Cardiac and extra-cardiac anomalies as indicators for trisomies 13 and 18: A prenatal ultrasound study

The purpose of the present study was to establish sonographic markers for prenatal diagnosis of trisomies 13 and 18. Retrospective analysis of sonographic morphology was therefore carried out in seven fetuses with trisomy 13, and 16 fetuses with trisomy 18. Gestational age ranged between 17 and 39 weeks (median 28 weeks). Polyhydramnios and symmetrical growth retardation were present in 14 of 23 fetuses. A cardiac anomaly was diagnosed in all 23 fetuses, the majority representing a ventricular septal defect (n = 8) or double outlet right ventricle (n = 8). Extra-cardiac anomalies were characterized by a high incidence of limb deformities (polydactyly, clenched hands, club feet; n = 15) and omphalocele (n = 7). We conclude that the combined appearance of cardiac and extra-cardiac anomalies should prompt fetal karyotyping. Cardiac anomalies in combination with fetal limb deformities and omphalocele are suspicious for trisomies 13 and 18.     

Fetal ear measurements in the prenatal detection of trisomy 21

Although prominent fetal nuchal folds, short long bones, echogenic bowel, and renal pelviectasis have been shown to be associated with trisomy 21, none has acceptable diagnostic efficacy. Diminished fetal ear lengths measured by ultrasound have recently been reported as yet another potential morphological marker for the prenatal detection of trisomy 21. To investigate this further, we measured ear lengths and widths of normal (n = 107) and trisomy 21 (n = 25) second-trimester formalin-preserved fetuses. The normal ear growth characteristics are described and compared with those of trisomy 21 fetuses. The normal fetal ear shape, not unlike that of the neonates, manifested a marked variation. When the ear lengths and widths were regressed against gestational age, the slopes of the regression lines for the two groups were found to be different (P < 0·001). However, despite the statistically significant difference between the ear sizes of normal and trisomy 21 fetuses, the wide range of normal variation seen at each gestational age means that the fetal ear measurements are not diagnostically helpful.     

Measurement of the fetal mandible—feasibility and construction of a centile chart

The prenatal diagnosis of micrognathia is usually based on a subjective impression of the size of the jaw when examining the fetal profile. We have constructed a centile chart for mandibular length between 12 and 27 post-menstrual weeks in a cross-sectional study of 184 fetuses. The application of this chart in clinical practice may permit a more objective diagnosis of micrognathia in the prenatal period.     

Normal fetal growth in women with antiphospholipid syndrome treated with high-dose intravenous immunoglobulin (IVIG)

Antiphospholid antibodies are associated with fetal distress and fetal death. Although different therapeutic regimens have been used, the incidence of fetal growth retardation varies between 30 and 60 per cent of reported cases. We report the evolution of fetal growth in patients with antiphospholipid antibody syndrome treated with high-dose intravenous immunoglobulins (IVIG). Fourteen patients with a history of recurrent spontaneous abortion and immunological diagnosis of antiphospholipid syndrome were followed longitudinally. Intravenous immunoglobulin at a dose of 0.5 g/kg body weight for two consecutive days was started from the fifth week of pregnancy and repeated every 4 weeks until the 33rd week of gestation. Fetal biometry was evaluated longitudinally from the appearance of the gestational sac at 4 weekly intervals. In the period between 26 and 34 weeks, the frequency of evaluation was increased to every 14 days. Data obtained were compared with a control group of 70 fetuses with uneventful pregnancies matched for gestational age. Neonatal weight is shown in relation to the centiles for the normal population. One patient out of 14 (7.1 per cent) developed gestational hypertension and abruptio placentae. No other pregnancy complications were seen. No proteinuria was found. The mean maternal age was 31.2±3.8 years. Median birth weight was 3433 g±287. The median centile of the birth weight was 65.3±18.6. Mean gestational age at delivery was 1.3 weeks. No fetal or neonatal growth retardation was seen. No significant differences were found in the biometrical parameters investigated in the various gestational ages vs. the control group (Student's t-test not significant); a significant increase in head circumference (P< 0.001) and abdominal circumference (P< 0.05) was found at 36–37 weeks gestational age in the IVIG-treated fetuses. The presence of antiphospholipid antibodies is considered detrimental for pregnancy outcome because of their negative effects on placental vascular perfusion and fetal transfer of metabolites. The use of IVIG seems to avoid or inhibit the reduced availability of nutrients for the fetal anabolic functions, as the expected reduction in fetal growth was not seen in our series.     

The development of the fetal eye: In utero ultrasonographic measurements of the vitreous and lens

Our objective was to establish nomograms for fetal eye measurements from 12 weeks' gestation by using transvaginal and transabdominal high-resolution ultrasound techniques. A prospective cross-sectional study was performed on 450 normal singleton pregnancies between 12 and 37 weeks' gestation. Vitreous and lens circumferences were measured by transvaginal ultrasonography until 17 weeks, and by abdominal ultrasound between 18 and 37 weeks' gestation. Regression analyses were used to create nomograms, and several transformations were done to obtain linearity. Eye measurements of 12 fetuses at risk for ocular disturbances were plotted on the constructed nomograms. Linear relationships were fitted between vitreous (r²=0.79) and lens (r²=0.88) circumferences and gestational age. In addition, there was a significant correlation between these measurements and the biparietal diameter. Data of the fetuses at risk showed that disturbances in ocular growth were associated mainly with abnormal cerebral development. These normative data may be helpful in the prenatal diagnosis of suspected congenital syndromes that include, among their manifestations, ocular growth disturbances such as microphthalmos and anophthalmos.     

Prenatal testing for inherited immune deficiencies by fetal blood sampling

We attempted to develop a prenatal diagnosis in fetuses at risk for immunodeficiency by fetal blood sampling performed under fetoscopy at 18–22 weeks of gestation. In order to obtain normal values, we first investigated thirty-five control fetuses whose blood punctures were undertaken for the diagnosis of haemoglobinopathies. Surface markers and in vitro mitogen-induced proliferation of the fetal lymphocytes were studied using micromethods. We then examined two fetuses at risk for two different types of severe combined immunodeficiency and established their immunological integrity, hence avoiding an unjustified termination of pregnancy. This immunological integrity was confirmed after birth.     

The significance of early second-trimester sonographic detection of minor fetal renal anomalies

A study of 6350 consecutive transvaginal ultrasound examinations was performed as part of a routine fetal evaluation. Twenty-one cases (0.33 per cent) of early second-trimester sonographic detection of minor renal abnormalities (unilateral renal agenesis, pelvic kidney, and double collecting system) are presented. The sonographic diagnosis was made at 14–18 weeks of pregnancy and confirmed, in all of the 21 fetuses, postnatally or by post-mortem. A high incidence of associated fetal anomalies (24 per cent) and parental renal abnormalities (14 per cent) was demonstrated. Transvaginal sonography was found to be a useful tool for diagnosing these renal anomalies as early as 14 weeks of pregnancy. The likelihood of various associated anomalies and long-term implications on renal function raise questions concerning the prenatal management of such patients.     

Creatine kinase estimation in pure fetal blood samples for the prenatal diagnosis of duchenne muscular dystrophy

This paper compares the results of a survey of plasma creatine kinase (CK) activity measured in fetuses at-risk for Duchenne muscular dystrophy (DMD) with a reliable control series. Only pure fetal blood samples obtained by fetoscopy at between 17–24 weeks gestational age were used. Of the at-risk group 19 male pregnancies, mostly at low risk for DMD, proceeded to term with a normal outcome; there was no significant difference between their fetal plasma CK activities and the control group. Another 21 male pregnancies were terminated. This group included the highest risk mothers and hence was expected to contain a significant proportion of affected fetuses. The fetal plasma CK activity range was overlapping but significantly higher than the control group. No grossly elevated CK value was obtained. We conclude that, on average, DMD fetuses at this gestational age have higher plasma CK activity than controls. The problems of applying this finding to the prenatal diagnosis of DMD are discussed.     

Transvaginal sonography—detection of findings suggestive of fetal chromosomal anomalies in the first and early second trimesters

Over a 4-year period, 14 dyskaryotic fetuses were diagnosed by amniocentesis, performed after early detection of malformations using transvaginal sonography (TVS). These 14 dyskaryotic fetuses were detected out of 4878 sonographic screenings performed by TVS between 9 and 16 weeks' gestation. Twenty-eight per cent of the referrals were at high risk and 72 per cent were at low risk for fetal malformations. Two hundred and twenty-nine fetuses (4.7 per cent) of the screened population had 265 anomalies, 39 per cent of them being transient. In 7 of the 14 dyskaryotic fetuses (50 per cent), the sonographically detected anomalies were transient, being undetected by follow-up sonographic screenings at later gestational ages (⩾18 weeks). Postponing the first sonographic scan aimed at malformation detection to a later gestational age may lead to transient anomalies and their associated dyskaryosis being missed.     

Prenatal diagnosis of anhidrotic ectodermal dysplasia

This paper reports on successful prenatal diagnosis of X-linked anhidrotic ectodermal dysplasia (AED) by means of light and electron microscopy on fetal skin biopsies obtained under fetoscopy. In the present family two brothers of the proband were severely affected with the full symptomatology of AED, the pregnant female and her mother revealed minor symptoms with patches of skin lacking vellus hair. Control of lesional skin of the affected family members by electron microscopy revealed no ultrastructural abnormalities. However, all biopsies lacked skin appendages including hair follicles, sebaceous glands, and sweat glands. The lack of pilosebaceous follicles can be used as a diagnostic criterion since these structures are fully developed in normal fetuses of 20 weeks whereas the development of sweat glands does not start before week 20 to 24 of fetal life. Skin biopsies were taken from various regions of the fetus at risk via fetoscopy in week 20 and processed for light and electron microscopy. All samples revealed complete absence of all skin appendages in contrast to a total of 61 non-AED fetuses. Thus positive prenatal diagnosis of AED was made and the pregnancy was terminated. Control investigations after abortion confirmed the diagnosis.     

Rapid whole exome sequencing in pregnancies to identify the underlying genetic cause in fetuses with congenital anomalies detected by ultrasound imaging

Objective

The purpose of this study was to explore the diagnostic yield and clinical utility of trio-based rapid whole exome sequencing (rWES) in pregnancies of fetuses with a wide range of congenital anomalies detected by ultrasound imaging.

Methods

In this observational study, we analyzed the first 54 cases referred to our laboratory for prenatal rWES to support clinical decision making, after the sonographic detection of fetal congenital anomalies. The most common identified congenital anomalies were skeletal dysplasia (n = 20), multiple major fetal congenital anomalies (n = 17) and intracerebral structural anomalies (n = 7).

Results

A conclusive diagnosis was identified in 18 of the 54 cases (33%). Pathogenic variants were detected most often in fetuses with skeletal dysplasia (n = 11) followed by fetuses with multiple major fetal congenital anomalies (n = 4) and intracerebral structural anomalies (n = 3). A survey, completed by the physicians for 37 of 54 cases, indicated that the rWES results impacted clinical decision making in 68% of cases.

Conclusions

These results suggest that rWES improves prenatal diagnosis of fetuses with congenital anomalies, and has an important impact on prenatal and peripartum parental and clinical decision making.     

Presentation of ventriculomegaly at 11–14 weeks of gestation: An analysis of longitudinal data

Objectives

The aim of this study was to examine the value of the sonographic measurements of the choroid plexus and the lateral ventricles at 11–14 gestational weeks in fetuses that had the diagnosis of second-trimester ventriculomegaly (VM) as a clinical reference.

Methods

The standard axial plane used for biparietal diameter measurement from 2D stored images in the first trimester was used to calculate the ratio between the choroid plexus and lateral ventricle diameter (PDVDR), the choroid plexus and lateral ventricle length (PLVLR) and the choroid plexus and lateral ventricle area (PAVAR) in 100 normal and 15 fetuses diagnosed with second-trimester VM.

Results

In fetuses with VM, the measurements of PDVDR, PLVLR and PAVAR were all significantly smaller compared to normal fetuses (p = < 0.001, <0.001, <0.01). Four out of seven cases with mild VM had measurements below the 5th percentile (57%). 75% of cases with moderate or severe VM had at least one measurement below the 5th percentile.

Conclusions

Since the axial plane of the fetal head is obtained in all first-trimester routine screenings, the measurements of PDVDR, PLVLR and PAVAR could easily be integrated into routine examinations for an early detection of VM.     

Prenatal diagnosis of congenital cytomegalovirus infection in 189 pregnancies with known outcome

An Erratum has been published for this article in Prenatal Diagnosis 21(7) 2001, 605. Prenatal diagnosis (PD) of fetal cytomegalovirus (CMV) infection was performed in 242 pregnancies, with known outcome in 189 cases. In 141/189 pregnancies, PD was carried out on account of suspicious maternal CMV serology up to gestational week (WG) 23, and in 48 cases on account of abnormal ultrasonic findings detected between WG 18 and 39. Chorionic villus samples (n=6), amniotic fluid (AF, n=176) and/or fetal blood specimens (n=80) were investigated for detection of virus by cell culture, shell vial assay, PCR and/or CMV-specific IgM antibodies. Of 189 fetuses correctly evaluated by CMV detection either in fetal tissue following therapeutic abortion/stillbirth (n=24) or in urine of neonates within the first 2 weeks of life (n=33), 57 were congenitally infected. In women with proven or suspected primary infection, the intrauterine transmission rates were 20.6% (7/34) and 24.4% (10/41), respectively. Of the congenitally infected live-born infants, 57.6% (19/33) had symptoms of varying degree. The overall sensitivity of PD in the serologic and ultrasound risk groups was 89.5% (51/57). A sensitivity of 100% was achieved by combining detection of CMV-DNA and CMV-specific IgM in fetal blood or by combined testing of AF and fetal blood for CMV-DNA or IgM antibodies. There was no instance of intrauterine death following the invasive procedure. The predictive value of PD for fetal infection was 95.7% (132/138) for negative results and 100% (51/51) for positive results. Correct results for congenital CMV infection by testing AF samples can be expected with samples obtained after WG 21 and after a time interval of at least 6 weeks between first diagnosis of maternal infection and PD. In case of negative findings in AF or fetal blood and the absence of ultrasound abnormalities at WG 22–23, fetal infection and neonatal disease could be excluded with high confidence. Positive findings for CMV infection in AF and/or fetal blood in combination with CMV suspicious ultrasound abnormalities predicted a high risk of cytomegalic inclusion disease (CID). Furthermore, detection of specific IgM antibodies in fetal blood was significantly correlated with severe outcome for the fetus or the newborn (p=0.0224). However, normal ultrasound of infected fetuses at WG 22–23 can neither completely exclude an abnormal ultrasound at a later WG and the birth of a severely damaged child nor the birth of neonates which are afflicted by single manifestations at birth or later and of the kind which are not detectable by currently available ultrasonographic techniques. Copyright © 2001 John Wiley & Sons, Ltd.     

Prenatal sonographic diagnosis of intracranial haemorrhage: Report of a case with a sinusoidal fetal heart rate tracing,and review of the literature

The sinusoidal fetal heart rate pattern has been described in association with severe fetal anaemia, with fetal hypoxaemia, and with the administration of parenteral narcotics. Here, we report a case of decreased fetal movement in which a sinusoidal tracing was recorded. The sonographic diagnosis of a massive fetal intracranial haemorrhage was made. A non-interventive approach was taken and the fetus died soon after in utero. We review 28 previous cases in which the prenatal sonographic diagnosis of fetal intracranial haemorrhage was made, including the underlying maternal and fetal factors and neonatal outcomes. We propose that the sinusoidal tracing in this case was due to the intracranial bleed and suggest that fetal intracranial haemorrhage be considered in the sonographic evaluation of the fetus with a sinusoidal pattern.     

Transabdominal chorionic villus sampling: Fetal loss rate in relation to maternal and gestational age

In this paper we report the fetal loss rate in relation to both maternal and gestational age in 1764 pregnant women who underwent transabdominal chorionic villus sampling (TA-CVS) between January 1986 and August 1990. The fetal loss rate, considered as a proportion of continuing pregnancies, decreased with advancing gestational age at sampling from 4.3 per cent before 9 weeks to 0.4 per cent at or after 13 weeks, the difference being statistically significant (p <0.025). The fetal loss rate increased from 1.6 per cent in women under 30 to 2.4 per cent in women of 40 years or over, but the difference was not statistically significant. Considering that the total fetal loss rate before 28 weeks' gestation was on average 1.91 percent (1.3 per cent under 35 years and 2.8 per cent in women of 35 or over), we believe that TA-CVS is a safe and effective technique for prenatal diagnosis of genetic diseases.     

False-negative prenatal exclusion of Wiskott-Aldrich syndrome by measurement of fetal platelet count and size

The study of the fetal platelet count and size can, according to the literature, be used for the prenatal diagnosis of the Wiskott-Aldrich syndrome (WAS). So far, no affected fetuses have been identified by this method. All pregnancies in which this method had been applied to resulted, as correctly predicted, in the birth of normal children. Here we report on a familial case of WAS where the haematological parameters failed to reveal the affected second child. Hence we assume that the platelet count and size of platelets remain normal in fetuses with WAS to the gestational age of 22 weeks and cannot be used for prenatal diagnosis.     

Isolated fetal hydrothorax with hydrops: a systematic review of prenatal treatment options

Objective To evaluate the effect of prenatal therapeutic interventions on perinatal outcome in pregnancies complicated by isolated fetal hydrothorax with hydrops. Methods A systematic review of the literature from January 1982 to January 2006 of perinatal outcome in pregnancies with isolated fetal hydrothorax with hydrops with any form of prenatal treatment was conducted. Results Forty-four articles met our selection criteria, reporting a total of 172 fetuses treated prenatally. Reported treatment options were single (n = 13) or serial thoracocentesis (n = 18), thoraco-amniotic shunt placement (n = 100) or a combination of thoracocentesis and shunting (n = 36). Four case-reports described pleurodesis with OK-432, (n = 3) and intrapleural injection of autologous blood (n = 2). Overall survival rate was 63%, ranging from 54% for single thoracocentesis to 80% in the 5 cases treated with pleurodesis, without statistically significant differences between the treatment modalities. Shunt-placement with or without prior thoracocentesis was most often described, with survival rates of 67 and 61% respectively. Discussion The available literature consists exclusively of case reports and case series. This systematic review suggests that with prenatal intervention, perinatal survival rates around 63% are possible. There is a need for prospective, adequately controlled studies with long-term follow-up to determine the best treatment and more reliable outcome data in pregnancies complicated by fetal hydrothorax with hydrops. Copyright © 2007 John Wiley & Sons, Ltd.     

Prenatal diagnosis of haemoglobin disorders by cordocentesis at 12 weeks' gestation

Prenatal diagnosis of haemoglobin disorders is accepted to be a useful procedure to avoid births of infants with homozygous diseases. Advances in sampling and molecular techniques, such as polymerase chain reaction (PCR) and chorionic villus sampling (CVS), have made earlier and safer first-trimester prenatal diagnosis possible. However, these procedures need previous studies of at-risk couples, which can be very time-consuming when a number of different β-thalassaemia mutations occur in the region. We describe the possibility of making a first-trimester prenatal diagnosis by cordocentesis and fetal blood analysis at the 12th week of gestation. We found no statistically significant difference (p>0.05) between β/γ values in fetuses at the 12th and 18th weeks of gestation. In seven affected fetuses aborted at the 12th week of gestation, the diagnosis was confirmed in all cases by PCR analysis. These findings suggest that early cordocentesis could be an alternative procedure to CVS and PCR analysis.     

Genetic considerations in the prenatal diagnosis of overgrowth syndromes

Large (>90%) for gestational age (LGA) fetuses are usually identified incidentally. Detection of the LGA fetus should first prompt the provider to rule out incorrect dates and maternal diabetes. Once this is done, consideration should be given to certain overgrowth syndromes, especially if anomalies are present. The overgrowth syndromes have significant clinical and molecular overlap, and are associated with developmental delay, tumors, and other anomalies. Although genetic causes of overgrowth are considered postnatally, they are infrequently diagnosed prenatally. Here, we review prenatal sonographic findings in fetal overgrowth syndromes, including Pallister-Killian, Beckwith-Wiedemann, Sotos, Perlman, and Simpson-Golabi-Behmel. We also discuss prenatal diagnosis options and recurrence risks. Copyright © 2009 John Wiley & Sons, Ltd.     

Normal blood cell values in the early mid-trimester fetus

Samples of pure fetal blood from 116 fetuses of 15–21 weeks' gestation were obtained by direct vision fetoscopy. Ninety nine of these fetuses, presumed to be haematologically normal, were suitable for analysis. The data obtained show that the erythropoietic system is evolving rapidly in this gestational age range. The myeloid series shows no significant increase or decrease in numbers apart from eosinophils and basophils which increase significantly with gestational age whereas the platelet count remains constant. The growing application of fetoscopic blood sampling to the prenatal diagnosis and management of fetal blood disorders renders mandatory a knowledge of normal fetal blood values.