Is Cardiomegaly an Indication of "Heart-Sparing Effect" in Small Fetuses?

INTRODUCTION: This study aimed to test the hypothesis that cardiac size is maintained in small fetuses presenting with cardiomegaly. MATERIALS AND METHODS: We identified singleton fetuses with estimated fetal weight <10th centile and with cardiomegaly without another more likely cardiac or extra-cardiac cause. We used Z-scores for cardiac and thoracic circumferences normalized for gestational age (GA), biparietal diameter (BPD), head circumference (HC), and femur length (FL), obtained from 188 normally grown fetuses. RESULTS: When comparing chest size, small fetuses had significantly lower thoracic circumferences median Z-scores (IQR) for GA = -4.82 (-6.15 to -3.51), BPD = -2.42 (-4.04 to -1.48), HC = -2.72 (-4.53 to -1.90), and FL = -1.60 (-2.87 to -0.71); p < 0.001 for all. When comparing heart size, small fetuses showed lower cardiac circumferences median Z-scores (IQR) for GA = -1.59 (-2.79 to -0.16); p < 0.001, similar cardiac circumferences Z-scores for BPD = 0.29 (-0.65 to 1.28); p = 0.284 and HC = 0.11 (-1.13 to 0.96); p = 0.953, and higher cardiac circumferences Z-scores for FL = 0.94 (-0.05 to 2.13); p < 0.001. CONCLUSIONS: Our results show that in small fetuses with cardiomegaly, the heart maintains normal dimensions when normalized to cranial diameters and higher dimensions when normalized to long bones. This provides insight into cardiac adaptation to adverse intrauterine environment.

Next Generation Sequencing Approach in a Prenatal Case of Cardio-Facio-Cutaneus Syndrome.

Cardiofaciocutaneous syndrome (CFCS) belongs to a group of developmental disorders due to defects in the Ras/Mitogen-Activated Protein Kinase (RAS/MAPK) signaling pathway named RASophaties. While postnatal presentation of these disorders is well known, the prenatal and neonatal characteristics are less recognized. Noonan syndrome, Costello syndrome, and CFCS diagnosis should be considered in pregnancies with a normal karyotype and in the case of ultrasound findings such as increased nuchal translucency, polyhydramnios, macrosomia and cardiac defect. Because all the RASopathies share similar clinical features, their molecular characterization is complex, time consuming and expensive. Here we report a case of CFCS prenatally diagnosed through Next Generation Prenatal Diagnosis (NGPD), a new targeted approach that allows us to concurrently investigate all the genes involved in the RASophaties.

Effects of exogenous progesterone on fetal nuchal translucency: an observational prospective study.

OBJECTIVE: Nuchal translucency (NT) seen ultrasonographically at 11-14 weeks' gestation is a sensitive marker for Down syndrome. Despite its important role for Down syndrome screening, its use is still considered controversial due to high false-positive rates. We speculated that progesterone could lead to abnormal blood flow patterns and, subsequently, to increased NT. Our primary endpoint was to evaluate the effects of exogenous progesterone on NT thickness compared to controls. The secondary endpoint was to evaluate these effects in a subgroup at low risk for fetal aneuploidies, identifying the strongest factors influencing NT variation. The tertiary endpoint was to evaluate, within the treatment group, if there is any difference in NT according to the type of progesterone administered, route of administration, and dose regimen. STUDY DESIGN: All women who came to measure NT at 11-14 weeks' gestation (crown-rump length between 45-84 mm) were considered eligible. We divided patients into 2 groups: women receiving exogenous progesterone and controls. Afterwards, 3 NT scans were performed for each case, and the largest value, accurate to 2 decimal points, was recorded. RESULTS: In all, 3716 women were enrolled and analyzed. In a crude analysis, NT (P < .05) increased in the exogenous progesterone group. The same results were obtained in the low-risk group (P < .05). The factorial analysis of variance model confirmed a correlation between altered NT and gestational age (P < .0001) and progesterone exposure (P < .05). The characteristics of treatment (route, formulation, dose) were examined separately and no statistically significant differences among the subgroups were observed. CONCLUSION: Exogenous progesterone increases NT.

What Is the Rate of Incomplete Fetal Anatomic Surveys During a Second-Trimester Scan? Retrospective Observational Study of 4000 Nonobese Pregnant Women.

OBJECTIVES: The purpose of this study was to estimate the rate of incomplete fetal anatomic surveys during a second-trimester scan due to an unfavorable fetal position in a nonobese population. METHODS: All pregnant women who came to the Altamedica Fetal-Maternal Medical Center, a specialized center for prenatal diagnosis, for a routine second-trimester scan between January 2012 and April 2013 were retrospectively included in the analysis. Patients with a body mass index higher than 30.0 kg/m(2) or anterior fibroids larger than 5 cm were not included in the study. RESULTS: Of 4000 pregnant women admitted for a second-trimester scan, 169 (4.2%) came back within 2 weeks to complete the examination because of an unfavorable fetal position. In particular, 104 (2.6%) needed visualization of only 1 view, and 65 (1.6%) needed more than 1 view. The most difficult organ to visualize was the corpus callosum, in 73 cases (1.8%); the face was not visualized in 69 cases (1.7%); the cerebellar vermis was not seen in 47 fetuses (1.1%); and the heart could not be completely examined in 40 fetuses (1.0%). Of the 4000 women, 169 (4.2%) had a nonexhaustive scan; 149 (3.7%) needed a second scan to complete the second-trimester survey; 14 (0.35%) needed a third scan; and 2 (0.05%) remained with a not completely exhaustive scan. CONCLUSIONS: There is always a small percentage of incomplete fetal anatomic surveys during a second-trimester scan, which cannot be modified by the sonographer's skill or by technical sonographic innovations.

Reference charts for fetal corpus callosum length: a prospective cross-sectional study of 2950 fetuses.

OBJECTIVES: The purpose of this study was to establish reference charts for fetal corpus callosum length in a convenience sample. METHODS: A prospective cross-sectional study was conducted at the Artemisia Fetal-Maternal Medical Center between December 2008 and January 2012. Among 16,975 fetal biometric measurements between 19 weeks and 37 weeks 6 days' gestation, 3438 measurements of the corpus callosum (20.3%) were available. After excluding 488 measurements (14.2%), a total of 2950 fetuses (85.8%) were considered and analyzed only once. Parametric and nonparametric quantile regression models were used for the statistical analysis. To evaluate the robustness of the proposed reference charts with respect to various distributional assumptions on the sonographic measurements at hand, we compared the gestational age (GA)-specific reference curves produced by the statistical methods used. RESULTS: The mean corpus callosum length was 26.18 mm (SD, 4.5 mm; 95% confidence interval, 26.01-26.34 mm). The linear regression equation expressing the length of the corpus callosum as a function of GA was length (mm) = -11.17 + 1.62 × GA. The correlation between the dimension and gestation was expressed by the coefficient r = 0.83. Normal mean lengths according the parametric and nonparametric methods were defined for each week of gestation. CONCLUSIONS: This work provides new quantile-based reference charts for corpus callosum length measurements that may be useful for diagnosis of congenital corpus callosum anomalies in fetal life.

Uterine fibroids and risk for complications following second-trimester amniocentesis.

OBJECTIVE: To compare the abortion rate and preterm premature rupture of membranes (PPROM) after amniocentesis in women who have undergone antibiotic prophylaxis with uterine fibroids and control. STUDY DESIGN: Retrospective study using the Antibiotic Prophylaxis before Second-Trimester Genetic Amniocentesis trial database carried out between January 1999 and December 2005 at the Artemisia Fetal-Maternal Medical Center (Rome, Italy). All women underwent antibiotic prophylaxis before amniocentesis. A follow-up within 4 weeks from the procedure was available. RESULTS: A total of 2,497 of 21,219 (11.8%) women with uterine fibroids were identified. The rate of abortion was 2 of 2,497 (0.08%) in women with fibroids and 4 of 18,722 (0.03%) in women without fibroids (p = 0.42). The rate of PPROM was 4 of 2,497 (0.16%) in women with fibroids and 10 of 18,722 (0.05%) in women without fibroids (p = 0.12). CONCLUSION: The risk for abortion and PPROM does not increase in the presence of uterine fibroids in women who have undergone antibiotic prophylaxis.

The introduction of the absolute risk for the detection of fetal aneuploidies in the first-trimester screening.

PURPOSE: Maternal age is a crucial factor in fetal aneuploidy screening, resulting in an increased rate of false-positive cases in older women and false-negative cases in younger women. The absolute risk (AR) is the simplest way to eliminate the background maternal age risk, as it represents the amount of improvement of the combined risk from the maternal background risk. The aim of this work is to assess the performance of the AR in the combined first-trimester screening for aneuploidies. MATERIALS AND METHODS: A retrospective validation of the AR in the combined first-trimester screening for fetal aneuploidies, in an unselected population at Altamedica Fetal-Maternal Medical Center in Rome, between March 2007 and December 2008. RESULTS: Of 3845 women included in the study, we had a complete follow-up on 2984. We evaluated that an AR < 3 would individuate 22 of 23 cases of aneuploidy with a detection rate of 95.7% (95%CI 87.3-100), a false-positive rate of 8.7% (95%CI 7.7-9.7) and a false-negative rate of 4.3% (95%CI 0-12.7). CONCLUSIONS: In our study, the AR ameliorates the detection rate for aneuploidy. Further research and a prospective study on a larger population would help us to improve the AR in detecting most cases of aneuploidy.

Testosterone decreases adiponectin levels in female to male transsexuals.

AIM: To evaluate the effect of testosterone (T) on adiponectin serum levels in transsexual female patients. METHODS: We measured adiponectin, leptin, luteinizing hormone and follicle stimulating hormone, T, estradiol, lipid profile, biochemical parameters and body composition in 16 transsexual female patients at baseline and after 6 months of T treatment (100 mg Testoviron Depot /10 days, i.m.). RESULTS: Adiponectin levels were 16.9 +/- 7.3 mg/mL at baseline and 13.5 +/- 7.4 mg/mL at month 6 of T treatment (P < 0.05). Leptin and high-density lipoprotein cholesterol decreased significantly, whereas body mass index, waist circumference and lean body mass increased significantly after 6 months of T treatment. No changes in insulin or Homeostasis Model Assessment were detected. CONCLUSION: T can significantly reduce adiponectin serum levels in transsexual female patients.

Supplementation with a dietary multicomponent (Lafergin(®)) based on Ferric Sodium EDTA (Ferrazone(®)): results of an observational study.

During pregnancy, iron deficiency anemia is recognized as a specific risk factor for both adverse maternal and perinatal outcome. We decided to test the hypothesis that the daily administration of Lafergin(®), a dietary multicomponent based on Ferrazone(®) (Ferric Sodium EDTA), Lactoferrin, Vitamin C and Vitamin B12, from first trimester of pregnancy until the end of gestation, may significantly reduce, in anemic women, the severity of anemia compared to controls who received ferrous sulfate or liposomal iron.

Tubal primary metastatic choriocarcinoma coexistent with a viable early pregnancy: a case report.

INTRODUCTION: fallopian tube choriocarcinoma coexistent with viable intrauterine pregnancy is an extremely rare condition. CASE REPORT: we present the first case reported in literature of tubal choriocarcinoma coexistent with viable intrauterine pregnancy detected at early gestational age (20 weeks) and successfully managed by seriate monitoring of maternal and fetal health status until 31 weeks, then treated by cesarean section followed by etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine (EMA-CO) chemotherapy protocol. CONCLUSIONS: the outcome was favorable for both the mother and her fetus.

Comparative study of aCGH and Next Generation Sequencing (NGS) for chromosomal microdeletion and microduplication screening.

BACKGROUND: prenatal genetic diagnosis of rare disorders is undergoing in recent years a significant enhancement through the application of methods of massive parallel sequencing. Despite the quantity and quality of the data produced, just few analytical tools and software have been developed in order to identify structural and numerical chromosomal anomalies through NGS, mostly not compatible with benchtop NGS platform and routine clinical diagnosis. METHODS: we developed technical, bioinformatic, interpretive and validation pipelines for Next Generation Sequencing to identify SNPs, indels, aneuploidies, and CNVs (Copy Number Variations). RESULTS: we show a new targeted resequencing approach applied to prenatal diagnosis. For sample processing we used an enrichment method for 4,813 genes library preparation; after sequencing our bioinformatic pipelines allowed both SNPs analysis for approximately thirty diseases or diseases family involved in fetus development and numerical chromosomal anomalies screening. CONCLUSIONS: results obtained are compatible with those obtained through the gold standard technique, aCGH array, moreover allowing identification of genes involved in chromosome deletions or duplications and exclusion of point mutation on allele not affected by chromosome aberrations.

Next generation sequencing in the identification of a rare genetic disease from preconceptional couple screening to preimplantation genetic diagnosis.

INTRODUCTION: the use of Next Generation Sequencing (NGS) in the diagnosis of rare genetic pathologies is becoming ever more widespread in clinical practice. The following study reports the first case of preimplantation diagnosis through NGS of a form of LAMA2-related muscular dystrophy. CASE REPORT: a couple came to our Reproductive Medicine Centre for a preconceptional genetic consultation and for advice regarding secondary infertility. The couple already had a 3-year-old child who was suffering from a form of muscular dystrophy that has yet to be genetically defined. The disease had been diagnosed at the age of 6 months. A blood sample was taken from both parents and the child in order to analyze the DNA through the Illumina NextSeq 500 platform and an enrichment protocol, Trusight One Sequencing Panel, created by Illumina for the simultaneous sequencing of the exon regions of 4,813 clinically relevant genes. This led to the identification of 2 point mutations in the LAMA2 gene, each inherited by a parent. The couple then underwent a cycle of IVF (in vitro fertilization). A preimplantation genetic diagnosis was carried out on the embryos obtained after setting up a protocol for the analysis of a point mutation in the LAMA2 gene, (this mutation has yet to be described in literature) and the normal embryos together with the recessive LAMA2-related muscular dystrophy related carriers were transferred. There were no complications during pregnancy, which terminated with a cesarean section at 39 weeks and the birth of healthy 3430-gram baby. CONCLUSIONS: given its robustness, reliability and reproducibility, NGS could also be useful in prenatal diagnosis. This technique could guarantee an ample and quick analysis of the genes involved in development, making it possible to organize medical interventions during pregnancy and after birth.

Six consecutive false positive cases from cell-free fetal DNA testing in a single referring centre.

INTRODUCTION: recent studies have proposed the introduction of cell-free fetal DNA testing (NIPT-Non Invasive Prenatal Testing) in routine clinical practice emphasizing its high sensibility and specificity. In any case, false positive and false negative findings may result from placental mosaicism, because cell-free fetal DNA originates mainly from placenta. CASE: WE REPORT SIX CASES OF WOMEN WHO UNDERWENT CHORIONIC VILLUS SAMPLING (CVS) OR AMNIOCENTESIS TO CONFIRM THE RESULTS FROM NIPT: two Turner syndromes, two Triple X, one Patau syndrome, one Edward syndrome. RESULTS: using classic cytogenetic analysis and, also, Array - Comparative Genomic Hybridization (Array CGH) the karyotype of all 5 fetuses was found to be normal. CONCLUSION: results from NIPT must always be confirmed by invasive prenatal diagnosis. It is mandatory to inform the patient that the CVS and amniocentesis still represent the only form of prenatal diagnostic test available.

Comparison between modified Misgav-Ladach and Pfannenstiel-Kerr techniques for Cesarean section: review of literature.

In the last decades cesarean section rates increased in many countries becoming the most performed intraperitoneal surgical procedure. Despite its worldwide spread, a general consensus on the most appropriate technique to use has not yet been reached. The operative technique performed is made chiefly on the basis of the individual experience and preference of operators, the characteristics of patients, timing and urgency of intervention. We compared the two most known and used techniques, modified Misgav-Ladach and traditional Pfannenstiel-Kerr, and analyzed their impact on primary, short- and long-term outcomes and outcome related to health service use.

Retrospective study evaluating the performance of a first-trimester combined screening for trisomy 21 in an Italian unselected population.

OBJECTIVES: to assess the performance of a combined first-trimester screening for trisomy 21 in an unselected Italian population referred to a specialized private center for prenatal medicine. METHODS: a retrospective validation of first-trimester screening algorithms [risk calculation based on maternal age and nuchal translucency (NT) alone, maternal age and serum parameters (free ß-hCG and PAPP-A) alone and a combination of both] for fetal aneuploidies evaluated in an unselected Italian population at Artemisia Fetal-Maternal Medical Centre in Rome. All measurements were performed between 11(+0) and 13(+6) weeks of gestation, between April 2007 and December 2008. RESULTS: of 3,610 single fetuses included in the study, we had a complete follow-up on 2,984. Fourteen of 17 cases of trisomy 21 were detected when a cut-off of 1:300 was applied [detection rate (DR) 82.4%, 95% confidence interval (CI) 64.2-100; false-positive rate (FPR) 4.7%, 95% CI 3.9-5.4; false-negative rate (FNR) 17.6%, 95% CI 0-35.8%]. CONCLUSION: in our study population the detection rate for trisomy 21, using the combined risk calculation based on maternal age, fetal NT, maternal PAPP-A and free ß-hCG levels, was superior to the application of either parameter alone. The algorithm has been validated for first trimester screening in the Italian population.

Placental mesenchymal dysplasia, a case of intrauterine sudden death in a normal-sized fetus.

INTRODUCTION: placental mesenchymal dysplasia (PMD) is a rare placental anomaly characterized by placentomegaly and grape-like vesicles which resemble molar pregnancy. CASE: we report the case of 33-year-old woman (1-gravid) who visited our clinic at 11 weeks of gestation due to a suspected molar pregnancy. Ultrasound examination showed an enlarged placenta with multiple vesicular lesions. Maternal human chorionic gonadotropin level was normal and chorionic villus sampling showed a normal male karyotype (46 XY). The fetus exhibited no specific anomalies and fetal growth was normal during pregnancy with no signs of fetal suffering. At 31 weeks, the pregnancy ended owing to intrauterine fetal death (IUFD). The patient delivered a normal-sized male fetus (1800 g) with no definite anomalies. A pathological examination led to a diagnosis of placental mesenchymal dysplasia. CONCLUSION: in the presence of placental ultrasound anomalies with no other sign of fetal suffering, the pregnancy should be considered at risk and, therefore, should be monitored carefully including the option of hospitalization.

Significance of heterozygosis M34T mutation of GJB2 gene in non-syndromic congenital deafness. Retrospective analysis of 12,472 samples of amniotic fluid.

OBJECTIVE: to determinate the role of heterozygosis of M34T mutation of GJB2 gene in non syndromic congenital deafness. METHODS: retrospective study between March 2010 and June 2013. Molecular screening for 35delG and M34T mutations of the GJB2 gene was offered to all women undergoing to second trimester genetic amniocentesis. Patients were excluded from the study group if one of the following conditions were present: infections, fetal abnormalities, family history for congenital deafness, diagnosis of chromosomal abnormalities, and consanguinity between parents. RESULTS: a total of 12.472 Caucasian women gave informed consent for this test. Seventy-seven cases were excluded. From the 12.395 amniotic fluid analysis remained, the following was found: 2 cases of 35delG homozygosis and 352 cases of heterozygous carriers (42 M34T mutation, 298 35delG mutation, 12 double heterozygosis M34T/35delG). The follow up in first year of life in the 42 newborns with heterozygosis for M34T mutation showed a mild deafness in 23 cases. CONCLUSIONS: in our series, presence of heterozygosis M34T mutation is associated in more than 50% of cases to mild congenital deafness.

Cytomegalovirus infection in pregnancy: review of the literature.

The aim of this review is to summarize the principles of cytomegalovirus (CMV) infection in pregnancy.In particular, the aim of this review is to evaluate:Incidence and mother-to-child transmissionThe value of screening of pregnant womenDiagnosis of CMV maternal infectionDiagnosis of fetal infection (evaluate the value of ultrasound examination and amniocentesis and evaluate whether the amniotic viral load of mothers with primary cytomegalovirus infection correlate with fetal or neonatal outcomes)Diagnosis of infection in newbornsTherapy in pregnancy, postnatal therapy and prevention.

Prenatal Diagnosis of a Fetus with de novo Supernumerary Ring Chromosome 16 Characterized by Array Comparative Genomic Hybridization.

A fetus with de novo ring chromosome 16 is presented. At 20 weeks' gestation, ultrasound examination demonstrated bilateral clubfoot, bilateral renal pyelectasis, hypoplasia of the corpus callosum, and transposition of the great vessel. Amniocentesis was performed. Chromosome analysis identified a ring chromosome 16 [47,XY,r(16)] and array comparative genomic hybridization (a-CGH) demonstrated that the ring included the euchromatic portion 16p11.2. Postmortem examination confirmed prenatal findings. This is the first case of de novo ring chromosome 16 diagnosed prenatally with a new phenotypic pattern and also reinforces the importance of offering amniocentesis with a-CGH if fetal anomalies are detected.

The role of ultrasonography in the diagnosis of fetal isolated complete agenesis of the corpus callosum: a long-term prospective study.

OBJECTIVE: To evaluate the role of a dedicated neurosonographer in prenatal diagnosis of isolated complete agenesis of the corpus callosum (iCACC) and to asses the postnatal outcome of these infants. METHODS: Prospective study between January 2004 to December 2004 at Fetal Maternal Medical Centre 'Artemisia', Rome, Italy. A detailed ultrasound scan was performed in fetuses affected by iCACC by a dedicated fetal neurosonographer (CG). In all cases, magnetic resonance imaging (MRI) within 5 weeks and 13-15 months after birth was performed. A comparison was made between prenatal findings following the ultrasound scan and postnatal MRI. In these cases, a follow-up of 4-years was performed with a neurological evaluation. RESULTS: Among 23 cases of ACC diagnosed at our centre in the study period, CACC was diagnosed in 17 fetuses. Two were then excluded due to associated malformations, one was lost at follow-up and one patient opted to terminate her pregnancy. Newborn MRI confirmed the ultrasonographic diagnosis of iCACC in all 13 cases. A regular development was present in 92.3% of prenatally diagnosed iCACC. CONCLUSION: A dedicated neurosonographer could diagnose the iCACC with the same accuracy as MRI and in up to 90% of cases the newborn will have a regular development.