Risk factors for preterm birth: an umbrella review of meta-analyses of observational studies.

BACKGROUND: Preterm birth defined as delivery before 37 gestational weeks is a leading cause of neonatal and infant morbidity and mortality. The aim of this study is to summarize the evidence from meta-analyses of observational studies on risk factors associated with PTB, evaluate whether there are indications of biases in this literature, and identify which of the previously reported associations are supported by robust evidence. METHODS: We searched PubMed and Scopus until February 2021, in order to identify meta-analyses examining associations between risk factors and PTB. For each meta-analysis, we estimated the summary effect size, the 95% confidence interval, the 95% prediction interval, the between-study heterogeneity, evidence of small-study effects, and evidence of excess-significance bias. Evidence was graded as robust, highly suggestive, suggestive, and weak. RESULTS: Eighty-five eligible meta-analyses were identified, which included 1480 primary studies providing data on 166 associations, covering a wide range of comorbid diseases, obstetric and medical history, drugs, exposure to environmental agents, infections, and vaccines. Ninety-nine (59.3%) associations were significant at P < 0.05, while 41 (24.7%) were significant at P < 10-6. Ninety-one (54.8%) associations had large or very large heterogeneity. Evidence for small-study effects and excess significance bias was found in 37 (22.3%) and 12 (7.2%) associations, respectively. We evaluated all associations according to prespecified criteria. Seven risk factors provided robust evidence: amphetamine exposure, isolated single umbilical artery, maternal personality disorder, sleep-disordered breathing (SDB), prior induced termination of pregnancy with vacuum aspiration (I-TOP with VA), low gestational weight gain (GWG), and interpregnancy interval (IPI) following miscarriage < 6 months. CONCLUSIONS: The results from the synthesis of observational studies suggest that seven risk factors for PTB are supported by robust evidence. Routine screening for sleep quality and mental health is currently lacking from prenatal visits and should be introduced. This assessment can promote the development and training of prediction models using robust risk factors that could improve risk stratification and guide cost-effective preventive strategies. TRIAL REGISTRATION: PROSPERO 2021 CRD42021227296.

Antenatal corticosteroids prior to planned caesarean at term for improving neonatal outcomes.

BACKGROUND: Infants born at term by elective caesarean section are more likely to develop respiratory morbidity than infants born vaginally. Prophylactic corticosteroids in singleton preterm pregnancies accelerate lung maturation and reduce the incidence of respiratory complications. It is unclear whether administration at term gestations, prior to caesarean section, improves the respiratory outcomes for these babies without causing any unnecessary morbidity to the mother or the infant. OBJECTIVES: The objective of this review was to assess the effect of prophylactic corticosteroid administration before elective caesarean section at term, as compared to usual care (which could be placebo or no treatment), on fetal, neonatal and maternal morbidity. We also assessed the impact of the treatment on the child in later life. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov (20 January 2021) and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials comparing prophylactic antenatal corticosteroid administration (betamethasone or dexamethasone) with placebo or with no treatment, given before elective caesarean section at term (at or after 37 weeks of gestation). Quasi-randomised and cluster-randomised controlled trials were also eligible for inclusion. DATA COLLECTION AND ANALYSIS: We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis. Two review authors independently assessed trials for inclusion, assessed risk of bias, evaluated trustworthiness (based on predefined criteria developed by Cochrane Pregnancy and Childbirth), extracted data and checked them for accuracy and assessed the certainty of the evidence using the GRADE approach. Our primary outcomes were respiratory distress syndrome (RDS), transient tachypnoea of the neonate (TTN), admission to neonatal special care for respiratory morbidity and need for mechanical ventilation. We planned to perform subgroup analyses for the primary outcomes according to gestational age at randomisation and type of corticosteroid (betamethasone or dexamethasone). We also planned to perform sensitivity analysis, including only studies at low risk of bias. MAIN RESULTS: We included one trial in which participants were randomised to receive either betamethasone or usual care. The trial included 942 women and 942 neonates recruited from 10 UK hospitals between 1995 and 2002. This review includes only trials that met predefined criteria for trustworthiness. We removed three trials from the analysis that were included in the previous version of this review. The risk of bias was low for random sequence generation, allocation concealment and incomplete outcome data. The risk of bias for selective outcome reporting was unclear because there was no published trial protocol, and therefore it is unclear whether all the planned outcomes were reported in full. Due to a lack of blinding we judged there to be high risk of performance bias and detection bias. We downgraded the certainty of the evidence because of concerns about risk of bias and because of imprecision due to low event rates and wide 95% confidence intervals (CIs), which are consistent with possible benefit and possible harm Compared with usual care, it is uncertain if antenatal corticosteroids reduce the risk of RDS (relative risk (RR) 0.34 95% CI 0.07 to 1.65; 1 study; 942 infants) or TTN (RR 0.52, 95% CI 0.25 to 1.11; 1 study; 938 infants) because the certainty of evidence is low and the 95% CIs are consistent with possible benefit and possible harm. Antenatal corticosteroids probably reduce the risk of admission to neonatal special care for respiratory complications, compared with usual care (RR 0.45, 95% CI 0.22 to 0.90; 1 study; 942 infants; moderate-certainty evidence). The proportion of infants admitted to neonatal special care for respiratory morbidity after treatment with antenatal corticosteroids was 2.3% compared with 5.1% in the usual care group. It is uncertain if antenatal steroids have any effect on the risk of needing mechanical ventilation, compared with usual care (RR 4.07, 95% CI 0.46 to 36.27; 1 study; 942 infants; very low-certainty evidence). The effect of antenatal corticosteroids on the maternal development of postpartum infection/pyrexia in the first 72 hours is unclear due to the very low certainty of the evidence; one study (942 women) reported zero cases. The included studies did not report any data for neonatal hypoglycaemia or maternal mortality/severe mortality. AUTHORS' CONCLUSIONS: Evidence from one randomised controlled trial suggests that prophylactic corticosteroids before elective caesarean section at term probably reduces admission to the neonatal intensive care unit for respiratory morbidity. It is uncertain if administration of antenatal corticosteroids reduces the rates of respiratory distress syndrome (RDS) or transient tachypnoea of the neonate (TTN). The overall certainty of the evidence for the primary outcomes was found to be low or very low, apart from the outcome of admission to neonatal special care (all levels) for respiratory morbidity, for which the evidence was of moderate certainty. Therefore, there is currently insufficient data to draw any firm conclusions.  More evidence is needed to investigate the effect of prophylactic antenatal corticosteroids on the incidence of recognised respiratory morbidity such as RDS. Any future trials should assess the balance between respiratory benefit and potential immediate adverse effects (e.g. hypoglycaemia) and long-term adverse effects (e.g. academic performance) for the infant. There is very limited information on maternal health outcomes to provide any assurances that corticosteroids do not pose any increased risk of harm to the mother.  Further research should consider investigating the effectiveness of antenatal steroids at different gestational ages prior to caesarean section. There are nine potentially eligible studies that are currently ongoing and could be included in future updates of this review.

Timing of primary maternal cytomegalovirus infection and rates of vertical transmission and fetal consequences.

OBJECTIVE: Cytomegalovirus infection is the most frequent congenital infection and a major cause of long-term neurologic morbidity. The aim of this meta-analysis was to calculate the pooled rates of vertical transmission and fetal impairments according to the timing of primary maternal infection. DATA SOURCES: From inception to January 2020, MEDLINE, Scopus, Cochrane Library, and gray literature sources were used to search for related studies. STUDY ELIGIBILITY CRITERIA: Cohort and observational studies reporting the timing of maternal cytomegalovirus infections and rate of vertical transmission or fetal impairments were included. The primary outcomes were vertical transmission and fetal insult, defined as either prenatal findings from the central nervous system leading to termination of pregnancy or the presence of neurologic symptoms at birth. The secondary outcomes included sensorineural hearing loss or neurodevelopmental delay at follow-up and prenatal central nervous system ultrasonography findings. STUDY APPRAISAL AND SYNTHESIS METHODS: The pooled rates of the outcomes of interest with their 95% confidence intervals (CI) were calculated for primary maternal infection at the preconception period, periconception period, first trimester, second trimester, and third trimester. RESULTS: A total of 17 studies were included. The pooled rates of vertical transmission (10 studies, 2942 fetuses) at the preconception period, periconception period, first trimester, second trimester, and third trimester were 5.5% (95% CI, 0.1-10.8), 21.0% (95% CI, 8.4-33.6), 36.8% (95% CI, 31.9-41.6), 40.3% (95% CI, 35.5-45.1), and 66.2% (95% CI, 58.2-74.1), respectively. The pooled rates of fetal insult in case of transmission (10 studies, 796 fetuses) were 28.8% (95% CI, 2.4-55.1), 19.3% (95% CI, 12.2-26.4), 0.9% (95% CI, 0-2.4%), and 0.4% (95% CI, 0-1.5), for maternal infection at the periconception period, first trimester, second trimester, and third trimester, respectively. The pooled rates of sensorineural hearing loss for maternal infection at the first, second, and third trimester were 22.8% (95% CI, 15.4-30.2), 0.1% (95% CI, 0-0.8), and 0% (95% CI, 0-0.1), respectively. CONCLUSION: Vertical transmission after maternal primary cytomegalovirus infection increases with advancing pregnancy, starting from the preconception period. However, severe fetal impairments are rare after infection in the first trimester of pregnancy.

Emergency cerclage in singleton pregnancies with painless cervical dilatation: A meta-analysis.

INTRODUCTION: Emergency cerclage is the most common active intervention in pregnant women with cervical insufficiency. This meta-analysis aimed to compare the effectiveness of emergency cerclage vs expectant management on maternal and perinatal outcomes, and to assess the current status of evidence. MATERIAL AND METHODS: A search was conducted from 1 June 2019 until 1 September 2019 and eligible studies were identified in the MEDLINE, Scopus, Cochrane and US clinical trials registry without limitations concerning the publication dates and languages. Randomized controlled trials (RCTs), non-RCTs and observational studies comparing emergency cerclage with no cerclage/expectant management, in women presenting with painless cervical dilatation were included. RESULTS: The electronic search yielded 3607 potential studies, of which 38 were fully reviewed and 12 observational studies (1021 participants) were included. Cerclage was superior to expectant management for the primary outcomes of preterm birth before 28 and 32 gestational weeks, OR 0.25 (95% CI 0.16-0.39, five studies, N = 392, I2 = 41%, low quality) and 0.08 (95% CI 0.02-0.29, four studies, N = 176, I2 = 51%, low quality), respectively. Cerclage was also superior to expectant management for the secondary outcomes of fetal loss OR 0.26 (95% CI 0.12-0.56, 8 studies, N = 455, I2 = 46%, very low-quality), pregnancy prolongation in days mean difference 47.45 (95% CI 39.89-55.0, 12 studies, N = 1027 I2 = 86%, very low quality), gestational age at birth in weeks mean difference 5.68 (95% CI 4.69-6.67, 9 studies, N = 892, I2 = 73%, very low quality), admission to neonatal intensive care OR 0.21 (95% CI 0.07-0.70, two studies, N = 79, I2 = 36%, very low quality) and neonatal death OR 0.12 (95% CI 0.04-0.34, five studies, N = 130, I2 = 0%, very low quality). There were no differences between cerclage and expectant management concerning premature rupture of membranes during or after the procedure OR 0.68 (95% CI 0.31-1.48, two studies, N = 155, I2 = 85%, very low quality) and chorioamnionitis OR 1.14 (95% CI 0.31-4.25, three studies, N = 88, I2 = 33%, very low quality). CONCLUSIONS: Emergency cerclage in pregnant women with painless cervical dilatation seems to decrease preterm births, prolong the pregnancy, and decrease the neonatal deaths and fetal losses, but does not increase the risk of chorioamnionitis and premature rupture of membranes. Despite the extremely favorable estimates for cerclage, the results should be viewed with caution because, as a result of the lack of randomized control trials, the quality of evidence is low to very low.

Voiding urosonography and voiding cystourethrography in primary vesicoureteral reflux associated with mild prenatal hydronephrosis: a comparative study.

BACKGROUND: Contrast-enhanced harmonic voiding urosonography has been introduced as a sensitive, radiation-free imaging method for the diagnosis of vesicoureteric reflux. OBJECTIVE: To evaluate the occurrence/severity of vesicoureteric reflux in infants with mild prenatal hydronephrosis comparing voiding cystourethrography and voiding urosonography. MATERIALS AND METHODS: Sixty infants with prenatal hydronephrosis were studied (anteriοposterior pelvic diameter 5-9 mm on ultrasound [US] at gestational weeks 21-30). Postnatal US was performed within the first month of life, as well as voiding cystourethrography and contrast-enhanced voiding urosonography at 1.5-2.5 months at the same session. RESULTS: Vesicoureteric reflux was diagnosed on at least one modality in 19/60 (32%) infants, and more often on contrast-enhanced voiding urosonography (18/60, 30%) than on voiding cystourethrography (8/60, 13%), P=0.046. Among girls, reflux was more often seen on contrast-enhanced voiding urosonography (6/16, 38%) than on voiding cystourethrography (1/16, 6%), P=0.03. Vesicoureteric reflux missed by voiding cystourethrography was more severe (Grades I, II and III in one, nine and four kidney-ureter-units, respectively), compared with a single case missed by contrast-enhanced voiding urosonography (Grade I in one kidney-ureter-unit). CONCLUSION: In the absence of a reference standard, our results imply that voiding cystourethrography might underdiagnose reflux, and/or contrast-enhanced voiding urosonography may overdiagnose reflux.

Corticosteroids for preventing neonatal respiratory morbidity after elective caesarean section at term.

BACKGROUND: Infants born at term by elective caesarean section are more likely to develop respiratory morbidity than infants born vaginally. Prophylactic corticosteroids in singleton preterm pregnancies accelerate lung maturation and reduce the incidence of respiratory complications. OBJECTIVES: The objective of this review was to assess the effect of prophylactic corticosteroid administration before elective caesarean section at term, as compared to usual management without corticosteroids, in reducing neonatal respiratory morbidity and admission to special care with respiratory complications. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (14 June 2017), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials comparing prophylactic antenatal corticosteroid administration (betamethasone or dexamethasone) with placebo or with no treatment, given before elective caesarean section at term (at or after 37 weeks of gestation). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: We included four trials (3956 women and 3893 neonates) at a moderate risk of bias, comparing prophylactic administration of betamethasone or dexamethasone versus placebo or usual treatment without steroids in term elective caesarean section. Women randomised to treatment group received either two intramuscular doses of betamethasone in the 48 hours before delivery, or intramuscular dexamethasone (two or four doses) prior to delivery (at 37 weeks' gestation or 48 hours before delivery), and were compared to the control group who received a saline placebo or treatment as usual.Prophylactic antenatal corticosteroid administration appeared to decrease the risk of respiratory distress syndrome (RDS) (risk ratio (RR) 0.48; 95% confidence interval (CI) 0.27 to 0.87; 4 studies; 3817 participants; low-quality evidence), transient tachypnoea of the neonate (TTN) (RR 0.43; 95% CI 0.29 to 0.65; 4 studies; 3821 participants; low-quality evidence), admission to the neonatal intensive care unit (NICU) for respiratory morbidity (RR 0.42; 95% CI 0.22 to 0.79; 3 studies; 3441 participants), and admission to neonatal special care (all levels) for respiratory complications (RR 0.45; 95% CI 0.22 to 0.90; 1 study; 942 participants; low-quality evidence). Administration of antenatal corticosteroids also appeared to reduce admission to neonatal special care (RR 0.62; 95% CI 0.43 to 0.89; 2 studies; 2169 participants) and neonatal intensive care (RR 0.14; 95% CI 0.03 to 0.61; 1 study; 452 participants) for any indication, compared to placebo or usual care. Finally, prophylactic antenatal corticosteroids also appeared to reduce the length of stay in NICU by 2.70 days (mean difference (MD) -2.70; 95% CI -2.76 to -2.64; 2 studies; 32 participants).No reduction was found in the need for mechanical ventilation (RR 0.67; 95% CI 0.27 to 1.68; 3 studies; 3441 participants; very-low quality), perinatal death (RR 0.67; 95% CI 0.11 to 4.10; 4 studies; 3893 participants) or neonatal sepsis (RR 1.00; 95% CI 0.06 to 15.95; 2 studies; 2214 participants) .There were no reported events of neonatal respiratory complications (other than RDS and tachypnoea of the newborn (TTN)), chronic lung disease, duration of mechanical ventilation or maternal postpartum infection, therefore results on these outcomes are non-estimable. The studies did not provide data on other pre-defined outcomes.The quality of evidence, as assessed using GRADE was low for the outcomes of RDS, TTN and admission to NICU for respiratory morbidity, indicating that the true effect could potentially be substantially different from our estimate of effect. AUTHORS' CONCLUSIONS: The results from the four trials are promising, but more high-quality studies with larger sample sizes that are adequately powered to detect the effect of prophylactic antenatal corticosteroids on outcomes of respiratory morbidity are needed, given the potential of the current studies for bias. Consideration should be given to the balance between statistical significance and clinical significance, particularly in view of the low event rates of significant respiratory morbidity (RDS or admission to NICU for respiratory complications) in this population. In addition, further trials on the long-term outcomes of these infants are needed to identify any potential harms and complications of antenatal corticosteroid administration at term.

Fetal aneuploidy diagnosed at celocentesis for early prenatal diagnosis of congenital hemoglobinopathies.

INTRODUCTION: Currently, prenatal diagnosis of genetic disorders requires chorionic villus sampling or amniocentesis carried out after 11 and 16 weeks of gestation, respectively. Celocentesis is a procedure for prenatal diagnosis that could be used from as early as 7 weeks. The present investigation evaluated the feasibility of performing diagnosis for monogenic diseases using celomic fluid containing cells of fetal origin. MATERIAL AND METHODS: Analysis consisted of 489 singleton pregnancies undergoing celocentesis for the prenatal diagnosis of hemoglobinopathies (n = 367) or before surgical termination of pregnancy for social indications (n = 122). Embryo-fetal cells were isolated from celomic fluid using CD71 antibodies or by micromanipulation. Quantitative fluorescent polymerase chain reaction of short tandem repeat sequences of chromosomes 13, 18, 21, X and Y were used to determine the presence of maternal DNA. RESULTS: 357/489 (73%) of celomic fluid samples were contaminated with maternal cells. In two cases, diagnosis was not possible due to the high contamination of celomic fluid. Eighty-seven (23.8%) fetuses were affected by hemoglobinopathies and, in five cases, chromosomal aneuploidies were found, including three cases of trisomy 21, one of trisomy 13 and one of triploidy. In all cases, the diagnosis of hemoglobinopathies and chromosomal abnormalities was confirmed by molecular and traditional cytogenetic analysis after amniocentesis, chorionic villus or placental tissue collection following pregnancy termination. CONCLUSIONS: The findings of this study demonstrate that embryo-fetal cell selection from celomic fluid allows reliable and early prenatal diagnosis of hemoglobinopathies and can give more information on any fetal aneuploidy following the control of maternal contamination by quantitative fluorescent-PCR.

Embryo-fetal erythroid cell selection from celomic fluid allows earlier prenatal diagnosis of hemoglobinopathies.

OBJECTIVE: Celocentesis, which involves aspiration of celomic fluid at 7-9 weeks' gestation, can potentially provide early prenatal diagnosis of single-gene disorders. The main barrier to wide acceptability of this technique is contamination of the sample by maternal cells. This problem can be overcome through selection of embryo-fetal erythroid precursors, which are found in celomatic fluid. METHOD: Embryo-fetal erythroid precursors were selected by an anti-CD71 MicroBeads method or by direct micromanipulator pickup of the cells selected on the basis of their morphology. RESULTS: In our series of 302 singleton pregnancies at high risk for hemoglobinopathies, Celocentesis provided a sample of celomic fluid in all cases. In 100 (33.1%) samples, maternal contamination was absent or very low (< 5%), and unambiguous results were obtained without the need for any preliminary procedures. In 160 (53%) cases, the contamination was between 5% and 60%, and selection of embryo-fetal erythroid precursors was successfully achieved by anti-CD71 MicroBeads. In 42 (13.9%) cases, the contamination was > 60%, and selection of embryo-fetal cells was achieved by micromanipulation. In all 302 cases, there was concordance between DNA obtained from celomic fluid samples and fetal or newborn DNA. CONCLUSIONS: Celocentesis can be a reliable procedure for earlier prenatal diagnosis of fetal monogenic diseases.

Identification of embryo-fetal cells in celomic fluid using morphological and short-tandem repeats analysis.

OBJECTIVE: The main problem to wide acceptability of celocentesis as earlier prenatal diagnosis is contamination of the sample by maternal cells. The objective of this study was to investigate the cellular composition of celomic fluid for morphological discrimination between maternal and embryo-fetal cells. METHOD: Celomic fluids were aspired by ultrasound-guided transcervical celocentesis at 7-9 weeks' gestation from singleton pregnancies before surgical termination for psychological reasons. DNA extracted from celomic fluid cells showed the same morphology, and quantitative fluorescent polymerase chain reaction (PCR) assay was performed to evaluate their fetal or maternal origin. RESULTS: Six different types of non-hematological maternal and four different types of embryo-fetal cells were detected. The most common maternal cells were of epithelial origin. The majority of embryo-fetal cells were roundish with a nucleus located in an eccentric position near the wall. These cells were considered to be erythroblasts, probably derived from the yolk sac that serves as the initial site of erythropoiesis. CONCLUSIONS: The combined use of morphology and DNA analysis makes it possible to select and isolate embryo-fetal cells, even when maternal contamination is high. This development provides the opportunity for the use of celocentesis for early prenatal diagnosis of genetic diseases and application of array comparative genomic hybridization. © 2016 John Wiley & Sons, Ltd.

Early Non-Invasive Prenatal Testing at 6-9 Weeks of Gestation.

Non-invasive prenatal testing (NIPT) is usually performed beyond 10 weeks of gestation, because earlier in pregnancy, the fetal fraction is low, resulting in failure to obtain reliable results. This study aimed to evaluate the clinical performance of NIPT earlier in pregnancy using a method for cell-free DNA (cfDNA) analysis that eliminates the need for polymerase chain reaction (PCR), DNA sequencing, or microarrays (Vanadis® system, PerkinElmer, Waltham, MA, USA). Cell-free DNA was extracted from the maternal plasma of 30 singleton pregnancies at 6-9 weeks of gestation (group 1) and at 11-14 weeks of gestation of the same patients (group 2). The mean crown-rump length (CRL) and gestational age in group A was 16.12 mm and that in group B was 61.45 mm. In group A, results were obtained in all, but one, cases (97%). From the remaining pregnancies, one miscarried at 8 weeks and, therefore, the follow-up NIPT at 12 weeks could not be performed. The fetal sex was diagnosed correctly in the 28 cases that had a successful early test, and the results were in accordance with the examination at 12 weeks. There were no cases of aneuploidies and disomy was diagnosed correctly in all. The "Vanadis" prenatal NIPT assay can successfully be used early during the first trimester at 6-9 weeks of gestation (early NIPT) to identify the fetal sex. Further studies are needed to explore the diagnostic potential for aneuploidies.

Prenatal Diagnosis of Cystic Fibrosis by Celocentesis.

Celocentesis is a new sampling tool for prenatal diagnosis available from 7 weeks in case of couples at risk for genetic diseases. In this study, we reported the feasibility of earlier prenatal diagnosis by celocentesis in four cases of cystic fibrosis and one case of cystic fibrosis and ß-thalassemia co-inherited in the same fetus. Celomic fluids were aspired from the celomic cavity between 8+2 and 9+3 weeks of gestation and fetal cells were picked up by micromanipulator. Maternal DNA contamination was tested and target regions of fetal DNA containing parental pathogenetic variants of CFTR and HBB genes were amplified and sequenced. Four of the five fetuses resulted as being affected by cystic fibrosis and, in all cases, the women decided to interrupt the pregnancy. In the other case, the fetus presented a healthy carrier of cystic fibrosis. The results were confirmed in three cases on placental tissue. In one case, no abortive tissue was obtained. In the last case, the woman refused the prenatal diagnosis to confirm the celocentesis data; the pregnancy is ongoing without complications. This procedure provides prenatal diagnosis of monogenic diseases at least four weeks earlier than traditional procedures, reducing the anxiety of patients and providing the option for medical termination of the affected fetus at 8-10 weeks of gestation, which is less traumatic and safer than surgical termination in the second trimester.

The HPV-DNA Test in Pregnancy: A Review of the Literature.

Human papillomavirus (HPV) is a virtually necessary cause of cervical cancer, and HPV genotypes are categorized either as high-risk or low-risk based on their potential to cause malignancy of the cervix. HPV-DNA detection is used widely for screening women at risk. However, its clinical significance is not proven sufficiently in pregnancy. The aim of this review was to summarize published data referring to the integration of the HPV-DNA test in cervical cancer screening during pregnancy. PubMed and Scopus were searched for articles investigating the HPV-DNA test during pregnancy as a primary association; greater interest was placed on studies published after 2000. Retrieved articles reported similarities or discrepancies in the HPV-DNA test in pregnant women compared to those who are not pregnant, its accuracy, and its integration in cervical cancer screening. The HPV-DNA test may constitute a helpful tool utilized for monitoring, risk stratification, and triage of cases that require colposcopy. If combined with the HPV-mRNA test, this might improve its specificity. However, when compared to HPV-DNA detection rates in non-pregnant women, the results were ambiguous, without giving the opportunity to draw safe conclusions. Both those findings and the high cost hold it back from wide use. Hence, the Papanicolaou smear (Pap smear) is still the first-line diagnostic tool and colposcopy-guided cervical biopsy is the "gold standard" method for the management of cervical intraepithelial neoplasia (CIN) treatment during pregnancy.

A Large Exophytic Tumor of the Cervix Causing Vaginal Bleeding in Pregnancy: A Case Report.

Vaginal bleeding in the second and third trimesters of pregnancy is usually due to placental causes, namely placental abruption and placenta previa. Other causes include uterine rupture, vasa previa, and hematologic disorders. However, benign or malignant lesions of the vagina and the cervix may also cause vaginal bleeding or spotting. Although cervical cancer in pregnancy is rare, about 8% of pregnant women have an abnormal Pap smear and 3% of the total cervical cancers are diagnosed during pregnancy. We report a case of a 20-week pregnant woman who presented with vaginal bleeding; a visual inspection revealed a large exophytic lesion of the cervix. The Pap smear demonstrated a low-grade squamous intraepithelial lesion (LSIL) related to human papillomavirus (HPV) infection. The differential diagnosis based on the findings of the colposcopy included invasive cervical carcinoma, warty lesions, and perishable lesion. A cesarean section and the removal of the cervical tumor were scheduled and carried out as planned at 37 weeks of gestation. The histologic examination showed extensive lesions of low-grade squamous intraepithelial cervical neoplasia (LSIL/CIN1). Despite the fact that exophytic tumors of the cervix are extremely rare, in women presenting with vaginal bleeding or spotting during the second or third trimester of pregnancy, the ultrasound scan must be followed by a visual inspection of the vagina and the cervix.

Risk factors for preterm labor: An Umbrella Review of meta-analyses of observational studies.

Preterm birth defined as delivery before 37 gestational weeks, is a leading cause of neonatal and infant morbidity and mortality. Understanding its multifactorial nature may improve prediction, prevention and the clinical management. We performed an umbrella review to summarize the evidence from meta-analyses of observational studies on risks factors associated with PTB, evaluate whether there are indications of biases in this literature and identify which of the previously reported associations are supported by robust evidence. We included 1511 primary studies providing data on 170 associations, covering a wide range of comorbid diseases, obstetric and medical history, drugs, exposure to environmental agents, infections and vaccines. Only seven risk factors provided robust evidence. The results from synthesis of observational studies suggests that sleep quality and mental health, risk factors with robust evidence should be routinely screened in clinical practice, should be tested in large randomized trial. Identification of risk factors with robust evidence will promote the development and training of prediction models that could improve public health, in a way that offers new perspectives in health professionals.

Pregnancy physical activity questionnaire: Translation and cross-cultural adaptation of a Greek version.

OBJECTIVE: The aim of this study was to translate and adapt the Pregnancy Physical Activity Questionnaire (PPAQ) into Greek culture. STUDY DESIGN: The procedure followed to translate the PPAQ included the stages: forward translation, synthesis, backward translation and an expert committee review. Members of the research team discussed ambiguities, discordances and equivalence at each stage. Then, the pre-final Greek version of the PPAQ was pre-tested on 46 pregnant women; a quantitative and qualitative analysis was conducted. RESULTS: Few modifications were done to the original PPAQ, in order to ensure cultural adaptation and clinical implementation. Appropriate changes to the international metric units were done. In addition, two items have been modified to achieve relevance with Greek culture. Two items were merged into one and three items were splitted, which maintained their initial meaning. Those changes were made to match the energy expenditure compendium update for physical activities. Participants at the pre-test had a mean age of 34,23 years, response time to the questionnaire varied between 5 and 10 min and there were no missing data. No difficulties or misunderstandings were reported by the participants during pre-testing. Thus, the research team agreed on the pre-final PPAQ Greek version. CONCLUSION: The final PPAQ Greek version indicated transcultural equivalence to the original PPAQ in English. It is also a unique questionnaire for assessing physical activity in Greek pregnant women and will be a useful tool in clinical routine.

Advantages and Limitations of Ultrasound as a Screening Test for Ovarian Cancer.

Ovarian cancer (OC) is the seventh most common malignancy diagnosed among women, the eighth leading cause of cancer mortality globally, and the most common cause of death among all gynecological cancers. Even though recent advances in technology have allowed for more accurate radiological and laboratory diagnostic tests, approximately 60% of OC cases are diagnosed at an advanced stage. Given the high mortality rate of advanced stages of OC, early diagnosis remains the main prognostic factor. Our aim is to focus on the sonographic challenges in ovarian cancer screening and to highlight the importance of sonographic evaluation, the crucial role of the operator΄s experience, possible limitations in visibility, emphasizing the importance and the necessity of quality assurance protocols that health workers have to follow and finally increasing the positive predictive value. We also analyzed how ultrasound can be combined with biomarkers (ex. CA-125) so as to increase the sensitivity of early-stage OC detection or, in addition to the gold standard examination, the CT (Computed tomography) scan in OC follow-up. Improvements in the performance and consistency of ultrasound screening could reduce the need for repeated examinations and, mainly, ensure diagnostic accuracy. Finally, we refer to new very promising techniques such as liquid biopsies. Future attempts in order to improve screening should focus on the identification of features that are unique to OC and that are present in early-stage tumors.

Neurodevelopment after prenatal diagnosis of isolated agenesis of the corpus callosum: an integrative review.

OBJECTIVE: To systematically review published data on the neurodevelopment of children that were diagnosed prenatally with isolated agenesis of the corpus callosum. STUDY DESIGN: Medline and Scopus searches (1960-July 2011); cross-referencing of retrieved articles. RESULTS: Sixteen reports (132 cases of apparently isolated agenesis of the corpus callosum) were included in the analysis. The rates of normal outcome, borderline or moderate disability and severe disability were 94/132 (71.2%; 95% confidence interval [CI], 63.0-78.3), 18/132 (13.6%; 95% CI, 8.8-20.5), and 22/132 (15.2%; 95% CI, 10.0-22.2), respectively. Magnetic resonance imaging detected additional cerebral abnormalities in 22.5% (95% CI, 12.3-37.5) of apparently isolated agenesis of the corpus callosum cases. In truly isolated agenesis of the corpus callosum (confirmed by magnetic resonance imaging), the rates of normal neurodevelopment and severe disability were 52/69 (75.4%; 95% CI, 64.0-84.0) and 8/69 (11.6%; 95% CI, 6.0-21.2), respectively. CONCLUSION: Prenatally diagnosed, isolated agenesis of the corpus callosum is usually associated with a favorable outcome. Larger, prospective series are required, as current data are limited, inconsistent, and prevent subgroup analyses (eg, complete vs partial agenesis of the corpus callosum).

Thalamic volume measurement in normal fetuses using three-dimensional sonography.

PURPOSE: Brain thalami are important for a wide range of sensorimotor and neuropsychiatric functions. This study was carried out to calculate normative values for thalami volume during fetal life. METHODS: Fetal thalami volumes were measured using 3D ultrasound in 122 normal, singleton fetuses at 20(+0) -34(+6) weeks' gestation. Virtual Organ Computer-aided AnaLysis (VOCAL) was used to obtain a sequence of six sections of each thalamus, starting from the transthalamic view of the brain at an axial plane. Thalamic contour was drawn manually. Volume contrast imaging was used to enhance image quality when needed. The volume of the thalamus distal to the transducer was also measured by a second operator in 30 randomly selected cases, blind to the measurements of the first, to calculate interobserver agreement. RESULTS: Thalamic volume increased with gestational age, following a quadratic equation (R(2) = 0.83). There was no significant difference in volume between the right and left thalamus. The mean volume of each thalamus increased from 0.45 ml at 20(+0) weeks, to 1.39 ml at 28(+0) weeks, to 2.17 ml at 34(+0) weeks. The 95% limits of interobserver agreement for thalamic volume were -14.3% to +17.2%. CONCLUSIONS: The increase in thalamic volume with gestation can be described adequately by a quadratic equation. The moderate interobserver repeatability is attributed to the similar echogenicity between the thalamus and its surrounding structures.

Novel and Founder Pathogenic Variants in X-Linked Alport Syndrome Families in Greece.

Alport syndrome (AS) is the most frequent monogenic inherited glomerulopathy and is also genetically and clinically heterogeneous. It is caused by semi-dominant pathogenic variants in the X-linked COL4A5 (NM_000495.5) gene or recessive variants in the COL4A3/COL4A4 (NM_000091.4/NM_000092.4) genes. The disease manifests in early childhood with persistent microhematuria and can progress to proteinuria and kidney failure in adolescence or early adulthood if left untreated. On biopsy, pathognomonic features include alternate thinning, thickening and lamellation of the glomerular basement membrane (GBM), in the presence of podocyte foot process effacement. Although previous studies indicate a prevalence of AS of about 1/50,000, a recent publication reported a predicted rate of pathogenic COL4A5 variants of 1/2320. We herewith present 98 patients (40 M/58 F) from 26 Greek families. We are selectively presenting the families segregating the X-linked form of AS with pathogenic variants in the COL4A5 gene. We found 21 different pathogenic variants, 12 novel: eight glycine and one proline substitutions in the collagenous domain, one cysteine substitution in the NC1 domain, two premature termination of translation codons, three splicing variants, one 5-bp insertion/frameshift variant, one indel-frameshift variant and four gross deletions. Notably, patients in six families we describe here and three families we reported previously, carried the COL4A5-p.G624D substitution, a founder defect encountered all over Europe which is hypomorphic with mostly milder symptomatology. Importantly, on several occasions, the correct genetic diagnosis reclassified patients as patients with AS, leading to termination of previous immunosuppressive/cyclosporine A therapy and a switch to angiotensin converting enzyme inhibitors (ACEi). With the understanding that all 98 patients span a wide range of ages from infancy to late adulthood, 15 patients (11 M/4 F) reached kidney failure and 11 (10 M/1 F) received a transplant. The prospects of avoiding lengthy diagnostic investigations and erroneous medications, and the advantage of delaying kidney failure with very early administration of renin-angiotensin-aldosterone system (RAAS) blockade, highlights the importance of timely documentation of AS by genetic diagnosis.