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Objective To evaluate a 20% downward shift in the pregnancy-associated plasma protein A (PAPP-A) concentration on the test performance of first-trimester combined screening (FTS) for Down syndrome (DS) following a flaw in the production of PAPP-A kits on FTS for DS. Methods A retrospective re-evaluation of PAPP-A in stored sera. Inclusion criteria were a maternal weight-corrected PAPP-A multiple of the median value ≥ 0.9 and a biochemical risk of DS at the time of testing. Results Of the 3100 women, 473 (15%) fulfilled the inclusion criteria. After combining the biochemical risk based on the incorrect PAPP-A values with nuchal translucency findings, an increased risk for DS was initially found in 107 women [false positive rate (FPR): 3.1]. Eighty-two (77%) of the 107 women opted for invasive testing. Following re-analysis of PAPP-A, the biochemical risk and the combined risk were statistically significantly different from the initial risk estimates (p < 0.001.). We noticed that 25 women (30%) had invasive testing, while this was unjustified given the re-analysed PAPP-A. Conclusion Erroneous PAPP-A kits resulted in an increase in the FPR by 1.2%. There were no reports of iatrogenic miscarriage. The occurrence of this problem reaffirms the importance of continuous monitoring of quality in FTS. Copyright © 2011 John Wiley & Sons, Ltd.

Objectives A retrospective analysis of the prognostic significance of the lung-to-head ratio (LHR) and other prenatal parameters on the outcome of fetuses with left-sided congenital diaphragmatic hernia (CDH). Methods A total of 26 fetuses with isolated left CDH without chromosomal abnormalities were included. Twenty-one LHR measurements could retrospectively be calculated from the last available ultrasonographic recordings before birth. The relationship between LHR and fetal outcome and the gestational age dependency of this relation was tested. Cutoff levels as previously published were applied to determine their predictive value in this population. The association between other prenatal predictive variables and fetal outcome was also determined. Survival was defined as discharge from the hospital. Results The overall survival rate was 50%. There was a statistically significant difference between the mean LHR of the survivors compared to the mean LHR of the nonsurvivors (1.78 vs 1.02), whereas the mean gestational age of these two groups did not differ. LHR was not gestational age dependent in the prediction of fetal outcome. The cutoff levels LHR 1.4 showed a good applicability in the prediction of fetal outcome within the present study population with a 100% survival if LHR >1.4 and a 100% mortality if LHR

To establish reproducibility and normal values for fetal hepatic volume and its significance in identification of fetal growth restriction relative to head and upper abdominal circumferences according to a cross-sectional study design.Pregnant women (n = 135) underwent ultrasonography. The coefficient of variation (CV) for hepatic volume scans obtained at 0 and 20 minutes and hepatic area tracings, performed twice for each scan, was determined (n = 20; range, 23-36 weeks). Normal data for hepatic volume and head and upper abdominal circumferences were obtained (n = 85; range, 20-36 weeks) and related to data from growth-restricted fetuses (birth weightP5 centile; n = 24; range, 22-36 weeks).CV was 2.9% for volume scans and 1.6% for area tracings. In 85 uncomplicated cases, mean fetal hepatic volume (P50 centile) was 9.7 mL +/- 4.4 (SD) at 20 weeks and 96.4 mL +/- 8.2 at 36 weeks of gestation. In 24 growth-restricted fetuses, hepatic volume, head circumference, and upper abdominal circumference expressed as percentages of the normal P50 centile were 45%, 90%, and 82%, respectively. Mean difference in hepatic volume between fetal growth restriction and normal fetal development, as expressed with the z score, -4.32 +/- 1.4, was significantly different (P.05) from that for head circumference, -3.04 +/- 1.3, but not from that for upper abdominal circumference, -4.7 +/- 1.2. Fetal hepatic measurement was obtained in 109 pregnancies.Acceptable reproducibility exists for hepatic volume determinations. In fetal growth restriction, reduction is more pronounced for hepatic volume than for head or upper abdominal circumference; hepatic volume is a better discriminator than head circumference but not upper abdominal circumference.

This review describes the pathogenesis of pulmonary hypoplasia and highlights its clinical, radiological and pathologic features, with emphasis on oligohydramnios-related pulmonary hypoplasia. Since pulmonary hypoplasia may lead to severe respiratory distress immediately after birth and even to neonatal death, an accurate and patient-friendly prenatal test for early detection and distinction between lethal and non-lethal pulmonary hypoplasia is still highly desirable. An extended overview of the proposed methods for the prenatal prediction of pulmonary hypoplasia is presented.

A literature survey is presented on normal fetal development during the embryonic, pseudoglandular, canalicular, saccular and alveolar stages in the human fetus. Normal anatomical and physiological aspects of fetal lung development including the fetal pulmonary circulation are described. Factors which may influence fetal lung growth and consequently may play a role in the development of pulmonary hypoplasia are discussed, such as intrauterine and intrathoracic space, lung fluid, fetal breathing movements, normal balance of volume and pressure in the lung and interference with the blood supply.

Objectives To establish the nature and gestational age dependency of flow velocity waveforms from fetal middle and distal arterial pulmonary branches in the second half of normal pregnancy and to determine repeatability and inter–relationship of flow velocity waveform recordings from proximal, middle and distal arterial pulmonary branches. Design Cross-sectional study. Subjects/methods A total of 111 singleton normal pregnancies between 20 and 40 weeks of gestation were studied using a color-coded Doppler ultrasound system. Pulmonary waveforms were obtained at the level of the fetal cardiac four-chamber view. Repeatability was tested from two recordings at 15 min time-intervals in 25 separate normal pregnancies. Results Acceptable repeatability of flow velocity waveforms from fetal arterial pulmonary branches was established with coefficients of variation below 15%. The nature of middle arterial pulmonary flow velocity waveforms was similar to that of proximal waveforms and showed a gestational age-related change for diastolic velocity parameters, peak systolic/peak diastolic ratio and pulsatility index. The distal arterial pulmonary branch displayed a monophasic forward flow velocity profile throughout the cardiac cycle. All velocity parameters of the distal branch remained unchanged with advancing gestation, with the exception of the pulsatility index. Significant inter–pulmonary changes were found for all pulmonary arterial waveform parameters. Conclusions Alteration in pulmonary vascular resistance may play a role in gestational age-related changes, whereas changes in vessel branching/diameter and in the distance between the heart and more distal arterial pulmonary vessels may cause inter–pulmonary differences. Copyright © 2000 International Society of Ultrasound in Obstetrics and Gynecology

Objectives To describe the nature of flow velocity waveforms from fetal middle and distal venous pulmonary branches in the second half of normal pregnancy in relation to gestation, and to test repeatability and interrelationships of flow velocity waveform recordings from proximal, middle and distal venous pulmonary branches. Design Cross-sectional study. Subjects/methods A total of 111 normal singleton pregnancies between 20 and 40 weeks’ gestation were studied using a color-coded Doppler ultrasound system. Pulmonary waveforms were obtained at the level of the fetal cardiac four-chamber view. Repeatability was tested from two recordings at 15-min time intervals in 25 separate normal pregnancies. Results The nature of middle and distal venous pulmonary flow velocity waveforms was comparable with that of proximal waveforms. Acceptable repeatability of pulmonary venous flow velocity waveforms with coefficients of variation below 15% was established for nearly all velocity parameters and their ratios. A gestational age-dependent change was found for all flow velocity waveform parameters including pulsatility index for veins at both middle and distal venous levels. Significant inter-pulmonary changes were observed for nearly all pulmonary venous waveform parameters. Conclusions It is speculated that increase in volume flow and venous pulmonary pressure gradient plays a role in gestational age-dependent changes, whereas changes in vessel diameter and distance between the heart and more distal venous pulmonary vessels are responsible for interpulmonary changes.

Objective To establish the nature and gestational age dependency of the pulmonary venous flow velocity pattern into the left atrium relative to systolic and diastolic phases of the cardiac cycle. Design This was a cross-sectional study of Doppler measurements of fetal pulmonary venous inflow velocities, which were correlated with simultaneous recordings of transmitral and aortic flow velocity waveforms based on an equal cardiac cycle length (±5%). Results Successful recordings were obtained in 28 out of 60 (47%) normal singleton pregnancies at 20–36 weeks of gestation. Reproducibility of waveform analysis of the various phases of the cardiac cycle was satisfactory, within-patient variance ranging between 1.7% and 6.5%. A statistically significant increase (p < 0.05) in pulmonary venous time average velocity and velocity integral with advancing gestational age was established. A statistically significant increase (p < 0.05) of the pulmonary flow velocity integral was also found when related to each of the systolic and diastolic segments of the cardiac cycle, with the exception of isovolemic relaxation time. The duration of each of the diastolic and systolic segments of the cardiac cycle, as well as the pulmonary venous velocity integral expressed as a percentage of the cardiac cycle, remained constant with advancing gestational age. Conclusions The second half of pregnancy is characterized by pulmonary venous inflow into the left atrium throughout the cardiac cycle. Pulmonary venous inflow into the left atrium occurs predominantly during the filling and ejection phases of the cardiac cycle. Absolute cardiac diastolic and systolic time intervals as well as the percentage distribution of pulmonary venous flow velocity integrals between these cardiac time intervals remain unchanged with advancing gestational age. Copyright © 1999 International Society of Ultrasound in Obstetrics and Gynecology

Objective: To establish the influence of fetal behavior states on venous and arterial pulmonary blood flow velocity waveforms in the normally developing term fetus. Methods: The relation between venous and arterial pulmonary blood flow velocity waveforms and fetal behavior states was investigated in 18 normal term fetuses. Recordings of the venous pulmonary blood flow velocity waveforms were obtained just proximal to the entrance in the left atrium, and the arterial pulmonary blood flow velocity waveforms were taken from the most proximal branch of the pulmonary artery in the same lung using color Doppler imaging. Time-averaged peak systolic, peak diastolic, and end-diastolic flow velocity; peak systolic to peak diastolic ratio; pulsatility index; and fetal heart rate were calculated from both venous and arterial Doppler recordings obtained during behavior states 1F (quiet sleep) and 2F (active sleep). Fetal behavior states were determined from combined recordings of fetal eye and body movements. Results: Recordings of sufficient quality for analysis were obtained from ten fetuses. Venous pulmonary blood flow velocity waveforms demonstrated a statistically significant increase in time-averaged peak diastolic and end-diastolic velocity during fetal behavior state 2F. No behavior-state-related changes were observed for the arterial pulmonary blood flow velocity waveform. Conclusion: The data suggest an increased pressure gradient between the pulmonary venous system and the left atrium during behavior state 2F. Flow velocity waveforms from the proximal arterial pulmonary branch are independent of behavioral state.

Objective To establish the application of three-dimensional ultrasonography in measuring fetal liver volume during the second half of normal pregnancy. Design A prospective cross-sectional study of normal fetal liver volume at 19–39 weeks of gestation (median 29 weeks). Subjects Thirty-four non-smoking women with a singleton pregnancy resulting in the delivery of a healthy infant with a birth weight between the 5th and 95th centiles according to the Kloosterman tables adjusted for maternal parity and fetal sex. Methods For fetal liver volume measurements, a simultaneous recording of a frontal section of the liver immediately anterior to the stomach and a sagittal section of the liver were obtained using a standard Combison 530 ultrasound machine with a 5-MHz annular array transducer for volume scanning. Results Technically acceptable fetal liver volume measurements were obtained in 25 of 34 participating women. Mean fetal liver volume data (P50) ranged between 8 ml at 20 weeks’ gestation and 116 ml at 38 weeks’ gestation. A statistically significant increase in normal fetal liver volume was found with advancing gestational age (p < 0.0001) and with increasing estimated fetal weight (p < 0.0001). Conclusions Three-dimensional ultrasound allows measurement of fetal liver volume, and this demonstrated an approximately 14-fold increase during the second half of pregnancy. It is speculated that three-dimensional fetal liver volume measurement may identify the fetus at risk of growth restriction.

The early second-trimester sonographic diagnosis of two infants with short rib (polydactyly) dysplasia type IV (Beemer-Langer dysplasia) is presented. In addition to short ribs, this syndrome is characterized by short limbs with or without polydactyly. There are often associated defects, particularly neural tube anomalies. The occurrence of consanguinity and of four affected siblings in this family support autosomal recessive inheritance. Copyright © 1998 International Society of Ultrasound in Obstetrics and Gynecology

The objective of this preliminary study was to evaluate three-dimensional ultrasonographic lung volume measurement in the normally developing fetus in the second half of pregnancy. Total fetal lung volume was determined by subtraction of fetal heart volume from thoracic volume, using the perpendicular transverse, sagittal and frontal planes of the fetus. Technically acceptable lung volume measurements were obtained in 29 out of 34 women with an uncomplicated pregnancy. A statistically significant increase in normal fetal lung volume was established with advancing gestational age and with increasing fetal estimated weight, demonstrating an approximately seven-fold rise in fetal lung volume during the second half of pregnancy. Three-dimensional ultrasonography can be applied for estimation of fetal lung volume. Whether this technique is useful in the prenatal prediction of pulmonary hypoplasia remains to be determined.

Combined color-coded Doppler and pulsed Doppler ultrasonography allows visualization of the fetal pulmonary circulation and study of pulmonary blood flow velocity waveforms. Systolic and diastolic changes were observed in fetal pulmonary artery flow velocity waveforms in a case of fetal pulmonary hypoplasia at 34 weeks of gestation. This observation supports our hypothesis that Doppler velocimetry can detect lung hypoplasia based on post- mortem examination of decreased total size of the pulmonary vascular bed, decreased number of pulmonary vessels per unit lung tissue and increased pulmonary vascular muscularization.

Our objectives were to describe the normal pulmonary venous blood flow velocity waveform and to establish reference ranges for the second half of pregnancy in healthy human fetuses. A total of 123 women with uncomplicated pregnancies of between 20 and 40 weeks were examined, using a combined color-coded Doppler and two-dimensional real-time ultrasound system. Pulsed Doppler flow velocity waveforms of pulmonary venous drainage into the left atrium were obtained from a transverse cross section of the fetal chest at the level of the cardiac four-chamber view. All waveforms were obtained during fetal apnea. The success rate in obtaining the pulmonary venous waveform was 81%. The waveform displayed a biphasic forward flow profile with a systolic and diastolic component. Peak systolic, peak diastolic and time-averaged velocities demonstrated a gestational age-related rise, whereas the peak systolic/peak diastolic ratio showed a gestational age-related reduction. The nature of the fetal pulmonary venous flow velocity waveform pattern suggests positive pressure towards the left atrium throughout the cardiac cycle. We speculate that an increase in volume flow and the pulmonary venous pressure gradient play a role in the gestational age-related changes in pulmonary venous flow velocities. Copyright © 1995 International Society of Ultrasound in Obstetrics and Gynecology

To evaluate a 20% downward shift in the pregnancy-associated plasma protein A (PAPP-A) concentration on the test performance of first-trimester combined screening (FTS) for Down syndrome (DS) following a flaw in the production of PAPP-A kits on FTS for DS.A retrospective re-evaluation of PAPP-A in stored sera. Inclusion criteria were a maternal weight-corrected PAPP-A multiple of the median value ≥ 0.9 and a biochemical risk of DS ≤ 1:200 at the time of testing.Of the 3100 women, 473 (15%) fulfilled the inclusion criteria. After combining the biochemical risk based on the incorrect PAPP-A values with nuchal translucency findings, an increased risk for DS was initially found in 107 women [false positive rate (FPR): 3.1]. Eighty-two (77%) of the 107 women opted for invasive testing. Following re-analysis of PAPP-A, the biochemical risk and the combined risk were statistically significantly different from the initial risk estimates (p0.001.). We noticed that 25 women (30%) had invasive testing, while this was unjustified given the re-analysed PAPP-A.Erroneous PAPP-A kits resulted in an increase in the FPR by 1.2%. There were no reports of iatrogenic miscarriage. The occurrence of this problem reaffirms the importance of continuous monitoring of quality in FTS.

Prenatal investigations can be divided into specific diagnostic investigations i.e. chorionic villus sampling, amniocentesis and selective ultrasonography for the detection of fetal abnormality, and screening tests which estimate the chances of the condition being present. These include routine ultrasonography and tests based on biochemical and echoscopic markers. Amniocentesis is the most reliable test to detect chromosomal anomalies, but is associated with a low risk of miscarriage and the results are known only relatively late in pregnancy. Implementing the prenatal screening tests will enable the better identification of those women with an increased risk of chromosomal anomalies, and consequently to fewer invasive diagnostic procedures. The choice whether to have prenatal screening should always be made by the parents after they have been told of the advantages and disadvantages of these investigations.

Pulmonary hypoplasia, an expression of delayed lung development, is most often a result of prolonged oligohydramnios after premature rupture of membranes (PROM) or renal or urinary tract malformation. Severe respiratory distress and neonatal death are possible consequences. A practical and accurate prenatal test for detecting this condition and distinguishing between lethal and nonlethal lung hypoplasia (LH) is still needed. Fetal two-dimensional biometric indices are late indicators of LH that are insufficiently accurate. Autopsy findings of an underdeveloped and structurally altered pulmonary vascular bed prompted a study to show whether recording Doppler flow velocity waveforms from fetal pulmonary arterial branches when prolonged oligohydramnios is present can predict lethal LH. Forty-two women with singleton pregnancies and prolonged oligohydramnios (31 cases) or bilateral renal disease (11 cases) underwent cross-sectional, color-coded Doppler ultrasonography at a gestational age of 20 to 36 weeks (mean, 28 weeks). Thoracic, cardiac, and abdominal circumferences and the largest vertical amniotic fluid pocket were measured. Pulsed Doppler measurements of pulmonary artery branches were made on the cardiac four-chamber view. Membrane rupture began at a mean of 23 weeks' gestation and lasted a mean of 8 weeks. Real-time ultrasonography and Doppler studies were done using a unit with combined transabdominal real-time, color, and pulsed Doppler imaging facilities. Mortality from LH was 43% in this series. Nine of the 18 deaths due to LH were associated with PROM, and 9 with renal pathology. All 11 infants with renal disease died, as did 39% of the group with PROM. Seven of nine fetuses in this group died within 24 hours of birth, a majority of them within the first hour. Severely affected infants never achieved adequate oxygenation despite vigorous artificial ventilation with pure oxygen. Histopathologic evidence of intrauterine infection was noted in 11 cases in the PROM group. Lethal LH was most accurately predicted by an onset of PROM at 20 weeks or earlier, oligohydramnios lasting 8 weeks or longer, and oligohydramnios of 1 cm or less. These factors combined were 87% accurate in predicting LH, with a positive predictive value of 86%. For all cases together and for the PROM subgroup, overall accuracy in predicting lethal LH was highest for the ratio of thoracic to abdominal circumference, peak systolic velocity in the proximal branch, and time-averaged and end-diastolic velocity in the middle branch of the pulmonary artery. Combining the clinical, biometric, and Doppler findings proved 93% accurate in predicting lethal LH, with a positive predictive value of 100% and sensitivity of 71%. Adding Doppler velocimetry to clinical and biometric features enhances the ability to predict lethal LH. Predictive ability is best in cases of PROM, but sensitivity is disappointingly low.

Objective To investigate the potential value of antenatally determined intrathoracic herniation of the liver and the ratio of fetal lung area to head circumference (LHR) in the prediction of postnatal survival in isolated, left-sided congenital diaphragmatic hernia (CDH). Methods In this multicenter study, we searched the antenatal-CDH-Registry for fetuses with isolated leftsided CDH that were liveborn after 30 weeks of gestation and were followed up postnatally for at least 3 months after discharge from hospital. The patients were subdivided into those with and those without intrathoracic herniation of the liver and into subgroups according to the LHR that had been measured between 22 + 0 and 28 + 0 weeks of gestation. The rate of survival in each group and subgroup of patients was determined and compared. Results The registry search identified 184 patients that fulfilled the entry criteria. Logistic regression analysis demonstrated that significant predictors of survival were the presence or absence of intrathoracic herniation of the liver and the LHR. In 86 cases there was liver herniation (Group A) and in 98 the liver was confined to the abdomen (Group B). In Group A, the survival rate was 50.0% and was significantly associated with LHR; in Group B the survival rate was 76.5% and was unrelated to LHR. Conclusion In isolated, left-sided CDH, the postnatal mortality rate is substantially higher if there is intrathoracic herniation of the liver. In fetuses with liver herniation, measurement of LHR at 22–28 weeks of gestation is useful in the prediction of subsequent survival. Copyright  2005 ISUOG. Published by John Wiley & Sons, Ltd.

Objectives To determine the value of Doppler flow velocity waveforms from the fetal arterial pulmonary branches relative to fetal biometric indices and clinical correlates in the prenatal prediction of lethal lung hypoplasia (LH) in prolonged oligohydramnios. Study design 42 singleton pregnancies with oligohydramnios associated with premature rupture of membranes (PROM, n = 31) or bilateral renal pathology (n = 11) were examined using a combined color coded Doppler and 2d real-time ultrasound system. Thoracic (TC), cardiac (CC) and abdominal circumference (AC) and the largest vertical amniotic fluid pocket were measured. Pulsed Doppler measurements of the arterial pulmonary branches were made at the level of the cardiac four-chamber view after visualization with color Doppler. Diagnosis of LH was based on pathological, clinical and radiological criteria. Results The prevalence of lethal LH was 43%. In the PROM-subset, combination of onset of PROM = 20 weeks; duration of oligohydramnios = 8 weeks and degree of oligohydramnios = 1 cm, presented the highest clinical prediction rate for lethal LH. For both the total group and the PROM-subset, the highest prediction rate for lethal LH from biometric and Doppler parameters was presented by TC/AC ratio, peak systolic velocity in the proximal branch and time-averaged and end-diastolic velocity in the middle branch of the pulmonary artery. In the prom subset, combination of all three clinical, biometric and Doppler parameters revealed the most favorable combination to predict lethal LH (PPV 100%, accuracy 93%, and sensitivity 71%). Conclusion Doppler velocimetry may detect changes in blood velocity waveforms from the arterial branches of the fetal pulmonary circulation in the presence of LH, but fails to be the ultimate test for the prenatal prediction of lethal LH. The best prediction can be achieved by combining clinical, biometric and Doppler parameters.

Background To establish reproducibility and normal values for fetal liver volume and its significance in identifying fetal growth restriction relative to head (HC) and abdominal circumference (AC) according to a cross-sectional study design. Method The measurements were obtained using a Voluson 530-D for volume scanning. The coefficient of variation (CV) for liver volume scans (t0, t20 min) and liver area tracings (t0: 2x; t20: 2x) was determined (n: 20; 23–36 weeks). Normal charts for liver volume, HC, AC were constructed (n: 60; 22–37 weeks) and related to data from growth-restricted fetuses (birthweight