[NUCHAL TRANSLUCENCY CONCURRENT WITH EARLY ANOMALY SCAN: TIME TO RECONSIDER].

INTRODUCTION: During the last decades, a major achievement was reported in detecting Down's syndrome in the first trimester of pregnancy. This is attributed to the use of high-resolution accurate ultrasound machine allowing the detection of a "nuchal translucency" in the back of the fetus during 11-14 weeks' gestation. This is considered to be a physiologic finding, but when increased, may alert for chromosomal abnormality (mainly Down's syndrome), cardiac and other organ anomalies and other genetic syndromes. Later additional sonographic findings were found, including nasal bone assessment, and Doppler flow studies of the ductus venosus and tricuspid regurgitation Technology advancement accompanied by sonographers' skills enhancement allows (at the time frame of the nuchal scan) a detailed anomaly scan. Additional screening for pregnancy complication was achieved using first trimester multi marker assessment, alerting for preeclamptic toxemia or placenta accreta. Currently, many national and international professional organizations recommend performing the nuchal scan concurrent with an early anomaly scan both at the same time of gestation. This approach is different than the one performed in Israel, whereas the nuchal scan is conducted separately and 2-3 weeks later an anomaly scan is offered. We call for reconsideration of the sequential approach and performing all the tests in a comprehensive first trimester clinic.

[ENDOMETRIAL-PATTERN IN EARLY PREGNANCY AND CORRELATION WITH ECTOPIC-PREGNANCY].

INTRODUCTION: Ectopic-pregnancy is a leading cause of pregnancy-related maternal death in the first trimester. Early sonographic diagnostic ability of ectopic-pregnancy is limited. There is an increasing need to identify sonographic markers that can assist with the diagnosis. OBJECTIVES: To characterize the endometrial-pattern by transvaginal-ultrasound as an early marker for ectopic-pregnancy, before demonstration of tubal mass. METHODS: A multicenter prospective study that included 52 women with a positive HCG test, referred to the ultrasound-unit with a diagnosis of pregnancy of unknown location. A transvaginal ultrasound was performed focusing on the endometrial-pattern, and classifying findings into four categories: homogeneous, heterogeneous, three-laminar and existence of fluid collection within the endometrial cavity. RESULTS: A total of 38 women were diagnosed with ectopic-pregnancy. Three women demonstrated normal intrauterine pregnancy, 3 others had an early miscarriage and 8 women were excluded from the study. No statistically significant differences were found between the groups in terms of demographic, clinical, or laboratory characteristics. Three-laminar pattern had 94% positive predictive value and 18% negative predictive value for ectopic-pregnancy, with sensitivity and specificity of 42% and 83%, respectively. Changes in the endometrial-pattern were demonstrated during subsequent tests when performed. CONCLUSIONS: The use of transvaginal-ultrasound to identify the endometrial-pattern in early pregnancy does not require significant expertise. The identification of three-laminar endometrium in pregnancies of an unknown location, should raise the suspicion of ectopic-pregnancy. DISCUSSION: Three-laminar pattern has high PPV for predicting ectopic pregnancy in women with pregnancy of an unknown location. The changes in the endometrial-pattern during subsequent tests, especially the transition of three-laminar into homogeneous pattern, a phenomenon not reported in previous studies, raised the need for further studies.

[FETAL WEIGHT CHARTS IN THE ISRAELI POPULATION].

BACKGROUND: Sonographic estimated fetal weight is performed by measuring the fetal organs' biometry and introducing the data into a formula. The calculated value is then compared with reference charts and serves as a critical component in pregnancy follow-up. Ideally the charts should be appropriate to the specific population. OBJECTIVES: To display and validate sonographic based Israeli-matched, intrauterine fetal weight curves. METHODS: The international Hadlock and Souka formulas, were chosen and assessed using over 70,000 ultrasound examinations from Israel. Since the Souka formula is appropriate only after 30 weeks of pregnancy, we used Hadlock's formula for pregnancies under 30 weeks and the comparison between the Hadlock and Souka formulas was made thereafter. In order to evaluate the Israeli population charts, 6389 pregnant women were examined sonographically in the last three days of pregnancy, and the estimated fetal weights were compared with the actual newborn weights. RESULTS: Fetal weight charts were constructed. Both equations were efficient, but the combination of Hadlock formula until 30 weeks and Souka between 31 to 42 weeks tended to be more accurate. CONCLUSIONS: We described fetal weight charts based on common equations, using biometric measurements derived from the Israeli population. We recommend the charts presented here as the universal reference for all the professionals involved in perinatal care in Israel. DISCUSSION: Fetal growth abnormalities are determined by the curve chosen. Birthweight curves may underdiagnose restrictions in fetal growth because of the disorders associated with preterm delivery. Sonographic biometric curves represent physiological growth more reliably.

Dilated cerebral venous system observed in growth-restricted fetuses.

PURPOSE: The dilation of the fetal cerebral veins is a rare phenomenon that may be associated to a bad obstetric outcome, and is usually connected to antenatal thrombosis of the posterior dural venous sinuses. There are several descriptions of cerebral vein distension on magnetic resonance imaging (MRI), but all of them are detected postnatally. We present herein two cases of fetal antenatal cerebral dilation of the venous system, without any association to any sign of vein thrombosis, and a systematic review of literature regarding pathogenesis, diagnosis and outcomes associated to the antenatal detection of this condition with the use of MRI. MATERIALS AND METHODS: To identify potentially eligible studies, we searched PubMed, Scopus, Cochrane Library (all from inception to October 20th, 2016) and applied no language restrictions. RESULTS: The electronic database search provided a total of 22,843 results. After the exclusion of duplicates, manuscripts that resulted not relevant to the review based on title and abstract screening, and analysis of manuscripts eligible for full-text assessment, no papers were found related to the subject reported in the present manuscript. CONCLUSIONS: Our report adds importance to MRI as a tool in cases of complex ultrasound finding with the presence of fetal heart failure and deterioration of fetal growth, in order to improve the prognostic evaluation and patient?s counseling.

A homozygous PIGO mutation associated with severe infantile epileptic encephalopathy and corpus callosum hypoplasia, but normal alkaline phosphatase levels.

We describe two sisters from a consanguineous Arab family with global developmental delay, dystrophy, axial hypotonia, epileptic encephalopathy dominated by intractable complex partial seizures that were resistant to various anti-epileptic treatments. Dysmorphic features comprised low set ears, hypertelorism, upslanting palpebral fissures, a broad nasal bridge, and blue sclera with elongated eyelashes. Brain MRI in both children showed a corpus callosum hypoplasia that was evident already in utero and evolving cortical atrophy. Autozygosity mapping in combination with Whole Exome Sequencing revealed a homozygous missense mutation in the PIGO gene [c.765G > A, NM_032634.3] that affected a highly conserved methionine in the alkaline phosphatase-like core domain of the protein [p.(Met255Ile), NP_116023.2]. PIGO encodes the GPI-ethanolamine phosphate transferase 3, which is crucial for the final synthetic step of the glycosylphosphatidylinositol-anchor that attaches many enzymes to their cell surfaces, such as the alkaline phosphatase and granulocyte surface markers. Interestingly, measurement of serum alkaline phosphatase activities in both children was normal or only slightly elevated. Quantification of granulocyte surface antigens CD16/24/59 yielded reduced levels only for CD59. Phenotype analysis of our and other published patients with PIGO mutations reveals a more severe affectation and predominantly neurological presentation in individuals carrying a mutation in the alkaline phosphatase-like core domain thereby hinting towards a genotype-phenotype relation for PIGO gene mutations.

Fetal Biometry in the Israeli Population: New Reference Charts.

BACKGROUND: Selection of appropriate reference charts for fetal biometry is mandatory to ensure an accurate diagnosis. Most hospitals and clinics in Israel use growth curves from the United States. Charts developed in different populations do not perform well in the Israeli population. OBJECTIVES: To construct new reference charts for fetal biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur length (FL), using a large sample of fetuses examined at 14-42 weeks gestational age in a medical center and a community ultrasound unit located in two different regions of Israel. METHODS: Data from the medical center and the community clinic were pooled. The mean and standard error of each measure for each week was calculated. Based on these, reference charts were calculated using quantiles of the normal distribution. The performance of the reference charts was assessed by comparing the new values to empiric quantiles. RESULTS: Biometric measurements were obtained for 79,328 fetuses. Growth charts were established based on these measurements. The overall performance of the curves was very good, with only a few exceptions among the higher quantiles in the third trimester in the medical center subsample. CONCLUSIONS: We present new local reference charts for fetal biometry, derived from a large and minimally selected Israeli population. We suggest using these new charts in routine daily obstetric practice.

Outcomes From Polyhydramnios With Normal Ultrasound.

OBJECTIVE: To investigate the short- and long-term outcomes of children from pregnancies complicated with polyhydramnios, defined as amniotic fluid index (AFI) >24 cm, and with a normal detailed ultrasound examination. METHODS: This retrospective cohort study examined 134 children aged 4 to 9 years with polyhydramnios and normal detailed ultrasound examination during pregnancy compared with 268 controls with normal AFI and normal detailed ultrasound examination matched for maternal age, year of delivery, gestational week at delivery, and presence or absence of diabetes. The primary outcome was the rate of malformations diagnosed postnatally. Additional outcomes were obstetrics outcomes, genetic syndromes, and neurodevelopment. RESULTS: Polyhydramnios was associated with increased risk for cesarean delivery (CD) and birth weight >90th percentile. This elevation in CD was attributed to increased rate of elective CD due to suspected macrosomia. Polyhydramnios was associated with increased risk for congenital malformations (n = 25 [19%] compared with 27 [10%], respectively; P = .016) without a statistically significant increase in the rate of major malformations (11 [8%] vs. 10 [4%]; P = .057). Genetic syndromes were more prevalent in the polyhydramnios group (5 [3.7%] vs. 2 [0.75%]; P = .043), as were neurologic disorders and developmental delay (9.7% vs. 3%; P = .004). CONCLUSIONS: Despite a normal detailed ultrasound examination, polyhydramnios is associated with increased rate of fetal malformations, genetic syndromes, neurologic disorders, and developmental delay, which may be diagnosed only after birth.

A comparison of methods for construction of fetal reference charts.

Reference charts for fetal measures are used for early detection of pregnancies that should be monitored closely. Construction of reference charts corresponds to estimation of quantiles of a distribution as a function of gestational age. Existing methods have been developed under various modeling assumptions, typically by fitting a polynomial regression to certain functionals of the distributions (e.g., mean, standard deviation, and quantiles). We use a large dataset to compare various existing methods for construction of reference charts. We also relax the assumptions of a parametric polynomial link between the distribution parameters and age and consider cubic splines and discretization of age in order to compare charts based on more flexible and simpler models, respectively. We compare the different methods using various tools and demonstrate the importance of considering performance measures calculated from age-stratified data. We also examine the question of sample size. We compare our charts to similar charts that have been recently published and emphasize that the source of an apparent heterogeneity should be investigated. We conclude that the choice of which method to use for construction of reference charts should take the following into account: available sample size, validity of normality assumption, and results of various performance measures.

Monochorionic diamniotic in vitro fertilization twins have a decreased incidence of twin-to-twin transfusion syndrome.

OBJECTIVE: To compare the incidence of twin-to-twin transfusion syndrome (TTTS) in spontaneous versus IVF-conceived twin pregnancies. DESIGN: Retrospective multicenter study. SETTING: University-affiliated tertiary medical centers. PATIENT(S): Women admitted for 11-14 week's scan between January 1997 and July 2013 who were diagnosed with monochorionic (MC) diamniotic twin pregnancies. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Mode of conception, TTTS. RESULT(S): The study cohort included 327 pregnant women with live MC diamniotic twins. Of them, 284 (86.9%) and 43 (13.1%) were spontaneous and IVF conceived, respectively. The mean maternal age was significantly higher in IVF compared with in spontaneously conceived pregnancies (33.8 ± 5.5 vs. 31.6 ± 5.4, respectively). Thirty-seven twins (11.3%) had TTTS, of whom 36/284 (12.7%) versus 1/43 (2.3%) were spontaneously and IVF conceived, respectively. The mean week of delivery was significantly lower in MC twins diagnosed with TTTS compared with those without TTTS (32.7 ± 3.3 vs. 35.5 ± 2.5, respectively). Furthermore, there was a significantly higher birthweight discordancy in twins diagnosed with TTTS compared with those without (20.6% vs. 11%, respectively). CONCLUSION(S): The significantly lower proportion of TTTS found in IVF-conceived twins may suggest a different embryological process that lies at the core of IVF conception of monozygotic twinning.

The association of crown-rump length discrepancy with birthweight discordance in spontaneous versus IVF monochorionic twins: a multicenter study.

OBJECTIVE: The objective of this study was to compare the associations of crown-rump length (CRL) discrepancy with birthweight discordance in spontaneous versus in vitro fertilization (IVF) monochorionic (MC) twin pregnancies. METHOD: This is a multicenter retrospective study on women with twin pregnancies assessed for nuchal translucency between January 1997 and July 2013. The study group was subdivided into MC twins conceived spontaneously and after IVF. Pregnancies with later fetal death or twin transfusion syndrome were excluded. A large-weight discordance was defined as a difference of birthweights of >15%. RESULTS: The study group included 171 pregnancies; of them, 142 (83%) were spontaneous and 29 (17%) were IVF conceived. In the entire cohort, we found a significant correlation between birthweight discordance and CRL discrepancy (r = 0.173, P < 0.05). While a significant correlation was found between CRL discrepancy and birthweight discordance in spontaneous-conceived pregnancies (n = 142, r = 0.24, P = 0.005), such correlation was not present in IVF pregnancies (n = 29, r = -0.7, P = 0.724). A logistic regression analysis found significant odds of larger-weight discordance for each increase of 1% in CRL discrepancy among spontaneously conceived pregnancies (odds ratio = 1.1, confidence interval = 1.03-1.2, P = 0.005). A receiver operating characteristic (ROC) for large-weight discordance in the spontaneously conceived pregnancies demonstrated an area under the ROC curve of 0.613 (P = 0.039). CONCLUSION: The significant correlation between CRL discrepancy and birthweight discordance in spontaneous versus IVF MC twin pregnancies might suggest differential monozygotic twinning process.

[TURNING THE PYRAMID IN PRENATAL CARE].

Most complications of pregnancy manifest towards the latter part of pregnancy. Nevertheless, present day diagnostic techniques, such as sonography, Doppler, biochemical screening tests, and the newly developed ability to study free fetal DNA in maternal blood, enables early identification of high risk groups for maternal and fetal morbidity, as well as fetal genetic and anatomical pathology. Dr. Nicolaides has coined this changing trend with the term "Turning the Pyramid". Early screening enables earlier and more directed follow-up with the application of relevant diagnostic tests. Obvious advantages include the potential to reduce maternal-fetal morbidity before it becomes apparent clinically. Additionally, the earlier diagnosis of fetal pathology, allows more time for parents and medical staff to assess the situation, and reach a decision regarding the continuation of the pregnancy. A possible drawback of such an approach, of early identification of high risk groups, is the uncertainty it arouses, sometimes for a long duration, with the accompanying apprehension and stress parents have to endure. A multidisciplinary team, consisting of specialists in fetal-maternal medicine, genetics, ultrasound, and perinatology, will be needed in order to best deal with the often complex information, which is becoming increasingly available at a very early stage of pregnancy.

Establishment of fetal biometric charts using quantile regression analysis.

OBJECTIVES: Fetal growth evaluation is an essential component of pregnancy surveillance. There have been several methods used to construct growth charts. The conventional charts used in current daily practice are based on small numbers and traditional statistical methods. The purpose of this study was to improve fetal biometric charts based on a much larger number of observations with an alternative statistical method: quantile regression analysis. A comparison between the charts is presented. METHODS: During the 12 years of study, 17,708 sonographic examinations of pregnant women from the north of Israel, between 12 and 42 weeks of pregnancy, were performed. Fetal measurements were obtained by several operators using various equipment and included head circumference, abdominal circumference, and femur length. RESULTS: Growth charts were established based on these measurements. CONCLUSIONS: In this study, we constructed biometric growth charts using a large cohort of pregnant women. These charts offer the advantages of specific estimated regression parameters for each specified percentile, thus better defining the normal range. We suggest using these new charts in routine daily obstetric practice.

Matrix metalloproteinase-2 is elevated in midtrimester amniotic fluid prior to the development of preeclampsia.

OBJECTIVE: To evaluate levels of matrix metalloproteinases (MMP) and their inhibitors (TIMP) in second trimester amniotic fluid of women with hypertensive disorders compared to normotensive women. STUDY DESIGN: Amniotic fluid was obtained from 133 women undergoing genetic second trimester amniocentesis. Zymography was performed for MMP characterization and an MMP-2 ELISA kit was used to determine MMP-2 levels. TIMP-2 expression was evaluated using western blot. RESULTS: Mean amniotic fluid MMP-2 and TIMP-2 levels were significantly higher in women who developed a hypertensive disorder compared to normotensive women (P < 0.0004 and P < 0.01, respectively). When subdivided into subgroups, amniotic fluid from women who eventually developed preeclampsia or superimposed preeclampsia showed significantly higher MMP-2 levels than normotensive women (P < 0.05). However, no statistical difference in MMP-2 levels was found between patients with gestational hypertension and normotensive patients. CONCLUSION: Higher amniotic fluid MMP-2 and TIMP-2 levels are found in women who eventually develop preeclampsia.

Sickle cell anemia in northern Israel: screening and prevention.

BACKGROUND: Sickle cell anemia is a hemolytic anemia caused by a single mutation in position 6 of the beta globin molecule. About 80 patients with SCA in northern Israel are currently receiving treatment. OBJECTIVES: To assess a screening program in northern Israel aimed at detecting couples at risk for having offspring with SCA. METHODS: Since 1987, screening for beta thalassemia in pregnant women in northern Israel has been conducted, and from 1999 all the samples were also tested for hemoglobin S, Hgb C, Hgb D, Hgb O Arab and others. RESULTS: During the 20 year period 1987-2006 a total of 69,340 women were screened; 114 couples who carried Hgb S were detected and 187 prenatal diagnoses were performed in couples at risk for having an offspring with Hgb S. The mean gestational age was 13 +/- 4 weeks. Fifty-four of those diagnoses revealed affected fetuses and in 4 cases the couple declined to perform therapeutic abortion. CONCLUSIONS: The economic burden to the health services for treating SCA patients is about U.S.$ 7000 per year, and the institution of prevention programs has proven cost-effective in populations with a high frequency of carriers. Since our program is aimed to also detect beta thalassemia, a disease that is more frequent in this area (> 2.5%), the added cost for the prevention of SCA is less significant despite the low incidence of the S gene in our population, namely < 1%.

Wide clinical spectrum in a family with hereditary lymphedema type I due to a novel missense mutation in VEGFR3.

Hereditary lymphedema type I (HL-I), also known as Milroy disease, is an autosomal dominant disorder characterized by typical phenotype of infantile onset lower-limb lymphedema accompanied by variable expression of recurrent episodes of cellulites, toenail changes, and papillomatosis. Mutations in the vascular endothelial growth factor receptor 3 (VEGFR3), also known as FLT4 gene, which encodes a lymphatic endothelial-specific tyrosine kinase receptor, have been identified as a genetic cause of HL-I. We report a large Muslim Arab family residing in northern Israel with 14 individuals presenting clinical features of HL-I. Genetic analysis revealed novel missense mutation E1106K in the tyrosine kinase domain II of VEGFR3 that cosegregates with the disorder in the family. Most affected individuals presented with bilateral congenital lower-limb lymphedema. Wide intrafamilial phenotypic variability included two asymptomatic individuals, a case of prenatal hydrothorax evolving to hydrops fetalis, and a late-onset complication, yet unreported, of chronic degenerative joint disease of the knees. This report broadens the known "classic" phenotype of HL-I.

Hydrops fetalis: an unusual prenatal presentation of hereditary congenital lymphedema.

OBJECTIVES: To report a rare case of primary congenital lymphedema (PCL) presenting as hydrops fetalis. METHODS: The patient presented at 33(+4) weeks' gestation with polyhydramnios, massive bilateral hydrothorax, skin edema, scalp edema and minimal ascites. In utero thoracocentesis was performed and delivery was induced. Follow-up at 12 months of age revealed moderate bilateral foot edema with otherwise normal development. RESULTS: The diagnosis of PCL was suspected on the basis of the family history. DNA analysis revealed a novel missense mutation, E1106K, in the tyrosine kinase domain of the vascular endothelial growth factor receptor 3 gene (VEGFR3/FLT4). CONCLUSION: PCL should be considered in the differential diagnosis of hydrops fetalis. Knowledge of the favorable course, variable clinical presentation, therapy options and genetic basis should contribute to better pregnancy counseling and management.

Umbilical-placental blood flow gradient during the early second trimester of pregnancy.

OBJECTIVE: To characterize umbilical-placental blood flow gradient during early second trimester of pregnancy. METHODS: Forty normal pregnant women with a singleton fetus gave their informed consent to participate in this study. All scans were preformed between 12 and 20 weeks' gestation using the simultaneous multigate spectral Doppler imaging (MS-SDI) modality available on the Diasonics Synergy system. The umbilical-placental circulation was scanned at three locations: (1) umbilical artery at the cord insertion, (2) superficial placenta at a point close to the cord insertion, and (3) deep placenta branches at the area adhere to the decidua basalis. The mean value of pulsatility index (PI) and resistance index (RI) were recorded. RESULTS: PI and RI were both significantly lower in the superficial and deep placenta compared with the cord insertion area. No significant differences were found comparing between superficial and deep placenta. In 30 women we found lower values and in 10 women we found a higher value of PI and RI in the superficial and deep placenta compared with the cord insertion. Four of five cases with complicated pregnancies occurred in patients with negative placental gradient compared with only one case with positive placental gradient (p < 0.05). CONCLUSIONS: In this preliminary report the umbilical placental blood flow gradient was characterized during the early second trimester of normal pregnancy. The presence of decreasing gradient was established. Absent or opposite gradient between the umbilical artery and the placental vessels was associated with adverse pregnancy outcome.

The association of umbilical cord hemangioma with fetal vascular birthmarks.

OBJECTIVE: To report a rare case of umbilical cord hemangioma and to discuss its association with vascular birthmarks. METHODS: A case of umbilical cord hemangioma diagnosed by ultrasound at 28 weeks of gestation is reported. After labor induction at 38 weeks of gestation, a male infant was born. Examination of the newborn showed disseminated port wine flat skin lesions covering a significant part of his body. Reviewing the scientific literature revealed the association between umbilical cord hemangioma and fetal mortality and morbidity, in particular, vascular malformations. RESULTS: A total of 24 umbilical cord hemangioma cases were reported in detail. Of them, 37.5% were associated with perinatal mortality and 29.2% ended in the delivery of a normal healthy infant. Fetal morbidity was recognized in 33.3%. CONCLUSION: This case illustrates the importance of prenatal diagnosis of umbilical cord hemangioma for prenatal counseling.

For how long should oxytocin be continued during induction of labour?

OBJECTIVE: To answer the question of whether oxytocin induction of labour should be discontinued when active labour begins. DESIGN: We enrolled patients admitted for induction of labour with oxytocin. Exclusion criteria for induction of labour included non-vertex presentation, past history of more than one caesarean delivery, multiple pregnancies, persistent non-reassuring fetal heart rate before induction of labour and estimated fetal weight of more than 4250 g. SETTING: Department of Obstetrics and Gynecology, Ha'Emek Medical Center, Afula, Israel. POPULATION: Patients who were admitted for induction of labour in Ha'Emek Medical Center from 1st February 1998 to 29th February 2000. METHODS: Patients were randomly divided into two groups. In group A, infusion of oxytocin was incremental until 5 cm dilation and maintained at the same level from that point throughout the labour. In group B, infusion of oxytocin was incremental but was discontinued when cervical dilatation reached 5 cm. Comparison between the two groups was made using Wilcoxon rank-sum test and Fisher's exact test. MAIN OUTCOME MEASURE: Primary outcome variable was duration from induction to delivery. The secondary outcome variables included: duration of labour stages, maximal dosage and total amount of oxytocin used, the use of analgesia, abnormalities in fetal heart rate and episodes of uterine hyperstimulation. We also recorded mode of delivery, together with maternal and neonatal outcome. RESULTS: One hundred and four patients participated in this study. The active phase of labour was shorter in group B compared with group A, but this difference was not statistically significant (2.6 +/- 2 vs 3.3 +/- 2.9, P= 0.07). In group A there were six caesarean deliveries and in group B only three. No significant differences were found when the other outcome parameters were compared. CONCLUSIONS: There is no advantage in continuing oxytocin infusion after the onset of active labour.