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The two papers on fetal lung volume published in this issue of the journal highlight the intensified interest in measuring fetal lung volume following the introduction of three-dimensional (3D) ultrasound techniques. The reason for this is clear. The incidence being 1.1 per 1000 live births with a mortality rate of over 50%1, fetal lung hypoplasia poses a major diagnostic challenge. It is reasonable to assume that measurement of lung volume will signify a major step forward in the detection of fetal lung hypoplasia. But will it provide us with the complete picture? The crucial question to be addressed is whether we are dealing with a lethal or non-lethal form of fetal lung hypoplasia in a given case. For this purpose a positive predictive value (PPV) of 100% is needed.

Fetal lung size was initially estimated from two-dimensional (2D) ultrasound images. Measurements include lung area, lung circumference and lung length/diameter2–13. Lung length has been established in a plane through the long axis of the thorax from the superior end of the sternum to the level of the diaphragm or the inferior surface of the heart9 or from the apex to the base of the lung11. Others studied the ratio of lung area to head circumference (LHR)14–16, lung length to thoracic circumference12 and lung length × width to head circumference17, particularly relative to congenital diaphragmatic hernia. From the data reported so far, it appears that none of these biometric parameters is reliable enough to be applied in clinical management. In a recent study18, it was pointed out that the most reproducible method of measuring fetal lung area was by manual tracing of the limits of the lungs. Multiplication of the longest lung diameter by the longest perpendicular diameter turned out to be the least reliable method18. Also the biometric ratios fail to provide an acceptable prenatal prediction of lethal lung hypoplasia. Moreover, LHR increases exponentially with gestational age18, which is in contrast to the initial assumption that calculation of the LHR would minimize the effects of gestational age on lung size.

In another recent study19 it was assumed that the lung represents a geometrical pyramid. An equation was produced (surface area of right + left lung base [cm2] × 1/3 height of right lung [cm]), allowing 3D volume (mL) to be calculated from 2D measurements. It was proposed that this approach could serve as an alternative to 3D ultrasonography and magnetic resonance imaging (MRI). Data on sensitivity and specificity of this method in determining lung hypoplasia are not yet available. Moreover, lung hypoplasia is mostly associated with severe oligohydramnios or anhydramnios, which may alter the pyramidal shape of the lungs owing to outside compression of the thorax.

So, will 3D ultrasonography provide us with the ultimate solution? The introduction of 3D ultrasonography would allow for the assessment and correction of surface irregularities20. The more conventional 3D sonographic approach involves scrolling through one plane of the multiplanar display while delineating the lungs in a different plane. Alternatively, the VOCAL technique (Virtual Organ Computer-aided Analysis, General Electric Medical Systems) allows volume calculation around a fixed axis through a number of sequential steps21. Contradictory reports have appeared on the reliability and reproducibility of both techniques concerning volume measurements. Whereas in an in vitro setting, rotational measurements of volume proved to be superior to the conventional technique20, an in vivo study of fetal lung volume demonstrated that the rotational method with VOCAL was less reproducible than the common multiplanar technique21. On the other hand, Moeglin et al.19 found no statistically significant difference between lung volume values obtained using the two 3D ultrasound modes. Not only different 3D sonographic techniques, but also different methods for measuring fetal lung volume have been reported. Mainly in earlier work, fetal lung volume was obtained by subtracting fetal heart volume from thoracic volume19, 22, 23. The disadvantage of this approach is the inclusion of mediastinal structures (thymus, trachea, esophagus and great vessels) in the measurement of lung volume19. The lack of reproducibility of this indirect measurement limited its introduction into clinical practice.

Accuracy may be improved by direct determination of fetal lung volume, including separate measurement of the left and right lungs21, 24–28. Ruano et al.26 found that direct 3D sonographic estimates of fetal right and left lung volume using a rotational multiplanar technique were highly accurate when compared with postmortem measurements of lung volume achieved by water displacement.

In the two studies of fetal lung volume in this issue, one used the VOCAL technique28, while the other used a Technos MX (Esaote) ultrasound machine and a freehand scanning technique with a position sensor attached to the transducer27. As pointed out by Peralta et al.28, the advantage of the VOCAL technique is that the lower parts of the lung that extend below the dome of the diaphragm can be included and the contour of the lung in each plane can be modified to ensure a more accurate lung volume measurement.

Most reports on direct lung volume measurement by 3D ultrasonography provide a definition of the upper and lower border, e.g. the level of the clavicles and the dome of the diaphragm. This was the case in the study by Gerards et al.27 and was further highlighted by Peralta et al.28, who also emphasize the importance of defining the medial border of the lungs and distinction from the heart and mediastinal organs as well as the lateral border of the lungs and distinction from the thoracic cage.

Differences also exist in the design of published 3D sonographic fetal lung volume studies. Like the study by Peralta et al.28, most are cross-sectional. Some are longitudinal24, 29, including the study by Gerards et al.27, allowing references with respect to fetal lung growth. For the first time, fetal lung volumes have been determined as early as the first half of the second trimester of pregnancy28. In both papers published in this issue the technical problems encountered when measuring fetal lung volume in the third trimester of pregnancy are pointed out27, 28. This limitation has no real clinical implication, since clinical management in case of suspected lung hypoplasia is made before 30–32 weeks of gestation. Despite different ultrasound techniques and study designs employed in both studies27, 28, similar values for normal mean fetal lung volume were obtained, particularly in early pregnancy. Moreover, comparable differences were found for left vs. right lung volume. Lung volume data were more at variance at 30 weeks of gestation, with higher values in the study by Gerards et al.27. It is not clear whether this discrepancy is technique- or design-related. The gender-related difference (4.3%) in normal mean lung volume established by Gerards et al.27 is unlikely to be of clinical relevance when suspecting lung hypoplasia.

In addition to 3D ultrasonography, another imaging technique is increasingly attracting attention. In the last 6–7 years a number of interesting reports have appeared on MRI. The development of the single-shot rapid-acquisition with relaxation enhancement sequence, a rapid spin-echo-based T2 weighted sequence, has been a major step forward in fetal MRI30. Well-defined fetal MRI images with fewer motion artifacts can be obtained without the need for fetal immobility30, 31. On MRI the fetal lungs are well depicted on T2-weighted images29, 32. Fast-spin echo T2-weighted MR images of the fetal thorax provide a well-defined contrast between lung parenchyma and surrounding structures, which include the trachea, esophagus, diaphragm and thoracic wall structures33. The accurate delineations of the boundaries of the fetal lungs resulted in a good interobserver agreement for fetal lung volume measurements, with MRI results showing a difference of less than 10% from lung volumes established at postmortem examination33. Moreover, the MR signal intensity of the fetal lung is a good indicator of fetal lung maturation34. MRI has been shown to be helpful in determining ipsilateral lung volume in cases of congenital diaphragmatic hernia34. Sheep experiments have demonstrated that axially-measured fetal lung volumes were more accurate than those obtained in the coronal or sagittal plane35. MRI values appear to be consistently higher than ultrasound values in most studies on fetal lung size.

Is there a preference for MRI or 3D ultrasonography concerning fetal lung volume measurements? 3D ultrasonography has the advantage of cost-effectiveness, ease and speed of use and patient acceptability27. On the other hand, optimal 3D ultrasound resolution may not always be possible owing to fetal position, oligohydramnios, maternal obesity, fetal cardiac activity and fetal (breathing) movements. The accurate delineation of the contour of the lung may be hampered because of reduced differentiation between fetal lung and liver. Further studies comparing the two imaging modalities are needed to establish whether there is a preference for one of the techniques or whether they complement each other.

Assuming that accurate fetal lung volume measurements can be obtained in both normal and pathological circumstances, will these measurements suffice in detecting lethal pulmonary hypoplasia? We know that prolonged and pronounced oligohydramnios, particularly during the canalicular phase of lung development (from 18 to 26 weeks of gestation), may cause a delay or even an arrest in pulmonary vascular development, resulting in reduced lung volume and raised pulmonary vascular resistance36, 37. Doppler velocimetry of the fetal arterial lung circulation has shown that peak systolic velocity (PSV) in the proximal pulmonary artery flow velocity waveform is reduced in lethal lung hypoplasia38. Nevertheless, as a single test it turned out not to be reliable enough for clinical application. A combination of clinical (onset, duration, degree of oligohydramnios), biometric (thoracic to abdominal ratio) and Doppler (PSV in proximal lung artery) parameters demonstrated a PPV of 100%, an overall accuracy of 93% and a sensitivity of 71%38. Again, the clinical significance of this combined test is limited as a result of the restrictions in obtaining the necessary components of it and the low sensitivity of the combination38. In three other studies a raised pulsatility index (PI) in the arterial lung circulation was found in a substantial number of fetuses that had developed lung hypoplasia39–41. Of interest is the non-reactivity of the flow pattern in the fetal proximal pulmonary artery during exposure to maternal breathing, by mask, of 60% oxygenated air42. This test, with a PPV of 79%, a sensitivity of 92% and a specificity of 82%, seems quite promising. A different approach was taken by Fuke et al.43, who found the acceleration time/ejection time ratio in the fetal pulmonary arterial flow velocity waveform to be reduced in the presence of lung hypoplasia. The number of fetuses studied, however, was small.

Altogether, it can be said that changes have been established in the fetal pulmonary artery waveforms in association with developing lung hypoplasia. Although promising, a well-defined and reliable circulatory test to predict lethal lung hypoplasia has not emerged so far.

In summary, the reference data on normal fetal lung volumes in the two well-designed studies27, 28 in this issue of the journal should be further tested with regard to their prediction of lung hypoplasia. As pointed out in an earlier opinion by Deprest et al.44 in this journal, it may take more than only 3D sonographic or MRI lung volume measurements to enable us to reliably and reproducibly predict gestational lung function. It would be of interest to see whether Doppler interrogation of the fetal lung circulation will produce an independent test which, in combination with lung volume measurements, becomes a clinically acceptable predictor of fetal lung hypoplasia.

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