Seminars in Fetal & Neonatal Medicine 19 (2014) 331e337
Contents lists available at ScienceDirect
Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/siny
Review
Advances in prenatal diagnosis of congenital diaphragmatic hernia €l Cordier a, b, Mieke Cannie c, Jacques Jani d Alexandra Benachi a, b, *, Anne-Gae a
Department of Obstetrics, Gynecology and Reproductive Medicine, Hospital Antoine Beclere, APHP, Paris Sud University, Clamart, France Centre Maladies Rares: Hernie de Coupole Diaphragmatique, Hospital Antoine Beclere, APHP, Clamart, France c Department of Radiology, University Hospital Brugmann, Brussels, Belgium d Department of Obstetrics and Gynecology, University Hospital Brugmann, Brussels, Belgium b
s u m m a r y Keywords: Congenital diaphragmatic hernia Prenatal ultrasound Magnetic resonance imaging Lung-to-head ratio
Over the past 20 years, prenatal detection of congenital diaphragmatic hernia (CDH) has improved worldwide, reaching up to 60% in Europe. Pulmonary hypoplasia and persistent pulmonary hypertension are the two main determinants of neonatal mortality and morbidity, so new tools have been focused on their evaluation. Fetal surgery for severe cases requires proper evaluation of the prognosis of fetuses with CDH. Observed-to-expected lung-to-head ratio, liver position, and total lung volume measured by magnetic resonance are the prognostic factors most often used, and have been shown to correlate not only with neonatal mortality but also with morbidity. In daily practice, pulmonary hypertension by itself, although most often associated with lung hypoplasia, is more difficult to predict. © 2014 Published by Elsevier Ltd.
1. Introduction Congenital diaphragmatic hernia (CDH) is a widespread abnormality, with an incidence of one in 2500 live births [1]. Prenatal detection rates by ultrasound reach up to 60% in Europe [2]. In isolated cases, postnatal mortality can vary between 15% and 50%, especially when population-based studies are considered [2,3]. The prenatal diagnosis of this malformation has improved worldwide over the past 20 years and it has been well established that organizing the birth of affected fetuses in a center with an optimal neonatal intensive care unit and pediatric surgery improves outcome. Selected centers with a high case load of CDH per year report an increase in survival rates [4,5]. Twenty years ago, survival was also around 60%, but we were not dealing with the same sorts of babies. Today, as more than half of cases [1] are diagnosed prenatally, the hidden mortality is lower and fetuses that are taken care of in pediatric surgery departments happen to have, overall, more severe forms than before. Various factors have improved the outcome of CDH babies: improvement of prenatal diagnosis and of prenatal evaluation of postnatal prognosis, delivery in appropriate centers and improvement of postnatal care. Pulmonary hypoplasia and persistent pulmonary hypertension are the two main determinants of neonatal mortality and
* Corresponding author. Address: Department of Obstetrics, Gynecology and cle re, 92140 Clamart, France. Tel.: þ33 1 Reproductive Medicine, Hospital Antoine Be 45374476; fax: þ 33 1 45374967. E-mail address: [email protected] (A. Benachi). http://dx.doi.org/10.1016/j.siny.2014.09.005 1744-165X/© 2014 Published by Elsevier Ltd.
morbidity, so new tools have been focused on their evaluation. Fetal surgery for severe cases requires proper evaluation of the prognosis of fetuses with CDH. It is very important to identify reliable prenatal prognostic factors that can be used worldwide for the following reasons: (i) patient counseling is more accurate; (ii) the results of pre- and postnatal treatments will be comparable across different institutions; (iii) fetuses eligible for fetal surgery will be selected correctly; and (iv) a woman expecting a child with a very poor prognosis can prepare herself for the postnatal demise of her baby or, in some countries, opt for termination of pregnancy. In countries such as France, proper prognostic evaluation is saving fetuses with good and fair prognosis, because women have the option to terminate the pregnancy only when the prognosis is poor. 2. Brief history of prenatal evaluation in CDH Fetal surgical correction of the diaphragmatic defect in utero, first performed by Harrison, was proposed for all patients with isolated CDH. In 1993 it was shown that fetuses with herniated liver in the thorax died during or immediately after surgery due to ductus-venosus plicature [6]. Harrison's team therefore decided to offer the in-utero treatment only to those cases with intraabdominal liver. In 1998, a randomized controlled trial showed that open in-utero surgery was unable to improve neonatal mortality, length of hospital stay or requirement for extracorporeal membrane oxygenation in the CDH group compared with the control group given standardized postnatal care [7]. Fetuses with
332
A. Benachi et al. / Seminars in Fetal & Neonatal Medicine 19 (2014) 331e337
liver in the abdomen are now known to have the best prognosis, which highlights the fact that the key to success in fetal intervention is proper patient selection. It should be pointed out that at the time of this trial, prognostic evaluation of CDH was unreliable, and that clinicians had very few prenatal ultrasound markers. The prognosis was given to the parents of the enrolled fetuses on the basis of various markers, including left or right occurrence of the hernia, age at diagnosis, position of the liver and/or the deviation of the umbilical vein, stomach's position, left-to-right ventricle ratio, amniotic fluid volume, and different lung parameters such as lung diameter to thoracic circumference ratio [8e12]. These markers were not reliable when used alone, and their positive predictive value was very low. 3. Update on lung-to-head ratio (LHR) and observed-toexpected LHR in predicting outcome Because pulmonary hypoplasia is the major predictor of mortality and morbidity, it was logical to try to evaluate lung volume prenatally using ultrasound. Mektus et al. [13] first described the use of lung-to-head ratio (LHR), i.e. the ultrasonographic measurement of the fetal lung area to head circumference ratio, as a method for antenatal prediction of outcome (Fig. 1). The rationale for the use of LHR is that it provides an indirect assessment of the contralateral lung volume, and therefore the likelihood of pulmonary hypoplasia. When the LHR was first introduced, it was considered to be a gestational age-independent prognostic marker of lung hypoplasia in fetuses with CDH. Since there were no normal ranges of lung area at that time, an acceptable way to adjust for gestation was to do it with a fetal biometricl parameter that was not affected by the disease. Nevertheless, it was later demonstrated that both lungs grew faster than the head circumference in 650 normal fetuses, so that between 12 and 32 weeks of gestation there is a 16-fold increase in lung area and a four-fold increase in head circumference [14]. To a lesser degree, this was also shown in fetuses with CDH [15]. Consequently, in fetuses with normal lungs and in fetuses with CDH, the left and right LHRs increase with gestational age and it is therefore inappropriate to use LHR in a wide range of gestation with the same cut-offs used between 24 and 26 weeks. Observed-to-expected (O/E) LHR was
therefore introduced as a measure that would be independent of gestational age at measurement. There has been some confusion in the literature concerning the formula of the expected LHR to be used. First, we have always referred to the reference intervals published in 2005, where only the formulas of the tracing method were presented [14], although we have used in our calculation the expected LHR using the longest diameter method without publishing the formula. Second, we have recently published two different formulas to calculate the expected LHR using the longest diameter method. In fact, both are valid, but one uses the gestational age in complete weeks [16] and the other uses gestational age with decimals [17]. In this report, we have provided all six formulas (for use with gestational age expressed in complete weeks and weeks plus decimals) (Table 1). Table 2 summarizes single-center studies using LHR in CDH and highlights the methodological limitations and potential biases that could have been introduced in each of these studies. The metaanalysis by Ba’ath et al. failed to highlight the methodological errors in previous studies with LHR and uses exclusion criteria based on that and therefore cannot be considered as conclusive [31]. Our earlier study of 354 cases of isolated CDH, which remains the largest to date, had the disadvantage of being a multicenter study which potentially could introduce bias due to non-standardization of the postnatal management of CDH in the different institutions involved. Presently, determination of the O/E LHR provides a useful prediction of subsequent survival. The sensitivity in the prediction of survival, however, is only 46% for a false-positive rate of 10% independently of liver position. LHR as well as other measurements obtained by twodimensional (2D) ultrasonography assess lung size through 2D measurement of the lung surface area. Therefore, due to the huge improvement in ultrasound technology in the last decade, it is currently possible to determine the lung volume threedimensionally (3D). Two studies have shown that lung volume can be estimated by 3D imaging and correlated with neonatal outcome. This volume is well correlated with morbidity, but is still operator- and ultrasound machine-dependent and does not seem to be a better predictor than LHR measurements, which can be performed with 2D ultrasonography [32,33]. 4. Liver position
Fig. 1. Lung-to-head ratio measurement using the longest axis method: in a fourchamber view of the heart, measurement of the largest length multiplied by the greatest width and divided by the cephalic perimeter.
In addition to LHR or total fetal lung volume measurements, the severity of CDH is often estimated based on the non-quantitative presence or absence of intrathoracic liver [34,35]. Until recently, the latter was often used as a categoric marker. Subsequently, the degree of volumetric intrathoracic liver herniation, determined using magnetic resonance imaging (MRI), was better than nonquantitative “liver-up” versus “liver-down” anatomy in the prediction of postnatal survival [30,36e38]. Intrathoracic position of the liver is more easily evaluated prenatally by MRI than by prenatal ultrasound due to the difference in tissue contrast between the liver and other intrathoracic structures such as the lungs [39]. Furthermore, intrathoracic quantification of liver herniation has only been described on MRI and seems to be a very promising predictive marker of postnatal survival in CDH [36,37,40]. Intrathoracic liver quantification has never previously been described using prenatal ultrasound. This is probably due to the difficulty of distinguishing between liver, bowels and lungs, all of which have nearly the same echogenicity. In contrast, the stomach is an anechogenic structure, which is very easy to recognize on ultrasound. In a large number of cases of left-sided CDH, the stomach is in an intrathoracic position and is often used as an
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Table 1 Formulas for expected lung-to-head ratio (LHR) in left- and right-sided congenital diaphragmatic hernia (CDH), using different methods for lung area measurements, based on gestational age in complete weeks (GA) or GA with decimals. Method for lung area measurement
Right LHR in left-sided CDH
Anterioreposterior method Longest diameter method Tracing method
Left LHR in right-sided CDH
GA with decimals
GA in complete weeks
GA with decimals
GA in complete weeks
3.1597 þ (0.3615 GA) (0.0041 GA2) 3.4802 þ (0.3995 GA) (0.0048 GA2) 2.3271 þ (0.27 GA) (0.0032 GA2)
3.0055 þ (0.359 GA) (0.0042 GA2) 3.3148 þ (0.3972 GA) (0.0049 GA2) 2.2184 þ (0.2684 GA) (0.0032 GA2)
1.0224 þ (0.1314 GA) (0.0011 GA2) 2.5957 þ (0.3043 GA) (0.0042 GA2) 1.4994 þ (0.1778 GA) (0.0021 GA2)
0.9624 þ (0.1305 GA) (0.0011 GA2) 2.4497 þ (0.2998 GA) (0.0042 GA2) 1.4247 þ (0.1765 GA) (0.0021 GA2)
indirect sign for diagnosis of CDH. Kitano et al. were the first to describe in CDH a simple method of stomach grading, using 2D ultrasound, and showed a relationship between stomach position and the proportion of fetuses with intrathoracic liver [41]. Recently, we described a different method of stomach grading and showed a significant correlation between this method and the degree of intrathoracic liver, rather than the proportion of cases with intrathoracic liver [42]. We have shown that, in left-sided CDH, describing the stomach position in relation to the heart using ultrasound can be used as a simple indirect marker of intrathoracic liver position and/or liver quantification. We have also shown that, in expectantly managed CDH, stomach position and O/E LHR independently predicted postnatal survival, plus long-term morbidity (unpublished data).
measured with high reliability [45]. Prediction of fetal outcome in CDH by MRI is feasible and might be more accurate than 2D LHR [46]. In a recent single-center study, Bebbington et al. reported the postnatal outcome of 85 fetuses with isolated CDH over a nine-year period [30]. They showed that MRI parameters, namely the O/E total fetal lung volume and percent herniated liver, offered a better predictive value than LHR and O/E LHR. Finally, MRI lung volume measurement is superior to ultrasound not only because of its better prediction of postnatal survival, but also its greater repeatability. In a recent study we have shown that intra-observer variability of fetal lung volume measurements is higher for 3D ultrasound than for MRI, in the absence of experience with either one of the methods [47]. This difference seems to be even more pronounced when comparing intra-observer variabilities of experienced operators for the respective imaging modality.
5. Advances in fetal MRI assessment of lung volume Fetal MRI is widely used in the evaluation of fetal lung disorders including CDH [43], and is currently the referral technique for fetal lung volume estimation [44]. Shorter acquisition time eliminates the problem of fetal movements, but further improvement in resolution is needed to use this technique earlier in gestation (Fig. 2). Lung volume measurement by MRI has been shown to be accurate, and both the contra- and ipsilateral lung can be visualized and
6. Update on prenatal assessment of persistent pulmonary hypertension Neonatal death is a consequence of pulmonary hypoplasia, but also of pulmonary hypertension. This represents the weak point of prenatal prognostic assessment. Although fetal volume estimation is now feasible by 2D ultrasound, 3D ultrasound or MRI determinations, the prediction of occurrence and severity of
Table 2 Single-center studies reporting the value of fetal lung area to head circumference ratio (LHR) in the prediction of survival in isolated congenital diaphragmatic hernia (CDH), with their methodological limitations and potential biases. Study
N
Intrathoracic liver
Gestational age at LHR measurement (weeks)
LHR predictive
Methodological limitations and potential biases
None Percentage with intrathoracic liver not given, small series Small series Percentage with intrathoracic liver not given Relatively wide range of gestation at LHR measurement, assessment only in fetuses with intra-abdominal liver, small series Relatively wide range of gestation at LHR measurement, percentage with intrathoracic liver not given, small series Using LHR in right CDH instead of O/E LHR, wide range of gestation at LHR measurement, small series Small group with intrathoracic liver in a relatively small series, wide range of gestation at LHR measurement and O/E LHR not used Wide range of gestation at LHR measurement and O/E LHR not used Wide range of gestation at LHR measurement and O/E LHR not used Relatively small series, small group with intrathoracic liver. Small group with intrathoracic liver Wide range of gestation at LHR measurement and O/E LHR not used Percentage of fetuses with intrathoracic liver not given
Metkus et al. 1996 [13] Lipshutz et al. 1997 [18] Harrison et al. 1998 [19] Flake et al. 2000 [20] Sbragia et al. 2000 [21]
38 15 13 47 20
80% Not given 100% Not given 0%
25 24e26 20 23e25 16e26
Yes Yes Yes Yes No
Laudy et al. 2003 [22]
21
Not given
28e37
Yes
Heling et al. 2005 [23]
22
64%
16e38
No
Arkovitz et al. 2007 [24]
28
33%
17e36
No
Hedrick et al. 2007 [25]
89
55%
19e36
Yes
107
82%
20e34
Yes
22e28 18e38 22e39
Yes Yes Yes
18e39
Yes
Yang et al. 2007 [26]
a
Datin-Dorriere et al. 2008 [27] Alfaraj et al. 2011 [28] Aspelund et al. 2011 [29]
28 72 70
27% 31% 60%
Bebbington et al. 2014 [30]
85
Not given
a
For the whole series of 79 patients. Percentage of liver herniation for the series of 28 fetuses where an LHR measurement is not given.
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Fig. 2. Magnetic resonance imaging of a fetus with left congenital diaphragmatic hernia (CDH). Left-sided CDH at 27 weeks of gestation, showing (a) in sagittal plane a massive liver herniation (arrow) and (b) in axial plane, herniation of the liver (Li), stomach (St), small bowels (SB). H, heart; LL, left lung; RL, right lung.
pulmonary hypertension is still part of research programs. Lung volume is not always correlated with lung function. Ideally, we should be able to predict persistent pulmonary hypertension (PPHT) independently of pulmonary hypoplasia. The use of Doppler measurements for lung vasculature assessment has been reported in numerous studies. With advancing gestational age, there is an increase in perfusion and a decrease in vascular resistance and pressure, which reflects the increasing cross-sectional capillary area with lung development and maturation [48,49]. Several techniques can be used to image and quantify pulmonary blood flow and vascularization. Pulmonary artery Doppler and resistance index (RI), pulsatility index (PI) [50], and peak systolic velocity (PSV) [51] are not used in clinical practice as they are not predictive of PPHT or outcome and are dependent on O/E LHR [52]. Fuke et al. have suggested that when the acceleration time/ejection time ratio decreases, the risk of PPHT is higher. Although interesting, the measurement of this ratio was reproducible in both lungs in only nine out of 16 cases [53]. The diameter of the main pulmonary arteries has been studied, but is correlated with pulmonary hypoplasia, not with vascular development [54]. One study has shown that the McGoon index [(right pulmonary artery diameter þ left pulmonary artery diameter)/aorta diameter] measured by MRI is correlated with PPHT at three weeks of life [55]. Power Doppler imaging has been used, but results in a qualitative evaluation only and does not predict morbidity accurately [56]. Fractional moving blood flow [57] has also been evaluated, as has the use of vascular indices measured with 3D ultrasonography [58]. With 2D ultrasonography, vascular bed study is limited to a 2D plane chosen in a subjective manner. Three-dimensional ultrasonography, which allows evaluation of the volume and quantification of the Doppler signal in the whole organ, could therefore be the method of choice for predicting pulmonary hypertension. Hyperoxygenation tests have been developed as it is well known that high concentrations of O2 given to the mother increase
pulmonary blood flow secondary to a decrease in pulmonary circulation resistance. These tests seem to be independent of O/E LRH and predictive of postnatal severity of CDH, but are only useful after 28 weeks when the alveolar lung stage of development is beginning [59]. Notwithstanding these publications, such measurements are not easily reproducible in daily practice. Blood flow decrease in the pulmonary vessels due to the increase in vascular resistance as well as the distortion of the vessels due to the visceral herniation itself prevent accurate measurement of the various parameters studied. 7. Right diaphragmatic hernia Right diaphragmatic hernia accounts for 15% of all cases of CDH. The exact prognosis of right CDH is difficult to evaluate because: (i) 50e80% of literature cases are diagnosed prenatally and isolated cases are often mixed with syndromic cases; (ii) subgroup analyses have been performed in large studies from various institutions using different postnatal protocols; (iii) the side of the hernia is often not taken into account in subgroup analysis; and (iv) few right hernias are included in subgroup analysis. For the purposes of statistical analysis, cases of left and right CDH have often been studied together, but we now know that this should not be done. The overall severity of right CDH compared to left CDH remains controversial. Schaible et al. have reported that in terms of mortality the outcome of right CDH is the same (or even better), but that right CDH carries a higher risk of long-term morbidity, especially that of chronic lung disease [60]. Survival after extracorporeal membrane oxygenation was higher in right (88%) than in left-sided CDH (38%). The authors hypothesized that the outcome of right CDH is better because left heart underdevelopment is commonly observed in fetuses with left CDH, due to compression of the left atrium by herniated abdominal organs, redistribution of fetal cardiac output and/or low pulmonary venous return. Preferential right
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ultrasound scan by a well-trained sonographer, as well as fetal echocardiography. The use of microarrays in addition to regular karyotyping is discussed elsewhere in this issue. O/E LHR is now used worldwide, but sonographers must be trained in performing this measurement. The percentage obtained with this measurement should be the same as the relative volume obtained by MRI, especially if the two examinations are done on the same day. The size of the stomach might vary from one day to another and therefore modify the comparison, but not enough to alter the prognosis (unpublished data). Further work is required to refine methods to prognosticate right CDH. We present herein an algorithm that can be used to evaluate the prognosis of fetuses with CDH (Fig. 3). In order to evaluate PPHT it is mandatory to find a way of analyzing the resistance of the more distal vessels, not the main pulmonary arteries which are only correlated with the degree of pulmonary hypoplasia. More research in this field is needed, to correlate with early and long-term outcomes.
Practice points
Fig. 3. Algorithm for the management of a fetus with congenital diaphragmatic hernia (CDH). LHR O/E: observed/expected lung-to-head ratio; US, ultrasound; MRI, magnetic resonance imaging; Li, Liver; TR, Thoracic Ratio; TLV, total lung volume; WA, week of amenorrhea.
or left heart underdevelopment is not usually a feature of right CDH. Stressig et al. have shown that in left CDH, ductus venosus and inferior cava vein streaming are preferentially directed toward the fetal right heart, suggesting a hemodynamic mechanism for left heart underdevelopment [61]. The ability to prenatally prognosticate right CDH outcome is poorly understood. Since all right CDH patients have liver herniation, this factor is less predictive. The reverse LHR or O/E LHR and lung volumes have not been shown to be consistently accurate. Although the extremes of severity (e.g. liver herniated to top of the hemithorax with corresponding tiny lung volumes) may be predictive, a graded system of prediction has not been established. Only one study has assessed prognostic factors for right CDH separately from left CDH [15]. For right CDH (25/329 left), the overall survival was 44% and O/E LHR
Contents lists available at ScienceDirect
Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/siny
Review
Advances in prenatal diagnosis of congenital diaphragmatic hernia €l Cordier a, b, Mieke Cannie c, Jacques Jani d Alexandra Benachi a, b, *, Anne-Gae a
Department of Obstetrics, Gynecology and Reproductive Medicine, Hospital Antoine Beclere, APHP, Paris Sud University, Clamart, France Centre Maladies Rares: Hernie de Coupole Diaphragmatique, Hospital Antoine Beclere, APHP, Clamart, France c Department of Radiology, University Hospital Brugmann, Brussels, Belgium d Department of Obstetrics and Gynecology, University Hospital Brugmann, Brussels, Belgium b
s u m m a r y Keywords: Congenital diaphragmatic hernia Prenatal ultrasound Magnetic resonance imaging Lung-to-head ratio
Over the past 20 years, prenatal detection of congenital diaphragmatic hernia (CDH) has improved worldwide, reaching up to 60% in Europe. Pulmonary hypoplasia and persistent pulmonary hypertension are the two main determinants of neonatal mortality and morbidity, so new tools have been focused on their evaluation. Fetal surgery for severe cases requires proper evaluation of the prognosis of fetuses with CDH. Observed-to-expected lung-to-head ratio, liver position, and total lung volume measured by magnetic resonance are the prognostic factors most often used, and have been shown to correlate not only with neonatal mortality but also with morbidity. In daily practice, pulmonary hypertension by itself, although most often associated with lung hypoplasia, is more difficult to predict. © 2014 Published by Elsevier Ltd.
1. Introduction Congenital diaphragmatic hernia (CDH) is a widespread abnormality, with an incidence of one in 2500 live births [1]. Prenatal detection rates by ultrasound reach up to 60% in Europe [2]. In isolated cases, postnatal mortality can vary between 15% and 50%, especially when population-based studies are considered [2,3]. The prenatal diagnosis of this malformation has improved worldwide over the past 20 years and it has been well established that organizing the birth of affected fetuses in a center with an optimal neonatal intensive care unit and pediatric surgery improves outcome. Selected centers with a high case load of CDH per year report an increase in survival rates [4,5]. Twenty years ago, survival was also around 60%, but we were not dealing with the same sorts of babies. Today, as more than half of cases [1] are diagnosed prenatally, the hidden mortality is lower and fetuses that are taken care of in pediatric surgery departments happen to have, overall, more severe forms than before. Various factors have improved the outcome of CDH babies: improvement of prenatal diagnosis and of prenatal evaluation of postnatal prognosis, delivery in appropriate centers and improvement of postnatal care. Pulmonary hypoplasia and persistent pulmonary hypertension are the two main determinants of neonatal mortality and
* Corresponding author. Address: Department of Obstetrics, Gynecology and cle re, 92140 Clamart, France. Tel.: þ33 1 Reproductive Medicine, Hospital Antoine Be 45374476; fax: þ 33 1 45374967. E-mail address: [email protected] (A. Benachi). http://dx.doi.org/10.1016/j.siny.2014.09.005 1744-165X/© 2014 Published by Elsevier Ltd.
morbidity, so new tools have been focused on their evaluation. Fetal surgery for severe cases requires proper evaluation of the prognosis of fetuses with CDH. It is very important to identify reliable prenatal prognostic factors that can be used worldwide for the following reasons: (i) patient counseling is more accurate; (ii) the results of pre- and postnatal treatments will be comparable across different institutions; (iii) fetuses eligible for fetal surgery will be selected correctly; and (iv) a woman expecting a child with a very poor prognosis can prepare herself for the postnatal demise of her baby or, in some countries, opt for termination of pregnancy. In countries such as France, proper prognostic evaluation is saving fetuses with good and fair prognosis, because women have the option to terminate the pregnancy only when the prognosis is poor. 2. Brief history of prenatal evaluation in CDH Fetal surgical correction of the diaphragmatic defect in utero, first performed by Harrison, was proposed for all patients with isolated CDH. In 1993 it was shown that fetuses with herniated liver in the thorax died during or immediately after surgery due to ductus-venosus plicature [6]. Harrison's team therefore decided to offer the in-utero treatment only to those cases with intraabdominal liver. In 1998, a randomized controlled trial showed that open in-utero surgery was unable to improve neonatal mortality, length of hospital stay or requirement for extracorporeal membrane oxygenation in the CDH group compared with the control group given standardized postnatal care [7]. Fetuses with
332
A. Benachi et al. / Seminars in Fetal & Neonatal Medicine 19 (2014) 331e337
liver in the abdomen are now known to have the best prognosis, which highlights the fact that the key to success in fetal intervention is proper patient selection. It should be pointed out that at the time of this trial, prognostic evaluation of CDH was unreliable, and that clinicians had very few prenatal ultrasound markers. The prognosis was given to the parents of the enrolled fetuses on the basis of various markers, including left or right occurrence of the hernia, age at diagnosis, position of the liver and/or the deviation of the umbilical vein, stomach's position, left-to-right ventricle ratio, amniotic fluid volume, and different lung parameters such as lung diameter to thoracic circumference ratio [8e12]. These markers were not reliable when used alone, and their positive predictive value was very low. 3. Update on lung-to-head ratio (LHR) and observed-toexpected LHR in predicting outcome Because pulmonary hypoplasia is the major predictor of mortality and morbidity, it was logical to try to evaluate lung volume prenatally using ultrasound. Mektus et al. [13] first described the use of lung-to-head ratio (LHR), i.e. the ultrasonographic measurement of the fetal lung area to head circumference ratio, as a method for antenatal prediction of outcome (Fig. 1). The rationale for the use of LHR is that it provides an indirect assessment of the contralateral lung volume, and therefore the likelihood of pulmonary hypoplasia. When the LHR was first introduced, it was considered to be a gestational age-independent prognostic marker of lung hypoplasia in fetuses with CDH. Since there were no normal ranges of lung area at that time, an acceptable way to adjust for gestation was to do it with a fetal biometricl parameter that was not affected by the disease. Nevertheless, it was later demonstrated that both lungs grew faster than the head circumference in 650 normal fetuses, so that between 12 and 32 weeks of gestation there is a 16-fold increase in lung area and a four-fold increase in head circumference [14]. To a lesser degree, this was also shown in fetuses with CDH [15]. Consequently, in fetuses with normal lungs and in fetuses with CDH, the left and right LHRs increase with gestational age and it is therefore inappropriate to use LHR in a wide range of gestation with the same cut-offs used between 24 and 26 weeks. Observed-to-expected (O/E) LHR was
therefore introduced as a measure that would be independent of gestational age at measurement. There has been some confusion in the literature concerning the formula of the expected LHR to be used. First, we have always referred to the reference intervals published in 2005, where only the formulas of the tracing method were presented [14], although we have used in our calculation the expected LHR using the longest diameter method without publishing the formula. Second, we have recently published two different formulas to calculate the expected LHR using the longest diameter method. In fact, both are valid, but one uses the gestational age in complete weeks [16] and the other uses gestational age with decimals [17]. In this report, we have provided all six formulas (for use with gestational age expressed in complete weeks and weeks plus decimals) (Table 1). Table 2 summarizes single-center studies using LHR in CDH and highlights the methodological limitations and potential biases that could have been introduced in each of these studies. The metaanalysis by Ba’ath et al. failed to highlight the methodological errors in previous studies with LHR and uses exclusion criteria based on that and therefore cannot be considered as conclusive [31]. Our earlier study of 354 cases of isolated CDH, which remains the largest to date, had the disadvantage of being a multicenter study which potentially could introduce bias due to non-standardization of the postnatal management of CDH in the different institutions involved. Presently, determination of the O/E LHR provides a useful prediction of subsequent survival. The sensitivity in the prediction of survival, however, is only 46% for a false-positive rate of 10% independently of liver position. LHR as well as other measurements obtained by twodimensional (2D) ultrasonography assess lung size through 2D measurement of the lung surface area. Therefore, due to the huge improvement in ultrasound technology in the last decade, it is currently possible to determine the lung volume threedimensionally (3D). Two studies have shown that lung volume can be estimated by 3D imaging and correlated with neonatal outcome. This volume is well correlated with morbidity, but is still operator- and ultrasound machine-dependent and does not seem to be a better predictor than LHR measurements, which can be performed with 2D ultrasonography [32,33]. 4. Liver position
Fig. 1. Lung-to-head ratio measurement using the longest axis method: in a fourchamber view of the heart, measurement of the largest length multiplied by the greatest width and divided by the cephalic perimeter.
In addition to LHR or total fetal lung volume measurements, the severity of CDH is often estimated based on the non-quantitative presence or absence of intrathoracic liver [34,35]. Until recently, the latter was often used as a categoric marker. Subsequently, the degree of volumetric intrathoracic liver herniation, determined using magnetic resonance imaging (MRI), was better than nonquantitative “liver-up” versus “liver-down” anatomy in the prediction of postnatal survival [30,36e38]. Intrathoracic position of the liver is more easily evaluated prenatally by MRI than by prenatal ultrasound due to the difference in tissue contrast between the liver and other intrathoracic structures such as the lungs [39]. Furthermore, intrathoracic quantification of liver herniation has only been described on MRI and seems to be a very promising predictive marker of postnatal survival in CDH [36,37,40]. Intrathoracic liver quantification has never previously been described using prenatal ultrasound. This is probably due to the difficulty of distinguishing between liver, bowels and lungs, all of which have nearly the same echogenicity. In contrast, the stomach is an anechogenic structure, which is very easy to recognize on ultrasound. In a large number of cases of left-sided CDH, the stomach is in an intrathoracic position and is often used as an
A. Benachi et al. / Seminars in Fetal & Neonatal Medicine 19 (2014) 331e337
333
Table 1 Formulas for expected lung-to-head ratio (LHR) in left- and right-sided congenital diaphragmatic hernia (CDH), using different methods for lung area measurements, based on gestational age in complete weeks (GA) or GA with decimals. Method for lung area measurement
Right LHR in left-sided CDH
Anterioreposterior method Longest diameter method Tracing method
Left LHR in right-sided CDH
GA with decimals
GA in complete weeks
GA with decimals
GA in complete weeks
3.1597 þ (0.3615 GA) (0.0041 GA2) 3.4802 þ (0.3995 GA) (0.0048 GA2) 2.3271 þ (0.27 GA) (0.0032 GA2)
3.0055 þ (0.359 GA) (0.0042 GA2) 3.3148 þ (0.3972 GA) (0.0049 GA2) 2.2184 þ (0.2684 GA) (0.0032 GA2)
1.0224 þ (0.1314 GA) (0.0011 GA2) 2.5957 þ (0.3043 GA) (0.0042 GA2) 1.4994 þ (0.1778 GA) (0.0021 GA2)
0.9624 þ (0.1305 GA) (0.0011 GA2) 2.4497 þ (0.2998 GA) (0.0042 GA2) 1.4247 þ (0.1765 GA) (0.0021 GA2)
indirect sign for diagnosis of CDH. Kitano et al. were the first to describe in CDH a simple method of stomach grading, using 2D ultrasound, and showed a relationship between stomach position and the proportion of fetuses with intrathoracic liver [41]. Recently, we described a different method of stomach grading and showed a significant correlation between this method and the degree of intrathoracic liver, rather than the proportion of cases with intrathoracic liver [42]. We have shown that, in left-sided CDH, describing the stomach position in relation to the heart using ultrasound can be used as a simple indirect marker of intrathoracic liver position and/or liver quantification. We have also shown that, in expectantly managed CDH, stomach position and O/E LHR independently predicted postnatal survival, plus long-term morbidity (unpublished data).
measured with high reliability [45]. Prediction of fetal outcome in CDH by MRI is feasible and might be more accurate than 2D LHR [46]. In a recent single-center study, Bebbington et al. reported the postnatal outcome of 85 fetuses with isolated CDH over a nine-year period [30]. They showed that MRI parameters, namely the O/E total fetal lung volume and percent herniated liver, offered a better predictive value than LHR and O/E LHR. Finally, MRI lung volume measurement is superior to ultrasound not only because of its better prediction of postnatal survival, but also its greater repeatability. In a recent study we have shown that intra-observer variability of fetal lung volume measurements is higher for 3D ultrasound than for MRI, in the absence of experience with either one of the methods [47]. This difference seems to be even more pronounced when comparing intra-observer variabilities of experienced operators for the respective imaging modality.
5. Advances in fetal MRI assessment of lung volume Fetal MRI is widely used in the evaluation of fetal lung disorders including CDH [43], and is currently the referral technique for fetal lung volume estimation [44]. Shorter acquisition time eliminates the problem of fetal movements, but further improvement in resolution is needed to use this technique earlier in gestation (Fig. 2). Lung volume measurement by MRI has been shown to be accurate, and both the contra- and ipsilateral lung can be visualized and
6. Update on prenatal assessment of persistent pulmonary hypertension Neonatal death is a consequence of pulmonary hypoplasia, but also of pulmonary hypertension. This represents the weak point of prenatal prognostic assessment. Although fetal volume estimation is now feasible by 2D ultrasound, 3D ultrasound or MRI determinations, the prediction of occurrence and severity of
Table 2 Single-center studies reporting the value of fetal lung area to head circumference ratio (LHR) in the prediction of survival in isolated congenital diaphragmatic hernia (CDH), with their methodological limitations and potential biases. Study
N
Intrathoracic liver
Gestational age at LHR measurement (weeks)
LHR predictive
Methodological limitations and potential biases
None Percentage with intrathoracic liver not given, small series Small series Percentage with intrathoracic liver not given Relatively wide range of gestation at LHR measurement, assessment only in fetuses with intra-abdominal liver, small series Relatively wide range of gestation at LHR measurement, percentage with intrathoracic liver not given, small series Using LHR in right CDH instead of O/E LHR, wide range of gestation at LHR measurement, small series Small group with intrathoracic liver in a relatively small series, wide range of gestation at LHR measurement and O/E LHR not used Wide range of gestation at LHR measurement and O/E LHR not used Wide range of gestation at LHR measurement and O/E LHR not used Relatively small series, small group with intrathoracic liver. Small group with intrathoracic liver Wide range of gestation at LHR measurement and O/E LHR not used Percentage of fetuses with intrathoracic liver not given
Metkus et al. 1996 [13] Lipshutz et al. 1997 [18] Harrison et al. 1998 [19] Flake et al. 2000 [20] Sbragia et al. 2000 [21]
38 15 13 47 20
80% Not given 100% Not given 0%
25 24e26 20 23e25 16e26
Yes Yes Yes Yes No
Laudy et al. 2003 [22]
21
Not given
28e37
Yes
Heling et al. 2005 [23]
22
64%
16e38
No
Arkovitz et al. 2007 [24]
28
33%
17e36
No
Hedrick et al. 2007 [25]
89
55%
19e36
Yes
107
82%
20e34
Yes
22e28 18e38 22e39
Yes Yes Yes
18e39
Yes
Yang et al. 2007 [26]
a
Datin-Dorriere et al. 2008 [27] Alfaraj et al. 2011 [28] Aspelund et al. 2011 [29]
28 72 70
27% 31% 60%
Bebbington et al. 2014 [30]
85
Not given
a
For the whole series of 79 patients. Percentage of liver herniation for the series of 28 fetuses where an LHR measurement is not given.
334
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Fig. 2. Magnetic resonance imaging of a fetus with left congenital diaphragmatic hernia (CDH). Left-sided CDH at 27 weeks of gestation, showing (a) in sagittal plane a massive liver herniation (arrow) and (b) in axial plane, herniation of the liver (Li), stomach (St), small bowels (SB). H, heart; LL, left lung; RL, right lung.
pulmonary hypertension is still part of research programs. Lung volume is not always correlated with lung function. Ideally, we should be able to predict persistent pulmonary hypertension (PPHT) independently of pulmonary hypoplasia. The use of Doppler measurements for lung vasculature assessment has been reported in numerous studies. With advancing gestational age, there is an increase in perfusion and a decrease in vascular resistance and pressure, which reflects the increasing cross-sectional capillary area with lung development and maturation [48,49]. Several techniques can be used to image and quantify pulmonary blood flow and vascularization. Pulmonary artery Doppler and resistance index (RI), pulsatility index (PI) [50], and peak systolic velocity (PSV) [51] are not used in clinical practice as they are not predictive of PPHT or outcome and are dependent on O/E LHR [52]. Fuke et al. have suggested that when the acceleration time/ejection time ratio decreases, the risk of PPHT is higher. Although interesting, the measurement of this ratio was reproducible in both lungs in only nine out of 16 cases [53]. The diameter of the main pulmonary arteries has been studied, but is correlated with pulmonary hypoplasia, not with vascular development [54]. One study has shown that the McGoon index [(right pulmonary artery diameter þ left pulmonary artery diameter)/aorta diameter] measured by MRI is correlated with PPHT at three weeks of life [55]. Power Doppler imaging has been used, but results in a qualitative evaluation only and does not predict morbidity accurately [56]. Fractional moving blood flow [57] has also been evaluated, as has the use of vascular indices measured with 3D ultrasonography [58]. With 2D ultrasonography, vascular bed study is limited to a 2D plane chosen in a subjective manner. Three-dimensional ultrasonography, which allows evaluation of the volume and quantification of the Doppler signal in the whole organ, could therefore be the method of choice for predicting pulmonary hypertension. Hyperoxygenation tests have been developed as it is well known that high concentrations of O2 given to the mother increase
pulmonary blood flow secondary to a decrease in pulmonary circulation resistance. These tests seem to be independent of O/E LRH and predictive of postnatal severity of CDH, but are only useful after 28 weeks when the alveolar lung stage of development is beginning [59]. Notwithstanding these publications, such measurements are not easily reproducible in daily practice. Blood flow decrease in the pulmonary vessels due to the increase in vascular resistance as well as the distortion of the vessels due to the visceral herniation itself prevent accurate measurement of the various parameters studied. 7. Right diaphragmatic hernia Right diaphragmatic hernia accounts for 15% of all cases of CDH. The exact prognosis of right CDH is difficult to evaluate because: (i) 50e80% of literature cases are diagnosed prenatally and isolated cases are often mixed with syndromic cases; (ii) subgroup analyses have been performed in large studies from various institutions using different postnatal protocols; (iii) the side of the hernia is often not taken into account in subgroup analysis; and (iv) few right hernias are included in subgroup analysis. For the purposes of statistical analysis, cases of left and right CDH have often been studied together, but we now know that this should not be done. The overall severity of right CDH compared to left CDH remains controversial. Schaible et al. have reported that in terms of mortality the outcome of right CDH is the same (or even better), but that right CDH carries a higher risk of long-term morbidity, especially that of chronic lung disease [60]. Survival after extracorporeal membrane oxygenation was higher in right (88%) than in left-sided CDH (38%). The authors hypothesized that the outcome of right CDH is better because left heart underdevelopment is commonly observed in fetuses with left CDH, due to compression of the left atrium by herniated abdominal organs, redistribution of fetal cardiac output and/or low pulmonary venous return. Preferential right
A. Benachi et al. / Seminars in Fetal & Neonatal Medicine 19 (2014) 331e337
335
ultrasound scan by a well-trained sonographer, as well as fetal echocardiography. The use of microarrays in addition to regular karyotyping is discussed elsewhere in this issue. O/E LHR is now used worldwide, but sonographers must be trained in performing this measurement. The percentage obtained with this measurement should be the same as the relative volume obtained by MRI, especially if the two examinations are done on the same day. The size of the stomach might vary from one day to another and therefore modify the comparison, but not enough to alter the prognosis (unpublished data). Further work is required to refine methods to prognosticate right CDH. We present herein an algorithm that can be used to evaluate the prognosis of fetuses with CDH (Fig. 3). In order to evaluate PPHT it is mandatory to find a way of analyzing the resistance of the more distal vessels, not the main pulmonary arteries which are only correlated with the degree of pulmonary hypoplasia. More research in this field is needed, to correlate with early and long-term outcomes.
Practice points
Fig. 3. Algorithm for the management of a fetus with congenital diaphragmatic hernia (CDH). LHR O/E: observed/expected lung-to-head ratio; US, ultrasound; MRI, magnetic resonance imaging; Li, Liver; TR, Thoracic Ratio; TLV, total lung volume; WA, week of amenorrhea.
or left heart underdevelopment is not usually a feature of right CDH. Stressig et al. have shown that in left CDH, ductus venosus and inferior cava vein streaming are preferentially directed toward the fetal right heart, suggesting a hemodynamic mechanism for left heart underdevelopment [61]. The ability to prenatally prognosticate right CDH outcome is poorly understood. Since all right CDH patients have liver herniation, this factor is less predictive. The reverse LHR or O/E LHR and lung volumes have not been shown to be consistently accurate. Although the extremes of severity (e.g. liver herniated to top of the hemithorax with corresponding tiny lung volumes) may be predictive, a graded system of prediction has not been established. Only one study has assessed prognostic factors for right CDH separately from left CDH [15]. For right CDH (25/329 left), the overall survival was 44% and O/E LHR
