The history of the second-trimester sonographic markers for detecting fetal Down syndrome,and their current role in obstetric practice

This review summarizes the development, history and use of second-trimester sonographic markers for the detection of fetal Down syndrome over three decades. Starting with the nuchal fold thickening in 1985 and culminating in the genetic sonogram in the 1990s. The combination of second-trimester serum screening with the ultrasound markers improved the detection rate of affected fetuses but also allowed patients to decrease their risk of carrying a fetus with Down syndrome if the genetic sonogram was normal. More recently the role of the genetic sonogram and its markers have changed with the wide spread use of first-trimester screening. This prior screening ultimately decreases the prevalence of fetal Down syndrome in the second trimester to less than 85% of what it was in the first-trimester as most fetuses with Down syndrome are now identified early. Current interpretation of the second-trimester Down syndrome markers must be based on the result of the first trimester and combined screening to achieve the most accurate risk estimate of an affected fetus. Copyright © 2010 John Wiley & Sons, Ltd.     

Evaluation of prenatal diagnosis of associated congenital heart diseases by fetal ultrasonographic examination in Europe

Ultrasound scans in the mid trimester of pregnancy are now a routine part of antenatal care in most European countries. With the assistance of Registries of Congenital Anomalies a study was undertaken in Europe. The objective of the study was to evaluate prenatal detection of congenital heart defects (CHD) by routine ultrasonographic examination of the fetus. All congenital malformations suspected prenatally and all congenital malformations, including chromosome anomalies, confirmed at birth were identified from the Congenital Malformation Registers, including 20 registers from the following European countries: Austria, Croatia, Denmark, France, Germany, Italy, Lithuania, Spain, Switzerland, The Netherlands, UK and Ukrainia. These registries follow the same methodology. The study period was 1996–1998, 709 030 births were covered, and 8126 cases with congenital malformations were registered. If more than one cardiac malformation was present the case was coded as complex cardiac malformation. CHD were subdivided into ‘isolated’ when only a cardiac malformation was present and ‘associated’ when at least one other major extra cardiac malformation was present. The associated CHD were subdivided into chromosomal, syndromic non-chromosomal and multiple. The study comprised 761 associated CHD including 282 cases with multiple malformations, 375 cases with chromosomal anomalies and 104 cases with non-chromosomal syndromes. The proportion of prenatal diagnosis of associated CHD varied in relation to the ultrasound screening policies from 17.9% in countries without routine screening (The Netherlands and Denmark) to 46.0% in countries with only one routine fetal scan and 55.6% in countries with two or three routine fetal scans. The prenatal detection rate of chromosomal anomalies was 40.3% (151/375 cases). This rate for recognized syndromes and multiply malformed with CHD was 51.9% (54/104 cases) and 48.6% (137/282 cases), respectively; 150/229 Down syndrome (65.8%) were livebirths. Concerning the syndromic cases, the detection rate of deletion 22q11, situs anomalies and VATER association was 44.4%, 64.7% and 46.6%, respectively. In conclusion, the present study shows large regional variations in the prenatal detection rate of CHD with the highest rates in European regions with three screening scans. Prenatal diagnosis of CHD is significantly higher if associated malformations are present. Cardiac defects affecting the size of the ventricles have the highest detection rate. Mean gestational age at discovery was 20–24 weeks for the majority of associated cardiac defects. Copyright © 2001 John Wiley & Sons, Ltd.     

Second-trimester echogenic small bowel: An increased risk for adverse perinatal outcome

2267 singleton fetuses who had one ultrasound examination between 15 and 21 weeks' gestation were prospectively evaluated for echogenic small bowel. Thirty-two cases of echogenic small bowel were detected—a prevalence of 1·4 per cent. Echogenic fetal small bowel was divided into two grades: grade 1, where the small bowel was more echogenic than the liver; and grade 2, where the small bowel had the echogenicity of bone. In contrast to 19/23 fetuses with grade 1 small bowel echogenicity, only 2/9 fetuses with grade 2 echogenic bowel had a normal pregnancy outcome (Fisher's exact test; P⩽0·01). Complications associated with second-trimester echogenic small bowel included in utero cytomegalovirus infection, second-trimester growth restriction, intrauterine fetal demise, and chromosomal abnormalities. Second-trimester fetal echogenic small bowel is associated with an increased risk of an adverse outcome. The prevalence of perinatal and neonatal complications is significantly greater when small bowel echogenicity approaches that of bone.     

Adverse perinatal outcome in patients screen-positive for neural tube defects and fetal down syndrome

An association between various abnormal mid-trimester maternal serum analyte values and adverse perinatal outcome has been reported. From an original sample of 14 857 women, we observed five women who were ‘screen-positive’ for both neural tube defects [maternal serum alpha-fetoprotein (MSAFP) ≥2·5 multiples of the median] and Down syndrome [risk ≥1/274 using MSAFP, maternal serum unconjugated oestriol (MSuE3), maternal serum human chorionic gonadotropin (MShCG), and maternal age]. The four patients who elected to undergo amniocentesis all demonstrated both normal karyotype and normal amniotic fluid AFP levels. All five cases were associated with intrauterine growth retardation (IUGR) and abnormal pregnancy outcomes. Two cases exhibiting severe IUGR on ultrasound examination were terminated at 19·1 and 21·2 weeks, respectively; the former also exhibited fetal calcifications and positive maternal serology for toxoplasmosis. In another case, fetal demise occurred at 36 weeks' gestation in a patient who had been treated for syphilis in the second trimester. Neither infection was confirmed in fetal tissue studies. Though resulting in live births, the remaining two cases required operative deliveries; emergency Caesarean sections for fetal distress were performed at 38 and 32 weeks, respectively, the latter case being associated with severe pre-eclampsia. We conclude that elevated mid-trimester MSAFP levels concurrent with maternal serum analyte values associated with increased risk for fetal Down syndrome may presage a poor perinatal outcome, particularly IUGR and possibly congenital infection.     

Does nuchal translucency have a role in fetal cardiac screening?

Increased nuchal translucency is the strongest single marker for chromosomal abnormality. Consequently, it is currently becoming established as the foundation of most early screening programmes for Down syndrome. In the absence of chromosomal abnormality, increased nuchal translucency has been shown to be associated with other congenital anomalies including cardiac defects. Several datasets have now reported this association and here these are reviewed to assess the effectiveness of nuchal translucency measurement as a screening tool for the prenatal detection of congenital heart disease. Copyright © 2004 John Wiley & Sons, Ltd.     

Hyperechoic fetal bowel: The perinatal consequences

A number of publications have reported an association between the finding of hyperechoic fetal bowel on prenatal sonogram and disorders such as aneuploidy and cystic fibrosis. To define more precisely the significance of this finding, we systematically reviewed the published material on the subject. Based on a total of 357 reported cases, we documented a high prevalence of cystic fibrosis (25·6 per cent) and chromosome abnormality (12·4 per cent) associated with increased bowel echogenicity in the fetus. High rates of intrauterine growth retardation (14·9 per cent), fetal demise (9·0 per cent), and prematurity (15·3 per cent) were also found. The data were obtained from a population at high a priori risk for aneuploidy and included fetuses at 1 in 4 risk for cystic fibrosis reported in two studies. This increased the bias towards an adverse outcome. The rate of complications when a hyperechoic abdomen is noted in a low-risk fetal population has so far not been delineated. Although the high frequency of complications found is of concern and warrants investigation, extrapolation of these risk figures to a fetal population at low a priori risk may not be appropriate.     

The 18-week fetal examination and detection of anomalies

From its beginning in the fifties the use of ultrasound in gynaecology and obstetrics has expanded extensively. Ultrasound technology has taken us from a time when the mother was our prime focus to the present where it is the unborn baby. Ultrasound assessments may have significant consequences for pregnancy care by optimizing the time, the mode and the location of the delivery as well as preparing the postnatal staff for a prenatally defined fetal problem. A major factor in the development was the groundbreaking work of an obstetrician, Ian Donald, and an engineer, Tom Brown, at Queen Mother's Hospital in Glasgow, who produced an ultrasound instrument called the Diasonograph. The first screening program offering a systematic ultrasound examination to a large pregnant population began in Malmoe, in 1973 and aimed to detect twins. Since then the examination has evolved over the years to include a systematic evaluation of the intrauterine contents. A number of randomized controlled trials have been reported and several large studies have reported the efficiency of routine fetal examinations for the detection of anomalies. Detection rates for the various subsets are presented. The learning curve regarding the ability to detect anomalies and the importance of proper training has also been shown. The procedure ‘routine fetal examination’ has been significant in supporting the continuous development of fetal medicine. The consequences of the improved dating of every pregnancy and the in utero transport of a sick fetus rather than an emergency transportation of a sick neonate, have an established evidence base. Ultrasound technology has had a remarkable ability to trigger great technical minds to move the technology forward year after year. Through a continuous cooperation between technicians and clinicians, this impressive technology of ultrasound will continue to support our work for the unborn child. Copyright © 2010 John Wiley & Sons, Ltd.     

Minor sonographic signs of trisomy 21 at 15–20 weeks' gestation in fetuses born without malformations: a prospective study

A prospective study was performed on 2119 pregnancies that underwent genetic amniocentesis. Indications for amniocentesis were either maternal age (⩾35) or triple-test results (risk⩾1/380). The study covered a 36-month period and assessed the prevalence of minor ultrasound markers both in fetuses with Down syndrome and normal control fetuses at 15–19 week' gestation. Only fetuses with normal karyotype or trisomy 21 were considered. Six minor sonographic markers were considered: nuchal thickness, pyelectasia, femur observed/expected and humerus observed/expected ratios, bowel echogenicity, and choroid plexus cysts. One or more ultrasound soft markers were present in 23 out of 33 fetuses with Down syndrome (70%) and in 572 out of 2069 normal fetuses (28%). Copyright © 2001 John Wiley & Sons, Ltd.     

Outcome of fetal echogenic bowel: A systematic review and meta-analysis

The main aim of this systematic review was to explore the outcome of fetuses with isolated echogenic bowel (EB) on antenatal ultrasound. Inclusion criteria were singleton pregnancies with isolated EB no associated major structural anomalies at the time of diagnosis. The outcomes observed were: chromosomal anomalies, cystic fibrosis (CF), associated structural anomalies detected only at follow-up scans and at birth, regression during pregnancy, congenital infections, intra-uterine (IUD), neonatal (NND) and perinatal (PND) death. Twenty-five studies (12 971 fetuses) were included. Chromosomal anomalies occurred in 3.3% of the fetuses, mainly Trisomy 21 and aneuploidies involving the sex chromosomes. Cystic fibrosis occurred in 2.2%. Congenital infections affected 2.2%, mainly congenital Cytomegalovirus (CMV) infection. The majority of fetuses with EB experienced regression or disappearance of the EB at follow-up scans. Associated anomalies were detected at a follow-up scan in 1.8%. Associated anomalies were detected at birth and missed at ultrasound in 2.1% of cases. IUD occurred in 3.2% of cases while the corresponding figures for NND and PND were 0.4% and 3.1%. Fetuses with EB are at increased risk of adverse perinatal outcome, highlighting the need for a thorough antenatal management and postnatal follow-up. Assessment during pregnancy and after birth should be performed in order to look for signs of fetal aneuploidy, congenital infections and associated structural anomalies.     

Diagnosis of polyhydramnios in early gestation: Indication for prenatal diagnosis?

Previously published reports have indicated that idiopathic polyhydramnios may be associated with trisomies 18 and 21 and that chromosomal analysis is indicated. Furthermore, the natural history and fetal outcome of polyhydramnios diagnosed in early gestation have not been well delineated. We identified 138 pregnancies with polyhydramnios prior to 26 weeks' gestation. Of 131 complete cases, 21 were diagnosed as severe, 18 as moderate, and 92 as mild polyhydramnios. Congenital abnormalities were noted in 18 of 21 severe cases (86 per cent). Two of the remaining three cases were twin-to-twin transfusion. Thirteen of 18 cases with moderate polyhydramnios (72 per cent) were associated with anomalies; six of the remaining cases were twin-to-twin transfusion. Sixteen of 92 cases of mild polyhydramnios (17 per cent) were associated with congenital abnormalities. In 69 of 76 cases of mild hydramnios not associated with anomalies (91 per cent), the hydramnios resolved prior to delivery. Only 2 of 16 (13 per cent) associated with anomalies resolved. In 4 of 5 cases (80 per cent) with moderate hydramnios and no anomalies, the amniotic fluid volume was normal on subsequent ultrasound. No case of moderate polyhydramnios associated with anomalies or maternal conditions nor any case of severe polyhydramnios resolved. There were seven cases of chromosomal abnormalities in this series; all were associated with sonographic findings in addition to the presence of polyhydramnios. On the basis of these data, we doubt the benefit of amniocentesis following the early diagnosis of idiopathic polyhydramnios in the absence of other ultrasound findings.     

Second trimester ultrasound screening for chromosomal abnormalities

The use of prenatal ultrasound has proven efficacious for the prenatal diagnosis of chromosomal abnormalities. The first sonographic sign of Down syndrome, the thickened nuchal fold, was first described in 1985. Since that time, multiple sonographically-identified markers have been described as associated with Down syndrome. The genetic sonogram, involving a detailed search for sonographic signs of aneuploidy, can be used to both identify fetuses at high risk for aneuploidy and, when normal, can be used to decrease the risk for aneuploidy for a pregnancy when no sonographic markers are identified. Combining the genetic sonogram with maternal serum screening may be the best method of assessing aneuploidy risk for women who desire such an assessment in the second trimester. Trisomy 18, Trisomy 13, and triploidy are typically associated with sonographically identified abnormalities and have a high prenatal detection rate. The use of the described sonographic signs in low-risk women requires further investigation, however, patients at increased risk for aneuploidy due to advanced maternal age or abnormal serum screening can benefit from a genetic sonogram screening for sonographic signs of aneuploidy to adjust their baseline risk of an affected fetus. Copyright © 2002 John Wiley & Sons, Ltd.     

Elevated delta OD 450 due to transient abnormal myelopoiesis in a Down syndrome fetus with hepatosplenomegaly on ultrasound

Transient abnormal myelopoiesis (TAM) is a relatively common finding in children with Down syndrome but has also been diagnosed prenatally, most often presenting with fetal hepatosplenomegaly. We report a case of TAM with hepatosplenomegaly found on ultrasound and associated with an increased amniotic fluid Δ OD 450 value. TAM is most commonly transient but can be associated with fatality and therefore should be considered in the differential diagnosis when fetal hepatosplenomegaly is found on ultrasound. Amniocentesis with chromosomal analysis and a Δ OD 450 may aid in diagnosing TAM and predicting the severity of the liver involvement. © 2013 John Wiley & Sons, Ltd.     

Accuracy of ultrasound diagnoses in pregnancies complicated by suspected fetal anomalies

Referral of pregnancies complicated by suspected fetal anomalies to level III perinatal centres for further evaluation and management is increasing as use of real-time ultrasound spreads, but the sensitivity and specificity of the prenatal diagnoses made in this population are unknown. We undertook a prospective study that followed pregnancies referred to a designated programme dealing with suspected fetal abnormalities. Follow-up of 257 pregnancies revealed that 282 separate anomalies were accurately diagnosed in 212 cases. Normal anatomy was correctly predicted in 42 cases, 16 per cent of the referred population. False-positive and false-negative rates were 1·5 per cent (4/257) and 2 per cent (1/46), respectively. However, 37 per cent of those infants born with anomalies had additional problems not prenatally detected by ultrasound. These results indicate that prenatal ultrasound diagnoses are remarkably accurate overall but that they may be insensitive to associated anomalies in individual cases.     

Elevated alpha-fetoprotein and human chorionic gonadotropin as a marker for placental trisomy 16 in the second trimester?

In a series of 2961 consecutive cases with second-trimester biochemical triple screening for Down's syndrome and neural tube defect (NTD), ten (0.3 per cent) showed an apparent increased risk for both conditions. Three cases had chromosomal abnormalities, namely trisomy 16 confined to the placenta. Since placental trisomy 16 as well as cases with increased alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG) are associated with (intrauterine growth retardation (IUGR), oligohydramnios, and fetal demise, at least some cases with this atypical biochemical profile could be explained by this chromosomal abnormality. From our results we recommend that in cases with increased risk for both Down's syndrome and NTD, fetal karyotyping should preferably be done on a placental biopsy, especially when ultrasound in the absence of anomalies demonstrates early IUGR.     

Maternal urinary β-core fragment of hCG/creatinine ratios and fetal chromosomal abnormalities in the second trimester of pregnancy

Our aim was to evaluate the potential value of the ratio of the maternal urinary beta-core fragment of human chorionic gonadotropin (βC-hCG) to creatinine (Cr) in discriminating between normal pregnancies and pregnancies associated with fetal chromosomal abnormalities. We hypothesized that pregnancies with fetal chromosomal abnormalities had abnormal quantities of βC-hCG in the urine. The aims of the present study were to investigate retrospectively whether maternal urinary ratios of βC-hCG/Cr are abnormal in women carrying fetuses with chromosome aberrations and to determine normative median values and a reference range for βC-hCG/Cr between 14 and 19 weeks' gestation. Maternal urinary βC-hCG and Cr concentrations were measured in 150 healthy women from 14 to 19 weeks and compared with ten cases of fetal chromosomal abnormalities matched for gestational age. The preliminary cut-off points corresponded to 0·29 multiple of the normal median (MOM) and 2·83 MOM, which were equivalent to the tenth and 90th centiles of the normal range. Of ten cases of fetal chromosomal abnormalities, one out of one (100 per cent) case with trisomy 18 and three of four (75 per cent) cases of variant 9 chromosome had low βC-hCG/Cr (≤0·29 MOM). One of five (20 per cent) cases with Down syndrome had elevated βC-hCG/Cr (≤2·83 MOM). Urinary βC-hCG/Cr ratios obtained in the second trimester may be useful for improved detection efficiency of Down syndrome, trisomy 18, and inversion of chromosome 9. Second-trimester maternal urinary βC-hCG/Cr should be investigated further as a potential marker for fetal chromosome anomalies.     

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.     

Congenital small bowel obstruction: Prenatal detection and outcome

Objective

To evaluate and compare the outcome of fetuses and neonates with congenital small bowel obstructions (SBO), evaluate the screening performance of prenatal ultrasound for SBO and identify possible risk factors for adverse outcomes.

Methods

All cases referred to the Amsterdam University Medical Centers between 2007 and 2021 for a prenatal suspected SBO, supplemented by cases of postnatal diagnosis of SBO, were included. The primary outcome was survival after 24 weeks of gestation until the first year of life.

Results

147 cases of SBO were included with a survival rate of 86.2% (119/138) after 24 weeks of gestation until the first year of age. Additional structural or chromosomal anomalies were found to have an increased risk of adverse outcomes. Intrauterine fetal demise occurred in 10/147 (6.8%) cases and 9/147 (6.1%) cases died during postnatal follow-up. The overall positive predictive value of all prenatally diagnosed cases was 91.5%. Surgical correction was performed in 123/128 (96.0%) of the live-born cases.

Conclusions

Congenital SBO has an overall favorable prognosis, but the outcome is negatively impacted by the possible presence of additional structural or chromosomal anomalies. Fetal monitoring in the early third trimester should be considered, since all cases of Intrauterine fetal demise occurred between 30 and 35 weeks of gestation.     

Vaginal bleeding in pregnancies associated with fetal Down syndrome

It has been suggested that vaginal bleeding in pregnancy is associated with an increased risk of fetal Down syndrome. To investigate this, information on vaginal bleeding, collected at the first antenatal visit, was abstracted from the medical notes of 70 pregnancies associated with Down syndrome and 140 unaffected controls matched for maternal age. Fourteen cases (20 per cent) and 23 controls (16 per cent) had some evidence of bleeding (relative risk estimated as the odds ratio= 1.3; P=0.26, one-sided; 95 per cent confidence interval 0.6–2.8). When these results were pooled with those from the two other controlled studies already published the combined relative risk estimate was 1.8 (P=0.02, two-sided; 95 per cent confidence interval 1.1–3.0). On the basis of present evidence, there is some reason to regard vaginal bleeding prior to the first antenatal visit as a risk factor for Down syndrome but the association and its biological significance remains uncertain.     

Genetic syndromes associated with isolated fetal growth restriction

Early onset fetal growth restriction (FGR) may be due to impaired placentation, environmental or toxic exposure, congenital infections or genetic abnormalities. Remarkable research, mainly based on retrospective series, has been published on the diverse genetic causes. Those have become more and more relevant with the improvement in the accuracy of the analysis techniques and the rising of breakthrough genomewide methods such as the whole genome sequencing. However, no publication has presented an integrated view of management of those fetuses with an early and severe affection. In this review, we explored to which extent genetic syndromes can cause FGR fetuses without structural defects. The most common chromosomal abnormalities (Triploidies and Trisomy 18), submicroscopic chromosomal anomalies (22q11.2 microduplication syndrome) and single gene disorders (often associated with mild ultrasound findings) related to early and severe FGR had been analysed. Finally, we addressed the impact of epigenetic marks on fetal growth, a matter of growing importance. At the end of this review, we should be able to provide an adequate counseling to parents in terms of diagnosis, prognosis and management of those pregnancies.     

Ultrasound diagnosis of fetal abnormalities and cytogenetic evaluation

Over a 65½ year period, in 288 pregnancies a variety of fetal malformations were detected by ultrasound. Two hundred and ten fetuses (73 per cent) were karyotyped. Gestational age at detection ranged from 11 to 38 weeks. The incidence of an abnormal karyotype in the total series was 14 per cent and 14.7 per cent in the 210 pregnancies in which a karyotype was performed. Single structural anomalies were found in 149 cytogenetically investigated fetuses, of which 25 had a chromosomal abnormality (17 per cent). Multiple structural malformations were present in 61 fetuses, of which 16 had an abnormal karyotype (26 per cent). Trisomy 18 was the most frequent finding. The most constant ultrasound finding in cases of an abnormal karyotype was polyhydramnios and severe IUGR in combination with structural defects. There is a need for extensive detailed ultrasound examination in high-risk pregnancies.