Size-based molecular diagnostics using plasma DNA for noninvasive prenatal testing.

Noninvasive prenatal testing using fetal DNA in maternal plasma is an actively researched area. The current generation of tests using massively parallel sequencing is based on counting plasma DNA sequences originating from different genomic regions. In this study, we explored a different approach that is based on the use of DNA fragment size as a diagnostic parameter. This approach is dependent on the fact that circulating fetal DNA molecules are generally shorter than the corresponding maternal DNA molecules. First, we performed plasma DNA size analysis using paired-end massively parallel sequencing and microchip-based capillary electrophoresis. We demonstrated that the fetal DNA fraction in maternal plasma could be deduced from the overall size distribution of maternal plasma DNA. The fetal DNA fraction is a critical parameter affecting the accuracy of noninvasive prenatal testing using maternal plasma DNA. Second, we showed that fetal chromosomal aneuploidy could be detected by observing an aberrant proportion of short fragments from an aneuploid chromosome in the paired-end sequencing data. Using this approach, we detected fetal trisomy 21 and trisomy 18 with 100% sensitivity (T21: 36/36; T18: 27/27) and 100% specificity (non-T21: 88/88; non-T18: 97/97). For trisomy 13, the sensitivity and specificity were 95.2% (20/21) and 99% (102/103), respectively. For monosomy X, the sensitivity and specificity were both 100% (10/10 and 8/8). Thus, this study establishes the principle of size-based molecular diagnostics using plasma DNA. This approach has potential applications beyond noninvasive prenatal testing to areas such as oncology and transplantation monitoring.

Prenatal Visualization of the Pulmonary and Aortic Valves and Leaflets Is Feasible Using 4-Dimensional Sonography.

OBJECTIVES: The purpose of this study was to determine whether the morphologic characteristics and area of the semilunar valves in healthy fetuses and fetuses with cardiac defects can be visualized by using spatiotemporal image correlation (STIC). METHODS: Spatiotemporal image correlation volumes from 74 healthy fetuses were recorded in 5 examinations between the 15th and 36th weeks of pregnancy. Second, we recorded STIC volumes from 64 fetuses with various cardiac defects. The quality of the volumes was rated. The areas of the aortic and pulmonary valves were measured in systole by rendering the valves on 4-dimensional sonography. The number of leaflets was examined. Longitudinal data analysis using linear mixed models was performed. RESULTS: Two hundred ninety-three volumes from normal hearts were examined. In 82.5%, the quality of the normal volumes was sufficient. Visualization of the valve opening was feasible in 96.1% of the normal hearts and 97.4% of the abnormal hearts. The success rate of visualization of the pulmonary and aortic valve leaflets was dependent on the gestational age, with the highest percentage (72.1% in normal hearts) at 19 to 24 weeks. Longitudinal regression analysis showed a positive relationship of the aortic and pulmonary valve areas with gestational age (P < .0001) and fetal biometric measurements (P < .0001). Fifty-eight abnormal volumes were examined. Cardiac defects with abnormal valve areas due to aortic and pulmonary stenosis could be clearly visualized by using STIC. CONCLUSIONS: Examination of the morphologic characteristics of the semilunar valves using STIC is feasible, which is difficult when using 2-dimensional sonography. With increasing implementation of 4-dimensional sonography, the understanding of rendered images might be useful for anyone practicing fetal echocardiography.

Women's and healthcare professionals' preferences for prenatal testing: a discrete choice experiment.

OBJECTIVE: This study evaluates pregnant women's and healthcare professionals' preferences regarding specific prenatal screening and diagnostic test characteristics. METHOD: A discrete choice experiment was developed to assess preferences for prenatal tests that differed in seven attributes: minimal gestational age, time to test results, level of information, detection rate, false positive rate, miscarriage risk and costs. RESULTS: The questionnaire was completed by 596 (70.2%) pregnant women and 297 (51.7%) healthcare professionals, of whom 507 (85.1%) and 283 (95.3%), respectively, were included in further analyses as their choice behavior indicated prenatal testing was an option to them. Comparison of results showed differences in relative importance attached to attributes, further reflected by differences in willingness to trade between attributes. Pregnant women are willing to accept a less accurate test to obtain more information on fetal chromosomal status or to exclude the risk of procedure-related miscarriage. Healthcare professionals consider level of information and miscarriage risk to be most important as well but put more emphasis on timing and accuracy. CONCLUSION: Pregnant women and healthcare professionals differ significantly in their preferences regarding prenatal test characteristics. Healthcare professionals should take these differences into consideration when counseling pregnant women on prenatal testing.

Small biparietal diameter and head circumference are part of the phenotype instead of independent prognostic markers in fetuses with spinal dysraphism.

OBJECTIVE: The aim of this retrospective study was to assess the fetal biparietal diameter (BPD) and head circumference (HC) in the second trimester of pregnancy in fetuses with open spinal dysraphism. METHODS: BPD and HC were measured at 16-26 weeks in 74 fetuses with open spinal dysraphism and compared with reference values. RESULTS: BPD was smaller in fetuses with open spinal dysraphism. Of all cases with open spinal dysraphism, 62.2% had a BPD <3rd percentile and 79.7% had a BPD <10th percentile. Of all patients, 54.1% had an HC <3rd percentile and 74.3% had an HC <10th percentile. CONCLUSION: Almost all fetuses with open neural tube defects have a smaller BPD and HC at 16-26 weeks compared with reference values, which implicates that this is part of the phenotype of children with open spinal dysraphism instead of an independent prognostic marker for a poor cognitive outcome.

The effectiveness of multifetal pregnancy reduction in trichorionic triplet gestation.

OBJECTIVE: The objective of the study was to assess in trichorionic triplet pregnancies the effectiveness of elective reduction to twins. STUDY DESIGN: This was a nationwide retrospective cohort study. We compared the time to delivery and perinatal mortality in trichorionic triplet pregnancies electively reduced to twins with ongoing trichorionic triplets and primary dichorionic twins. RESULTS: We identified 86 women with reduced trichorionic triplet pregnancies, 44 with ongoing trichorionic triplets, and 824 with primary twins. Reduced triplets had a median gestational age at delivery of 36.1 weeks (interquartile range [IQR], 33.3-37.5 weeks) vs 33.3 (IQR, 28.1-35.2) weeks for ongoing triplets and 37.1 (IQR, 35.3-38.1) weeks for primary twins (P < .001). The total number of surviving children in the reduced group was 155 (90%) vs 114 (86%) in the ongoing triplet group. After reduction, 75 of women (87%) had all their fetuses surviving, compared with 36 (82%) (relative risk [RR], 1.3; 95% confidence interval [CI], 0.72-2.3) for ongoing triplets and 770 (93%) (RR, 0.91; 95% CI, 0.82-1) for primary twins. There were 6 women without any surviving children (7%) after reduction vs 5 (11.4%) (RR, 0.81; 95% CI, 0.47-1.4) among women with ongoing triplets and 32 (3.9%) (RR, 1.7; 95% CI, 0.8-3.7) in women with primary twins. CONCLUSION: In women with a triplet pregnancy, fetal reduction increases gestational age at birth with 3 weeks as compared with ongoing triplets. However, there the impact on neonatal survival is limited.

First-trimester screening for down syndrome with serum sampling at different gestational ages: the effect on screening performance.

INTRODUCTION: The objective of this study was to evaluate the performance of first-trimester Down syndrome (DS) screening with serum sampling at different weeks of gestation. MATERIAL AND METHODS: We studied 35,431 singleton pregnancies (2005-2011), including 145 DS cases. Screening performance was determined in different maternal age groups with serum sampling between weeks 9 + 0 and 13 + 6. RESULTS: No significant differences were found between the detection rates at different gestational weeks. The false-positive rate (FPR) in week 9 (6%) was comparable to the FPR in week 10 (6.5%; p = 0.214), whereas it was significantly lower compared to weeks 11 (7.2%; p = 0.007), 12 (7.4%; p = 0.003) and 13 (8.5%; p < 0.001). The odds of receiving a false-positive result was significantly increased with serum sampling in week 11 (OR 1.32, 95% CI 1.08-1.63; p = 0.008) for women ≥36 years and from week 12 onwards (OR 1.28, 95% CI 1.01-1.61; p = 0.04) for women <36 years. There were no differences in mean log10 multiple of the median values of pregnancy-associated plasma protein-A, free ß-human chorionic gonadotrophin or nuchal translucency between both age groups, nor in mean maternal age between the different gestational weeks in either age group. DISCUSSION: Early serum sampling (<11 weeks) resulted in higher screening performance. The impact of the increase in the FPR was highest in women ≥36 years.

ADAM12s and PP13 as first trimester screening markers for adverse pregnancy outcome.

BACKGROUND: The aim of the study was to assess the screening performance of first trimester maternal serum measurements of A-disintegrin-and-metalloprotease 12-s (ADAM12s) and placental protein 13 (PP13) for preeclampsia (PE), gestational hypertension (GH) and small-for-gestational-age (SGA) fetuses. METHODS: In this retrospective case-control study 220 pregnant women were matched for gestational and maternal age at sampling. Results were expressed as multiples of the median (MoM) and compared using Kruskal-Wallis and Mann-Whitney U-test. Screening performance was assessed by receiver operator characteristics (ROC) curves and area under the curve (AUC). RESULTS: Seventeen cases of PE, 30 cases of GH and eight cases of SGA fetuses were matched with 165 controls. ROC-analysis yielded AUCs for ADAM12s and PP13 of 0.63 and 0.59 for PE, 0.68 and 0.57 for GH and 0.59 and 0.62 for SGA, respectively. Combined ADAM12 and PP13 did not improve the AUC value. When the specificity was set at 80%, corresponding detection rate of ADAM12s was 52% for GH. CONCLUSIONS: Combined ADAM12s and PP13 measurements do not predict adverse pregnancy outcome, but decreased first trimester ADAM12s levels are associated with GH.

Monochorionic dizygous twins presenting with blood chimerism and discordant sex.

Monochorionic dizygous twins are probably more frequent than considered previously as many cases remain unrecognized, especially when the children have the same sex. Here we present a pair of dizygous, sex-discordant monochorionic twins who were conceived after artificial insemination. Histological examination of the placenta and extensive genetic studies of the healthy boy and girl clearly proved that they indeed were monochorionic dizygous twins with a fully joined blood circulation. We conclude that when counseling parents expecting monochorionic twins of discordant sex, not only a disorder of sexual differentiation in one of the twins should be addressed but also the possibility of dizygosity with a completely normal (sexual) development of both children.

Validation of correction factors for serum markers for first-trimester Down syndrome screening in singleton pregnancies conceived with assisted reproduction.

OBJECTIVE: To validate previously computed correction factors for free ß-human chorionic gonadotrophin (fß-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) pregnancies with hormone treatment and to determine the effect on false-positive rate (FPR). METHODS: Retrospective study on 249 IVF and 250 ICSI cases and 20,190 controls. Correction factors 1.42 (PAPP-A), 1.17 (fß-hCG) in IVF; 1.56 (PAPP-A) in ICSI were applied on the absolute serum concentrations. Analysis was done on log10-transformed multiples of medians (MoMs). RESULTS: In the controls, mean PAPP-A and fß-hCG MoM were 1.004 and 1.062. Before correction, mean PAPP-A MoM was significantly lower in IVF (0.757; p < 0.001) and in ICSI (0.671; p < 0.001) and after correction comparable (1.071; p = 0.053 in IVF; 1.048; p = 0.178 in ICSI). Before correction, mean fß-hCG MoM was comparable (1.054; p = 0.59 in IVF and 1.051; p = 0.56 in ICSI) and after correction significantly higher in IVF (1.241; p < 0.001). After correction the likelihood for receiving a false-positive result was 1.03 in IVF pregnancies (95% CI 0.98-1.09; p = 0.248) and 1.02 in ICSI pregnancies (95% CI 0.97-1.07; p = 0.448). CONCLUSIONS: After correction the FPR in IVF and ICSI pregnancies with hormone treatment reduces to the observed FPR in the controls.

Non-targeted whole genome 250K SNP array analysis as replacement for karyotyping in fetuses with structural ultrasound anomalies: evaluation of a one-year experience.

OBJECTIVE: We evaluated both clinical and laboratory aspects of our new strategy offering quantitative fluorescence (QF)-PCR followed by non-targeted whole genome 250K single-nucleotide polymorphism array analysis instead of routine karyotyping for prenatal diagnosis of fetuses with structural anomalies. METHODS: Upon the detection of structural fetal anomalies, parents were offered a choice between QF-PCR and 250K single-nucleotide polymorphism array analysis (QF/array) or QF-PCR and routine karyotyping (QF/karyo). RESULTS: Two hundred twenty fetal samples were included. In 153/220 cases (70%), QF/array analysis was requested. In 35/153 (23%), an abnormal QF-PCR result was found. The remaining samples were analyzed by array, which revealed clinically relevant aberrations, including two known microdeletions, in 5/118 cases. Inherited copy number variants were detected in 11/118 fetuses, copy number variants with uncertain clinical relevance in 3/118 and homozygous stretches in 2/118. In 67/220 (30%) fetuses, QF/karyo was requested: 23/67 (34%) were abnormal with QF-PCR, and in 3/67, an abnormal karyotype was found. CONCLUSION: Even though QF/array does not reveal a high percentage of submicroscopic aberrations in fetuses with unselected structural anomalies, it is preferred over QF/karyo, as it provides a whole genome scan at high resolution, without additional tests needed and with a low chance on findings not related to the ultrasound anomalies.

Performance of first-trimester combined test for Down syndrome in different maternal age groups: reason for adjustments in screening policy?

OBJECTIVE: To evaluate the performance of the first-trimester combined test (FCT) in different maternal age groups and to discuss whether adjustments in screening policies should be made. METHODS: In this retrospective study data (n = 26 274) from a fetal medicine center on FCT (maternal age, fetal NT, free ß-human chorionic gonadotrophin, pregnancy-associated plasma protein-A) were studied. RESULTS: 70.6% of cases was <36 years and 43% of the Down syndrome (DS) cases were detected in this age group. For women <36 years and advanced maternal age (AMA) women (≥36 years) detection rate (DR) and false positive rate (FPR) were 94.5% and 4.1%, and 95.8% and 13.0%, respectively (cut-off 1:200). Lowering the cut-off showed an improved balance in DR and FPR. With increasing maternal age FPR and DR increased and odds of being affected given a positive result (OAPR) decreased. CONCLUSION: FCT is effective in women <36 and ≥36 years. The balance between FPR and DR is more favourable in women <36 years with comparable OAPR. Although FPR increases with increasing maternal age, performance of FCT in AMA women is more effective than screening based on maternal age alone. Lowering the cut-off to 1:100 in AMA women is suggested to improve screening performance. Routinely offering diagnostic testing to AMA women as a screening policy for the detection of DS seems not reasonable.

Aberrant lymphatic development in euploid fetuses with increased nuchal translucency including Noonan syndrome.

OBJECTIVE: Increased nuchal translucency in the human fetus is associated with aneuploidy, structural malformations and several syndromes such as Noonan syndrome. In 60­70% of the Noonan syndrome cases, a gene mutation can be demonstrated. Previous research showed that aneuploid fetuses with increased nuchal translucency (NT) demonstrate an aberrant lymphatic endothelial differentiation. METHOD: Fetuses with increased NT and normal karyotype (n = 7) were compared with euploid controls having normal NT (n = 5). A Noonan syndrome gene mutation was found in three out of seven fetuses with increased NT. Endothelial differentiation was evaluated by immunohistochemistry using lymphatic markers (PROX-1, Podoplanin, LYVE-1) and blood vessel markers vascular endothelial growth factor-A (VEGF-A), Neuropilin-1 (NP-1), Sonic hedgehog, von Willebrand factor, and the smooth muscle cell marker, smooth muscle actin. RESULTS: Nuchal edema and enlarged jugular lymphatic sacs (JLSs) were observed in fetuses with increased NT, together with abnormal lymphatic endothelial differentiation i.e. the presence of blood vessel characteristics, including high levels of VEGF-A and NP-1 expression. The enlarged JLSs contained erythrocytes and were surrounded by smooth muscle cells. CONCLUSION: This study shows an aberrant lymphatic endothelial differentiation in fetuses with increased NT and a normal karyotype (including Noonan syndrome fetuses), as was previously reported before in aneuploid fetuses.

Spatiotemporal image correlation artifacts in an in vitro model.

An experimental in vitro setting with a latex miniature balloon was designed to test the accuracy of volumetric measurements by spatiotemporal image correlation. Two-dimensional images clearly showed the round balloon as a thin echogenic ring in a translucent area. Four-dimensional reconstructed images, however, showed a severely distorted balloon. The artifacts disappeared when the surroundings of the balloons were made echogenic, mimicking the in vivo setting. We hypothesize that the artifacts were the result of gating errors. These experiments can be relevant for analysis of spatiotemporal image correlation volumes in daily practice.

Altered jugular vein and ductus venosus flow velocities in fetuses with increased nuchal translucency and distended jugular lymphatic sacs.

OBJECTIVE: We sought to assess blood flow in relation to jugular lymphatic distension in fetuses with increased and normal nuchal translucency (NT). STUDY DESIGN: In all, 72 fetuses with normal NT and 71 fetuses with NT >95th percentile were evaluated. NT size, jugular lymphatic sacs (JLS), jugular vein and ductus venosus pulsatility index for veins (PIV), and intracardiac velocities were measured. RESULTS: JLS were visualized in 22/72 fetuses with normal and in 55/71 fetuses with increased NT. Jugular vein and ductus venosus PIV was higher in fetuses with increased NT compared to normal NT (P < .01). Visibility of JLS was associated with a higher ductus venous PIV (P < .05), but not with a higher jugular vein PIV. Larger NT and larger JLS volumes were associated with higher jugular vein and ductus venosus PIV (P < .05). CONCLUSION: This study shows a relation among increased NT, jugular lymphatic distension, and altered blood flow in jugular vein and ductus venosus.

Abnormal ductus venosus flow in first-trimester fetuses with increased nuchal translucency: relationship with the type of cardiac defect?

OBJECTIVE: The purpose of this study was to evaluate ductus venosus flow velocities and a possible relationship with the type of cardiac defect in fetuses with increased nuchal translucency (NT). METHODS: Seventy-two fetuses with normal NT and 137 fetuses with increased NT (>95th percentile) were evaluated. The ductus venosus pulsatility index for veins (PIV), late diastolic velocity (velocity during atrial contraction [a-V]), and intracardiac velocities were evaluated. In cases of pregnancy termination, a postmortem examination was performed. Cardiac defects were grouped into septal defects, left and right inflow obstruction, left and right outflow obstruction, and other defects. Data were evaluated by multilevel analysis. RESULTS: A cardiac defect was found in 45 fetuses with increased NT. Fetuses with increased NT showed a higher ductus venosus PIV and a lower a-V compared to fetuses with normal NT (P < .05). Within the group of fetuses with increased NT, a higher PIV and a lower a-V were found in cases with a cardiac defect compared to cases with a normal heart (P < .001). No differences in PIV and a-V were found between the types of cardiac defects. Intracardiac velocities showed no differences between fetuses with normal and increased NT, irrespective of the presence of a cardiac defect. CONCLUSIONS: Ductus venosus flow velocities in fetuses with increased NT are not related to a certain type of cardiac defect. This indicates that the altered ductus venosus flow velocities found in fetuses with increased NT cannot be explained by cardiac failure due to a specific altered cardiac anatomy.

Abnormal Shh and FOXC2 expression correlates with aberrant lymphatic development in human fetuses with increased nuchal translucency.

OBJECTIVE: Previous research in fetuses with increased nuchal translucency (NT) showed abnormal lymphatic endothelial differentiation characteristics, including increased vascular endothelial growth factor (VEGF)-A expression, and aberrant smooth muscle cells (SMCs) surrounding enlarged jugular lymphatic sacs (JLS). We hypothesized that abnormal Sonic hedgehog (Shh) expression would result in altered VEGF-A signaling in the lymphatic endothelial cells of the JLS and that aberrant acquisition of SMCs could be caused by downregulation of forkhead transcription factor FOXC2 and upregulation of platelet-derived growth factor (PDGF)-B in the lymphatic endothelial cells of the JLS. METHODS: Five trisomy 21 fetuses and four controls were investigated using immunohistochemistry for Shh, VEGF-A, FOXC2 and PDGF-B expression in the lymphatic endothelial cells of the JLS. RESULTS: An increased Shh, VEGF-A and PDGF-B expression, and decreased FOXC2 expression were shown in the lymphatic endothelial cells of the JLS of the trisomic fetuses. CONCLUSIONS: Increased Shh and VEGF-A expression is correlated with an aberrant lymphatic endothelial differentiation in trisomy 21 fetuses. The SMCs surrounding the JLS can possibly be explained by an increase of PDGF-B-induced SMC recruitment and/or differentiation. This underscores earlier findings that indicate the loss of lymphatic identity in trisomy 21 fetuses and a shift towards a blood vessel wall phenotype.

Feasibility of automated 3-dimensional fetal cardiac screening in routine ultrasound practice.

OBJECTIVE: The purpose of this study was to prospectively assess the clinical feasibility of an automated 3-dimensional (3D) software tool for extended basic cardiac screening in routine ultrasound practice. METHODS: During the 2-month study period, all gravidas fitting our inclusion criteria were consecutively included. Cardiac 3D volumes were acquired within the time slot allocated for the usual 2-dimensional fetal examination. All volumes were assessed on their quality, based on display of the 4-chamber view, and on the ability to sufficiently display diagnostic cardiac planes (left ventricular outflow tract [LVOT], right ventricle outflow tract [RVOT], and stomach location) with Sonography-Based Volume Computer-Aided Diagnosis software (SonoVCAD; GE Healthcare, Milwaukee, WI). RESULTS: Volume acquisition was successful in 107 of 126 cases (85%). For each sonographer, more than 70% of the acquired cardiac volumes were of high or sufficient quality. Separately analyzed, diagnostic planes of the LVOT, RVOT, and stomach location were visible in 62.1%, 81.6%, and 92.2%, respectively. An extended basic fetal cardiac examination based on retrieval of all diagnostic cardiac planes from a single volume using SonoVCAD could be performed in 46.6% of the cases. CONCLUSIONS: This study shows that cardiac volume acquisition can be incorporated in a routine ultrasound screening program without much difficulty. However, currently, SonoVCAD software still lacks the consistency to be clinically feasible for cardiac screening purposes. Further advances in ultrasound technology and familiarization with 3D ultrasound might improve its performance.

Longitudinal Doppler measurements of spiral artery blood flow in relation to uterine artery blood flow.

OBJECTIVE: The purpose of this study was to examine the longitudinal relationship between Doppler flow velocity waveforms of the spiral artery (SA) and uterine artery (UA) in pregnant women. METHODS: Ninety-seven primigravidas with uncomplicated singleton pregnancies were analyzed. Spiral artery and combined UA velocity waveforms were assessed by transabdominal color Doppler sonography at gestational ages of 11 through 13, 14 through 17, and 18 through 24 weeks; each measurement was performed twice. The pulsatility index (PI) was calculated for the left and right UA, and the results were averaged as a combined UA. In addition, the presence of UA bilateral notching was reported. Bland-Altman plots and generalized estimating equations were used to assess intraobserver variability and the longitudinal relationship between SA and UA blood velocities. RESULTS: A total of 284 UA and 263 SA Doppler flow measurements were analyzed. Intraobserver variability rates for the SA and UA were 0.54 and 0.90, respectively. Results showed a continuous decrease of the mean PI in the SA and UA with increasing gestational age. Uterine artery bilateral notching was reported in 35%, 9%, and 3% of the cases at gestational ages of 11 through 13, 14 through 17, and 18 through 24 weeks. Generalized estimating equation analysis showed a significant correlation (r = 0.41) between the SA and UA (P < .0001). CONCLUSIONS: Uterine artery Doppler measurements in early pregnancy seem to accurately reflect peripheral resistance of SAs. Furthermore, trophoblastic invasion seems a continuous process in the first half of pregnancy, in which early UA bilateral notching is a physiologic event.

Predicting pulmonary hypoplasia with 2- or 3-dimensional ultrasonography in complicated pregnancies.

OBJECTIVE: The aim of this study was to compare 3-dimensional (3D) lung volume measurements with 2-dimensional (2D) biometric parameters in predicting pulmonary hypoplasia in complicated pregnancies. STUDY DESIGN: In this prospective study, 1-4 scans of the fetal lungs were obtained in 33 pregnancies complicated by various disorders or complications with regard to pulmonary hypoplasia. The 3D lung volumes vs gestational age or estimated fetal weight, the thoracic circumference vs gestational age or femur length, the thoracic/abdominal circumference ratio, and the thoracic/heart area ratio were measured. RESULTS: Of the 33 infants, 16 (48.5%) were diagnosed with pulmonary hypoplasia on postmortem examination or the clinical and radiological presentation. Three dimensional lung volume measurements had a better diagnostic accuracy for predicting pulmonary hypoplasia (sensitivity, 94%; specificity, 82%; positive predictive value [PPV], 83%; negative predictive value [NPV], 93%), compared with the best 2D biometric measurement thoracic/heart area ratio (sensitivity, 94%; specificity, 47%; PPV, 63%; NPV, 89%). CONCLUSION: 3D lung volume measurements seem to be useful in predicting pulmonary hypoplasia prenatally.