DOI: 10.1148/radiol.2481070952
(Radiology 2008;248:240-246.)
© RSNA, 2008
MR Relative Fetal Lung Volume in Congenital Diaphragmatic Hernia: Survival and Need for Extracorporeal Membrane Oxygenation1
Karen A. Büsing, MD,
A. Kristina Kilian, MD,
Thomas Schaible, MD,
Claudia Endler,
Regine Schaffelder, MD, and
K. Wolfgang Neff, MD, PhD
1 From the Departments of Clinical Radiology (K.A.B., A.K.K., C.E., K.W.N.), Pediatrics (T.S.), and Obstetrics and Gynecology (R.S.), University Hospital Mannheim, University of Heidelberg, Theodor Kutzer Ufer 1-3, 68167 Mannheim, Germany. Received June 3, 2007; revision requested August 3; revision received October 31; accepted December 21; final version accepted January 28, 2008.
Address correspondence to K.A.B. (e-mail: karen.buesing@rad.ma.uni-heidelberg.de).
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ABSTRACT
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Purpose: To retrospectively evaluate the accuracy of the absolute fetal lung volume (FLV) measured at magnetic resonance (MR) imaging and seven formulas for calculating relative FLV to predict neonatal survival and the need for extracorporeal membrane oxygenation (ECMO) in fetuses with congenital diaphragmatic hernia (CDH).
Materials and Methods: This retrospective study was approved by the research ethics committee, and informed consent was received from all mothers for previous prospective studies. In total, 68 fetuses with CDH were assessed by using MR image FLV measurement within 23–39 weeks gestation. The relative FLV was expressed as a percentage of the predicted lung volume calculated with biometric parameters according to seven formulas previously described in the literature. Applying the area under the curve (AUC), the various relative FLVs and the absolute FLV were investigated for their prognostic accuracy to predict neonatal survival and the need for ECMO therapy.
Results: All relative FLVs and the absolute FLV revealed a significant difference in mean lung volume between neonates who survived and neonates who did not survive (P = .001 to P < .001) and measurement accuracy was excellent for each method (AUC, 0.800–0.900). For predicting neonatal ECMO requirement, differences in FLVs were smaller but still significant (P = .05 to <.009) and measurement accuracy was acceptable throughout (AUC, 0.653–0.739).
Conclusion: The various relative FLVs and the absolute FLV measured at MR planimetry are each highly valuable in predicting survival in fetuses with CDH. For predicting whether neonatal ECMO therapy is required, the accuracy of the absolute FLV (AUC, 0.68) and that of the relative FLVs (AUC, 0.653–0.739) was acceptable.
© RSNA, 2008
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INTRODUCTION
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Congenital diaphragmatic hernia (CDH) occurs in 1:2500 live births and is the most common malformation associated with pulmonary hypoplasia (1). Once associated defects such as lethal chromosomal abnormalities have been excluded, the degree of pulmonary hypoplasia represents the major determinant of survival (2). Therefore, an accurate estimate of fetal lung volume (FLV) in fetuses with CDH provides valuable information for parental counseling. In addition, fetal surgery has emerged as a therapeutic option and thus has increased the importance of predicting the prognosis during prenatal evaluation (3).
Magnetic resonance (MR) imaging has been used to measure antenatal lung volume and quantify fetal pulmonary hypoplasia. Aiming to improve prognostic accuracy, some investigators have expressed the lung volume measured at planimetry as a percentage of the expected lung volume (4–9). This ratio has been referred to as the relative FLV. For calculating the relative FLV, several formulas derived from nomograms of healthy fetal lungs can be applied to determine the expected lung volume (5,8–11). Of these formulas, those that are based on multiple biometric measurements (8–10) have been reported to predict the expected FLV more accurately (R2 = 0.61–0.93) than formulas that are based exclusively on gestational age (R2 = 0.58–0.77) (5,10,11). Unfortunately, except for a small cohort assessed by Paek et al (4), only those formulas based solely on gestational age (5,10) and with a low correlation coefficient (10) have been applied to evaluate the degree of pulmonary hypoplasia as a prognostic indicator in fetuses with CDH (5–7). Although the investigators independently found that mortality was significantly higher when the relative FLV was less than 25%–40% of the expected lung volume, to the best of our knowledge, the prognostic accuracy of each of these formulas has not been investigated so far. In addition, improvement in prognostic strength by assessing the relative FLV compared with the absolute FLV measured at antenatal MR imaging has not been validated.
Thus, the purpose of our study was to retrospectively evaluate the accuracy of the absolute FLV measured at MR imaging and seven formulas for calculating relative FLV to predict neonatal survival and the need for extracorporeal membrane oxygenation (ECMO) in fetuses with CDH.
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MATERIALS AND METHODS
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Patients
One author (C.E.) conducted a chart review of all fetuses who underwent fetal MR imaging between December 2001 and August 2006 for previous prospective studies. Twenty-three of 103 fetuses were excluded because of incomplete biometric measurements at ultrasonography (US) or because US was performed more than 3 days prior to or after fetal MR imaging. Five neonates were lost to follow-up, and another seven fetuses were excluded because of associated malformation diagnosed by using US (n = 3), because of chromosomal abnormality (n = 2), and because of terminated pregnancies (n = 2). This left 66 singleton pregnancies and two twin pregnancies, with one fetus in each diagnosed with CDH. Sixty-seven fetuses were delivered at our institution, and one was followed up by staff at another tertiary care center. Data are from 24 patients who were previously reported (12), and data from 61 patients overlap with data reported in another manuscript in this issue of Radiology (13). The mean maternal age was 30.8 years ± 5.7 (standard deviation), with an age range of 19–43 years. The mean gestational age at MR imaging was 32.3 weeks ± 3.5 (range, 23–39 weeks). CDH was left sided in 60 (88%) neonates, right sided in seven (10%) neonates, and bilateral in one (1%) neonate. Data about whether the birth was live, survival at discharge, the reason for death, and the need for ECMO were recorded.
The study was approved by the research ethics committee of our hospital. Informed consent was received from all mothers for previous prospective studies.
ECMO Therapy
In neonates, ECMO therapy was instituted according to previously published guidelines (13–16).
MR Imaging
MR imaging studies were performed with a 1.5-T supraconducting system (Sonata or Avanto; Siemens Medical Solutions, Erlangen, Germany) by using a phased-array body coil. All fetuses underwent T2-weighted half-Fourier acquired single-shot turbo spin-echo MR imaging (echo time, 166 msec; flip angle, 150°; section thickness, 4 mm; no intersection gap; and matrix, 512 x 512) oriented in all three orthogonal planes of the fetal thorax and epigastrium. From 2005 onwards, we also performed a true fast imaging with steady-state precession sequence (repetition time msec/echo time msec, 3.6/1.5; flip angle, 59°). The mothers were positioned in either the supine or partial left decubitus position. No sedative was administered to reduce fetal movements. All examinations were monitored by a radiologist (K.A.B., K.W.N., with 4 and 10 years of experience, respectively, in fetal MR imaging).
MR Planimetry
Volumes of each fetal lung and liver were assessed once by either one of two radiologists (K.A.B. and A.K.K., with 4 years of experience in fetal MR imaging each) by using volume analysis software (Argus; Siemens Medical Solutions). Each volume was calculated by multiplying the area of the region of interest, drawn by following the lung boundaries or the liver contour on consecutive images, by the section thickness. The region of interest did not include the main vessels of the pulmonary hila or the hepatic portal system (Fig 1). For fetal lung and liver planimetry, at least two different section orientations of good imaging quality were assessed, and the mean organ volume was used for further calculations. Approximately 8–15 minutes were required for FLV measurements, whereas time for assessment of the liver volume was up to 30 minutes (13).
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Figure 1: Coronal true fast imaging with steady-state precession MR images (3.6/1.5; flip angle, 59°) of fetal lung (left) and liver (right) at 30 weeks gestation. Volume assessment was performed by determining region of interest, hand-drawn by following lung boundaries (left) and liver contour (right).
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US Measurements
US biometric measurements of the head circumference, biparietal diameter, abdominal circumference, and femoral length were performed in all fetuses in a standard fashion (17). The fetal body weight was estimated according to Hadlock et al (18). This examination was performed by two obstetricians (including R.S., with about 6 years of experience in fetal US) either on the same day or within 3 days prior to or after fetal MR imaging. Measurements were performed by using a 3.5-MHz convex transducer (EUB 5500E; Hitachi, Wiesbaden, Germany). The obstetricians were unaware of the FLV measured at antenatal MR imaging, and biometric US measurements were not given to the radiologists prior to FLV measurement.
Calculation of Relative FLV
The expected FLV was calculated by either of two authors (K.A.B., C.E.) according to seven formulas. In 1999, Duncan et al (11) published an article with the following formula:
 | (1) |
where g is gestational age. In 2000, Coakley et al (8) published their calculation as follows:
 | (2) |
where LV is liver volume at MR imaging, BD is biparietal diameter at US, and FL is femoral length at US. In another study in 2001, Rypens et al (10) conveyed two calculations as follows:
 | (3) |
and
 | (4) |
where w is fetal weight at US. In 2001, Mahieu-Caputo et al (5) also published their calculation thus:
 | (5) |
In 2004, Williams et al (9) published two other formulas as follows:
 | (6) |
and
 | (7) |
where HC is head circumference.
The relative FLV was then expressed as a ratio of the absolute FLV, measured by using MR imaging, to the expected FLV (Table 1).
Statistical Analysis
The receiver operating characteristic analysis was used to assess accuracy. We applied the area under the curve (AUC) to determine the accuracy of the various calculated relative FLVs to predict neonates' survival to discharge and neonatal ECMO requirement by using software (SAS, release 8.02; SAS Institute, Cary, NC).
The t test and Fisher exact test were applied to evaluate the effect of FLV, gestational age, maternal age, and the location of the hernia on ECMO requirement and neonatal survival. A result with a difference with P < .05 was considered to be significant.
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RESULTS
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Neonates, Survival, and ECMO Therapy
Overall survival at discharge was 79% (n = 54), including the neonate delivered elsewhere. All deaths were related to respiratory failure and/or persistent pulmonary hypertension.
In all, 14 (21%) neonates did not survive. Of 14 neonates who died before discharge, six (43%) died before ECMO therapy, whereas the remaining eight died despite ECMO therapy. Mean FLV in these children was not significantly lower than in those eight neonates who received ECMO therapy but died thereafter (7.4 mL ± 2.1 vs 10.1 mL ± 4.7, P = .218). ECMO therapy was not withheld in any patient because of preexisting contraindications.
In all, 24 (35%) newborns received ECMO therapy. Children who survived to discharge required neonatal ECMO therapy less frequently (30%) than did children who did not survive to discharge (57%). However, this difference did not reach significance (P = .067) (Table 2).
Prognostic Accuracy of MR Image FLV
Survival.—There were no relevant differences in maternal age, fetal gestational age, and location of the defect between neonates who survived and neonates who did not survive (Table 2).
According to all calculations, the difference between the relative FLV of children who survived and children who died before discharge was highly significant (P = .001 to P < .001), and the prognostic accuracy was very high, with an AUC ranging from 0.800 for Equation (1) (Duncan et al [11]) to 0.900 for the US-based formula, Equation (7). The three formulas that are based solely on gestational age were only marginally less accurate than formulas that also took into account multiple biometry parameters. In addition, formulas requiring planimetry of the fetal liver were not superior to those based on less time-consuming parameters (AUC, 0.838–0.843 vs 0.800–0.900).
On average, the absolute FLV measured at antenatal MR imaging planimetry was significantly higher in neonates with CDH who survived to discharge than in neonates who did not (P < .001), and we found the prognostic accuracy to be nearly as good as the best formula for the relative FLV (AUC, 0.890 vs 0.900).
For all relative FLVs and the absolute FLV, we found a considerable overlap in lung volumes for neonates who survived and neonates who did not survive (Table 3, Fig 2). According to results with the most accurate formula, Equation (7), no neonate with a mean relative FLV of 13.4% or less survived, whereas no neonate with an antenatally measured lung volume of 29.5% or greater died.
ECMO requirement.—Neonates who received ECMO therapy and those coping without ECMO therapy were comparable with respect to maternal age, gestational age, and location of the defect (Table 2).
All formulas yielded a significantly lower relative FLV for neonates who required ECMO therapy than for neonates who did not require ECMO (P = .05 to <.009), but the predictive accuracy was lower compared with that for neonates' survival. The AUC ranged from 0.653 for the calculation of Duncan et al (11), Equation (1), to 0.739 for the calculation of Williams et al (9), Equation (6), which required the time-consuming MR planimetry of the fetal liver (Table 4). Formulas for the relative FLV that were based solely on gestational age had a slightly poorer prognostic accuracy (AUC, 0.653–0.677) than formulas that were based on multiple biometric parameters (AUC, 0.688–0.739) (Table 4, Fig 3). Calculations requiring liver planimetry were only marginally superior to formulas that did not include the fetal liver volume (AUC, 0.737–0.739 vs 0.653–0.705).
The prognostic accuracy of the absolute FLV to predict the need for neonatal ECMO therapy was similar to the results with the various relative FLVs. The absolute FLV could help to distinguish, to a significant degree, between neonates that required ECMO therapy and those who could cope without it, but the disparity of the FLV was slightly smaller than it was for neonates' survival (P = .017). The prognostic strength of the absolute FLV reached an AUC of 0.680 (Table 4).
There was a substantial overlap in lung volumes for the absolute FLV and all relative FLVs for neonates who received ECMO therapy and those who were coping without it (Table 4, Fig 3). According to calculations that were based on the best ECMO formula, Equation (6), no neonate with a relative FLV of 55.8% or greater required ECMO therapy.
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DISCUSSION
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US remains the first-line technique to noninvasively examine fetal lungs, and several prospective and retrospective studies have described the utility of the lung-to-head ratio in predicting postanatal survival of fetuses with isolated left-sided CDH (19–22). Lipshutz et al (21) and Laudy and co-workers (20) independently reported that a lung-to-head ratio of less than 1.0 was associated with 100% mortality, and a ratio greater than 1.4 was associated with 100% survival. However, a considerable number of fetuses have intermediate values, with survival rates ranging from 38% to 61% (19–21), and for these patients we are currently not able to determine postnatal outcome more accurately. Furthermore, some recent studies could not confirm the prognostic value of the lung-to-head ratio for either children's survival or the postnatal clinical course, including the need for ECMO therapy (23–25).
For some years, MR fetal lung volume measurement has been used to assess the probability of neonatal survival. In healthy fetuses and in fetuses with CDH, the method has proved to be highly reliable, with low intra- and interrater variability (12,26). However, even in a healthy population of fetuses, the measurement of FLV has a substantial interpatient variability (5,10,11), leading to a standard deviation of the expected lung volume–measured lung volume of 35% (5). In all studies, the spread of values increased with age, resulting in a low correlation between FLV and gestational age. This variability was most likely caused by true physiologic variation in FLV, as well as increased pulmonary crowding and chest compression within the uterus, as suggested by Duncan at al (11), who observed a decrease in FLV toward term in up to one-third of all fetuses included in a longitudinal study.
Because of these variations in normal FLVs, some investigators have aimed to improve the assessment of fetal pulmonary hypoplasia by focusing on the relative FLV (4–9). However, to use the relative FLV as a predictive parameter, its prognostic accuracy must be validated.
Assessing 68 fetuses with CDH, we found that both the absolute FLV and the various relative FLVs are equally valuable in antenatally predicting survival in fetuses with CDH. Thus, correction for biometric parameters did not considerably increase the prognostic accuracy of the method, no matter whether the calculation was based solely on gestational age or it took multiple biometric parameters into account, especially the time-consuming assessment of the fetal liver volume. Surprisingly, all gestational age–based formulas were slightly less accurate than the absolute FLV measured at MR image planimetry. The formula that showed the highest prognostic validity for patients' survival (AUC, 0.900) was Equation (7), which is based solely on standard US parameters (head circumference, biparietal diameter, and femoral length).
The prediction of neonatal ECMO requirement was found to be less accurate than the prediction of survival. However, for the absolute FLV and each of the relative FLVs, the difference between the treatment groups was significant. Equation (6), which included fetal liver planimetry, showed the best prognostic accuracy for predicting the need for neonatal ECMO therapy, but it was only marginally superior to formulas that did not require fetal liver volumetry and to the absolute FLV.
Despite the high prognostic accuracy of the absolute FLV and relative FLVS, all parameters showed a considerable overlap in FLVs (eg, in neonates surviving postnatally and neonates with a poor outcome). Consequently, the relative FLV and the absolute FLV do not allow a definite prediction of neonatal outcome in an individual case but they may be applied to calculate a probability of surviving and the ECMO requirement in fetuses with CDH (4–6).
Overall, these results support the thinking that lung volume is a major parameter, but not the only one, for determining the postnatal course of a neonate with CDH (27,28) and that lung volume does not necessarily correlate with function. It still poses a considerable problem, in that measurement of FLV by using MR imaging is only an indirect, and by far not the only, characteristic of pulmonary hypoplasia. For example, in affected lungs, the total size of the pulmonary vascular bed is reduced, and this reduction causes functional abnormalities such as pulmonary hypertension (29,30). Furthermore, the expression of growth factors, including insulin-like growth factor, epidermal growth factor, and transforming growth factor 
, has been shown to be abnormal in neonates with CDH (31,32). Also, retinoic acid may have some effect on the development of CDH and associated lung function abnormalities (33–36).
A limitation of our study was that the estimated risk for ECMO therapy calculated in this study could not necessarily be assigned to other centers, as there are no universally accepted ECMO criteria. Although the inclusion and exclusion criteria used at our institution correspond to classic objective criteria for the need to institute ECMO therapy (14–16), procedures may vary among the different tertiary care centers.
In summary, in CDH, MR image FLV measurement is valuable for the prognosis of neonatal survival and acceptable for predicting the need for neonatal ECMO therapy. Predictive power of the relative FLV for neonatal survival and ECMO requirement is not influenced, to any considerable degree, by the underlying formula applied to calculate it. However, the relative FLV is not markedly superior to the absolute FLV measured at antenatal MR imaging either. Thus, estimation of postnatal outcome in fetuses with CDH does not necessarily require calculation of the relative FLV from biometric measurements, as this calculation does not considerably improve prognostic strength compared with the absolute FLV.
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ADVANCES IN KNOWLEDGE
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- In congenital diaphragmatic hernia (CDH), the accuracy for the MR image relative fetal lung volume (FLV) is excellent for prediction of neonatal survival (area under the curve [AUC], 0.800–0.900).
- MR image relative FLV also can be used for estimating the need for neonatal extracorporeal membrane oxygenation therapy (AUC, 0.653–0.739).
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IMPLICATION FOR PATIENT CARE
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- Estimation of patients' outcome in CDH does not necessarily require calculation of the relative FLV from biometric measurements, as its prognostic strength is as accurate as the absolute FLV measured at antenatal MR imaging.
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FOOTNOTES
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Abbreviations: AUC = area under the curve • CDH = congenital diaphragmatic hernia • ECMO = extracorporeal membrane oxygenation • FLV = fetal lung volume
See also the other article by Büsing et al in this issue.
Author contributions: Guarantors of integrity of entire study, K.A.B., K.W.N.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, K.A.B., C.E.; clinical studies, K.A.B., A.K.K., T.S., C.E., R.S.; statistical analysis, K.A.B., T.S., K.W.N.; and manuscript editing, K.A.B., R.S., K.W.N.
Authors stated no financial relationship to disclose.
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Related Article
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MR Lung Volume in Fetal Congenital Diaphragmatic Hernia: Logistic Regression Analysis—Mortality and Extracorporeal Membrane Oxygenation
- Karen A. Büsing, A. Kristina Kilian, Thomas Schaible, Dietmar J. Dinter, and K. Wolfgang Neff
Radiology 2008 248: 233-239.
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ABSTRACT
INTRODUCTION
= mean relative FLV ± standard deviation for neonates who did not survive; 
= mean relative FLV ± standard deviation for neonates who survived; Rypens1 and Rypens2 = Equations (3) and (4), respectively; Williams1 and Williams2 = Equations (6) and (7), respectively.
= mean relative FLV ± standard deviation for neonates who did not receive ECMO therapy;