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.

     

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.     

Intermittent absent and reversed umbilical artery flows in appropriately grown monochorionic diamniotic twins in relation to proximate cord insertion: A harmful combination?

Objective

To compare the prevalence of intermittent absent or reversed end-diastolic flow (iAREDF) in the umbilical artery in appropriately grown monochorionic diamniotic (MCDA) pregnancies with and without proximate cord insertion (PCI), and to evaluate pregnancy outcome.

Methods

The prevalence of iAREDF in MCDA pregnancies with PCI (n = 11) was compared with a control group without PCI (n = 33). PCI was defined as a distance between the cord insertions below the fifth percentile. Placental sharing, number, and diameter of anastomoses were assessed by placental examination. Pregnancy outcome was evaluated.

Results

iAREDF was present in 7/11 PCI pregnancies, compared with 0/33 in the control group (P ≤ .01). All PCI pregnancies and 94% of controls had arterioarterial (AA)-anastomoses (P = .56), the diameter was larger in the PCI group, respectively 3.3 vs 2.1 mm (P = .03). Three cases with iAREDF had adverse outcome, two resulted in fetal death of which one with brain damage in the co-twin, another underwent early premature emergency section for fetal distress.

Conclusion

iAREDF occurs in a large proportion of MCDA pregnancies with PCI and is related to the diameter of the AA anastomosis. We hypothesize that iAREDF in appropriately grown MCDA twin pregnancies reflects an unstable hemodynamic balance with an increased risk for fetal deterioration. Whether outcome in these pregnancies can be improved by altered management requires further investigation.

     

Perinatal outcome after selective fetal reduction in monochorionic twin pregnancies: A comparison of techniques over a 20-year period

Objective

To assess the perinatal outcome after fetal reduction in complicated monochorionic (MC) twin pregnancies by comparing different techniques.

Methods

A retrospective cohort study at a national referral center comparing data between four techniques: interstitial laser coagulation, radiofrequency ablation (RFA), fetoscopic laser coagulation (FLC) and bipolar cord coagulation (BCC). The primary outcome was the mortality of the co-twins. Secondary outcomes were preterm pre-labor rupture of membranes (PPROM), gestational age at delivery and neonatal morbidity.

Results

259 MC twin pregnancies underwent selective fetal reduction: 29 IL, 64 RFA, 85 FLC and 81 BCC. The perinatal mortality rate was 29% and fetal demise of the co-twins occurred in 19%. The lowest mortality rate was seen after BCC (17%, p = 0.012). PPROM occurred in 18% patients without significant differences between techniques. The mean gestational age at delivery in liveborn children was 35 weeks and did not differ between techniques. Severe cerebral injury and neonatal morbidity were reported in 4% and 14%, respectively, without significant differences between techniques.

Conclusions

Selective fetal reductions in MC twins are precarious procedures with an increased risk of perinatal mortality of the co-twins. Our results show the lowest mortality rates after BCC. However, high PPROM rates were seen irrespective of the technique.     

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.     

Confined placental mosaicism for trisomy 14 and maternal uniparental disomy in association with elevated second trimester maternal serum human chorionic gonadotrophin and third trimester fetal growth restriction

A case of confined placental mosaicism (CPM) and maternal uniparental isodisomy 14 identified after placental karyotype revealed trisomy 14 in a newborn with intrauterine growth restriction (IUGR) and minor dysmorphic features is reported. During the second trimester of the pregnancy, multiple marker screening revealed an increased risk for Down syndrome of >1 in 10. The maternal serum human chorionic gonadotrophin (MShCG) was markedly elevated at 4.19 MoM. Amniocentesis revealed a normal 46,XX karyotype. Fetal growth restriction has been associated with elevated MShCG and placental aneuploidy with CPM for chromosomes 2, 7, 9 and 16. The present case of CPM for chromosome 14 was also associated with fetal growth restriction and elevated second trimester MShCG, suggesting a common link. Further studies need to be done to determine if indeed elevation of second trimester MShCG is associated with increased risk of CPM. The present case again demonstrates the need to perform placental karyotype in unexplained fetal growth restriction. Copyright © 2001 John Wiley & Sons, Ltd.     

Cell-free DNA fetal fraction in twin gestations in single-nucleotide polymorphism-based noninvasive prenatal screening

Objectives

The performance of noninvasive prenatal screening (NIPS) for fetal aneuploidy in twin pregnancies is dependent on the amount of placentally derived cell-free DNA, the “fetal fraction (FF),” present in maternal plasma. We report FF values in monozygotic (MZ) and dizygotic (DZ) pregnancies.

Methods

We reviewed FF in pregnancies at 10 to 20 completed weeks gestational age based on single-nucleotide polymorphism (SNP)-based NIPS where zygosity was routinely established in twin pregnancies. The cohort included 121 446 (96.3%) singleton, 1454 (1.2%) MZ, and 3161 (2.5%) DZ pregnancies. For DZ twins, individual FFs were measured.

Results

Combined FF for DZ and MZ fetuses were 35% and 26% greater than singletons, respectively. The individual FF contributions from each fetus in DZ twins were, on average, 32% less than singletons. FF in DZ twin pairs were moderately correlated (Pearson correlation coefficient.66). When a threshold of 2.8% FF was applied to define uninterpretable results, 1.7% (2102/121 446) of singletons, 0.8% (11/1454) of MZ pairs, and 5.6% (178/3161) of DZ pairs were uninterpretable.

Conclusion

For optimal aneuploidy NIPS in twin pregnancies, zygosity should be established and in DZ twins FF for both fetuses should be determined to identify those cases where results can be reliably interpreted.     

Severe early-onset fetal growth restriction: What do we tell the prospective parents?

Fetal growth restriction (FGR) is a common complication of pregnancy, associated with higher risk of perinatal mortality and adverse health and developmental outcomes for surviving infants. True FGR relates to a pathological restriction of fetal growth resulting from complex interactions between maternal, placental, fetal, and environmental factors. Early-onset FGR (onset <32 weeks' gestation) is often first suspected at routine mid-trimester sonographic assessment of fetal morphology, or identified as part of the placental syndrome, commonly maternal pre-eclampsia. Prenatal investigations may identify the cause of FGR. Timing of delivery is guided by serial sonographic surveillance of fetal growth and well-being and maternal condition, balancing the risk of stillbirth with the benefits of advancing gestation. This is particularly pertinent to severe early-onset FGR, a leading iatrogenic cause of very preterm birth. Prognosis is largely determined by the severity of FGR and its causes, gestation at birth, and birthweight. Pregnancy termination may be considered. Antenatal care and delivery in a tertiary center, provided by a multi-disciplinary team with expertise in managing high-risk pregnancies, are imperative to optimizing outcomes.     

Stereological quantification of placental villus vascularization and its relation to umbilical artery Doppler flow in intrauterine growth restriction

The aim of this study was to investigate the changes in the number of vessels within tertiary stem villi and intermediate/terminal villi which may be responsible for the abnormalities in placental vascular resistance and Doppler velocity index values in growth-restricted fetuses. The placentas of 20 cases with intrauterine growth restriction and 30 cases which were appropriate for gestational age were studied. The umbilical artery resistance index, pulsatility index and systolic to diastolic ratio were measured in each case. The vessels were quantified by a stereological method described previously and vascular surface density and the volume portion of the villi were calculated. The placentas of preterm and term cases with intrauterine growth restriction displayed significant reductions in the vascular surface density of stem and intermediate/terminal villi and volume portion of intermediate/terminal villi stroma when compared with gestation-matched normally grown cases (p<0.05). There was no significant correlation between Doppler index values of the umbilical artery and the stereological parameters of the intermediate/terminal and stem villi in the intrauterine growth restriction group (p>0.05). Some of the pregnancies with intrauterine growth restriction (six patients) with normal Doppler flow velocity waveforms had reduced vascularization in the placentas, and these pregnancies were found to have no perinatal complications. We conclude that,although the placental villi show reduced vascularization in pregnancies with intrauterine growth restriction, the Doppler indices may be normal and this normal flow pattern is related to reduced complication rate. Copyright © 2002 John Wiley & Sons, Ltd.     

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.     

Shortened fetal long bones: A notable intrauterine phenotypic feature in SHOX-associated skeletal dysplasia

Objective

To explore the intrauterine phenotypic spectrum of short stature homeobox-containing (SHOX) gene-associated skeletal dysplasia and provide genetic counseling at-risk pregnancies.

Method

We analyzed the fetuses with SHOX-microdeletions identified by single nucleotide polymorphism (SNP)-array. The intrauterine phenotypes and outcomes were further elaborated.

Results

Nine fetuses carrying a single SHOX-microdeletion were reported, with deletion sizes ranging from 0.134 to 1.35 Mb. Shortened long bones were observed in all fetuses, varying from −2.0 standard deviation (SD) to −5.3 SD. Moreover, all cases had a femur length/foot ratio less than 0.87 and a femur/abdominal circumference ratio greater than 0.16, suggesting that non-lethal skeletal dysplasia may be involved. Two fetuses showed intrauterine growth restriction, and two had nasal bone hypoplasia. Prenatal ultrasonography did not reveal other obvious anomalies, including the Madelung deformity. Five microdeletions were inherited and one was de novo. Five terminations and four newborns were recorded. Two newborns had normal stature, and two were short-statured (height <3rd percentile), with one having inflexible wrists.

Conclusions

SHOX haploinsufficiency may manifest with shortened fetal long bones. The combination of history taking, prenatal ultrasonography, and SNP-array can prompt early prenatal diagnosis and timely postnatal treatment of SHOX-associated skeletal dysplasia.     

Access to prenatal exome sequencing for fetal malformations: A qualitative landscape analysis in the US

Objective

There is increasing evidence supporting the clinical utility of next generation sequencing for identifying fetal genetic disorders. However, there are limited data on the demand for and accessibility of these tests, as well as payer coverage in the prenatal context. We sought to identify clinician perspectives on the utility of prenatal exome sequencing (ES) and on equitable access to genomic technologies for the care of pregnancies complicated by fetal structural anomalies.

Method

We conducted two focus group discussions and six interviews with a total of 13 clinicians (11 genetic counselors; 2 Maternal Fetal Medicine/Geneticists) from U.S. academic centers and community clinics.

Results

Participants strongly supported ES for prenatal diagnostic testing in pregnancies with fetal structural anomalies. Participants emphasized the value of prenatal ES as an opportunity for a continuum of care before, during, and after a pregnancy, not solely as informing decisions about abortions. Cost and coverage of the test was the main access barrier, and research was the main pathway to access ES in academic centers.

Conclusion

Further integrating the perspectives of additional key stakeholders are important for understanding clinical utility, developing policies and practices to address access barriers, and assuring equitable provision of prenatal diagnostic testing.     

Brain cortical assessment by MRI in fetuses with left congenital diaphragmatic hernia

Objective

To evaluate fetal brain development using MRI (magnetic resonance imaging) in CDH (congenital diaphragmatic hernia).

Methods

52 isolated left CDH and 104 control fetuses were imaged using MRI. Brain morphometry (Biparietal diameter—BPD, brain fronto-occipital diameter—BFOD, third ventricle, posterior ventricles, transcerebellar diameter—TCD, anteroposterior and craniocaudal cerebellar vermis diameter—AP and CC) and cortical structures (bilateral cingulate fissure—CF, insular fissure—IF, insular depth - ID) were compared with controls using Mann–Whitney test.

Results

Median gestational age at MRI (p = 0.95)and the median biparietal diameter (p = 0.737) were comparable. Among morphometric parameters, only the brain fronto-occipital diameter was significantly smaller in CDH (p = 0.001) and the third ventricle was significantly greater in CDH (<0.0001). Among cortical structures, the cingulate and insular fissures were significantly deeper in CDH fetuses (p < 0.0001) as the insular depth ID was smaller in CDH (p < 0.03).

Conclusions

CDH fetuses have a smaller fronto-occipital diameter, reduced insular depth, deeper cingulate and insular fissure, and greater third ventricle width as compared to controls. These findings suggest that left CDH may have an impact on fetal brain development with an overall reduction in brain volume.     

Performance of single-gene noninvasive prenatal testing for autosomal recessive conditions in a general population setting

Objective

Carrier screening with reflex to single-gene noninvasive prenatal testing (sgNIPT) is an alternative approach for identifying pregnancies at risk for inherited autosomal recessive conditions without the need for a sample from the reproductive partner. This study is the largest clinical validation of this approach in a general population setting.

Methods

The clinical performance of carrier screening with reflex to sgNIPT for cystic fibrosis, spinal muscular atrophy, alpha thalassemias, and beta hemoglobinopathies was assessed by collecting pregnancy outcome data on patients who underwent this testing and comparing the neonatal outcome to the assay-predicted fetal risk.

Results

Of 42,067 pregnant individuals who underwent screening, 7538 carriers (17.9%) had reflex sgNIPT, and neonatal or fetal outcomes were obtained for 528 cases, including 25 affected pregnancies. Outcomes demonstrated high concordance with sgNIPT, for example, all pregnancies with 9 in 10 personalized fetal risk results were affected (positive predictive value (PPV) of 100% for the sub-group) and the sgNIPT assay showed a sensitivity of 96.0% (95% CI: 79.65%–99.90%), specificity of 95.2% (95% CI: 92.98%–96.92%), average PPV of 50.0% (95% CI: 35.23%–64.77%), and negative predictive value (NPV) of 99.8% (95% CI: 98.84%–99.99%). The end-to-end performance of carrier screening with reflex to sgNIPT was calculated to have a sensitivity of 92.4% and specificity of 99.9%, which are unaffected by partner carrier screening or misattributed paternity unlike a traditional carrier screening workflow, which has a 35% sensitivity and a maximum of 25% PPV (1 in 4) in a real-life setting.

Conclusion

This study builds upon earlier findings to confirm that carrier testing with reflex to sgNIPT is highly accurate for general population screening. Given this high accuracy and an NPV of 99.8%, this workflow should be considered as an option for most of the general pregnant population. When the biological partner sample is unavailable, this workflow should be recommended as the first-line approach.     

Comprehensive prenatal diagnostics: Exome versus genome sequencing

Objective

This study aimed to assess the diagnostic yield of prenatal genetic testing using trio whole exome sequencing (WES) and trio whole genome sequencing (WGS) in pregnancies with fetal anomalies by comparing the results with conventional chromosomal microarray (CMA) analysis.

Methods

A total of 40 pregnancies with fetal anomalies or increased nuchal translucency (NT ≥ 5 mm) were included between the 12th and 21st week of gestation. Trio WES/WGS and CMA were performed in all cases.

Results

The trio WES/WGS analysis increased the diagnostic yield by 25% in cases with negative CMA results. Furthermore, all six chromosomal aberrations identified by CMA were independently detected by WES/WGS analysis. In total, 16 out of 40 cases obtained a genetic sequence variant, copy number variant, or aneuploidy explaining the phenotype, resulting in an overall WES/WGS diagnostic yield of 40%. WES analysis provided a more reliable identification of mosaic sequence variants than WGS because of its higher sequencing depth.

Conclusions

Prenatal WES/WGS proved to be powerful diagnostic tools for fetal anomalies, surpassing the diagnostic yield of CMA. They have the potential to serve as standalone methods for prenatal diagnosis. The study highlighted the limitations of WGS in accurately detecting mosaic variants, which is particularly relevant when analyzing chorionic villus samples.     

Development of a simulator for training of fetoscopic myelomeningocele surgery

Objective

To develop a realistic simulation model for laparotomy-assisted fetoscopic spina bifida aperta (SBa) surgery, to be used for training purposes and preoperative planning.

Methods

The predefined general requirement was a realistic model of an exteriorized uterus, allowing all neurosurgical steps of the intervention. The uterus was modelled using ultrasound and MRI images of a 25 weeks’ gravid uterus, consisting of flexible polyurethane foam coated with pigmented silicone. The fetal model, contained an opening on the dorsal side for a customizable spinal insert with all the aspects of a SBa, including a cele, placode, and myofascial and skin layer. The model was assessed in a series of validation experiments.

Results

Production costs are low, uterus and fetus are reusable. Placental localization and the level and size of the spinal defect are adjustable, enabling case-specific adaptations. All aspects of the simulator were scored close to realistic or higher for both appearance and functional capacities.

Conclusions

This innovative model provides an excellent training opportunity for centers that are starting a fetoscopic SBa repair program. It is the first simulation model with adjustable spinal defect and placental localisation. Further objective validation is required, but the potential for using this model in preoperative planning is promising.     

Fetal intestinal loop dilatation: Follow-up and outcome of a series of 133 consecutive cases (the DILDIG study)

Objectives

To define the prognostic markers of fetal dilated bowel loops.

Methods

National non-interventional study of 133 consecutive prenatal observations of dilated loops including ultrasound examinations, complementary laboratory tests, magnetic resonance imaging (MRI), outcomes, and postnatal diagnosis.

Results

One hundred twenty seven cases were classified according to outcome: Group 1, very severe (n = 43), Group 2, children needing specific care (n = 39), and Group 3, healthy children (n = 45). Prenatal ultrasound scan suggested duodenal obstruction in 30 cases, small bowel obstruction in 81, colonic obstruction in 11, and diffuse dilatation in 5. Diameter of dilated loops did not significantly differ between the groups. A poor prognosis was significantly associated with duodenal obstruction, genetic anomalies (53% vs. 21.8%), including aneuploidies or CFTR gene mutations and abnormal amniotic fluid biochemistry (86.4% vs. 38.7%). A good prognosis was associated with regression of dilatation and normal MRI.

Conclusion

In this study, postnatal outcomes for fetuses with intestinal dilatation were best predicted by assessing the level of obstruction with prenatal ultrasound and MRI, determining the presence of associated malformations, amniotic fluid biochemical and genetic testing, and monitoring for regression of bowel dilatation. These results should help inform future guidelines on the prenatal and neonatal management of congenital intestinal obstruction.     

Methods for prenatal assessment of fetal cardiac function

Fetal cardiac function is increasingly recognized as a marker of disease severity and prognosis in selected fetal conditions. Magnetic resonance imaging (MRI) has been used in experimental (animal) fetal cardiology but the lack of a noninvasive fetal electrocardiogram (ECG) to trigger image acquisition remains a major limiting factor precluding its application in humans. Fetal medicine specialists are therefore limited to ultrasound to evaluate human fetal cardiac function. In this review, we aim to provide a complete overview of the different ultrasound techniques that can be used for fetal cardiac function assessment and we discuss their (theoretical) strengths and shortcomings. Conventional methods include M-mode assessment of ventricular contractility and Doppler assessment of the precordial veins and cardiac output (CO). More recent techniques such as the measurement of the myocardial performance index (MPI), myocardial motion analysis with tissue Doppler, speckle tracking and three-dimensional (3D) ultrasound techniques are also discussed. Copyright © 2009 John Wiley & Sons, Ltd.