assess fetal growth. Regarding the frequency of Doppler assessment, in case of absent or reversed end-diastolic flow in the umbilical artery 8.3% (1/12) CPGs recommended assessment every 24-48, 16.7% (2/12) every 48-72 h, 1 CPG generically recommended assessment 1-2 times per week, while 25 (3/12) did not specifically report the frequency of assessment. Only 3 CPGs reported recommendation on the type of Induction of Labor to adopt. The AGREE II standardized domain scores for the first overall assessment (OA1) had a mean of 50%. OUTLOOK: There is significant heterogeneity in the management of pregnancies complicated by FGR in published CPGs.

Placenta accreta spectrum disorders clinical practice guidelines: A systematic review.

OBJECTIVES: To objectively assess the quality of the published clinical practice guidelines (CPGs) on the management of pregnancies complicated by placenta accreta spectrum (PAS)disorders. METHODS: MEDLINE, Embase, Scopus, and ISI Web of Science databases were searched. The following aspects related to the management of pregnancies with suspected PAS disorders were evaluated: risk factors for PAS, prenatal diagnosis, role of interventional radiology and ureteral stenting, and optimal surgical management. The assessment of risk of bias and quality assessment of the CPGs were performed using the (AGREE II) tool (Brouwers et al., 2010). To define a CPG as of good quality we adopted a cut-off score >60%. RESULTS: Nine CPGs were included. Specific risk factors for referral were assessed by 44.4% (4/9) of CPGs, mainly consisting in the presence of placenta previa and a prior cesarean delivery or uterine surgery. About 55.6% of CPGs (5/9) suggested ultrasound assessment of women with risk factors for PAS in the second and third trimester of pregnancy and 33.3% (3/9) recommended magnetic resonance imaging (MRI); 88.9% (8/9) of CPGs recommended cesarean delivery at 34-37 weeks of gestation. There was not generally consensus on the use of interventional radiology and ureteral stenting before surgery for PAS. Finally, hysterectomy was the recommend surgical approach by 77.8% (7/9) of the included CPGs. CONCLUSION: Most of the published CPGs on PAS are generally of good quality. There was general agreement among the different CPGs on PAS as a regard as risk stratification, timing at diagnosis and delivery but not on the indication for MRI, use of interventional radiology and ureteral stenting.

Clinical practice guidelines on the use of aspirin in pregnancy: Systematic review.

BACKGROUND: Placental related disorders, including preeclampsia and fetal growth restriction (FGR) are among the main determinants of adverse maternal and perinatal outcomes in both singleton and twin pregnancies. In view of its relevance, aspirin administration is commonly recommended to women at high risk for preeclampsia or FGR by the various national and international guidelines. OBJECTIVES: To establish the clinical heterogeneity among the clinical practice guidelines (CPGs) on aspirin use in pregnancy and to investigate the quality of these CPGs. METHODS: We performed a systematic review of Clinical practice guidelines on main databases searching for all peer-reviewed guidelines into the literature, analyzing the following aspects related to use of aspirin in pregnancy: indications for aspirin administration, dosage, starting of therapy, ending of therapy, safety and side effects. The assessment of risk of bias and quality assessment of the included CPGs were performed using "The Appraisal of Guidelines for REsearch and Evaluation (AGREE II)" tool. RESULTS: 16 CPGs were included. There was an overall general agreement among the published CPGs as regards to the indication for aspirin intake in pregnancy, with prior preeclampsia, chronic hypertension, autoimmune disease, and diabetes mellitus type 1 or 2 recognized as solitary major risk factors for Aspirin administration in 93.7% (15/16) of CPGs. There was heterogeneity in the recommendations provided by the different CPGs as regards the gestational age at which aspirin should be commenced. CONCLUSION: There is general agreement in the reported indications for aspirin intake in pregnancy, with prior preeclampsia and maternal medical co-morbidity associated with increased risk of preeclampsia being the major indications for aspirin intake. Conversely, there was heterogeneity in the recommended dose, gestational age at initiation and discontinuation of therapy among the different CPGs.

Role of lactoferrin in preventing preterm birth and pregnancy complications: a systematic review and meta-analysis.

INTRODUCTION: The aim of this systematic review was to report the role of lactoferrin supplementation for the prevention of preterm birth (PTB) in women at risk. EVIDENCE ACQUISITION: PubMed and Embase databases were searched. Inclusion criteria were studies exploring maternal and perinatal outcomes in women at high-risk for preterm birth receiving compared to those not receiving lactoferrin during pregnancy. The primary outcome was preterm PTB<37 weeks; the secondary outcomes were gestational age at birth, PTB<34 and 28 weeks, preterm premature rupture of the membranes (PPROM), chorioamnionitis and admission to Neonatal Intensive Care Unit. Random effect meta-analyses were used to analyze the data. EVIDENCE SYNTHESIS: Six studies (333 pregnancies) were included. Overall, women taking lactoferrin had a lower risk of PTB<37 weeks of gestation with an OR of 0.43 (95% CI: 0.2-0.9). Likewise, gestational age at delivery was higher in women-taking compared to those not-taking lactoferrin (MD=0.46 weeks, SD=0.17, P=0.006). The other included studies explored the role of lactoferrin in affecting the inflammatory profile in the amniotic fluid of women undergoing invasive test, without reporting its actual role in preventing PTB. CONCLUSIONS: Prophylactic administration of lactoferrin can reduce the risk of PTB in women at risk. Further large and adequately powered randomized trial are needed in order to elucidate the actual role of lactoferrin in reducing the risk of preterm birth and in affecting perinatal outcomes in women at risk.

Systematic review and meta-analysis on placenta accreta spectrum disorders in twin pregnancies: risk factors, detection rate and histopathology.

INTRODUCTION: The occurrence of PAS has been recently associated with the presence of twin pregnancy. Aim of this review is to report the risk factors, histopathological correlation, diagnostic accuracy of prenatal ultrasound and clinical outcome of twin pregnancies complicated by placenta accreta spectrum (PAS) disorders. EVIDENCE ACQUISITION: PubMed, Embase, Cinahl, Clinical Trial.Gov and Google Scholar databases were searched. Inclusion criteria were studies on twin pregnancies complicated by PAS. The outcomes explored were risk factors for PAS (including placenta previa, prior uterine surgery or assisted reproductive technology, ART), histopathology (placenta accreta and increta/percreta), detection rate of prenatal ultrasound and clinical outcome, including need for blood transfusion, hysterectomy, emergency or scheduled Cesarean delivery (CD), and maternal death. Random effect meta-analyses of proportions were sued to combine the data. EVIDENCE SYNTHESIS: Two studies considering 103 pregnancies were included in this systematic review: 41.86% (95% CI 27.0-57.9) of twin pregnancies complicated by PAS disorders had a prior CD, 28.22% (95% CI 13.4-46.0) presented placenta previa and 58.14% (95% CI 42.1-73.0) of twin pregnancies were conceived by ART. 74.49% (95% CI 41.6-96.5) of PAS in twin pregnancies were placenta accreta, while 25.51% (95% CI 3.5-58.4) were placenta increta or percreta. Prenatal diagnosis of PAS in twin pregnancies was accomplished only in 27.91% (95% CI 15.3-43.7) of cases. Finally, only one study consistently reported the clinical outcome of PAS in twins. 31.67% (95% CI 20.3-45.0) of women required blood transfusion, 26.67% (95% CI 16.1-39.7) had hysterectomy, while there was no case of maternal death. 44.19% of women had an emergency CD. CONCLUSIONS: There is still limited evidence on the clinical course of PAS disorders in twin pregnancies. Placenta previa, prior uterine surgery (mainly CD), and ART are the most commonly risk factors for PAS disorders in twins. Prenatal diagnosis of PAS in twins is lower compared to what reported in singleton. Finally, about 30% of women with a twin pregnancy complicated by PAS required blood transfusion and hysterectomy.

Extracellular Vesicles in pregnancy: Their potential role as a liquid biopsy.

OBJECTIVE: Extracellular Vesicles (EVs) are cell-derived particles released during different pathophysiological processes, circulating in many body fluids and mediating the inter-cellular crosstalk. We have analyzed, for the first time, different EV phenotypes and concentrations in the peripheral blood of uncomplicated pregnant women. STUDY DESIGN: In this prospective case-control study, uncomplicated singleton pregnant women at term (N = 59) and aged matched non-pregnant women (N = 21) were enrolled. Freshly drowned peripheral blood samples were stained for flow cytometry analyses of EVs. RESULTS: EVs derived from platelets, leukocytes, endothelial and epithelial cells were identified and counted. Platelet-derived EVs were higher in pregnant compared to non-pregnant women, both in terms of absolute counts (2064.4 ± 1156.3 vs 701.1 ± 378.8; p < 0.0001) and percentages (27.6 ± 17.2 vs 10.7 ± 5.9; p < 0.0001). The opposite pattern was observed both for concentrations of endothelial-EV counts (525.8 ± 499.6 vs 844.7 ± 652.9; p = 0.007) and percentages (6.1 ± 5.5 vs 11.8 ± 8.0; p < 0.0001) and leukocyte-derived EV percentages (10.2 ± 7.4 vs 17.9 ± 11.2; p = 0.002) EVs. CONCLUSIONS: Uncomplicated pregnancies are characterized by a specific EV signature. These cell-derived particles may therefore represent promising biomarkers of different pathological conditions complicating pregnancies, such as preeclampsia or preterm birth.

Systematic review and critical evaluation of quality of clinical practice guidelines on the management of SARS-CoV-2 infection in pregnancy.

OBJECTIVE: To systematically identify and critically assess the quality of clinical practice guidelines for the management of SARS-CoV-2 infection in pregnancy. DATA SOURCES: Medline, Scopus, and ISI Web of Science databases were searched until February 15, 2022. STUDY ELIGIBILITY CRITERIA: Inclusion criteria were clinical practice guidelines on the management of SARS-CoV-2 infection in pregnancy. The risk of bias and quality assessments of the included clinical practice guidelines were performed using the Appraisal of Guidelines for REsearch and Evaluation II tool, which is considered the gold standard for quality assessment of clinical practice guidelines. To define a clinical practice guideline as of good quality, we adopted the cutoff score proposed by Amer et al: if the overall clinical practice guideline score was >60%, it was recommended. METHODS: The following clinical points related to the management of pregnant women with SARS-CoV-2 infection were addressed: criteria for maternal hospitalization, recommendations for follow-up fetal growth scan, specific recommendations against invasive procedures, management of labor, timing of delivery, postpartum care, and vaccination strategy. RESULTS: A total of 28 clinical practice guidelines were included. All recommended hospitalization only for severe disease; 46.1% (6/13) suggested a fetal growth scan after SARS-CoV-2 infection, whereas 23.1% (3/13) did not support this practice. Thromboprophylaxis with low-molecular-weight heparin was recommended in symptomatic women by 77.1% (7/9) of the clinical practice guidelines. None of the guidelines recommended administering corticosteroids only for the presence of SARS-CoV-2 infection in preterm gestation, unless specific obstetrical indication exists. Elective induction of labor from 39 weeks of gestation was suggested by 18.1% (2/11) of the clinical practice guidelines included in the present review, whereas 45.4% (5/11) did not recommend elective induction unless other obstetrical indications coexisted. There were 27% (3/11) of clinical practice guidelines that suggested shortening of the second stage of labor, and active pushing was supported by 18.1% (2/11). There was general agreement among the clinical practice guidelines in not recommending cesarean delivery only for the presence of maternal infection and in recommending vaccine boosters at least 6 months after the primary series of vaccination. The Appraisal of Guidelines for REsearch and Evaluation II standardized domain scores for the first overall assessment of clinical practice guidelines had a mean of 50% (standard deviation±21.82%), and 9 clinical practice guidelines scored >60%. CONCLUSION: A significant heterogeneity was found in some of the main aspects of the management of SARS-CoV-2 infection in pregnancy, as reported by the published clinical practice guidelines.

Reproductive and pregnancy outcomes of fertility-sparing treatments for early-stage endometrial cancer or atypical hyperplasia: A systematic review and meta-analysis.

OBJECTIVE: To report the pregnancy outcomes of women with prior endometrial cancer and endometrial hyperplasia managed with fertility-sparing treatments. METHODS: Medline and Embase databases were searched. Inclusion criteria were studies reporting the pregnancy outcomes of women who had undergone fertility-sparing treatments for endometrial hyperplasia or early endometrioid endometrial cancer. Outcomes explored were pregnancy, miscarriage and livebirth rates according to the type of progestin treatment used. Subgroup analyses according to the type of diagnostic follow-up were also performed. Meta-analyses of proportions using a random effects model were used to combine data. RESULTS: Twenty-nine studies (1036 women) were included, and 82.8% [95% confidence interval (CI) 72.3-91.2] of women achieved complete remission. Pregnancy rates were 56.3% (95% CI 41.6-70.5) with megestrol (MA) or medroxyprogesterone acetate (MPA), 63.1% (95% CI 37.0-85.6) with levonorgestrel-releasing intrauterine device (LNG-IUD), 57.9% (95% CI 37.7-76.8) with MA or MPA and metformin, 59.8% (95% CI 48.3-70.7) with MPA and LNG-IUD, 15.4% (95% CI 4.3-42.2) with gonadotropin-releasing hormone analogue (GnRHa) combined with LNG-IUD or letrozole, and 40.7% (95% CI 24.5-59.3) with LNG-IUD and GnRHa. Miscarriage rates were 17.4% (95% CI 12.2-23.4), 14.3% (95% CI 6.4-24.7), 57.9% (95% CI 37.7-76.8), 26.9% (95% CI 14.6-39.3), 100% (95% CI 34.0-100) and 18.2% (95% CI 5.1-47.7), respectively, and livebirth rates were 68.8% (95% CI 56.0-80.3), 80.8% (95% CI 69.5-90.0), 69.9% (95% CI 56.1-82.0), 25.97 (95% CI 14.6-39.3), 0% (95% CI 0-66.0) and 81.8% (95% CI 52.3-94.8), respectively. Finally, stratifying the analysis considering the endometrial sampling method alone, the pregnancy rate was 68.6% (95% CI 51.2-83.6; 10 studies, I2 = 83.5%) in women who underwent hysteroscopy and 60.5% (95% CI 53.4-67.5; 13 studies, I2 = 39.8%) in women managed with dilatation and curettage biopsy; the miscarriage and livebirth rates were 13.2% (95% CI 8.0-19.5; I2 = 0%) and 81.2% (95% CI 67.4-91.8; I2 = 67.3%), respectively, for hysteroscopy, and 25.2% (95% CI 17.8-33.3; I2 = 15.5%) and 67.5% (95% CI 58.8-75.5; I2 = 0%), respectively, for dilatation and curettage biopsy. CONCLUSION: Fertility-sparing treatment in women with endometrial cancer or hyperplasia is associated with an overall good response to therapy, good chance of achieving pregnancy and a good livebirth rate. Diagnostic follow-up with hysteroscopy was associated with a higher pregnancy rate, although this requires confirmation in adequately powered randomized trials.

The Obesogenic Environment: Epigenetic Modifications in Placental Melanocortin 4 Receptor Gene Connected to Gestational Diabetes and Smoking.

Background: Maternal metabolic insults as well as Gestational Diabetes Mellitus (GDM) influence the fetal health and may affect 'offspring's susceptibility to chronic diseases via epigenetic modifications. GDM, the most common metabolic disorder in pregnancy, can be considered the result of complex interactions between genetic and environmental factors. A critical point in this view is the identification of genes which are epigenetically modified under the influence of GDM. The melanocortin 4 receptor (MC4R) gene plays a crucial role in nutritional health by suppressing appetite and participating in energy control regulation. The correlations between pregnant 'women's metabolic profiles and placental epigenetic modifications of this gene have been poorly investigated. Objective: The aim of this study was to evaluate the effect of GDM and maternal clinical parameters at the third trimester of pregnancy to DNA methylation levels in the placenta at CpG sites of MC4R gene. Design and Methods: Socio-demographic and clinical characteristics, Mediterranean diet adherence, smoking habits, and physical activity were assessed at the third trimester of pregnancy of 60 Caucasian pregnant women, of which 33 with GDM. Clinical parameters of the newborns were recorded at birth. MC4R DNA methylation on maternal and fetal sides of the placenta was analyzed using bisulfite pyrosequencing. Results: MC4R DNA methylation levels at CpG1 and CpG2 were lower on the fetal side of the placenta in GDM-affected women than in non-GDM-affected recruits (p = 0.033). Moreover, DNA methylation levels on the maternal side at CpG1 were positively related to glucose concentration at 2-h oral glucose tolerance test (OGTT). On the other hand, CpG2 DNA methylation was positively related to both 1-h and 2-h during OGTT. Maternal DNA methylation level at CpG2 was also associated with low density lipoprotein cholesterol (LDL-C) at the third trimester of pregnancy (rho = 0.340, p < 0.05), while CpG1 methylation was negatively related to maternal weight variations at delivery (rho = -0.316, p < 0.05). Significant associations between MC4R DNA methylation on the maternal side and lipid profile at third trimester of pregnancy in women smokers were found. Conclusion: Our results suggest that MC4R methylation profile in the placenta is related to maternal metabolic and nutritional conditions, potentially affecting fetal programming and the future metabolic health of the newborn.

Methodological Quality of Fetal Brain Structure Charts for Screening Examination and Targeted Neurosonography: A Systematic Review.

INTRODUCTION: Several fetal brain charts have been published in the literature and are commonly used in the daily clinical practice. However, the methodological quality of these charts has not been critically appraised. MATERIAL AND METHODS: MEDLINE, EMBASE, CINAHL, and the Web of Science databases were searched electronically up to December 31, 2020. The primary outcome was to evaluate the methodology of the studies assessing the growth of fetal brain structures throughout gestation. A list of 28 methodological quality criteria divided into three domains according to "study design," "statistical and reporting methods," and "specific relevant neurosonography aspects" was developed in order to assess the methodological appropriateness of the included studies. The overall quality score was defined as the sum of low risk of bias marks, with the range of possible scores being 0-28. This quality assessment was applied to each individual study reporting reference ranges for fetal brain structures. Furthermore, we performed a subgroup analysis according to the different brain structures (ventricular and periventricular, fore-brain and midbrain cerebral and posterior fossa). RESULTS: Sixty studies were included in the systematic review. The overall mean quality score of the studies included in this review was 51.3%. When focusing on each of the assessed domains, the mean quality score was 53.7% for "study design," 54.2% for "statistical and reporting methods," and 38.6% for "specific relevant neurosonography aspects." The sample size calculation, the correlation with a postnatal imaging evaluation, and the whole fetal brain assessment were the items at the highest risk of bias for each domain assessed, respectively. The subgroup analysis according to different anatomical location showed the lowest quality score for ventricular and periventricular structures and the highest for cortical structures. CONCLUSIONS: Most previously published studies reporting fetal brain charts suffer from poor methodology and are at high risk of biases, mostly when focusing on neurosonography issues. Further prospective longitudinal studies aiming at constructing specific growth charts for fetal brain structures should follow rigorous methodology to minimize the risk of biases, guarantee higher levels of reproducibility, and improve the standard of care.

Assessment of pericallosal artery at 11-14 weeks of gestation: Cohort study and meta-analysis.

OBJECTIVES: To report the rate of visualization of the pericallosal artery (PCA) in the first trimester of pregnancy (11-14 weeks). METHODS: Prospective observational study of consecutive fetuses undergoing first trimester risk assessment for chromosomal anomalies. The presence of PCA was assessed in a midsagittal view of fetal brain using high-definition power Color Doppler. A normal course of the PCA was defined as the visualization of an artery emerging from the anterior cerebral artery running parallel the corpus callosum (CC). The reference standard was the visualization of CC and PCA between the 20 and 22 weeks of gestation. We also performed a systematic review and meta-analysis of the published literature. Multivariate logistic regression and random-effect meta-analyses of proportion were used to analyze the data. RESULTS: Cohort study: Five-hundred women were included. PCA was identified trans-abdominally or transvaginally at 11-14 weeks of gestation in 98.8% (95% CI 97.4-99.6: 494/500); of the four cases of PCA not identified one had a diagnosis of complete agenesis of the corpus callosum during the anomaly scan which was confirmed at birth. Systematic review of the published literature: Six studies (1093 fetuses, including the present series) were included. The PCA was detected at the 11-14 weeks scan and confirmed to co-exist with a normal CC at time of the anomaly scan in 96.9% (95% CI 93.8-99.0); 20.6% (95% CI 5.7-41.7) of fetuses with no clear identification of the PCA at the 11-14 weeks scan had a normal appearance of the CC at the time of anomaly scan. CONCLUSION: Prenatal ultrasonography has a high diagnostic accuracy in detecting PCA in the first trimester. Visualization of the PCA at the time of 11-14 scan is highly specific for the presence of a normal CC later in pregnancy.

Role of balloon tamponade during cesarean section in women with placenta previa: a systematic review and meta-analysis.

INTRODUCTION: To explore the role of balloon tamponade insertion in pregnancies complicated by placenta previa. EVIDENCE ACQUISITION: Medline, Embase and ClinicalTrials.gov databases were searched electronically on October 17. Inclusion criteria were women with placenta previa undergoing, compared to those not undergoing, balloon tamponade insertion at the time of the cesarean section (CS). The outcomes observed were total, intra- and post-operative estimated blood loss (EBL), need for blood transfusion, admission to intensive care unit (ICU), hysterectomy and additional surgical or medical procedures to achieve hemostasis. Results were reported as pooled odd ratios (OR) or mean difference (MD) according to the outcome investigated. EVIDENCE SYNTHESIS: Four studies (593 women) were included. Total EBL was significantly lower in women undergoing balloon tamponade insertion during CS compared to controls (MD: -556.3, 95% CI -496 to -617.0, P=0.001). Likewise, women undergoing balloon tamponade insertion had significantly lower intra- (MD: -699.8, 95% CI -766.1 to -633.5, P=0.001) and post-operative (MD: -1162 mL (95% CI -1211.1 to -1134.4, P<0.001) compared to women who did undergo such procedure. Furthermore, women undergoing balloon tamponade insertion had a significantly lower risk of requiring additional surgical (OR: 0.16, 95% CI 0.1-0.5, I2=0%; P=0.001) or medical (OR: 0.02, 95% CI 0.003-0.1, I2=0; P=0.001) procedures to achieve hemostasis. Conversely, there was no significant difference in either the need for blood transfusion (P=0.071), admission to ICU (P=0.459) or need for hysterectomy (P=0.312) between women undergoing, compared to those not undergoing, balloon tamponade insertion during CS for placenta previa. CONCLUSIONS: Elective balloon tamponade insertion at the time of CS for placenta previa seems to be associated with a lower EBL and a reduced risk of additional medical and surgical procedures to control hemostasis. Large and adequately powered randomized controlled trials are needed to validate these results and introduce elective balloon tamponade insertion at the time of CS for placenta previa in clinical practice.

Levothyroxine Supplementation in Euthyroid Pregnant Women With Positive Autoantibodies: A Systematic Review and Meta-Analysis.

OBJECTIVES: To explore the role of levothyroxine (LT4) supplementation in affecting the outcome of pregnant euthyroid women with thyroperoxidase (TPO) antibodies. METHODS: MEDLINE, EMBASE, Google Scholar, and the Web of Science databases were searched. The primary outcome was pre-term birth (PTB), defined as live birth before 37 weeks of gestation; secondary outcomes were gestational hypertension, pre-eclampsia (PE), placental abruption, miscarriage, intra-uterine death (IUD), and admission to neonatal intensive care unit (NICU). All these outcomes were explored in euthyroid women with TPO antibodies receiving compared to those not receiving LT4 supplementation in pregnancy. Random-effect meta-analyses were used to analyze the data and results reported as pooled odds ratios (OR) with their 95% confidence intervals (CI). RESULTS: The risk of PTB was lower in women with TPO antibodies receiving compared to those not receiving LT4 supplementation (OR of 0.60 (95% CI 0.4-0.9). However, this association came mainly from observational studies (OR: 0.29, 95% CI 0.1-0), while RCTs did not show any beneficial effect of LT4 supplementation in affecting such outcomes. Conversely, there was no difference in the risk of gestational hypertension, preeclampsia, placental abruption, miscarriage, and admission to NICU between the two groups. CONCLUSIONS: LT4 supplementation in TPO euthyroid women is not associated with a reduced risk of PTB in TPO-positive women with normal thyroid function.

Prenatal risk factors for urgent atrial septostomy at birth in fetuses with transposition of the great arteries: a systematic review and meta-analysis.

MATERIAL AND METHODS: Medline, Embase, and Cochrane databases were searched. The primary aim was to explore the differences in prenatal echocardiographic parameters among fetuses diagnosed with TGA that required urgent BAS within 24 h of birth due to life-threatening cyanosis compared to those who did not require such procedure. Random-effect meta-analyses were used to compute the data. RESULTS: Six studies (292 fetuses) were included. Restrictive appearance of the FO was present in 64.5% (95% CI = 39.8-85.7) of fetuses with TGA requiring BAS at birth compared to 7.9% (95% CI = 2.1-16.8) not requiring such procedure (OR = 71.1; 95% CI = 8.3-608.5, p < .0001). Hypermobile appearance of the atrial septum was present in 39.1% (95% CI = 26.4-56.5) of fetuses requiring BAS at birth compared to 9.8% (95% CI = 1.4-24.3) of those which did (OR 3.6; 95% CI = 1.4-9.0, p = .05). There was no difference in the prevalence of redundant (p = .374) or fixed (p = .051) atrial septum, bidirectional flow in the DA (p = .26) or an abnormal size of the DA (p = .06) in fetuses requiring urgent BAS at birth compared to those which did not. Mean (±SD) size of the right atrium was smaller in the fetuses with TGA undergoing urgent BAS at birth (23.4 ± 6.7) compared to those which did not (29.2 ± 6.2, p = .01). The mean (±SD) ratio between the FO and the aortic valve diameters (1.01 ± 0.41 versus 1.41 ± 0.43, p = .009) and the mean (±SD) ratio between the FO diameter and the septal length (0.36 ± 0.13 versus 0.51 ± 0.14, p = .001) were significantly smaller in fetuses requiring compared to those not undergoing urgent BAS at birth. The diagnostic accuracy of each independent ultrasound marker of the need for urgent BAS showed an overall good specificity but a low sensitivity. CONCLUSION: Fetal echocardiography prior to birth can stratify the risk of BAS in fetuses with TGA. Further studies are needed to validate these findings and build individualized multiparametric predictive models in order to more accurately identify those fetuses with TGA at a higher risk of urgent BAS after birth.

Neonatal Morbidity of Monoamniotic Twin Pregnancies: A Systematic Review and Meta-analysis.

OBJECTIVE: This study was aimed to report the incidence of neonatal morbidity in monochorionic monoamniotic (MCMA) twin pregnancies according to gestational age at birth and type of management adopted (inpatient or outpatient). STUDY DESIGN: Medline and Embase databases were searched. Inclusion criteria were nonanomalous MCMA twins. The primary outcome was a composite score of neonatal morbidity, defined as the occurrence of at least one of the following outcomes: respiratory morbidity, overall neurological morbidity, severe neurological morbidity, and infectious morbidity, necrotizing enterocolitis at different gestational age windows (24-30, 31-32, 33-34, and 35-36 weeks). Secondary outcomes were the individual components of the primary outcome and admission to neonatal intensive care unit (NICU). Subanalysis according to the type of surveillance strategy (inpatient compared with outpatient) was also performed. Random effect meta-analyses were used to analyze the data. RESULTS: A total of 14 studies including 685 MCMA twin pregnancies without fetal anomalies were included. At 24 to 30, 31 to 32, 33 to 34, and 35 to 36 weeks of gestation, the rate of composite morbidity was 75.4, 65.5, 37.6, and 18.5%, respectively, the rate of respiratory morbidity was 74.2, 59.1, 35.5, and 12.2%, respectively, while overall neurological morbidity occurred in 15.3, 10.2, 4.3, and 0% of the cases, respectively. Infectious morbidity complicated 13, 4.2, 3.1, and 0% of newborns while 92.1, 81.6, 58.7, and 0% of cases required admission to NICU. Morbidity in pregnancies delivered between 35 and 36 weeks of gestation was affected by the very small sample size of cases included. When comparing the occurrence of overall morbidity according to the type of management (inpatient or outpatient), there was no difference between the two surveillance strategies (p = 0.114). CONCLUSION: MCMA pregnancies are at high risk of composite neonatal morbidity, mainly respiratory morbidity that gradually decreases with increasing gestational age at delivery with a significant reduction for pregnancies delivered between 33 and 34 weeks. We found no difference in the occurrence of neonatal morbidity between pregnancies managed as inpatient or outpatient. KEY POINTS: · MCMA pregnancies are at high risk of composite neonatal morbidity, mainly respiratory morbidity.. · Neonatal morbidity gradually decreases with increasing GA at delivery, mostly between 33 and 34 weeks.. · There is no difference in the occurrence of neonatal morbidity between in- or outpatient management..