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Fetal lung volume after endoscopic tracheal occlusion in the prediction of postnatal outcome
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Fetal lung volume after endoscopic tracheal occlusion in the prediction of postnatal outcome Cleisson F. A. Peralta, MD, PhD; Jacques C. Jani, MD; Dominique Van Schoubroeck, MD; Kypros H. Nicolaides, MD; Jan A. Deprest, MD, PhD OBJECTIVE: The objective of the study was to investigate the volume response of the contralateral lung in the prediction of postnatal outcome in fetuses with congenital diaphragmatic hernia (CDH) treated by fetoscopic endotracheal occlusion (FETO).
after FETO, the lung volume increased to above the 2.5th percentile in 14/21 (66%) that survived, compared with 1/9 (11%) that died. The respective percentages at 7 days after FETO were 95% and 11%, respectively.
STUDY DESIGN: In 30 fetuses with isolated severe CDH that underwent FETO, the volume of the contralateral lung was measured by 3-dimesional ultrasound the day before and 2 and 7 days after FETO. The measurements of fetuses that subsequently died were compared to those who survived.
CONCLUSION: In fetuses with CDH, the lung responsiveness within 2 and 7 days after FETO provides useful prediction of subsequent survival.
RESULTS: In all fetuses before FETO, the lung volume was below the
2.5th percentile of the normal range for gestation (60%). Within 2 days
Key words: diaphragmatic hernia, fetal lung volume, fetoscopic endotracheal occlusion, 3-dimensional ultrasound, virtual organ computer-aided analysis
Cite this article as: Peralta CFA, Jani JC, Van Schoubroeck D, et al. Fetal lung volume after endoscopic tracheal occlusion in the prediction of postnatal outcome. Am J Obstet Gynecol 2008:198:60.e1-60.e5.
I
solated congenital diaphragmatic hernia (CDH) is associated with a high postnatal mortality because of pulmonary hypoplasia and/or pulmonary hypertension because of chronic intrathoracic compression of the lungs by the herniated abdominal viscera.1,2 It has been demon-
From the Departments of Obstetrics and Gynecology, Fetal Medicine Units, King’s College Hospital, London, United Kingdom (Drs Peralta and Nicolaides), and University Hospital Gasthuisberg, Leuven, Belgium (Drs Jani, Van Schoubroeck, and Deprest). Received Nov. 19, 2006; revised March 10, 2007; accepted May 22, 2007. Supported in part by the European Commission within the 5th (QLG1 CT2002 01632; EuroTwin2Twin) and the 6th Framework Programme (EuroSTEC; LSHCCT-2006-037409) as well as by the Fetal Medicine Foundation (Registered Charity 1037116). Reprints: Professor K. H. Nicolaides, Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital Medical School, Denmark Hill, London SE5 8RX, United Kingdom. 0002-9378/$34.00 © 2008 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2007.05.034
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strated that when the measurement of the lung area to head circumference ratio (LHR) is below 1.0 and the liver is herniated into the chest, the prognosis is extremely poor, with a postnatal survival rate of ⬍ 10%.3,4 In such cases, survival may be improved from ⬍ 10% to ⬎ 50% by fetoscopic endotracheal occlusion (FETO) with a detachable balloon, which is associated with increase in fetal lung size.5,6 Three-dimensional (3D) ultrasound has enabled the measurement of fetal lung volume in both normal and pathological pregnancies.7-10 In a study of 650 normal fetuses, we established reference intervals for both the left and right lung volumes, from 12-32 weeks’ gestation.9 In another study of 42 fetuses with CDH, we demonstrated that the volume of the contralateral lung to the herniated viscera was about 40% of the average lung volume of normal fetuses; the ipsilateral lung was also much smaller than normal (15%), but in 35% of patients, it could not be adequately identified.10 The aim of this study was to investigate whether in fetuses with severe CDH treated by FETO an increase in volume could be demonstrated and, if so, if the
American Journal of Obstetrics & Gynecology JANUARY 2008
degree of volume response was predictive of postnatal outcome.
M ATERIALS AND M ETHODS This was a prospective ongoing multicenter study of patients with severe CDH treated with FETO.3 In all cases, the patients were assessed and received counseling by a multidisciplinary team composed of fetal medicine specialists, neonatologists, and pediatric surgeons. The study was approved by the local ethics committees and/or Committee on Innovative Technologies, and all patients gave written informed consent to the procedure. The inclusion criteria for FETO were the presence of isolated CDH with an LHR below 1.0 and the liver herniated into the chest.3,4 The calculation of the LHR was obtained by the division of the lung area (mm2) by the head circumference (mm). The lung area was measured as described by Metkus et al3 by the multiplication of the longest diameter of the lung by its longest perpendicular diameter. The inclusion criteria for the present 3D study were first, consecutive cases of CDH treated by FETO before 28 weeks’ gestation with available 3D ultrasound measurements of the fetal
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A 2-sided P ⬍ .05 was considered statistically significant.
FIGURE 1
Measurement of the right lung volume
R ESULTS
Measurement of the right lung volume using the rotational technique (VOCAL) in a fetus with left-sided diaphragmatic hernia. The picture on the left represents the starting plane of rotation of the lung and includes its biggest anteroposterior diameter. The picture in the middle represents the transverse view of the lung after drawing of the contours in the 6 consecutive rotational planes. The picture on the right is the final right lung volume. Peralta. Fetal lung volume after FETO and postnatal outcome. Am J Obstet Gynecol 2008.
lungs before and during the first week after the procedure, and second, live birth after 32 weeks’ gestation with no major defect and either postnatal survival at discharge from the hospital or postnatal death because of pulmonary hypoplasia and/or hypertension. The volume of the contralateral lung to the CDH was measured using 3D ultrasound on 3 different occasions: the day before FETO, 2 days after FETO, and 7 days after FETO. For each lung measurement, several 3D volumes of the fetal chest were acquired by transabdominal sonography (RAB 4-8L probe, Voluson 730 Expert, GE Medical Systems, Milwaukee, WI) and the volumes with the best image quality (allowing clear identification of the landmarks: the diaphragm, the apex of the lung, and its lateral and medial limits) were chosen for analysis. During the acquisition of the volumes, our aim was that the fetus was not moving and was preferably facing toward the transducer. The sweep angle was set from 40°-85°, depending on the gestational age. The virtual organ computeraided analysis (VOCAL) technique was used to obtain a sequence of 6 sections of each lung around a fixed axis, from the apex to the base, each after a 30° rotation from the previous one (Voluson 730 Expert operation manual, GE Medical Systems). The contour of the contralateral lung was drawn manually in the 6 differ-
ent rotation planes to obtain the 3D volume measurement. The starting plane of rotation for the lung included its biggest anteroposterior diameter. Every measurement was done off-line after the scan (Figure 1).
Statistical analysis Each lung volume measurement was expressed as a percentage of the appropriate mean for gestation (observed/expected lung volume times 100), previously established from the study of 650 normal fetuses at 12-32 weeks.9 The data from the study of normal fetuses were also expressed as percentages of the expected mean for gestation, and the 95% confidence intervals for these values were calculated, for the left and the right lungs. The Mann–Whitney U test was used to compare fetuses that died with those who survived with regard to the gestational age at FETO, the gestational age at the removal of the balloon, the gestational age at delivery, and the lung volumes on the 3 different occasions. Receiver operating characteristic (ROC) curve was constructed for the lung volumes expressed as percentages of the normal mean for each of the 3 evaluations in the prediction of survival. The data were analyzed using the statistical software SPSS 13.0 (SPSS Inc, Chicago, IL) and Excel for Windows 2000 (Microsoft Corp, Redmond, WA).
During the study period, from April 2002-May 2006, FETO was performed in 58 fetuses with isolated CDH, intrathoracic herniation of the liver, and LHR below 1.0. The entry criteria for the present study were fulfilled by 30 of the 58 cases. In 26 of the 30 fetuses, the CDH was leftsided and in 4 it was right-sided. The median gestation at FETO was 27.1 (range, 24.1-28.0) weeks; at removal of the balloon, it was 33.9 (31.0-36.1) weeks; and at delivery it was 36.1 (32.0-40.7) weeks. The survival rate, defined as the discharge of a live neonate from the hospital, was 70% (21/30). In normal fetuses, the normal mean volume for gestation was 100% (2.5th percentile, 60% and 97.5th percentile, 140%).9 In all fetuses with CDH, the contralateral lung volume before FETO was below 60% of the expected normal mean for gestation, and it was 13-38% (median, 27%) in those that subsequently died and 21-59% (median, 37%) in those that survived (Figures 2 and 3; FIGURE 2
Ratios of the contralateral lung volumes
Observed expected ratios, expressed as percentages of the appropriate normal mean for gestation, of the contralateral lung volumes of fetuses with isolated diaphragmatic hernia before FETO, 2 days after FETO, and 7 days after FETO. The horizontal line at 100% of the observed to expected ratio represents the mean, and the interrupted lines the 95% confidence interval of the ratio in normal fetuses.19 Peralta. Fetal lung volume after FETO and postnatal outcome. Am J Obstet Gynecol 2008.
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FIGURE 3
Lung volumes of fetuses with isolated diaphragmatic hernia
ror ⫽ 0.03; Figure 5). In the prediction of fetuses that subsequently survived, with a sensitivity of 95%, the false-positive rate was 78% for lung volume measurements before FETO, 22% for measurements at 2 days after FETO, and 11% for measurements at 7 days after FETO. In view of the small number of cases examined, it is not possible to test the significance of differences between the areas under the curves. A minimum of 36 patients would be needed to provide a probability of 90% of detecting a difference between the area under the ROC curve before FETO with that from measurements 2 days after FETO.11
C OMMENT This study has demonstrated that in fetuses with CDH, the lung responsiveness within 2 and 7 days after FETO provides useful prediction of subsequent survival. In all cases the contralateral lung volume before FETO was below the 2.5th percentile of the normal range for gestation, which is 60%.9 In the survivors, the lung volume increased to above the 2.5th percentile in 66% of cases 2 days after FETO and 95% of cases 7 days after FETO. In contrast, in about 90% of those who died after birth because of pulmonary hypoplasia and/or hypertension, the lung volume remained below the 2.5th percentile at both 2 and 7 days after FETO. FIGURE 4 Reconstructed 3D ultrasound lung volumes of a fetus with isolated diaphragmatic hernia that died after birth (top) and a fetus that survived (bottom), measured before FETO at 27 weeks’ gestation, 2 days after FETO, and 7 days after FETO.
Lung volume at 2 and 7 days after FETO
Peralta. Fetal lung volume after FETO and postnatal outcome. Am J Obstet Gynecol 2008.
Table). Within 2 days after FETO, the lung volume increased to above the 2.5th percentile in 14/21 (66%) that survived (median volume, 69%; range, 44-137%), compared with 1 of the 9 (11%) that died (median volume, 41%; range 31-64%). At 7 days after FETO, the lung volume increased to above the 2.5th percentile in 20/21 (95%) that survived (median volume, 75%; range, 56-150%), compared with 1 of the 9 (11%) that died (median volume, 52%; range, 30-68%). There was a significant association between lung volume (%) at 2 days and lung vol60.e3
ume (%) at 7 days after FETO (r ⫽ 0.87; P ⬍ .001; Figure 4). Survival was significantly associated with the lung volumes on the 3 occasions but not by gestational age at FETO, gestational age at removal of the balloon, or gestational age at delivery (Table). The area under the ROC curves for prediction of survival from lung volumes before FETO was 0.772 (P ⫽ .002; standard error ⫽ 0.09), for volumes 2 days after FETO was 0.907 (P ⬍ .001; standard error ⫽ 0.06) and for 7 days after FETO was 0.976 (P ⬍ .001; standard er-
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Relation between contralateral lung volume (%) at 2 days and lung volume (%) at 7 days after FETO. The closed circles are the values of the babies that died and the open circles represent the survivors. Peralta. Fetal lung volume after FETO and postnatal outcome. Am J Obstet Gynecol 2008.
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TABLE
Outcomes of fetuses with isolated congenital diaphragmatic hernia and intrathoracic herniation of the liver treated by (FETO) in relation to gestational age at FETO, gestational age at removal of the balloon, gestational age at delivery and contralateral lung volumes before FETO and at 2 and 7 days after FETO Median (range)
Mann–Whitney U test
Variable
Alive (n ⴝ 21)
Dead (n ⴝ 9)
Gestation at FETO (wks)
27.0 (24.1-29.0)
27.8 (25.1-28.9)
.308
Gestation at removal of the balloon (wks)
33.9 (31.0-36.1)
33.5 (31.0-34.5)
.540
Gestation at delivery (wks)
36.1 (32.4-39.7)
35.4 (32.0-40.7)
.308
O/E lung volume pre-FETO (%)
37 (21-59)
27 (13-38)
.020
O/E lung volume two days post-FETO (%)
69 (44-137)
41 (31-64)
⬍.001
O/E lung volume seven days post-FETO (%)
75 (56-150)
52 (30-68)
⬍.001
P value
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FETO, endoscopic tracheal occlusion; O/E, Observed contralateral lung volume to the expected normal mean for gestation. Peralta. Fetal lung volume after FETO and postnatal outcome. Am J Obstet Gynecol 2008.
In fetuses with CDH, the contralateral lung volume before FETO provides a measure of the degree of impairment in lung growth. Inevitably, the degree of impairment was greater in those that subsequently died than in those that survived. A previous study in 12 expectantly managed fetuses with isolated CDH reported that the total lung volume, expressed as a percentage of the expected normal mean for gestation, was significantly lower in those that subsequently died than in those that survived (median, 19%; range, 16-66% vs median 44%; range, 36-66%).8 The prediction of survival was substantially better from the volume measurements after FETO than before the procedure. Thus, for a sensitivity of 95%, the
false-positive rate was 78% for lung volume measurements before FETO, decreasing to 22% and 11%, respectively, for measurements at 2 and 7 days after FETO. The expansion in lung volume within 2 days after tracheal occlusion is likely to be the consequence of retention of fluid rather than lung growth. However, the expansion observed at 7 days after FETO could be related to a combination of retained fluid and lung growth. Animal studies have demonstrated that tracheal occlusion reverses the structural and physiologic effects of pulmonary hypoplasia in CDH.12 Lung liquid volume doubles within the first 24 hours of occlusion,13 and pulmonary hyperplasia is evident by 1 week.14 Lung volume 2 days after FETO provides a measure of the ability of the lungs to
FIGURE 5
ROC curves for prediction of survival
ROC curves for prediction of survival according to cut-off values of observed to expected lung volumes before FETO, 2 days after FETO, and 7 days after FETO. Peralta. Fetal lung volume after FETO and postnatal outcome. Am J Obstet Gynecol 2008.
produce fluid and could therefore be considered to be a marker of the underlying degree of impairment in pulmonary development. This would be analogous to the oxytocin challenge test,15 which helps define the oxidative reserve of growth-restricted fetuses. Lung volume 7 days after FETO would then be a marker of the degree to which tracheal occlusion stimulates lung growth and development and the likelihood of postnatal survival. f REFERENCES 1. Colvin J, Bower C, Dickinson J, Sokol J. Outcomes of congenital diaphragmatic hernia: a population-based study in Western Australia. Pediatrics 2005;116:356-63. 2. Stege G, Fenton A, Jaffray B. Nihilism in the 1990s. The true mortality of CDH. Pediatrics 2003;112:532-5. 3. Metkus AP, Filly RA, Stringer MD, et al. Sonographic predictors of survival in fetal diaphragmatic hernia. J Pediatr Surg 1996;31:148-52. 4. Jani J, Keller RL, Benachi A, et al. Prenatal prediction of survival in isolated left-sided diaphragmatic hernia. Ultrasound Obstet Gynecol 2006;27:18-22. 5. Deprest J, Gratacos E, Nicolaides KH; The FETO Task Group. Fetoscopic tracheal occlusion (FETO) for severe congenital diaphragmatic hernia: evolution of a technique and preliminary results. Ultrasound Obstet Gynecol 2004;24:121-6. 6. Jani J, Nicolaides KH, Gratacos E, Vandecruys H, Deprest J, and the FETO Task Group. Fetal lung-to-head ratio in the prediction of survival in severe left-sided diaphragmatic hernia treated by fetal endoscopic tracheal occlusion (FETO). Am J Obstet Gynecol 2006;195: 1646-50. 7. Laudy JAM, Janssen MMM, Struyk PC, Stijnen T, Wladimiroff JW. Three-dimensional ul-
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trasonography of normal fetal lung volume: a preliminary study. Ultrasound Obstet Gynecol 1998;11:13-6. 8. Ruano R, Benachi A, Joubin L, et al. Threedimensional ultrasonographic assessment of fetal lung volume as prognostic factor in isolated congenital diaphragmatic hernia. BJOG 2004; 111:423-9. 9. Peralta CFA, Cavoretto P, Csapo B, Falcon O, Nicolaides KH. Lung and heart volumes by 3D ultrasound in normal fetuses at 12-32 weeks. Ultrasound Obstet Gynecol 2006; 27:128-33.
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www.AJOG.org 10. Peralta CFA, Jani J, Cos T, Nicolaides KH, Deprest J. Left and right lung volumes in fetuses with diaphragmatic hernia. Ultrasound Obstet Gynecol 2006;27:551-4. 11. Hanley JA, McNeil BJ. The meaning and use of the area under a Receiver Operating Characteristic (ROC) curve. Radiology 1982;143:29-36. 12. DiFiore JW, Fauza DO, Slavin R, Peters CA, Fackler JC, Wilson JM. Experimental fetal tracheal ligation reverses the structural and physiological effects of pulmonary hypoplasia in congenital diaphragmatic hernia. J Pediatr Surg 1994;29:248-56.
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13. Nardo L, Hooper SB, Harding R. Stimulation of lung growth by tracheal obstruction in fetal sheep: relation to luminal pressure and lung liquid volume. Pediatr Res 1998;43:184-90. 14. Hashim E, Laberge JM, Chen MF, Quillen EW Jr. Reversible tracheal obstruction in the fetal sheep: effects on tracheal fluid pressure and lung growth. J Pediatr Surg 1995;30: 1172-7. 15. Hon EH, Quilligan EJ. Electronic evaluation of the fetal heart. IX. Further observations on ‘pathological’ fetal bradycardia. Clin Obstet Gynecol 1968;11:145-67.
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OBSTETRICS
Fetal lung volume after endoscopic tracheal occlusion in the prediction of postnatal outcome Cleisson F. A. Peralta, MD, PhD; Jacques C. Jani, MD; Dominique Van Schoubroeck, MD; Kypros H. Nicolaides, MD; Jan A. Deprest, MD, PhD OBJECTIVE: The objective of the study was to investigate the volume response of the contralateral lung in the prediction of postnatal outcome in fetuses with congenital diaphragmatic hernia (CDH) treated by fetoscopic endotracheal occlusion (FETO).
after FETO, the lung volume increased to above the 2.5th percentile in 14/21 (66%) that survived, compared with 1/9 (11%) that died. The respective percentages at 7 days after FETO were 95% and 11%, respectively.
STUDY DESIGN: In 30 fetuses with isolated severe CDH that underwent FETO, the volume of the contralateral lung was measured by 3-dimesional ultrasound the day before and 2 and 7 days after FETO. The measurements of fetuses that subsequently died were compared to those who survived.
CONCLUSION: In fetuses with CDH, the lung responsiveness within 2 and 7 days after FETO provides useful prediction of subsequent survival.
RESULTS: In all fetuses before FETO, the lung volume was below the
2.5th percentile of the normal range for gestation (60%). Within 2 days
Key words: diaphragmatic hernia, fetal lung volume, fetoscopic endotracheal occlusion, 3-dimensional ultrasound, virtual organ computer-aided analysis
Cite this article as: Peralta CFA, Jani JC, Van Schoubroeck D, et al. Fetal lung volume after endoscopic tracheal occlusion in the prediction of postnatal outcome. Am J Obstet Gynecol 2008:198:60.e1-60.e5.
I
solated congenital diaphragmatic hernia (CDH) is associated with a high postnatal mortality because of pulmonary hypoplasia and/or pulmonary hypertension because of chronic intrathoracic compression of the lungs by the herniated abdominal viscera.1,2 It has been demon-
From the Departments of Obstetrics and Gynecology, Fetal Medicine Units, King’s College Hospital, London, United Kingdom (Drs Peralta and Nicolaides), and University Hospital Gasthuisberg, Leuven, Belgium (Drs Jani, Van Schoubroeck, and Deprest). Received Nov. 19, 2006; revised March 10, 2007; accepted May 22, 2007. Supported in part by the European Commission within the 5th (QLG1 CT2002 01632; EuroTwin2Twin) and the 6th Framework Programme (EuroSTEC; LSHCCT-2006-037409) as well as by the Fetal Medicine Foundation (Registered Charity 1037116). Reprints: Professor K. H. Nicolaides, Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital Medical School, Denmark Hill, London SE5 8RX, United Kingdom. 0002-9378/$34.00 © 2008 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2007.05.034
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strated that when the measurement of the lung area to head circumference ratio (LHR) is below 1.0 and the liver is herniated into the chest, the prognosis is extremely poor, with a postnatal survival rate of ⬍ 10%.3,4 In such cases, survival may be improved from ⬍ 10% to ⬎ 50% by fetoscopic endotracheal occlusion (FETO) with a detachable balloon, which is associated with increase in fetal lung size.5,6 Three-dimensional (3D) ultrasound has enabled the measurement of fetal lung volume in both normal and pathological pregnancies.7-10 In a study of 650 normal fetuses, we established reference intervals for both the left and right lung volumes, from 12-32 weeks’ gestation.9 In another study of 42 fetuses with CDH, we demonstrated that the volume of the contralateral lung to the herniated viscera was about 40% of the average lung volume of normal fetuses; the ipsilateral lung was also much smaller than normal (15%), but in 35% of patients, it could not be adequately identified.10 The aim of this study was to investigate whether in fetuses with severe CDH treated by FETO an increase in volume could be demonstrated and, if so, if the
American Journal of Obstetrics & Gynecology JANUARY 2008
degree of volume response was predictive of postnatal outcome.
M ATERIALS AND M ETHODS This was a prospective ongoing multicenter study of patients with severe CDH treated with FETO.3 In all cases, the patients were assessed and received counseling by a multidisciplinary team composed of fetal medicine specialists, neonatologists, and pediatric surgeons. The study was approved by the local ethics committees and/or Committee on Innovative Technologies, and all patients gave written informed consent to the procedure. The inclusion criteria for FETO were the presence of isolated CDH with an LHR below 1.0 and the liver herniated into the chest.3,4 The calculation of the LHR was obtained by the division of the lung area (mm2) by the head circumference (mm). The lung area was measured as described by Metkus et al3 by the multiplication of the longest diameter of the lung by its longest perpendicular diameter. The inclusion criteria for the present 3D study were first, consecutive cases of CDH treated by FETO before 28 weeks’ gestation with available 3D ultrasound measurements of the fetal
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A 2-sided P ⬍ .05 was considered statistically significant.
FIGURE 1
Measurement of the right lung volume
R ESULTS
Measurement of the right lung volume using the rotational technique (VOCAL) in a fetus with left-sided diaphragmatic hernia. The picture on the left represents the starting plane of rotation of the lung and includes its biggest anteroposterior diameter. The picture in the middle represents the transverse view of the lung after drawing of the contours in the 6 consecutive rotational planes. The picture on the right is the final right lung volume. Peralta. Fetal lung volume after FETO and postnatal outcome. Am J Obstet Gynecol 2008.
lungs before and during the first week after the procedure, and second, live birth after 32 weeks’ gestation with no major defect and either postnatal survival at discharge from the hospital or postnatal death because of pulmonary hypoplasia and/or hypertension. The volume of the contralateral lung to the CDH was measured using 3D ultrasound on 3 different occasions: the day before FETO, 2 days after FETO, and 7 days after FETO. For each lung measurement, several 3D volumes of the fetal chest were acquired by transabdominal sonography (RAB 4-8L probe, Voluson 730 Expert, GE Medical Systems, Milwaukee, WI) and the volumes with the best image quality (allowing clear identification of the landmarks: the diaphragm, the apex of the lung, and its lateral and medial limits) were chosen for analysis. During the acquisition of the volumes, our aim was that the fetus was not moving and was preferably facing toward the transducer. The sweep angle was set from 40°-85°, depending on the gestational age. The virtual organ computeraided analysis (VOCAL) technique was used to obtain a sequence of 6 sections of each lung around a fixed axis, from the apex to the base, each after a 30° rotation from the previous one (Voluson 730 Expert operation manual, GE Medical Systems). The contour of the contralateral lung was drawn manually in the 6 differ-
ent rotation planes to obtain the 3D volume measurement. The starting plane of rotation for the lung included its biggest anteroposterior diameter. Every measurement was done off-line after the scan (Figure 1).
Statistical analysis Each lung volume measurement was expressed as a percentage of the appropriate mean for gestation (observed/expected lung volume times 100), previously established from the study of 650 normal fetuses at 12-32 weeks.9 The data from the study of normal fetuses were also expressed as percentages of the expected mean for gestation, and the 95% confidence intervals for these values were calculated, for the left and the right lungs. The Mann–Whitney U test was used to compare fetuses that died with those who survived with regard to the gestational age at FETO, the gestational age at the removal of the balloon, the gestational age at delivery, and the lung volumes on the 3 different occasions. Receiver operating characteristic (ROC) curve was constructed for the lung volumes expressed as percentages of the normal mean for each of the 3 evaluations in the prediction of survival. The data were analyzed using the statistical software SPSS 13.0 (SPSS Inc, Chicago, IL) and Excel for Windows 2000 (Microsoft Corp, Redmond, WA).
During the study period, from April 2002-May 2006, FETO was performed in 58 fetuses with isolated CDH, intrathoracic herniation of the liver, and LHR below 1.0. The entry criteria for the present study were fulfilled by 30 of the 58 cases. In 26 of the 30 fetuses, the CDH was leftsided and in 4 it was right-sided. The median gestation at FETO was 27.1 (range, 24.1-28.0) weeks; at removal of the balloon, it was 33.9 (31.0-36.1) weeks; and at delivery it was 36.1 (32.0-40.7) weeks. The survival rate, defined as the discharge of a live neonate from the hospital, was 70% (21/30). In normal fetuses, the normal mean volume for gestation was 100% (2.5th percentile, 60% and 97.5th percentile, 140%).9 In all fetuses with CDH, the contralateral lung volume before FETO was below 60% of the expected normal mean for gestation, and it was 13-38% (median, 27%) in those that subsequently died and 21-59% (median, 37%) in those that survived (Figures 2 and 3; FIGURE 2
Ratios of the contralateral lung volumes
Observed expected ratios, expressed as percentages of the appropriate normal mean for gestation, of the contralateral lung volumes of fetuses with isolated diaphragmatic hernia before FETO, 2 days after FETO, and 7 days after FETO. The horizontal line at 100% of the observed to expected ratio represents the mean, and the interrupted lines the 95% confidence interval of the ratio in normal fetuses.19 Peralta. Fetal lung volume after FETO and postnatal outcome. Am J Obstet Gynecol 2008.
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FIGURE 3
Lung volumes of fetuses with isolated diaphragmatic hernia
ror ⫽ 0.03; Figure 5). In the prediction of fetuses that subsequently survived, with a sensitivity of 95%, the false-positive rate was 78% for lung volume measurements before FETO, 22% for measurements at 2 days after FETO, and 11% for measurements at 7 days after FETO. In view of the small number of cases examined, it is not possible to test the significance of differences between the areas under the curves. A minimum of 36 patients would be needed to provide a probability of 90% of detecting a difference between the area under the ROC curve before FETO with that from measurements 2 days after FETO.11
C OMMENT This study has demonstrated that in fetuses with CDH, the lung responsiveness within 2 and 7 days after FETO provides useful prediction of subsequent survival. In all cases the contralateral lung volume before FETO was below the 2.5th percentile of the normal range for gestation, which is 60%.9 In the survivors, the lung volume increased to above the 2.5th percentile in 66% of cases 2 days after FETO and 95% of cases 7 days after FETO. In contrast, in about 90% of those who died after birth because of pulmonary hypoplasia and/or hypertension, the lung volume remained below the 2.5th percentile at both 2 and 7 days after FETO. FIGURE 4 Reconstructed 3D ultrasound lung volumes of a fetus with isolated diaphragmatic hernia that died after birth (top) and a fetus that survived (bottom), measured before FETO at 27 weeks’ gestation, 2 days after FETO, and 7 days after FETO.
Lung volume at 2 and 7 days after FETO
Peralta. Fetal lung volume after FETO and postnatal outcome. Am J Obstet Gynecol 2008.
Table). Within 2 days after FETO, the lung volume increased to above the 2.5th percentile in 14/21 (66%) that survived (median volume, 69%; range, 44-137%), compared with 1 of the 9 (11%) that died (median volume, 41%; range 31-64%). At 7 days after FETO, the lung volume increased to above the 2.5th percentile in 20/21 (95%) that survived (median volume, 75%; range, 56-150%), compared with 1 of the 9 (11%) that died (median volume, 52%; range, 30-68%). There was a significant association between lung volume (%) at 2 days and lung vol60.e3
ume (%) at 7 days after FETO (r ⫽ 0.87; P ⬍ .001; Figure 4). Survival was significantly associated with the lung volumes on the 3 occasions but not by gestational age at FETO, gestational age at removal of the balloon, or gestational age at delivery (Table). The area under the ROC curves for prediction of survival from lung volumes before FETO was 0.772 (P ⫽ .002; standard error ⫽ 0.09), for volumes 2 days after FETO was 0.907 (P ⬍ .001; standard error ⫽ 0.06) and for 7 days after FETO was 0.976 (P ⬍ .001; standard er-
American Journal of Obstetrics & Gynecology JANUARY 2008
Relation between contralateral lung volume (%) at 2 days and lung volume (%) at 7 days after FETO. The closed circles are the values of the babies that died and the open circles represent the survivors. Peralta. Fetal lung volume after FETO and postnatal outcome. Am J Obstet Gynecol 2008.
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TABLE
Outcomes of fetuses with isolated congenital diaphragmatic hernia and intrathoracic herniation of the liver treated by (FETO) in relation to gestational age at FETO, gestational age at removal of the balloon, gestational age at delivery and contralateral lung volumes before FETO and at 2 and 7 days after FETO Median (range)
Mann–Whitney U test
Variable
Alive (n ⴝ 21)
Dead (n ⴝ 9)
Gestation at FETO (wks)
27.0 (24.1-29.0)
27.8 (25.1-28.9)
.308
Gestation at removal of the balloon (wks)
33.9 (31.0-36.1)
33.5 (31.0-34.5)
.540
Gestation at delivery (wks)
36.1 (32.4-39.7)
35.4 (32.0-40.7)
.308
O/E lung volume pre-FETO (%)
37 (21-59)
27 (13-38)
.020
O/E lung volume two days post-FETO (%)
69 (44-137)
41 (31-64)
⬍.001
O/E lung volume seven days post-FETO (%)
75 (56-150)
52 (30-68)
⬍.001
P value
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
FETO, endoscopic tracheal occlusion; O/E, Observed contralateral lung volume to the expected normal mean for gestation. Peralta. Fetal lung volume after FETO and postnatal outcome. Am J Obstet Gynecol 2008.
In fetuses with CDH, the contralateral lung volume before FETO provides a measure of the degree of impairment in lung growth. Inevitably, the degree of impairment was greater in those that subsequently died than in those that survived. A previous study in 12 expectantly managed fetuses with isolated CDH reported that the total lung volume, expressed as a percentage of the expected normal mean for gestation, was significantly lower in those that subsequently died than in those that survived (median, 19%; range, 16-66% vs median 44%; range, 36-66%).8 The prediction of survival was substantially better from the volume measurements after FETO than before the procedure. Thus, for a sensitivity of 95%, the
false-positive rate was 78% for lung volume measurements before FETO, decreasing to 22% and 11%, respectively, for measurements at 2 and 7 days after FETO. The expansion in lung volume within 2 days after tracheal occlusion is likely to be the consequence of retention of fluid rather than lung growth. However, the expansion observed at 7 days after FETO could be related to a combination of retained fluid and lung growth. Animal studies have demonstrated that tracheal occlusion reverses the structural and physiologic effects of pulmonary hypoplasia in CDH.12 Lung liquid volume doubles within the first 24 hours of occlusion,13 and pulmonary hyperplasia is evident by 1 week.14 Lung volume 2 days after FETO provides a measure of the ability of the lungs to
FIGURE 5
ROC curves for prediction of survival
ROC curves for prediction of survival according to cut-off values of observed to expected lung volumes before FETO, 2 days after FETO, and 7 days after FETO. Peralta. Fetal lung volume after FETO and postnatal outcome. Am J Obstet Gynecol 2008.
produce fluid and could therefore be considered to be a marker of the underlying degree of impairment in pulmonary development. This would be analogous to the oxytocin challenge test,15 which helps define the oxidative reserve of growth-restricted fetuses. Lung volume 7 days after FETO would then be a marker of the degree to which tracheal occlusion stimulates lung growth and development and the likelihood of postnatal survival. f REFERENCES 1. Colvin J, Bower C, Dickinson J, Sokol J. Outcomes of congenital diaphragmatic hernia: a population-based study in Western Australia. Pediatrics 2005;116:356-63. 2. Stege G, Fenton A, Jaffray B. Nihilism in the 1990s. The true mortality of CDH. Pediatrics 2003;112:532-5. 3. Metkus AP, Filly RA, Stringer MD, et al. Sonographic predictors of survival in fetal diaphragmatic hernia. J Pediatr Surg 1996;31:148-52. 4. Jani J, Keller RL, Benachi A, et al. Prenatal prediction of survival in isolated left-sided diaphragmatic hernia. Ultrasound Obstet Gynecol 2006;27:18-22. 5. Deprest J, Gratacos E, Nicolaides KH; The FETO Task Group. Fetoscopic tracheal occlusion (FETO) for severe congenital diaphragmatic hernia: evolution of a technique and preliminary results. Ultrasound Obstet Gynecol 2004;24:121-6. 6. Jani J, Nicolaides KH, Gratacos E, Vandecruys H, Deprest J, and the FETO Task Group. Fetal lung-to-head ratio in the prediction of survival in severe left-sided diaphragmatic hernia treated by fetal endoscopic tracheal occlusion (FETO). Am J Obstet Gynecol 2006;195: 1646-50. 7. Laudy JAM, Janssen MMM, Struyk PC, Stijnen T, Wladimiroff JW. Three-dimensional ul-
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trasonography of normal fetal lung volume: a preliminary study. Ultrasound Obstet Gynecol 1998;11:13-6. 8. Ruano R, Benachi A, Joubin L, et al. Threedimensional ultrasonographic assessment of fetal lung volume as prognostic factor in isolated congenital diaphragmatic hernia. BJOG 2004; 111:423-9. 9. Peralta CFA, Cavoretto P, Csapo B, Falcon O, Nicolaides KH. Lung and heart volumes by 3D ultrasound in normal fetuses at 12-32 weeks. Ultrasound Obstet Gynecol 2006; 27:128-33.
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www.AJOG.org 10. Peralta CFA, Jani J, Cos T, Nicolaides KH, Deprest J. Left and right lung volumes in fetuses with diaphragmatic hernia. Ultrasound Obstet Gynecol 2006;27:551-4. 11. Hanley JA, McNeil BJ. The meaning and use of the area under a Receiver Operating Characteristic (ROC) curve. Radiology 1982;143:29-36. 12. DiFiore JW, Fauza DO, Slavin R, Peters CA, Fackler JC, Wilson JM. Experimental fetal tracheal ligation reverses the structural and physiological effects of pulmonary hypoplasia in congenital diaphragmatic hernia. J Pediatr Surg 1994;29:248-56.
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13. Nardo L, Hooper SB, Harding R. Stimulation of lung growth by tracheal obstruction in fetal sheep: relation to luminal pressure and lung liquid volume. Pediatr Res 1998;43:184-90. 14. Hashim E, Laberge JM, Chen MF, Quillen EW Jr. Reversible tracheal obstruction in the fetal sheep: effects on tracheal fluid pressure and lung growth. J Pediatr Surg 1995;30: 1172-7. 15. Hon EH, Quilligan EJ. Electronic evaluation of the fetal heart. IX. Further observations on ‘pathological’ fetal bradycardia. Clin Obstet Gynecol 1968;11:145-67.