Congenital heart anomalies in the first trimester: From screening to diagnosis.

Congenital heart defects occur in approximately 1% of liveborn children and represent the most common form of congenital malformation. Due to the small size and complexity of the heart structures, prenatal diagnosis is most often made in the second trimester of pregnancy. Early diagnosis however offers significant advantages regarding the timing of further investigations, prenatal counseling, and access to management options. In the last decade, advances in antenatal imaging have improved the detection of cardiac malformations with increasing emphasis on earlier pregnancy screening and diagnosis. We aim to summarize current "state of the art" imaging of the fetal heart in the first trimester.

Basic sonographic examination of the fetal brain at 11-13 weeks' gestation: Rationale for a simple and reliable four-step technique.

The widespread incorporation of first-trimester scanning between 11 and 13 weeks' gestation has shifted from the screening of chromosomal abnormalities, mainly by measuring nuchal translucency thickness and visualization of the nasal bone, to a more detailed study of the fetal anatomy leading to early detection of several structural congenital anomalies. This goal can be improved by the routine and focused sonographic assessment of specific anatomic planes and the identification of distinctive landmarks that can help disclosing a particular, non-evident condition. In this article we present the basis for a basic, early examination of the fetal brain during screening using a four-step technique, which can be readily incorporated during the first-trimester scan. The technique includes the focused visualization of the cranial contour, choroid plexuses of the lateral ventricles and midline, aqueduct of Sylvius, brainstem, fourth ventricle, and the choroid plexus of the fourth ventricle. The rationale for this approach is presented and discussed.

First-trimester ventriculomegaly in fetuses with callosal agenesis: Cause or association?

The sonographic findings in four fetuses presenting with ventriculomegaly at first-trimester ultrasound that were subsequently diagnosed as having agenesis of the corpus callosum (ACC) are described. The diagnosis of early ventriculomegaly was suspected subjectively by identification of increased cerebrospinal fluid within the lateral ventricles and confirmed by measuring choroid plexus-to-lateral ventricle length and area ratios. Subsequent scans revealed complete ACC in two cases and partial ACC in the other two. This report adds to the increasing evidence suggesting that first-trimester ventriculomegaly is a strong sonographic marker of underlying brain anomalies, including less evident malformations such as ACC. Detailed second-trimester fetal neurosonography in those women continuing their pregnancies should be performed.

Cell-free DNA screening for rare autosomal trisomies and segmental chromosome imbalances.

OBJECTIVE: To assess the outcomes of pregnancies at high-risk for rare autosomal trisomies (RATs) and segmental imbalances (SIs) on cell-free DNA (cfDNA) screening. METHOD: A retrospective study of women who underwent cfDNA screening between September 2019 and July 2021 at three ultrasound services in Australia. Positive predictive values (PPVs) were calculated using fetal chromosomal analysis. RESULTS: Among 23,857 women screened, there were 93 high-risk results for RATs (0.39%) and 82 for SIs (0.34%). The PPVs were 3.8% (3/78, 95% CI 0.8%-10.8%) for RATs and 19.1% (13/68, 95% CI 10.6%-30.5%) for SIs. If fetuses with structural anomalies were also counted as true-positive cases, the PPV for RATS increased to 8.5% (7/82, 95% CI 3.5%-16.8%). Among 85 discordant cases with birth outcomes available (65.4%), discordant positive RATs had a significantly higher proportion of infants born below the 10th and 3rd birthweight percentiles than expected (19.6% (p = 0.022) and 9.8% (p = 0.004), respectively), which was not observed in the SI group (2.9% < 10th (p = 0.168) and 0.0% <3rd (p = 0.305)). CONCLUSION: The PPVs for SI and RAT results are low, except when a structural abnormality is also present. Discordant positive RATs are associated with growth restriction.

Increased nuchal translucency after low-risk noninvasive prenatal testing: What should we tell prospective parents?

Three decades ago, the observation that first trimester fetuses with excess fluid accumulation at the back of the neck were more likely to be aneuploid, gave rise to a new era of prenatal screening. The nuchal translucency (NT) measurement in combination with serum biomarkers and maternal age, resulted in the first trimester combined screening (FTCS) program. The introduction of noninvasive prenatal testing (NIPT) over the past decade has introduced the option for parents to receive highly sensitive and specific screening information for common trisomy from as early as 10 weeks gestation, altering the traditional pathway FTCS pathway. The retention of the 11-13-week NT ultrasound remains important in the detection of structural anomalies; however, the optimal management of pregnancies with a low-risk NIPT result and an isolated increased NT measurement in an era of advanced genomic testing options is a new dilemma for clinicians. For parents, the prolonged period between the initial diagnosis in first trimester, and prognostic information at each successive stage of investigations up to 22-24 weeks, can be emotionally challenging. This article addresses the common questions from parents and clinicians as they navigate the uncertainty of having a fetus diagnosed with an increased NT after a low-risk NIPT result and presents suggested approaches to management.

Ultrasound findings and detection of fetal abnormalities before 11 weeks of gestation.

OBJECTIVE: To determine the proportion of major fetal structural abnormalities that can be detected before 11 gestational weeks. METHODS: We conducted a retrospective study of individual patient files at a tertiary provider of obstetric and gynecological ultrasound in Melbourne, Australia. All women who had a pre-cell-free DNA ultrasound with a crown-rump length of less than 45 mm and had one or more ultrasounds at a later gestation were included in the analysis. The primary outcome was the incidence of a fetal structural abnormality. RESULTS: A total of 3333 cases were included in the final analysis. Overall, 316 fetuses (9.5%) had a structural abnormality detected at any point throughout gestation, of which 86 were major structural abnormalities (2.6%). Sixteen fetal abnormalities were detected before 11 weeks of gestation, including 15 major abnormalities (17.4% of the major anomalies). All major fetal abnormalities detected before 11 gestational weeks were confirmed at later ultrasound examinations or the pregnancy did not continue (in four cases due to termination of pregnancy and in one case spontaneous miscarriage before first trimester morphology ultrasound). CONCLUSION: Detection of fetal abnormalities is possible before 11 weeks of gestation. Early suspicion is more likely in cases of major structural abnormalities.

Outcomes following the detection of fetal edema in early pregnancy prior to non-invasive prenatal testing.

OBJECTIVE: To investigate the incidence of structural and chromosomal abnormalities in cases of fetal edema on early ultrasound prior to non-invasive prenatal testing (NIPT). METHODS: A retrospective study of women undergoing pre-NIPT ultrasound with fetal crown-rump length (CRL) of 28 to 44 mm was conducted at a tertiary obstetric ultrasound clinic in Melbourne, Australia. Cases of reported fetal edema were included, and subclassified as isolated nuchal edema (>2.2 mm) or generalized edema/hydrops by two operators blinded to outcomes. RESULTS: We identified 104 cases of fetal edema. Nuchal edema and generalized edema were present in 40 (38.5%) and 64 (61.5%) cases, respectively. Relevant chromosomal anomalies were identified in 19.2% (20/104), occurring in 10.0% (4/40) of the nuchal edema and 25.0% (16/64) of the generalized edema/hydrops cases. Structural anomalies with normal karyotype occurred in four (3.8%) additional cases. Miscarriage occurred in four cases (3.8%) and termination of pregnancy in 18 cases (17.3%). Among cases that reached the 11 to 13+6 weeks ultrasound, the edema resolved in 81.9% and these cases had less adverse outcomes than those with NT≥3.5 mm (10.9% vs 76.5%, P < .001). CONCLUSIONS: Fetal edema in early pregnancy is associated with a high incidence of structural and/or chromosomal abnormalities; these rates increase with progressive severity.

Early detection of significant congenital heart disease: The contribution of fetal cardiac ultrasound and newborn pulse oximetry screening.

Fetal cardiac and newborn pulse oximetry screening has greatly facilitated the detection of cardiac abnormalities, which may be serious with potentially dire neonatal consequences. The prenatal diagnosis of a serious cardiac abnormality allows the attending obstetrician to organise the much safer in-utero transfer of the fetus for delivery at a tertiary centre, particularly if there is evidence of a duct-dependent lesion that may require the infusion of Prostaglandin E1 to maintain duct patency pending surgical intervention. Newborn pulse oximetry alerts the paediatrician that the baby may have a significant cardiac abnormality, which warrants further elucidation prior to discharge, rather than for the baby to represent unwell a few days later. Despite these advances, serious cardiac abnormalities may be missed on screening. Their detection then falls back onto the clinical acumen of the attending paediatrician/family physician to review the history, carefully elicit and evaluate the clinical signs further aided by whatever investigations that may be available at the birthing hospital, frequently less resourced than the tertiary centres. At the outset, a brief synopsis is provided of the clinical findings that may point to a cardiac abnormality. That is followed by a critical review of the accuracy of prenatal and newborn pulse oximetry screening with emphasis on the lesions that may be missed. Suggestions are made as to how to improve the diagnostic accuracy.

First-trimester sonographic diagnosis of sirenomelia: A multicenter series of 12 cases and review of the literature.

OBJECTIVE: To determine the key sonographic features for the diagnosis of sirenomelia in the first trimester of pregnancy. METHODS: Cases of sirenomelia from several prenatal diagnosis centers were retrospectively identified and reviewed. The diagnosis was established through the detection of fused lower limbs. Additional sonographic findings were also noted. RESULTS: A total of 12 cases were collected. The most striking sonographic finding was the detection of malformed lower limbs, which appeared to be fused and in an atypical position. Nuchal translucency thickness was mildly increased in three cases (25%). An abdominal cyst, representing the dilated blind-ending bowel, was noted in seven cases (58%). Color flow imaging detected a single umbilical artery in six cases (50%) and the associated intra-abdominal vascular anomalies in three cases (25%). No cases of aneuploidy were detected. The pregnancy was terminated in nine cases (75%) and intrauterine demise occurred in the remaining three cases (25%). CONCLUSIONS: The sonographic detection of abnormal lower limbs or an intra-abdominal cyst located laterally during the first-trimester scan may be warning signs of sirenomelia. This should prompt a detailed examination of the fetal lower body and intra-abdominal anatomy, including the main abdominal vessels, in order to look for additional confirmatory findings.

The importance of ultrasound preceding cell-free DNA screening for fetal chromosomal abnormalities.

OBJECTIVE: This study aims to determine the incidence of ultrasound findings that may change clinical management on the day of blood-sampling for cell-free DNA (cfDNA) screening. METHODS: A retrospective study was conducted at a tertiary provider of obstetric and gynecological ultrasound in Melbourne, Australia. Individual patient files were reviewed and results were collated for maternal characteristics, pre-cfDNA ultrasound reports, results and test characteristics of both cfDNA and diagnostic testing, and genetic counselling notes. The primary outcome was a potential change in patient management due to findings detected on the pre-cfDNA ultrasound. RESULTS: Of 6250 pre-cfDNA ultrasounds, 6207 were included in analysis. Of these, 598 (9.6%) pregnancies had a finding on pre-cfDNA ultrasound that had the potential to change management. The reasons for this potential change in management were detection of gestational age below 10 weeks (245, 3.9%), miscarriage (175, 2.8%), demised twin (43, 0.7%), fetal edema (115, 1.9%) and major structural abnormalities (20, 0.3%). These findings were more common in patients of advanced maternal age and in spontaneous conceptions. CONCLUSIONS: An ultrasound prior to cfDNA screening has the potential to change clinical management in almost one in 10 women. The proportion is higher in older age groups and lower in IVF-conceived pregnancies.

Cranial sonographic markers of fetal open spina bifida at 11 to 13 weeks of gestation.

OBJECTIVES: To compare the sonographic signs of spina bifida obtained on axial and sagittal views of the fetal head between 11 and 13+6 weeks of gestation. METHODS: This was a retrospective study including 27 cases of spina bifida and 1003 randomly selected controls. Indirect markers of spina bifida were evaluated on stored ultrasound images. Intracranial translucency (IT), ratio between the brainstem and the brainstem-occipital bone distance (BS/BSOB), and maxillo-occipital (MO) line were assessed on sagittal view, whereas biparietal diameter (BPD), BPD to abdominal circumference ratio (BPD/AC), and aqueduct to occipital bone (aqueduct of Sylvius [AoS]) distance were measured on the axial plane. Reference ranges were developed, and cases of spina bifida were examined in relation to the reference range. RESULTS: On the sagittal view, detection rates for IT below the fifth percentile, BS/BSOB above the 95th percentile, and an abnormal MO line were 52.3%, 96.3%, and 96.3%, respectively. On the axial view, detection rates for BPD, BPD/AC, and AoS below the fifth percentile were 66.7%, 70.4%, and 77.8%, respectively. CONCLUSION: The MO line and the BS/BSOB ratio appear to be the best indirect ultrasound markers of spina bifida and can be easily obtained during the routine first-trimester scan.

Early Diagnosis and Differences in Progression of Fetal Encephalocele.

In this case series, we present 3 cases of very early prenatal diagnosis of encephalocele that, despite similar appearances at diagnosis, had different disease progressions. Two of the cases were carried to term, whereas 1 resulted in a termination of pregnancy. The diagnoses were made via ultrasound examinations before cell-free DNA testing for chromosomal abnormality screening at 10 weeks' gestation, thereby highlighting the importance of performing a routine ultrasound examination before cell-free DNA testing antenatally.

An Unusual First-Trimester Ultrasound Presentation of the Acrania-Anencephaly Sequence: The "Turkish Turban" Sign.

A previously unrecognized first-trimester presentation of the acrania-anencephaly sequence is described. Ultrasound features included a constriction ring around the external base of the developing skull and an enlarged globular head, resembling a Turkish turban, with large cystic spaces replacing the brain. This constellation of findings was noted in 3 first-trimester fetuses. In 2 of them, it was possible to identify the amniotic membrane attached to the constriction ring. One case presented with anencephaly and fetal demise at 16 weeks. The other 2 women terminated the pregnancies and aborted anencephalic fetuses. This subtype of the acrania-anencephaly sequence could represent an earlier segmental rupture of the amnion, which subsequently entraps the developing fetal skull.

Ultrasound Appearances of the Acrania-Anencephaly Sequence at 10 to 14 Weeks' Gestation.

OBJECTIVES: The acrania-anencephaly sequence is a lethal condition with a high detection rate in experienced hands after 10 weeks' gestation. However, earlier in gestation, many cases remain undetected. Different phenotypic appearances have been described and might help increase the detection rate in less experienced hands and also earlier in gestation. The purpose of this study was to assess interobserver reliability in classifying cases of the acrania-anencephaly sequence during first trimester in 6 different subtypes according to their ultrasound appearances. METHODS: This was a retrospective descriptive cohort study at 3 centers for fetal imaging. Each case was classified according to its phenotypic appearance by 2 independent operators as "bilobular," "cystic," "elongated," "irregular," "foreshortened," or "overhanging." Frequencies of each type are described, and interoperator agreement was assessed with the intraclass correlation coefficient. RESULTS: From the 88 included cases, the frequencies of the different subtypes classified as overhanging, elongated, bilobular, cystic, foreshortened, and irregular were 31%, 25%, 19%, 11%, 8%, and 6%, respectively. The interoperator reliability was good, with an intraclass correlation coefficient of 0.903 (95% confidence interval, 0.853-0.937; P < .001). CONCLUSIONS: Using different subtypes may improve the detection of the acrania-anencephaly sequence. An accurate early diagnosis could lead to timely, less traumatic, and safer management of affected pregnancies.

Lipiodol flush under ultrasound guidance in Australia.

BACKGROUND: Lipiodol tubal flushing is offered to select subfertile women primarily to confirm tubal patency and to increase pregnancy rates. AIMS: To investigate the safety of hystero-salpingo contrast sonography (HyCoSy) using Lipiodol flush (through frequency of adverse events and mean recalled pain score) and secondarily to quantify pregnancy rates. MATERIALS AND METHODS: Retrospective observational Phase 1 study of subfertile women in three centres across Australia between June 2017 and June 2019. Cases were identified from medical records, and women telephoned to assess adverse outcomes, procedure tolerability and confirm pregnancy outcomes within six months from procedure. RESULTS: A total of 325 cases were identified; 14 were excluded due to incomplete or abandoned procedure, 32 were lost to follow-up, leaving 279 for analysis. Fourteen women (5% overall) experienced mild vasovagal reactions, with one case of infection and no reports of anaphylaxis or allergy. There were 141 conceptions reported (51%) within six months after Lipiodol flush, and an ongoing pregnancy in 43% (119) of women. For women with ongoing pregnancies, 55% (78/119) conceived spontaneously, and 45% (63/119) via artificial reproductive technology. Mean recalled pain score was 5.7 (SD 3.2; range 0-10) at a single site. CONCLUSIONS: This Phase 1 study has indicated that Lipiodol flush using HyCoSy may be a safe and efficacious alternative to hysterosalpingography in the workup for infertility. The low adverse effect profile observed in this study coupled with a substantial ongoing pregnancy rate indicates that further investigation of Lipiodol under HyCoSy is warranted.

The gap between the aorta and the superior vena cava: A sonographic sign of persistent left superior vena cava and associated abnormalities.

OBJECTIVES: To assess the distance between the right superior vena cava (SVC) and the aorta in fetuses with bilateral superior vena cava as a possible sonographic marker for this. METHODS: This was a nested case-control study including 20 cases of bilateral SVC and 40 gestational age-matched controls. The distance between the right SVC and the aorta was measured at the level of the three-vessel trachea view in stored images, as well as the diameters of the aorta and the right SVC. RESULTS: The distance between the aorta and the right SVC was significantly larger in the cases of a left SVC compared with controls, P < .001. A distance of 2.0 mm or more was found in 70% of the cases and 5% of the controls, with a gestational-age adjusted area under the receiver-operating characteristics (ROC) curve for the diagnosis of left SVC of 0.93 (95% CI 0.87-0.99). The aorta and the right SVC were significantly smaller in cases compared with controls, and there was a significant association with other cardiac and extracardiac abnormalities amongst cases of persistent left SVC. CONCLUSION: An increased distance between the aorta and the right SVC is associated with the diagnosis of bilateral SVC.

Noninvasive prenatal testing in routine clinical practice--an audit of NIPT and combined first-trimester screening in an unselected Australian population.

BACKGROUND: There are limited data regarding noninvasive prenatal testing (NIPT) in low-risk populations, and the ideal aneuploidy screening model for a pregnant population has yet to be established. AIMS: To assess the implementation of NIPT into clinical practice utilising both first- and second-line screening models. MATERIALS AND METHODS: Three private practices specialising in obstetric ultrasound and prenatal diagnosis in Australia offered NIPT as a first-line test, ideally followed by combined first-trimester screening (cFTS), or as a second-line test following cFTS, particularly in those with a calculated risk between 1:50 and 1:1000. RESULTS: NIPT screening was performed in 5267 women and as a first-line screening method in 3359 (63.8%). Trisomies 21 and 13 detection was 100% and 88% for trisomy 18. Of cases with known karyotypes, the positive predictive value (PPV) of the test was highest for trisomy 21 (97.7%) and lowest for monosomy X (25%). Ultrasound detection of fetal structural abnormality resulted in the detection of five additional chromosome abnormalities, two of which had high-risk cFTS results. For all chromosomal abnormalities, NIPT alone detected 93.4%, a contingent model detected 81.8% (P = 0.097), and cFTS alone detected 65.9% (P < 0.005). CONCLUSIONS: NIPT achieved 100% T21 detection and had a higher DR of all aneuploidy when used as a first-line test. Given the false-positive rate for all aneuploidies, NIPT is an advanced screening test, rather than a diagnostic test. The benefit of additional cFTS was the detection of fetal structural abnormalities and some unusual chromosomal abnormalities.