Congenital cytomegalovirus infection: the state of the art and future perspectives.

Congenital cytomegalovirus (cCMV) infection is the most common congenital infection, with an estimated incidence of approximately one in 200 infants in high-income settings. Approximately one in four children may experience life-long consequences, including sensorineural hearing loss and neurodisability. Knowledge regarding prevention, diagnosis, and treatment increased in the recent years, but some challenges remain. In this review, we tried to summarize the current knowledge on both the obstetrical and pediatric areas, while also highlighting controversial aspects and future perspectives. There is a need to enhance awareness among the general population and pregnant women through specific information programs. Further research is needed to better define the classification of individuals at birth and to have a deeper understanding of the long-term outcomes for so defined children. Finally, the availability of valaciclovir medication throughout pregnancy, where appropriate, has prompted the assessment of a universal serological antenatal screening. It is recommended to establish a dedicated unit for better evaluation and management of both mothers and children.

Longitudinal Doppler Assessments in Late Preterm Fetal Growth Restriction.

PURPOSE: To assess the longitudinal variation of the ratio of umbilical and cerebral artery pulsatility index (UCR) in late preterm fetal growth restriction (FGR). MATERIALS AND METHODS: A prospective European multicenter observational study included women with a singleton pregnancy, 32+ 0-36+ 6, at risk of FGR (estimated fetal weight [EFW] or abdominal circumference [AC] < 10th percentile, abnormal arterial Doppler or fall in AC from 20-week scan of > 40 percentile points). The primary outcome was a composite of abnormal condition at birth or major neonatal morbidity. UCR was categorized as normal (< 0.9) or abnormal (≥ 0.9). UCR was assessed by gestational age at measurement interval to delivery, and by individual linear regression coefficient in women with two or more measurements. RESULTS: 856 women had 2770 measurements; 696 (81 %) had more than one measurement (median 3 (IQR 2-4). At inclusion, 63 (7 %) a UCR ≥ 0.9. These delivered earlier and had a lower birth weight and higher incidence of adverse outcome (30 % vs. 9 %, relative risk 3.2; 95 %CI 2.1-5.0) than women with a normal UCR at inclusion. Repeated measurements after an abnormal UCR at inclusion were abnormal again in 67 % (95 %CI 55-80), but after a normal UCR the chance of finding an abnormal UCR was 6 % (95 %CI 5-7 %). The risk of composite adverse outcome was similar using the first or subsequent UCR values. CONCLUSION: An abnormal UCR is likely to be abnormal again at a later measurement, while after a normal UCR the chance of an abnormal UCR is 5-7 % when repeated weekly. Repeated measurements do not predict outcome better than the first measurement, most likely due to the most compromised fetuses being delivered after an abnormal UCR.

Fetal cerebral Doppler changes and outcome in late preterm fetal growth restriction: prospective cohort study.

OBJECTIVES: To explore the association between fetal umbilical and middle cerebral artery (MCA) Doppler abnormalities and outcome in late preterm pregnancies at risk of fetal growth restriction. METHODS: This was a prospective cohort study of singleton pregnancies at risk of fetal growth restriction at 32 + 0 to 36 + 6 weeks of gestation, enrolled in 33 European centers between 2017 and 2018, in which umbilical and fetal MCA Doppler velocimetry was performed. Pregnancies were considered at risk of fetal growth restriction if they had estimated fetal weight and/or abdominal circumference (AC) < 10th percentile, abnormal arterial Doppler and/or a fall in AC growth velocity of more than 40 percentile points from the 20-week scan. Composite adverse outcome comprised both immediate adverse birth outcome and major neonatal morbidity. Using a range of cut-off values, the association of MCA pulsatility index and umbilicocerebral ratio (UCR) with composite adverse outcome was explored. RESULTS: The study population comprised 856 women. There were two (0.2%) intrauterine deaths. Median gestational age at delivery was 38 (interquartile range (IQR), 37-39) weeks and birth weight was 2478 (IQR, 2140-2790) g. Compared with infants with normal outcome, those with composite adverse outcome (n = 93; 11%) were delivered at an earlier gestational age (36 vs 38 weeks) and had a lower birth weight (1900 vs 2540 g). The first Doppler observation of MCA pulsatility index < 5th percentile and UCR Z-score above gestational-age-specific thresholds (1.5 at 32-33 weeks and 1.0 at 34-36 weeks) had the highest relative risks (RR) for composite adverse outcome (RR 2.2 (95% CI, 1.5-3.2) and RR 2.0 (95% CI, 1.4-3.0), respectively). After adjustment for confounders, the association between UCR Z-score and composite adverse outcome remained significant, although gestational age at delivery and birth-weight Z-score had a stronger association. CONCLUSION: In this prospective multicenter study, signs of cerebral blood flow redistribution were found to be associated with adverse outcome in late preterm singleton pregnancies at risk of fetal growth restriction. Whether cerebral redistribution is a marker describing the severity of fetal growth restriction or an independent risk factor for adverse outcome remains unclear, and whether it is useful for clinical management can be answered only in a randomized trial. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

First-trimester ultrasound determination of chorionicity in twin gestations using the lambda sign: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the accuracy of first-trimester sonographic determination of chorionicity in twin gestations using the lambda sign. STUDY DESIGN: Electronic databases (MEDLINE, PROSPERO, Scopus, ClinicalTrials.gov, EMBASE, Sciencedirect) were searched from their inception until April 2016. We included only study assessing the accuracy lambda sign in prediction of monochorionicity in the first trimester. Forest plots for pooled sensitivity and specificity with 95% confidence intervals (CI) were generated. In addition, symmetric summary receiver-operating characteristic curves were plotted. The area under the curve (AUC) was also computed to evaluate the overall accuracy of the diagnostic test. RESULTS: Nine studies, including 2292 twins, were analysed. In all of these studies, identification of the lambda sign was used to diagnose chorionicity on real-time B-mode imaging. Twins were classified as monochorionic if there was a single placental mass in the absence of the lambda sign, and dichorionic if there was a single placental mass but the lambda sign was present or the placentas were not adjacent to each other. In all nine studies, placental histology or discordant fetal sex were used to confirm chorionicity. Pooled results from the meta-analysis showed that sensitivity of the presence of the lambda sign in the prediction of dichorionicity was 99% (95% CI 98-100%), and specificity was 95% (95% CI 92-97%). Pooled sensitivity of the absence of the lambda sign in the prediction of monochorionicity was 96% (95% CI 92-98%) and pooled specificity was 99% (95% CI 98-99%). The AUC for diagnostic accuracy was 0.99, and suggested very high diagnostic accuracy. CONCLUSION: The lambda sign predicts chorionicity with a high degree of accuracy before 14 weeks of gestation. Presence of the lambda sign indicates dichorionicity, and absence of the lambda sign indicates monochorionicity. All hospitals should encourage departments providing ultrasound services to determine chorionicity when examining women with twin pregnancies in the first trimester. As determination of chorionicity is most accurate before 14 weeks when the amnion and chorion have not yet fused, the first-trimester scan in twin pregnancy is paramount.

Omega-3 supplementation during pregnancy to prevent recurrent intrauterine growth restriction: systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the efficacy of omega-3 supplementation during pregnancy in preventing intrauterine growth restriction (IUGR) in women with apparently uncomplicated singleton pregnancy and previous IUGR pregnancy. METHODS: For this systematic review, the research protocol was designed a priori. Searches were performed in electronic databases for studies published from inception of each database to December 2014. A combination of search terms was used including 'fish oil', 'long chain polyunsaturated fatty acids', 'intrauterine growth restriction', 'small for gestational age' and 'omega-3'. We included all randomized controlled trials (RCTs) of women with an uncomplicated singleton pregnancy and a prior IUGR pregnancy who were randomized to receive prophylactic treatment with omega-3 supplementation or either placebo or no treatment (control). Trials that included women with multiple gestations and those with only biochemical outcomes available were excluded. Pooled estimates were based on relative risk (RR) with 95% CI. Primary outcome was incidence of IUGR as defined in the RCTs. RESULTS: Three RCTs including 575 women with uncomplicated singleton pregnancy with prior IUGR were analyzed. Women who received omega-3 supplementation during pregnancy had the same incidence of IUGR, defined as estimated fetal weight < 5(th) or < 3(rd) centiles, as had controls (22.8% vs 20.2%, respectively; RR, 1.13 (95% CI, 0.83-1.54)). Compared to controls, women who received omega-3 supplementation delivered later (mean difference, 1.4 (95% CI, 1.28-1.63) weeks), had a longer latency (mean difference, 2 (95% CI, 1.73-2.08) weeks), had a similar incidence of perinatal death (2.1% vs 3.3%, respectively; RR, 0.60 (95% CI, 0.15-2.42)) and similar birth weight (mean difference, 50 g (95% CI, -26 to 246 g)). CONCLUSIONS: Omega-3 supplementation during pregnancy does not prevent recurrence of IUGR in women with uncomplicated singleton pregnancy and a previous IUGR pregnancy.

Are there any relationships between umbilical artery Pulsatility Index and macrosomia in fetuses of type I diabetic mothers?

OBJECTIVE: To establish whether there are relationships between umbilical artery Pulsatility Index (PI) and fetal macrosomia in pregnancies complicated by type I diabetes. METHODS: In a retrospective observational study, 102 singleton pregnant women with type I diabetes were considered. Umbilical artery PI was measured by Doppler ultrasonography within one week from delivery and related to neonatal weight. Pregnancies were grouped according to birtweight in macrosomic group (≥4000 g) and normal growth group (<4000 g). Relationships between umbilical artery PI and birth weight and birth weight centile were tested by Pearson's correlation analysis. Further umbilical artery PI values were compared between macrosomic and normally grown fetuses. RESULTS: Birth weight was ≥4000 g in 24 pregnancies (23.5%). A significant relationship was found between umbilical artery PI and neonatal weight (r = 0.512; p < 0.01) and neonatal weight centile (r = 0.400; p < 0.01). Umbilical artery PI were significantly lower (t = -6.013; p < 0.001) in the macrosomic group (0.78; 95% confidence interval (CI) 0.73-0.84) than in the normal growth group (1.00; 95% CI 0.97-1.04). CONCLUSIONS: In pregnancies complicated by type I diabetes there is a significant relationship between umbilical artery PI value before delivery and absolute birth weight and birth weight centile. Macrosomic fetuses show a significant reduction in umbilical artery PI when compared with diabetic pregnancies without fetal overgrowth.

Characterization and predicted role of the microRNA expression profile in amnion from obese pregnant women.

Maternal obesity and nutrient excess in utero increase the risk of future metabolic diseases. The mechanisms underlying this process are poorly understood, but probably include genetic, epigenetic alterations and changes in fetal nutrient supply. We have studied the microRNA (miRNA) expression profile in amnion from obese and control women at delivery to investigate if a specific miRNA signature is associated with obesity. The expression profile of 365 human miRNAs was evaluated with the TaqMan Array in amnion from 10 obese and 5 control (prepregnancy body mass index (BMI) >30 and <25 kg m(-2), respectively) women at delivery. Target genes and miRNA-regulated pathways were predicted by bioinformatics. Anthropometric and biochemical parameters were also measured in mothers and newborns. Seven miRNAs were expressed only in obese women (miR-422b, miR-219, miR-575, miR-523, miR-579, miR-618 and miR-659), whereas 13 miRNAs were expressed at a higher level and 12 miRNAs at a lower level in obese women than in controls. MicroRNAs significantly downregulated the neurotrophin, cancer/ErbB, mammalian target of rapamycin, insulin, adipocytokine, actin cytoskeleton and mitogen-activated protein kinase signaling pathways. In conclusion, we show that the miRNA profile is altered in amnion during obesity and hypothesize that this could affect pathways important for placental growth and function, thereby contributing to an increase in the newborn's risk of future metabolic diseases.

Chorioamnionitis and prematurity: a critical review.

Chorioamnionitis is the inflammatory response to an acute inflammation of the membranes and chorion of the placenta. We provide a critical review of the relationship between chorioamnionitis and the risk of prematurity and adverse maternal-fetal outcome. Chorioamnionitis results as a major risk factor for preterm birth and its incidence is strictly related to gestational age. It is associated with a significant maternal, perinatal and long-term adverse outcomes. The principal neonatal complications are neonatal sepsis, pneumonia, bronchopulmonary dysplasia, perinatal death, cerebral palsy and intraventricular hemorrhage. The role in neonatal outcome is still controversial and more conclusive studies could clarify the relationship between chorioamnionitis and adverse neonatal outcome. Maternal complications include abnormal progression of labour, caesarean section, postpartum hemorrhage, abnormal response after use of oxytocin and placenta abruption. Prompt administration of antibiotics and steroids could improve neonatal outcomes.

OS064. Contribute of the L-cysteine/ H2S pathway in placenta homeostasisin hypertensive disorders.

INTRODUCTION: Hydrogen sulfide (H2S) is considered the third endogenous gas transmitter besides nitric oxide and carbon monoxide [1]. It is produced from L-cysteine or L-methionine via the enzymes cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE). H2S is involved in the control of vascular homeostasis, having either relaxant or contractant effect on smooth muscle cells. The H2S involvement in rat and human intrauterine tissues has also been shown [2]. OBJECTIVES: The aim of our study was to investigate the L-cysteine/ H2S pathway in rat and human placenta in hypertensive state. METHODS: Placental samples were collected from spontaneous hypertensive rats (SHR) and normotensive rat (Wistar Kyoto; WKY). In parallel, placental samples were collected from 10 pre-eclamptic women and 5 controls after caesarean sections. Pre-eclamptic women were divided into two subgroups: Group1 (women who developed Early Preeclampsia, n=4); Group2 (women who developed Late Preeclampsia, n=6). The expression of CBS and CSE was evaluated in sample tissues by Western blotting analysis. The enzymatic activity was assessed in basal and stimulated (L- cysteine) condiction by a colorimetric assay. Statistical analysis was performed by using Student's t test. P<0,05 was considered as statistically significant. RESULTS: The expression of CBS and CSE in placenta of SHR rats were significantly reduced (p<0.05) compared to WKY. The H2S production resulted significantly (p<0,05) lower in SHR than WKY rats. In human placenta, the basal H2S production was similar in the three groups; interestingly the H2S production by adding L-cysteine, was higher in Late Preeclampsia compared to control group. CONCLUSION: H2S was produced in rat and human placenta. CBS and CSE, the enzymes involved in the production of H2S, were down-regulated in SHR rats and, as a consequence the H2S production was significantly reduced. Starting from these data, we tried to analyze the role of hydrogen sulfide in preeclampsia to assess the contribute of this gas transmitter in the development of this condition. Unexpectedly, preliminary data demonstrated that in women developing Late Preeclampsia there was an higher production of H2S after stimulation with L-cysteine, not revealed in Early Preeclampsia or in healthy control group. Our results indicated that the L-cysteine/H2S pathway could contribute to the development of preeclampsia condition.

Prenatal diagnosis of congenital rubella infection and ultrasonography: a preliminary study.

AIM: The aim of this study was to analyze the role of ultrasonography in the prenatal diagnosis of women with confirmed rubella infection in pregnancy. METHODS: We performed a retrospective, population-based study on 175 women referred to our Centre of Infectious Disease in Pregnancy of AOU Federico II for rubella infection, in the period between January 1999 and December 2009. In confirmed cases of infection we performed periodic ultrasonographic assessment of fetal anatomy looking for prenatal findings of rubeovirus infection. Neonatal outcomes were collected. RESULTS: Among 175 women, 48 (27.4%) were confirmed cases, in 83 (47.4%) cases rubella infection remain suspected. The remaining 44 (25.1%) women were excluded to having rubella infection in pregnancy. No defined probable cases were found. Among children born to mother with confirmed rubella infection, 9 (18.7%) resulted infected by rubella virus. In particular 6 newborns (66% of the affected) were asymptomatic, two babies showed incomplete congenital rubella syndrome (CRS), due to the presence of deafness in the absence of other congenital abnormalities without showing any USG findings. Only one baby showed a complete CRS: USG prenatal rubella infection findings were IUGR, polydramnios, cardiomegaly, defects of atrial septum, hepatosplenomegaly, ascites, echogenic bowel, placentomegaly. USG specificity and sensitivity was 100% and 11% respectively. CONCLUSION: USG has an important role in the detection rubella intrauterine infection in case of severe abnormalities. The obstetricians should understand the limitations of ultrasound in detection of deafness and minor abnormalities.

Prenatal diagnosis of ß-thalassemia: nuchal translucency in affected fetuses.

AIM: Thalassemia syndromes are a group of blood disorders inherited in autosomal recessive manner. Prenatal diagnosis of disease is based on invasive procedures. Fetuses affected by homozygous thalassemia are not reported to be anemic. We studied their nuchal translucency (NT) measurements to identify as an ultrasonographic marker of disease and highlight any correlations. METHODS: Between April 2006 and July 2010 NT test was offered to women referred to our center for prenatal diagnosis of thalassemia. All the NT tests were performed in the time of chorionic villus sampling (CVS), according to the standards of the Fetal Medicine Foundation. Measurements of fetuses affected by homozygous thalassemia were compared with normal fetuses. RESULTS: A total of 55 fetuses were recruited. Of these, 15 were confirmed to be affected by homozygous thalassemia and 40 resulted to be carriers of thalassemia trait. Neither abnormal karyotype or structural abnormalities were detected and all the NT measurement were normal. NT was not different between the affected and normal fetuses. CONCLUSION: NT is not a marker of homozygous thalassemia in fetuses at risk. Invasive procedures remain the only available methods for diagnosis.

Prevalence and characteristics of symptomatic and asymptomatic tuboovarian masses in women with HIV: an ultrasonographic study.

HIV-positive women with pelvic inflammatory disease have been reported to have an increased prevalence of tuboovarian masses (TOMs). The aim of this study was to assess the prevalence of asymptomatic ultrasonographic TOMs in women with HIV and to identify associated factors in order to formulate a selective ultrasonographic screening strategy. Two-hundred and four HIV outpatients underwent transvaginal ultrasonography. Eight (3.9%) had a diagnosis of TOM (5 were asymptomatic). Two profiles of patients at risk for TOM were identified who could be considered for selective screening strategies: the 'long-term infected' (age>35 years, diagnosis of HIV infection more than 5 years ago, HIV clinical category C, CD4 counts below 200/mm(3), >5 lifetime partners and on antiretroviral therapy) and the 'recently diagnosed with HIV' (African ethnicity, age 25-35, HIV diagnosis in the previous year, >5 lifetime partners, HIV clinical category C and not on antiretroviral therapy).

Fetal borderline cerebral ventriculomegaly: clinical significance and management.

AIM: The aim of this study was to evaluate the clinical significance and the management of fetal borderline lateral cerebral ventriculomegaly. METHODS: Fetuses with a sonographic diagnosis of lateral cerebral ventriculomegaly isolated or associated to other fetal malformations were followed monthly and a review of the English-language literature was made. RESULTS: Of 86 fetuses analyzed, 30 suffered from hydrocephaly (monolateral, bilateral), 56 showed also several other malformations . Chromosomal aberrations is possible also in case of isolated hydrocephaly. Neurological sequelae, mostly a mild to moderate delay in cognitive and/or motor development, is present in 10% of the cases. CONCLUSIONS: In most cases, isolated borderline lateral cerebral ventriculomegaly has no consequence. However, the risk of cerebral maldevelopment, delayed neurological development and, possibly, chromosomal aberrations is increased. The optimum management of these cases remains uncertain.

Diagnosis of femoral hypoplasia-unusual facies syndrome in the fetus.

Femoral hypoplasia-unusual facies syndrome (FHUFS) is a rare condition characterized by a variable degree of unilateral or bilateral femoral hypoplasia associated with facial clefting and other minor malformations. The prenatal diagnosis of this condition is possible, but so far has been reported prospectively in only two cases. We review all cases of FHUFS reported in the literature and also describe three cases detected prenatally in the mid-trimester, underlining the variable expression of the syndrome. The reported association with maternal diabetes mellitus and differential diagnosis with other syndromes characterized by femoral hypoplasia are also discussed.