Erroneous production of PAPP-A kits: the impact of a downward shift in PAPP-A concentration on the test performance of first-trimester combined screening for Down syndrome.

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 ≤ 1:200 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.

Behavior-state-dependent changes in human fetal pulmonary blood flow velocity waveforms.

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.

[Prenatal investigations for Down's syndrome: medical-technical considerations and dilemmas arising from current screening methods]. / Prenataal onderzoek naar downsyndroom: medisch-technische overwegingen en dilemma's voortkomend uit de huidige toepassingsmogelijkheden.

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.

The fetal lung. 1: Developmental aspects.

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.

The fetal lung. 2: Pulmonary hypoplasia.

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.

Human fetal pulmonary artery velocimetry: repeatability and normal values with emphasis on middle and distal pulmonary vessels.

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.

Doppler velocimetry in branch pulmonary arteries of normal human fetuses during the second half of gestation.

The objective of the present study was to determine the characteristics of Doppler flow velocity wave forms in branch pulmonary arteries in relation to gestational age. A total of 111 singleton normal pregnancies were studied during the second half of pregnancy using a combined color-coded Doppler and two-dimensional real-time ultrasound system. Pulsed Doppler measurements of the most proximal branch of the right or left pulmonary artery were attempted during fetal apnea from a transverse cross-section of the fetal chest at the level of the cardiac four-chamber view after visualization with color Doppler. The success rate in obtaining the pulmonary arterial wave form was 85%. The wave form displayed a rapid systolic velocity acceleration, followed by an initially rapid but then more gradual velocity deceleration which was interrupted in most cases by a short reversed flow interval at the beginning of the diastolic phase of the cardiac cycle. The diastolic phase was characterized by forward flow. Peak systolic, end-diastolic and time-averaged velocity, pulsatility index, and systolic integral remained constant during gestation. Changes in vessel diameter or compliance may play a role in this. A gestational age-dependent rise was established for peak diastolic velocity, diastolic integral, and early peak diastolic reverse flow, whereas a gestational age-determined decline was found for the peak systolic/peak diastolic ratio. Fetal heart rate demonstrated a statistically significant increase relative to gestational age. However, the observed relation between the flow velocity wave form parameters, pulsatility index calculations, and gestational age was independent of fetal heart rate. It is speculated that peak diastolic velocity, diastolic integral, and peak systolic/peak diastolic ratio rather than the pulsatility index are useful in detecting gestational age-related changes in human fetal pulmonary vascular resistance.

Normal fetal pulmonary venous blood flow velocity.

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.

Fetal pulmonary venous flow into the left atrium relative to diastolic and systolic cardiac time intervals.

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.

Doppler velocimetry of normal human fetal venous intrapulmonary branches.

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 inter-pulmonary changes.

Three-dimensional ultrasonography of normal fetal lung volume: a preliminary study.

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.

Doppler ultrasound imaging: a new technique to detect lung hypoplasia before birth?

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.

Congenital diaphragmatic hernia: an evaluation of the prognostic value of the lung-to-head ratio and other prenatal parameters.

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, 1-1.4, >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 <1. An intrathoracic position of the stomach, mediastinal shift, polyhydramnios as individual variables and early diagnosis (<25 weeks' gestation) revealed to be poor sonographic predictors for fetal outcome. CONCLUSION: LHR proved to be a good predictor for fetal outcome, independent of gestational age at the time of the measurement. To substantiate our observation, a prospective multicenter study is warranted.

Fetal liver volume measurement by three-dimensional ultrasonography: a preliminary study.

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 < 0.00001). 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.

Early transvaginal ultrasonographic diagnosis of Beemer-Langer dysplasia: a report of two cases.

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.