Performance of comprehensive first trimester fetal anatomy assessment

Objective

Ultrasound assessment of the fetal anatomy and fetal echocardiography are feasible in the first trimester of pregnancy. This study was designed to assess the performance of a comprehensive fetal anatomy assessment in a high-risk population at a tertiary fetal medicine unit.

Methods

A retrospective review of high-risk patients undergoing comprehensive fetal anatomy ultrasound assessment between 11 weeks and 13 + 6 weeks of gestation was conducted. Findings of the early anatomy ultrasound scan were compared with those of the second trimester anatomy scan, and birth outcomes or post-mortem results.

Results

Early anatomy ultrasounds were performed in 765 patients. The sensitivity of the scan for detecting fetal anomalies compared to the birth outcome was 80.5% (95% CI 73.5–86.3) and specificity was 93.1% (95%CI 90.6–95.2). Positive and negative predictive values were 78.5% (95% CI 71.4–84.6) and 93.9% (95% CI 91.4–95.8), respectively. The most missed and overdiagnosed abnormalities were ventricular septal defects. The second trimester ultrasound had sensitivity of 69.0% (95% CI 55.5–80.5) and specificity of 87.5% (95% CI 84.3–90.2).

Conclusions

In a high-risk population, early assessments had similar performance metrics as the second trimester anatomy ultrasound. We advocate for a comprehensive fetal assessment in the care of high-risk pregnancies.     

Multicenter clinical experience with non-invasive cell-free DNA screening for monosomy X and related X-chromosome variants

Objective

We aimed to investigate how the presence of fetal anomalies and different X chromosome variants influences Cell-free DNA (cfDNA) screening results for monosomy X.

Methods

From a multicenter retrospective survey on 673 pregnancies with prenatally suspected or confirmed Turner syndrome, we analyzed the subgroup for which prenatal cfDNA screening and karyotype results were available. A cfDNA screening result was defined as true positive (TP) when confirmatory testing showed 45,X or an X-chromosome variant.

Results

We had cfDNA results, karyotype, and phenotype data for 55 pregnancies. cfDNA results were high risk for monosomy X in 48/55, of which 23 were TP and 25 were false positive (FP). 32/48 high-risk cfDNA cases did not show fetal anomalies. Of these, 7 were TP. All were X-chromosome variants. All 16 fetuses with high-risk cfDNA result and ultrasound anomalies were TP. Of fetuses with abnormalities, those with 45,X more often had fetal hydrops/cystic hygroma, whereas those with “variant” karyotypes had different anomalies.

Conclusion

Both, 45,X or X-chromosome variants can be detected after a high-risk cfDNA result for monosomy X. When there are fetal anomalies, the result is more likely a TP. In the absence of fetal anomalies, it is most often an FP or X-chromosome variant.     

Do first-trimester screening algorithms for preeclampsia aligned to use of preventative therapies reduce the prevalence of pre-term preeclampsia: A systematic review and meta-analysis

Objective

Traditional obstetric practice relies upon history-based assessment to screen for preeclampsia and guide preventative therapies but is hampered by low sensitivity, high false-positive rates and low treatment rates. First-trimester screening algorithms represent the most efficacious approach for risk prediction and could target early initiation of aspirin to well-defined high-risk populations. A large randomised controlled trial has demonstrated the clinical benefits of this approach, but widespread practice implementation has remained elusive.

Methods

We performed a systematic review and meta-analysis summarising studies linking first-trimester preeclampsia screening algorithms with the initiation of preventative therapy and examined their effect on pre-term preeclampsia rates compared with standard maternity care. Odds ratios were calculated together with 95% confidence intervals.

Results

7 studies with a total of 377,790 participants were included. Within singleton populations, early initiation of aspirin in response to a high-risk screening algorithm result reduced the prevalence of pre-term preeclampsia by 39% compared with routine antenatal care (odds ratio 0.61; 95% CI: 0.52–0.70). There were significant reductions in the prevalence of preeclampsia at <32–34 weeks, preeclampsia at any gestation and stillbirth.

Conclusion

First-trimester screening algorithms for preeclampsia aligned with early initiation of preventative therapy with aspirin reduce the prevalence of pre-term preeclampsia.     

First-trimester fetal heart block and increased nuchal translucency: an indication for early fetal echocardiography

Prevalence of congenital heart disease increases with nuchal translucency (NT) thickness. First-trimester fetal bradycardia may result from heart block associated with complex congenital heart disease. We report two cases detected in the first trimester of pregnancy, in which both fetuses showed an increased nuchal translucency and bradycardia. Fetal karyotype was normal in both fetuses. First-trimester fetal echocardiography was performed and, in both cases, complex congenital heart disease was diagnosed. We discuss the added role of fetal heart rate in first-trimester ultrasound screening, in fetuses with increased nuchal translucency and normal karyotype. We stress, as well, the importance of echocardiography performed in the first trimester as a potential tool for early diagnosis in selected cases. Copyright © 2005 John Wiley & Sons, Ltd.     

Prenatal diagnosis of congenital head,face, and neck malformations—Is complementary fetal MRI of value?

Objectives

The aim of this study was to evaluate the role of fetal magnetic resonance imaging (MRI) as a complement to ultrasound (US) in the prenatal diagnosis of craniofacial anomalies.

Methods

A historical cohort study including all pregnant women who were referred for fetal MRI because of antenatal diagnosis of craniofacial anomalies on screening US. Prenatal diagnostic US, MRI, and postnatal diagnosis were compared for consistencies and discrepancies.

Results

Forty-five pregnant women with 73 suspected fetal craniofacial anomalies diagnosed by US underwent MRI. In 40 out of 73 anomalies (54.8%), US and MRI findings were in complete agreement with postnatal diagnoses. MRI correctly ruled out the diagnosis of 24 anomalies suspected on US and diagnosed four additional pathologies that were not demonstrated by US. Out of the 85 anomalies (suspected by imaging or confirmed postnatally), confident diagnosis could be made by MRI in 68 anomalies (80%), not diagnosed in 10 (11.8%), and over-diagnosed in seven (8.2%). By US, confident diagnosis could be made in 44 anomalies (51.8%), not diagnosed in 11 (12.9%), and over-diagnosed in 30 (35.3%).

Conclusion

MRI is valuable in the antenatal evaluation of fetal craniofacial anomalies and may be useful as an adjunct to US in the prenatal work-up of craniofacial anomalies.     

Prenatal ultrasound finding of atypical genitalia: Counseling,genetic testing and outcomes

Objective

To report uptake of genetic counseling (GC) and prenatal genetic testing after the finding of atypical genitalia on prenatal ultrasound (US) and the clinical and genetic findings of these pregnancies.

Methods

A retrospective cohort study (2017–2019) of atypical fetal genitalia in a large expert center for disorders/differences of sex development. We describe counseling aspects, invasive prenatal testing, genetic and clinical outcome of fetuses apparently without [group 1, n = 22 (38%)] or with [group 2, n = 36 (62%)] additional anomalies on US.

Results

In group 1, 86% of parents opted for GC versus 72% in group 2, and respectively 58% and 15% of these parents refrained from invasive testing. Atypical genitalia were postnatally confirmed in 91% (group 1) and 64% (group 2), indicating a high rate of false positive US diagnosis of ambiguous genitalia. Four genetic diagnoses were established in group 1 (18%) and 10 in group 2 (28%). The total genetic diagnostic yield was 24%. No terminations of pregnancy occurred in group 1.

Conclusions

For optimal care, referral for an expert fetal US scan, GC and invasive diagnostics including broad testing should be offered after prenatal detection of isolated atypical genitalia.     

Detection rates and residual risk for a postnatal diagnosis of an atypical chromosome aberration following combined first-trimester screening

Objectives

To determine the detection rates of all types of chromosome aberrations and the residual risk for postnatal diagnosis of an atypical chromosome aberration depending on the strategy for further investigation with either noninvasive prenatal testing (NIPT) or invasive testing in pregnancies with increased risk following combined first-trimester screening (cFTS).

Methods

A review of all pregnancies examined with cFTS during 2010 to 2017.

Results

The cohort consisted of 129 493 pregnancies. There were 852 (0.7%) clinically significant chromosome aberrations, including aberrations detected later on or after birth. A total of 12% were atypical chromosome aberrations. Considering that 40% were detected due to a miscarriage/intrauterine fetal death or a malformation on ultrasound there is a 0.05% (1:2000) background risk of a postnatal diagnosis of a liveborn child with an atypical chromosome aberration if no further invasive test is performed during pregnancy. If all women with an increased risk (≥1:200) had an invasive test and NIPT was performed up to a risk of 1:1000, 95% of common trisomies/sex chromosome aberrations and 55% of atypical aberrations would be detected.

Conclusions

If NIPT was offered to all women with an increased risk following cFTS it would imply that three times as many children would be born with an atypical chromosome aberration.     

Sonographic detection of central nervous system defects in the first trimester of pregnancy

The fetal central nervous system can already be examined in the first trimester of pregnancy. Acrania, alobar holoprosencephaly, cephaloceles, and spina bifida can confidently be diagnosed at that stage and should actively be looked for in every fetus undergoing first-trimester ultrasound. For some other conditions, such as vermian anomalies and agenesis of the corpus callosum, markers have been identified, but the diagnosis can only be confirmed in the second trimester of gestation. For these conditions, data on sensitivity and more importantly specificity and false positives are lacking, and one should therefore be aware not to falsely reassure or scare expecting parents based on first-trimester findings. This review summarizes the current knowledge of first-trimester neurosonography in the normal and abnormal fetus and gives an overview of which diseases can be diagnosed. © 2016 John Wiley & Sons, Ltd.     

Is there still a role for nuchal translucency measurement in the changing paradigm of first trimester screening?

Objectives

To give an overview of the genetic and structural abnormalities occurring in fetuses with nuchal translucency (NT) measurement exceeding the 95th percentile at first-trimester screening and to investigate which of these abnormalities would be missed if cell-free fetal DNA (cfDNA) were used as a first-tier screening test for chromosomal abnormalities.

Methods

This is a national study including 1901 pregnancies with NT≥95th percentile referred to seven university hospitals in the Netherlands between 1 January 2010 and 1 January 2016. All cases with unknown pregnancy outcome were excluded. Results of detailed ultrasound examinations, karyotyping, genotyping, pregnancy and neonatal outcomes, investigation by a clinical geneticist and post-mortem investigations were collected.

Results

In total, 821 (43%) pregnancies had at least one abnormality. The rate of abnormalities was 21% for fetuses with NT between 95^th and 99^th percentile and 62% for fetuses with NT≥99^th percentile. Prevalence of single-gene disorders, submicroscopic, chromosomal and structural abnormalities was 2%, 2%, 30% and 9%, respectively.

Conclusion

Although cfDNA is superior to the combined test, especially for the detection of trisomy 21, 34% of the congenital abnormalities occurring in fetuses with increased NT may remain undetected in the first trimester of pregnancy, unless cfDNA is used in combination with fetal sonographic assessment, including NT measurement.     

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.     

Inclusion of sex chromosomes in noninvasive prenatal testing in Asia,Australia, Europe and the USA: A survey study

Objective

To examine the extent to which sex chromosomes are included in current noninvasive prenatal testing (NIPT) and the reporting practices with respect to fetal chromosomal sex and sex chromosome aberrations (SCAs), in addition to an update on the general implementation of NIPT.

Method

A questionnaire addressing the research objectives was distributed by email to fetal medicine and clinical genetics experts in Asia, Australia, Europe and the USA.

Results

Guidelines on NIPT are available in the majority of the included countries. Not all existing guidelines address reporting of fetal chromosomal sex and SCAs. In most settings, NIPT frequently includes sex chromosomes (five Australian states, China, Hong Kong, Israel, Singapore, Thailand, USA and 23 of 31 European countries). This occurs most often by default or when parents wish to know fetal sex. In most settings, a potential SCA is reported by stating the risk hereof as “low” or “high” and/or by naming the SCA. Less than 50% of all pregnant women receive NIPT according to respondents from three Australian states, China, Israel, Singapore, Thailand and 24 of 31 European countries. However, this percentage, the genomic coverage of NIPT and its application as primary or secondary screening vary by setting.

Conclusion

In most of the studied countries/states, NIPT commonly includes sex chromosomes. The reporting practices concerning fetal chromosomal sex and SCAs are diverse and most commonly not addressed by guidelines. In general, NIPT is variably implemented across countries/states.     

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.     

Couples experiences of receiving uncertain results following prenatal microarray or exome sequencing: A mixed-methods systematic review

Background

Tests in pregnancy such as chromosomal microarray analysis and exome sequencing are increasing diagnostic yield for fetal structural anomalies, but have greater potential to result in uncertain findings. This systematic review investigated the experiences of prospective parents about receiving uncertain results from these tests.

Methods

A systematic search of three electronic databases was conducted. Data extraction was performed for studies that met the eligibility and quality criteria. Results were synthesised following the principles of thematic analysis.

Results

Fourteen studies (10 qualitative, 4 quantitative) were included. Findings were grouped into three overarching themes. Sources of uncertainty included the testing procedure, the diagnosis and prognosis, and health professionals' own uncertainty. The clinical impact of the uncertainty included parents struggling to make clinical decisions with the information available, the emotional impact included decisional-regret, shock, worry and feeling overwhelmed. To manage the uncertainty, parents sought support from healthcare professionals, friends, family, the internet and other parents as well as remaining hopeful.

Conclusions

Prospective parents experience a myriad of uncertainties in the prenatal setting, which must be handled sensitively. Future research should explore optimal ways of managing uncertainty to minimise harm. Recommendations are made for discussing uncertainty during pre- and post-test counseling.     

Population screening for gestational hypertensive disorders using maternal,fetal and placental characteristics: A population-based prospective cohort study

Objective

To determine screening performance of maternal, fetal and placental characteristics for selecting pregnancies at risk of gestational hypertension and preeclampsia in a low-risk multi-ethnic population.

Method

In a prospective population-based cohort among 7124 pregnant women, we collected maternal characteristics including body mass index, ethnicity, parity, smoking and blood pressure in early-pregnancy. Fetal characteristics included second and third trimester estimated fetal weight and sex determined by ultrasound. Placental characteristics included first and second trimester placental growth factor concentrations and second and third trimester uterine artery resistance indices.

Results

Maternal characteristics provided the best screening result for gestational hypertension (area-under-the-curve [AUC] 0.79 [95% Confidence interval {CI} 0.76-0.81]) with 40% sensitivity at 90% specificity. For preeclampsia, the maternal characteristics model led to a screening performance of AUC 0.74 (95% CI 0.70-0.78) with 33% sensitivity at 90% specificity. Addition of second and third trimester placental ultrasound characteristics only improved screening performance for preeclampsia (AUC 0.78 [95% CI 0.75-0.82], with 48% sensitivity at 90% specificity).

Conclusion

Routinely measured maternal characteristics, known at the start of pregnancy, can be used in screening for pregnancies at risk of gestational hypertension or preeclampsia within a low-risk multi-ethnic population. Addition of combined second and third trimester placental ultrasound characteristics only improved screening for preeclampsia.

     

Noninvasive prenatal screening for cystic fibrosis using circulating trophoblasts: Detection of the 50 most common disease-causing variants

Objectives

Cystic fibrosis (CF) is one of the most common severe autosomal recessive disorders. Prenatal or preconception CF screening is offered in some countries. A maternal blood sample in early pregnancy can provide circulating trophoblasts and offers a DNA source for genetic analysis of both the mother and the fetus. This study aimed to develop a cell-based noninvasive prenatal test (NIPT) to screen for the 50 most common CF variants.

Methods

Blood samples were collected from 30 pregnancies undergoing invasive diagnostics and circulating trophoblasts were harvested in 27. Cystic fibrosis testing was conducted using two different methods: by fragment length analysis and by our newly developed NGS-based CF analysis.

Results

In all 27 cases, cell-based NIPT provided a result using both methods in agreement with the invasive test result.

Conclusion

This study shows that cell-based NIPT for CF screening provides a reliable result without the need for partner- and proband samples.     

Turner syndrome-omphalocele association: Incidence,karyotype, phenotype and fetal outcome

Objective

Omphalocele is known to be associated with genetic anomalies like trisomy 13, 18 and Beckwith–Wiedemann syndrome, but not with Turner syndrome (TS). Our aim was to assess the incidence of omphalocele in fetuses with TS, the phenotype of this association with other anomalies, their karyotype, and the fetal outcomes.

Method

Retrospective multicenter study of fetuses with confirmed diagnosis of TS. Data were extracted from a detailed questionnaire sent to specialists in prenatal ultrasound.

Results

680 fetuses with TS were included in this analysis. Incidence of small omphalocele in fetuses diagnosed ≥12 weeks was 3.1%. Including fetuses diagnosed before 12 weeks, it was 5.1%. 97.1% (34/35) of the affected fetuses had one or more associated anomalies including increased nuchal translucency (≥3 mm) and/or cystic hygroma (94.3%), hydrops/skin edema (71.1%), and cardiac anomalies (40%). The karyotype was 45,X in all fetuses. Fetal outcomes were poor with only 1 fetus born alive.

Conclusion

TS with 45,X karyotype but not with X chromosome variants is associated with small omphalocele. Most of these fetuses have associated anomalies and a poor prognosis. Our data suggest an association of TS with omphalocele, which is evident from the first trimester.     

First-trimester diagnosis of Meckel–Gruber syndrome by transabdominal sonography in a low-risk case

Meckel–Gruber syndrome is a rare autosomal recessive disorder often resulting in neonatal death within a few hours of life. The condition is usually diagnosed ultrasonographically in the second trimester and earlier diagnosis has been mainly confined to high recurrence risk pregnancies. We describe the earliest non-invasive diagnosis of this condition at 12⁺² weeks' gestation in a patient with no previous history using transabdominal ultrasound. Pregnancy termination was declined. Subsequent development of anhydramnios in the mid-trimester resulted in poor fetal visualization. We propose that first-trimester diagnosis of this condition is not only possible but preferable, as normal liquor volume facilitates visualization of fetal anatomy.     

First-trimester diagnosis of conjoined twins

Conjoined twins are a rare and complex complication of monozygotic twinning, which is associated with high perinatal mortality. Early prenatal diagnosis of conjoined twins allows better counselling of the parents regarding the management options, including continuation of pregnancy with post-natal surgery, termination of pregnancy or selective fetocide in case of a triplet pregnancy. With the introduction of high-resolution and transvaginal ultrasound imaging, accurate prenatal diagnosis of conjoined twins is possible early in pregnancy. We have reviewed the medical literature on the early prenatal diagnosis of suspected conjoined twins using a MEDLINE search. Although first-trimester diagnosis of conjoined twins is feasible, false-positive cases are common before 10 weeks because, earlier in gestation, fetal movements are limited and monoamniotic twins may appear conjoined. As most parents opt for immediate termination of pregnancy at confirmation of the diagnosis, there are limited data on the prenatal follow-up of conjoined twins. When the parents opt for conservative management, half of the fetuses die in utero and another 44% will die during the neonatal period. A detailed analysis of case reports where 3D imaging was used indicates that this modality does not improve on the diagnosis made by 2D ultrasound. Overall, very early prenatal diagnosis and first-trimester 3D imaging provide very little additional practical medical information compared to the 11–14 weeks' ultrasound examination. Copyright © 2005 John Wiley & Sons, Ltd.     

Is the first-trimester combined screening result associated with the phenotype of Down syndrome? A population-based cohort study

Objective

To investigate if the Down syndrome phenotype differs according to the result of first-trimester combined screening (FTS).

Method

We included all Down syndrome cases diagnosed by karyotype in pregnancy or after birth in Denmark during 2005–2018. We compared screen positive (odds ≥1:300) and screen negative (odds <1:300) cases as well as screen result subgroups with respect to anthropometrics, congenital malformations, childhood diseases, and hospitalization.

Results

Absolute measures of fetal and birth anthropometrics were comparable between groups. A prenatal malformation diagnosis was more prevalent among screen positive than screen negative cases. Analyses suggested that this could reflect a detection bias. Cases with a screen result of 1:2–1:10 had a higher probability of being diagnosed with a malformation prenatally and with severe congenital heart disease (CHD) postnatally compared with a result of 1:11–1:300. Screen positive cases more often had non-severe CHD but less often a non-heart malformation compared with screen negative cases, while proportions of severe CHD were similar in these groups. Data on hospitalizations showed inconsistent results.

Conclusion

The 1:300 screening threshold had limited or no value in predicting Down syndrome phenotype severity. In contrast, cases with a screen result between 1:2 and 1:10 may represent a more severe phenotype.