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Reliability of the lung-to-head ratio as a predictor of outcome in fetuses with isolated left congenital diaphragmatic hernia at gestation outside 24-26 weeks
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Reliability of the lung-to-head ratio as a predictor of outcome in fetuses with isolated left congenital diaphragmatic hernia at gestation outside 24-26 weeks Soon Ha Yang, MD, PhD; Kerilyn K. Nobuhara, MD; Roberta L. Keller, MD; Robert H. Ball, MD; Ruth B. Goldstein, MD; Vickie A. Feldstein, MD; Peter W. Callen, MD; Roy A. Filly, MD; Diana L. Farmer, MD; Michael R. Harrison, MD; Hanmin Lee, MD OBJECTIVE: The purpose of this study was to investigate the relationship between lung-to-head ratio (LHR) and gestational age (GA) in fetuses with isolated left congenital diaphragmatic hernia and to determine the applicability and reliability of LHR to predict postnatal outcome beyond 24-26 weeks of gestation. STUDY DESIGN: The institutional review board approved this retro-
spective review of the University of California, San Francisco, Fetal Treatment Center database for cases with left congenital diaphragmatic hernia who were referred between March 1995 and June 2004. LHR was determined at the initial evaluation. One hundred seven live-born fetuses at 20-34 weeks of gestation (excluding cases that were lost to follow-up, with factors that potentially could influence the LHR measurement or postnatal outcome, or that were terminated electively). RESULTS: The median GA at LHR measurement was 25.6 weeks; the
median LHR was 1.01; the median GA at birth was 37.7 weeks; and the overall survival rate was 59% (64/107). The median LHR of nonsurvivors was significantly lower than that of survivors, but neither GA at LHR measurement nor at delivery was significantly different between the groups. Multiple logistic regression analysis confirmed LHR to be an independent predictor of postnatal survival, and receiver-operator
characteristic curve analysis demonstrated that an LHR of ⱖ0.97 has the highest performance in predicting postnatal survival. When fetuses were grouped by GA at initial LHR measurement to determine reliability of LHR, specifically with respect to GA, in the 26-34 and 24-26 weeks of gestation groups, median LHR of survivors was significantly higher than that of nonsurvivors, and receiver-operator characteristic curve analysis confirmed LHR to be a reliable predictor of postnatal survival. However, for fetuses at 20-24 weeks of gestation, there was a trend toward a higher LHR in survivors, although this did not reach statistical significance. CONCLUSION: A significant positive linear relationship exists between LHR and GA at the time of measurement, such that LHR reliably predicts postnatal survival in fetuses with left congenital diaphragmatic hernia at 24-34 weeks of gestation and less reliable at 20-24 weeks. However, given the limitations of a retrospective, cross-sectional study, further prospective longitudinal studies that will investigate the change of LHR with GA and its association with fetal outcome are necessary.
Key words: Lung-to-head ratio, congenital diaphragmatic hernia, survival
Cite this article as: Yang SH, Nobuhara KK, Keller RL, et al. Reliability of the lung-to-head ratio as a predictor of outcome in fetuses with isolated left congenital diaphragmatic hernia at gestation outside 24-26 weeks. Am J Obstet Gynecol 2007;197:30.e1-30.e7.
D
espite advances in prenatal diagnosis, fetal intervention, and neonatal respiratory support, a recent metaanalysis reported that the median
mortality rate of neonates with congenital diaphragmatic hernia (CDH) still remains 48%.1 Postnatal outcome of isolated CDH is determined mainly by the
From the Fetal Treatment Center (all authors) and the Departments of Surgery (Drs Nobuhara, Farmer, Harrison, and Lee), Pediatrics (Dr Keller), Obstetrics, Gynecology and Reproductive Sciences (Dr Ball), and Radiology (Drs Goldstein, Feldstein, Callen, and Filly), University of California, San Francisco, San Francisco, CA. Received June 15, 2006; accepted Jan. 16, 2007. Reprints: Hanmin Lee, MD, Fetal Treatment Center, University of California, San Francisco, 513 Parnassus Ave, Suite HSW 1601, San Francisco, CA 94143-0570; [email protected]. 0002-9378/$32.00 © 2007 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2007.01.016
See Journal Club, page 110
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severity of pulmonary hypoplasia and subsequent pulmonary hypertension refractory to therapy.2 Over the years, various sonographic and clinical parameters that indicate the extent of pulmonary hypoplasia (the primary cause of death in neonates who are born with CDH) have been proposed as prenatal prognostic factors.3-8 We previously presented the sonographically measured lung-to-head ratio (LHR), which is a ratio of the contralateral lung size compared with the head circumference, as an indicator of the severity of pulmonary hypoplasia and a predictor of postnatal outcome in a fetus with CDH.9-13
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www.AJOG.org The LHR has been regarded as the most reliable predictor of outcome when determined between 24 and 26 weeks of gestation. However, there have been few studies that have investigated the reliability of LHR to predict fetal outcome outside of that period. In practice, many referrals for ultrasound assessment do not take place between 24 and 26 weeks of gestation, and the lack of a reliable predictor of postnatal survival can be a serious dilemma, with respect to the determination of prenatal treatment and counseling. Laudy et al14 recently reported that the LHR was independent of gestational age and that the same cut-off value for postnatal outcome would be applicable to cases at different gestation other than 24-26 weeks. However, we have observed that serial ultrasound evaluation for some fetuses with CDH demonstrated an increasing LHR as gestational age advances. Therefore, the objectives of this study were to investigate a relationship between the LHR and gestational age in fetuses with isolated left CDH and to determine the applicability and reliability of the LHR as a predictor of postnatal outcome outside the period of 24-26 weeks of gestation.
M ATERIALS AND M ETHODS We retrospectively reviewed the University of California, San Francisco (UCSF), Fetal Treatment Center database for all fetuses between 20 and 34 weeks of gestation and demonstrated a prenatally diagnosed left CDH. The patient cohort was confined to those patients who were referred for prenatal evaluation from March 1995 to June 2004. The LHR was determined at the initial evaluation, before decisions regarding treatment and fetal outcome were known. Fetal echocardiography and karyotyping were performed. Cases with factors that potentially could influence the LHR measurement or postnatal outcome (ie, major congenital anomaly, chromosomal abnormality, death in utero, growth restriction, severe oligohydramnios [amniotic fluid index, ⱕ2] and multiple gestation) were excluded. We also excluded cases that underwent termination of pregnancy and that were lost
to follow-up. Gestational age was estimated on the basis of the last menstrual period, when reliable, or preferably on sonography that had been performed in the first trimester. Fetal sonography was performed at UCSF by 1 of 4 experienced sonologists for the confirmation of left CDH, complete evaluation of fetal structures, and the determination of the LHR. The LHR was obtained by visualization of a 4-chamber view of the heart on a transverse image of fetal thorax, as described in a previous report.9 Briefly, the right lung area was the product of 2 measurements: a linear distance from the atria to the ribs posteriorly and the distance of a perpendicular line from the aorta to the ribs laterally. The LHR was calculated by a simple ratio of right lung area to head circumference (in millimeters). Postnatal care was either at UCSF or at an appropriate tertiary center that was capable of extracorporeal membrane oxygenation (ECMO). The primary outcome was postnatal survival that was defined as survival to hospital discharge. Data were analyzed with SPSS statistical software (SPSS Inc, Chicago, IL). Results among gestational age groups (group 1, 20-24 weeks; group 2, 24-26 weeks; group 3, 26⫹ weeks) were compared with the use of the chi-square test, Student t test, Mann-Whitney U test, Kruskal-Wallis test, and JonckheereTerpstra test and were compared as continuous variables, as appropriate. Multiple logistic regression analysis was performed to evaluate the relationships between LHR and postnatal survival, with adjustment for confounding variables. Correlation between the LHR and gestational age at the time of the LHR measurement was described by the Spearman rank correlation. Simple linear regression analysis was used to examine a relationship between the LHR as a dependent variable and gestational age at time of the LHR measurement as an independent variable. Receiver-operator characteristic (ROC) curves were constructed to describe the relationship between the sensitivity and the false-positive rate (1-specificity) for the LHR in the prediction of postnatal survival. We used analysis of covariance (ANCOVA) to
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determine whether the LHR is an independent predictor for neonatal survival, even after being controlled for gestational age at measurement. Two-tailed ␣ value of ⬍.05 was considered statistically significant.
R ESULTS One hundred seven fetuses were included in this study, all of whom were liveborn. The median gestational age at the LHR measurement was 25.6 weeks (range, 20.4 to 34.0 weeks); the median LHR was 1.01 (range, 0.50 to 2.60). Fetuses with an LHR of ⱕ1.40 and herniated liver were candidates for fetoscopic tracheal occlusion; 29 fetuses (27%) underwent this procedure. The median gestational age at birth was 37.7 weeks (range, 25.7-41.4 weeks); 28 infants (26%) required ECMO support. The overall survival rate was 59% (64/107 infants). Table 1 presents the comparisons of clinical characteristics and neonatal outcomes between postnatal survivors and nonsurvivors. The gestational ages at LHR measurement and at delivery were not significantly different between both groups. The proportion of fetuses with herniated liver and neonates who underwent ECMO therapy was greater in nonsurvivors than in survivors. The median LHR of nonsurvivors was significantly lower than that of survivors (median, 0.95; range, 0.50 to 1.50 vs median, 1.13; range, 0.60 to 2.60, respectively; P ⬍ .0001, by Mann-Whitney U test). The ROC curve that was constructed for analysis of the performance of the LHR as a predictor of postnatal survival indicated that there was a significant relationship between the LHR and neonatal survival (area under the curve, 0.74; standard error, 0.05; P ⬍ .0001; Figure 1). With an LHR of ⱖ0.97 as the cut-off value, the highest performance in the prediction of postnatal survival showed a sensitivity of 77% and a specificity of 63%. Of 14 fetuses with a LHR of ⬎1.40, 13 fetuses (81%) survived, whereas 10 of 13 fetuses (77%) with an LHR of ⬍0.80 did not. The survival rate for fetuses with LHRs between 1.00 and 1.40 was 66% (53/80 fetuses).3 Cut off value for 100%
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TABLE 1
Clinical characteristics and neonatal outcomes of postnatal survivors and nonsurvivors Variable
Survivors (n ⴝ 64)
Nonsurvivors (n ⴝ 43)
P value
Gestational age at LHR measurement (wk)*
25.7 (22.3-34.0)
25.6 (20.4-33.0)
NS
LHR*
1.13 (0.60-2.60)
0.95 (0.5-1.50)
⬍.0001
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
Liver herniation (n)
49 (77%)
⬍.02
39 (91%)
................................................................................................................................................................................................................................................................................................................................................................................
Early diagnosis ⬍25 weeks gestation (n)
21 (33%)
12 (28%)
NS
8/46 (17%)
7/31 (23%)
NS
17 (27%)
12 (28%)
NS
................................................................................................................................................................................................................................................................................................................................................................................
Polyhydramnios (n/N)
................................................................................................................................................................................................................................................................................................................................................................................
Fetal surgery (n)
................................................................................................................................................................................................................................................................................................................................................................................
Gestational age at birth (wk)*
38.0 (27.3-40.9)
37.1 (27.4-41.4)
NS
................................................................................................................................................................................................................................................................................................................................................................................
Preterm delivery ⬍34 weeks of gestation (n)
13 (20%)
13 (30%)
NS
................................................................................................................................................................................................................................................................................................................................................................................
ECMO (n)
8 (13%)
⬍.0001
20 (47%)
................................................................................................................................................................................................................................................................................................................................................................................
NS, not significant. * Data are given as median (range).
survival and 100% mortality were an LHR of ⬎1.50 (n ⫽ 8 fetuses) and ⬍ 0.60 (n ⫽ 3 fetuses), respectively. Multiple logistic regression analysis showed that the LHR was an independent predictor of postnatal survival, even after adjustment for confounding variables such as liver herniation, fetal surgery, gestational age at delivery, gestational age at LHR measurement, and ECMO therapy (odds ratio, 24.45 [95% CI, 2.26-264.27]; P ⫽ .008; Table 2). We divided the cohort into 3 groups with respect to gestational age at the time of initial LHR measurement at our center (Table 3). Group 1 included 30 fetuses with LHRs that were measured between 20 and 24 weeks of gestation. In group 2, 38 fetuses with LHRs that were measured between 24 and 26 weeks of FIGURE 1
ROC curve shows a significant relationship between LHR and postnatal survival
gestation were identified. Thirty-nine fetuses whose LHRs were evaluated at a gestational age of ⬎26 weeks were included in group 3. There were no statistically significant differences in clinical characteristics and neonatal survival among the 3 groups. The median LHR values of the 3 gestational age groups showed not only a significant difference (group 1, 0.96 [range, 0.60 to 1.40] vs group 2, 1.10 [range, 0.50 to 1.87] vs group 3, 1.11 [range, 0.50 to 2.60]; P ⫽ .028, by Kruskal-Wallis test; Figure 2) but also an increasing tendency with gestational age (P ⫽ .01, by JonckheereTerpstra test). When we compared median LHRs between survivors and nonsurvivors in respective groups (Figure 3), the nonsurvivors in groups 2 and 3 had significantly lower LHRs than survivors (group 2, 0.95 [range, 0.50-1.40] vs 1.20 [range, 0.80-1.87]; P ⫽ .005;
group 3, 0.96 [range, 0.50-1.50] vs 1.20 [range, 0.89-2.60]; P ⫽ .016). In group 1, the nonsurvivors appeared to have lower LHRs than the survivors but not with statistical significant (0.91 [range, 0.681.36] vs 1.07 [range, 0.60-1.40]; P ⫽ .065). Figure 4 shows the ROC curves of the 3 groups that show the performance of the LHR in the prediction of postnatal survival. The ROC curves that were constructed to compare groups 2 and 3 were both above the 45-degree line, which indicated that, in both groups, LHR is related significantly to neonatal survival (group 2: area under the curve, 0.76; standard error, 0.078; P ⫽ .005; group 3: area under the curve, 0.74; standard error, 0.086; P ⫽ .02). An LHR of ⱖ1.00 as the cut-off value by ROC curve analysis for group 2 showed the highest performance in the predic-
TABLE 2
Relationships between postnatal survival and confounding factors, analyzed by multiple logistic regression Odds ratio LHR
24.45
95% CI 2.26-164.27
P value ⬍.01
..............................................................................................................................................................................................................................................
Gestational age at LHR measurement
0.89
0.72-1.10
NS
Liver herniation
0.61
0.089-4.19
NS
Gestational age at birth
1.04
0.90-1.19
NS
Fetal surgery
1.04
0.34-3.24
NS
ECMO
0.17
0.055-0.53
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
⬍.005
..............................................................................................................................................................................................................................................
NS, not significant.
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TABLE 3
Comparisons of clinical characteristics and postnatal outcome among the 3 groups, according to gestational age Variable
Group 1 (n ⴝ 30)
Group 2 (n ⴝ 38)
Group 3 (n ⴝ 39)
P value
Gestational age at LHR measurement (wk)*
23.1 (20.4-24.0)
25.3 (24.1-26.0)
27.6 (26.1-34.0)
⬍.0001
LHR*
0.96 (0.60-1.40)
1.02 (0.50-1.87)
1.11 (0.50-2.60)
⬍.05
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
Liver herniation (n)
27 (90%)
31/37 (84%)
30/37 (81%)
NS
3/26 (12%)
10/28 (36%)
⬍.05
11 (29%)
7 (18%)
................................................................................................................................................................................................................................................................................................................................................................................
Polyhydramnios (n)
2/23 (9%)
................................................................................................................................................................................................................................................................................................................................................................................
Fetal surgery (n)
11 (36%)
NS
................................................................................................................................................................................................................................................................................................................................................................................
Gestational age at birth (wk)*
36.3 (27.3-39.6)
37.5 (27.4-41.4)
38.1 (29.9-40.9)
⬍.05
................................................................................................................................................................................................................................................................................................................................................................................
Preterm delivery ⬍34 week of gestation (n)
10 (32%)
ECMO (n)
12 (40%)
Survival (n)
18 (60%)
11 (29%)
5 (13%)
NS
8 (21%)
8 (21%)
NS
20 (53%)
26 (67%)
NS
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
NS, not significant. * Data are given as median (range).
tion of postnatal survival, with a sensitivity of 80% and a specificity of 68%. For group 3, an LHR of ⱖ1.06 was the best predictor, with a sensitivity of 65% and a specificity of 77%. However, the ROC curve for group 1 demonstrated only a marginal relationship between LHR and neonatal survival (area under the curve, 0.70; standard error, 0.099; P ⫽ .063). In group 2, no fetuses with an LHR of ⬍0.80 (n ⫽ 3 fetuses) survived, whereas all of those fetuses with an LHR of ⬎1.40 (n ⫽ 6 fetuses) did. In group 3, survival was 100% for the cases with an LHR of FIGURE 2
Median LHR values of the 3 different gestational age groups
Median LHR values of the 3 different gestational age groups demonstrate a significant difference among groups and an increasing tendency with gestational age. The shadowed box represents a 3-quartile range.
⬎1.50 (n ⫽ 6 fetuses), but none of the fetuses survived among those with an LHR of ⱕ0.80 (n ⫽ 4 fetuses). No cutoff values for 100% survival or 100% mortality could be determined for the fetuses in group 1. Spearman rank correlation between the LHR and gestational age at its measurement was found to be statistically significant (correlation coefficient, 0.26; P ⫽ .007). Before the curve estimation confirmed that the relationship between LHR and gestational age fitted the linear regression model, we performed linear regression analysis, which demonstrated a significant relationship between LHR as a dependent variable and gestational age at measurement as an independent variable (y ⫽ 0.034x ⫹ 0.22; r ⫽ 0.27; P ⫽ .006; Figure 5). Figure 6 shows the respective linear regression curves of postnatal survivors and nonsurvivors. The regression curve for survivors indicated that LHR significantly increased with advancing gestational age at its measurement (y ⫽ 0.047x – 0.018; r ⫽ 0.36; P ⬍ .005). On the contrary, no significant relationship was found between LHR and gestational age in nonsurvivors (y ⫽ 0.007x ⫹ 0.77; r ⫽ 0.071; P ⫽ .65). Survivors had significantly greater LHR than nonsurvivors, even after an adjustment for gestational age at measurement (P ⬍ .001 by ANCOVA).
C OMMENT In fetuses with CDH, a reliable prenatal evaluation for the severity of pulmonary hypoplasia can provide physicians and parents with valuable information for selecting appropriate treatment that ranges from termination of pregnancy to fetal surgery. We have found that LHR that is measured by sonography at 24-26 weeks of gestation is not only the best predictor of postnatal survival for fetuses with CDH but also is a good method of measurement in terms of reproducibility, including both inter- and intraobserver reliability.11 However, in cases that are diagnosed at ⬍24 or ⬎26 weeks of gestation, the applicability of the LHR has remained undetermined, primarily FIGURE 3
Median LHR values in survivors and nonsurvivors in 3 gestational age groups
Median LHR values show a significant difference between survivors (blank markers) and nonsurvivors (filled markers) in 3 different gestational age groups.
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FIGURE 4
ROC curves of LHR groups
ROC curves analyze the performance of the LHR as a predictor of postnatal survival in the 3 gestational age groups. There is a significant relationship between the LHR and survival in groups 2 and 3.
because of a lack of investigation. Therefore, we expanded on our previous work. This study demonstrates that LHR is a reliable predictor of postnatal outcome in fetuses with CDH at a gestational age between 24 and 34 weeks and is less reliable between 20 and 24 weeks. Our data show that the median LHR of nonsurvivors was significantly lower than that of survivors after 24 weeks of gestation and approaches significance at ⬍24 weeks of gestation. These findings suggest that the LHR has usefulness not only between 24 and 26 weeks of gestation but also between 26 and 34 weeks of gestation. The LHR measurement before 24 weeks of FIGURE 5
Simple linear regression analysis
Simple linear regression analysis demonstrates a significant positive linear relationship between the LHR and survival in groups 2 and 3.
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www.AJOG.org gestation appears to have a more limited predictability for postnatal survival. We hypothesize that the marginal significance in the group before 24 weeks of gestation could have been caused either by measurement variability, small size and immaturity of fetal organs, or a late manifestation of more pronounced pulmonary hypoplasia in some cases. Our results are consistent with those of a previous work by Laudy et al,14 which is the only published data that evaluate the prognostic value of LHR in fetuses with CDH at a gestational age outside the 24- to 26-week period to our knowledge. They examined a relationship between the LHR and outcomes of CDH cases between 28 and 37 weeks of gestation (mean, 34.8 weeks) and concluded that the LHR was a reliable independent predictor of fetal outcome, even when it was measured at a gestational age outside 24-26 weeks of gestation. Their cut-off values for 100% mortality and 100% survival were ⬍1.1 and ⬎1.4, which are slightly different from ours. We speculate that the difference in cutoff value is attributable either to a higher mean LHR (1.16) and the different characteristics of cases (eg, higher mean gestational age) in their study or to the variation in sonographic techniques in the measurement of the LHR between the 2 institutions. Those authors concluded that the LHR is unrelated to gestational age and that the LHR measurement can be extrapolated to different gestations (ie, the same cut-off of LHR can be used at different gestational ages). Our study demonstrates a significant relationship between LHR and gestational age at the time of its measurement, which is expressed as a primary equation by linear regression model (Figure 5) and which suggests that a fetus in later gestation has a higher LHR. As the relative head size decreases, one would expect the LHR to increase. In fact, LHR in normal fetuses has never been reported. In the report of Laudy et al,14 there was no statistically significant relation between the LHR and gestational age (P ⫽ .39). However, it seems that their study had some limitations because of the small sample size (n ⫽ 21 fetuses) and a relatively narrow range of gestation (32-37 weeks) at the
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FIGURE 6
Linear regression curves for survivors and nonsurvivors
Linear regression curves for survivors and nonsurvivors, respectively. The curve of survivors indicates an increasing LHR with gestational age at its measurement, whereas the curve of nonsurvivors shows no significant relationship between LHR and gestational age.
time of LHR measurement. We believe that those 2 factors may have contributed to a false-negative study result in the examination of a relationship between the LHR and gestational age. The positive linear relationship between LHR and gestational age that is shown in our results may suggest the following conclusions: First, it may simply reflect the linear growth pattern of 2-dimensional lung area,15,16 as compared with the quadratic growth of head circumference17 (ie, a relatively faster increase of a numerator than a denominator). On the other hand, of greater significance, it may indicate that the arrest of progression or even the regression of pulmonary hypoplasia may occur in a certain subgroup of fetuses as gestation advances. The latter speculation is supported, at least partly, by our data that show a positive linear relationship between the LHR and gestational age in survivors in contrast with no relation between the LHR and gestational age in nonsurvivors (Figure 6), which is perhaps the most intriguing observation of our study. In addition, ANCOVA clearly demonstrated that the difference of LHRs between survivors and nonsurvivors remained significant, even after an adjustment was made for gestational age at LHR measurement. These findings lead us to make 2 assumptions: (1) The LHR of normal fetuses and fetuses with CDH with a good postnatal prognosis increases as gestation advances. (2) Serial LHR evaluations could provide additional
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www.AJOG.org prognostic information among fetuses with CDH. In practice, we occasionally have observed an increasing LHR with gestation on serial sonography in fetuses with CDH who undergo expectant treatment and show favorable postnatal outcome. Providing that the LHR changes with gestational age, a nomogram for age-related LHR, different cut-off values of LHR for survival, and a protocol of prenatal ultrasonography for different gestations would be necessary for the more accurate prediction of postnatal outcome. According to our data, the cut-off value for 100% survival was 1.50 for fetuses at gestation of ⬎26 weeks at the time of LHR measurement, whereas an LHR of 1.40 indicated survivability for those fetuses between 24 and 26 weeks of gestation. On the other hand, our results suggest that the LHR in fetuses at a gestation of ⬍24 weeks seems to have a limited reliability; therefore, in the cases with CDH that were diagnosed at early gestation, an additional ultrasound examination after 24 weeks of gestation is necessary for a more predictive result from the LHR measurement. A possible weakness of this study relates to its retrospective nature. We also recognize that our study cannot exclude the possibility of selection bias. For instance, in cases with lower LHR at gestational ages of ⬍24 weeks, there is a much higher probability of early termination of pregnancy, hidden congenital defects, or lost follow-up examinations, which in turn might have contributed to the results that were not significant but approached significance in the group at 20-24 weeks of gestation. We attempted to overcome the weaknesses as a retrospective study and to avoid selection bias by excluding possible factors that affect the LHR measurement or fetal and neonatal outcome. For instance, intrauterine growth restriction, which frequently is associated with various congenital defects, can have effects on pre- and postnatal lung development and function; thus, these patients were excluded.18-20 We also excluded cases of termination of pregnancy that are likely to be the cases that were associated with the poorest prognostic factors, which had not been done in some studies, as a recent review
has pointed out.21 Heling et al22 published a prospective study that investigated the reliability of LHR as a predictor of outcome and neonatal ventilation parameters in fetuses with CDH. They concluded that LHR was not useful in the prediction of postnatal outcomes. However, their study had some significant limitations (eg, small sample size of 10 fetuses between 22 and 27 weeks of gestation), heterogeneity of the study group (left-sided and right-sided CDH were included), and inclusion of cases in which the pregnancy was terminated. In conclusion, this study demonstrates that the LHR is reliable as a predictor of postnatal survival in fetuses with left CDH between 20 and 34 weeks of gestation, particularly ⬎24 weeks. In addition, there is a positive linear relationship between LHR and gestational age; that is, LHR linearly increases as gestation advances. Significantly, the LHR in fetuses with poor postnatal outcome fails to show any relationship to gestational age. Given the limitations of this study as a retrospective cross-sectional study, we are unable to conclude whether the LHR changes as gestational age increases in normal fetuses or whether the increasing LHR with advancing gestation indicates favorable postnatal outcome. However, the advantage of LHR measurement by sonography as an easy, inexpensive, noninvasive, and reproducible method of fetal lung volume evaluation should not be ignored. Moeglin et al23 recently proposed 2-dimensional ultrasound as an alternative to magnetic resonance imaging or 3-dimensional ultrasound in clinical situations in which fetal prognosis depends on lung volume and its growth potential. Therefore, further prospective longitudinal studies that will investigate the change of LHR with gestational age and its association with fetal outcome are necessary. f REFERENCES 1. Beresford M, Shaw N. Outcome of congenital diaphragmatic hernia. Pediatr Pulmonol 2000;30:249-56. 2. Geary MP, Chitty LS, Morrison JJ, Wright V, Pierro A, Rodeck C. Perinatal outcome and prognostic factors in prenatally diagnosed congenital diaphragmatic hernia. Ultrasound Obstet Gynecology 1998;12:107-11.
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3. Adzick NS, Harrison MR, Glick PL, Nakayama DK, Manning FA, DeLorimier AA. Diaphragmatic hernia in the fetus: prenatal diagnosis and outcome in 94 cases. J Pediatr Surg 1985;30:357-61. 4. Adzick NS, Vacanti JP, Lillehei GW, O’Rourke PP, Crone RK, Wilson JM. Fetal diaphragmatic hernia: ultrasound diagnosis and clinical outcome in 38 cases. J Pediatr Surg 1989;24:654-8. 5. Bootstaylor BS, Filly RA, Harrison MR, Adzick NS. Prenatal sonographic predictors of liver herniation in congenital diaphragmatic hernia. J Ultrasound Med 1996;14:515-20. 6. Dommergues M, Louis-Sylvestre C, Mandelbrot L, et al. Congenital diaphragmatic hernia: can prenatal ultrasonography predict outcome? Am J Obstet Gynecol 1996;174: 1377-81. 7. Witters I, Legius E, Moerman P, et al. Associated malformations and chromosomal anomalies in 42 cases of prenatally diagnosed diaphragmatic hernia. Am J Med Genet 2001;103:278-82. 8. Laudy JA, Tibboel D, Robben SG, de Krijger RR, de Ridder MA, Wladimiroff JW. Prenatal prediction of pulmonary hypoplasia: clinical, biometric, and Doppler velocity correlates. Pediatrics 2002;109:250-8. 9. Mektus AP, Filly RA, Stringer MD, Harrison MR, Adzick NS. Sonographic predictors of survival in fetal diaphragmatic hernia. J Pediatr Surg 1996;31:148-52. 10. Lipshutz GS, Albanese CT, Feldstein VA, et al. Prospective analysis of lung-to-head ratio predicts survival for patients with prenatally diagnosed congenital diaphragmatic hernia. J Pediatr Surg 1997;32:1634-6. 11. Keller RL, Glidden DV, Paek BW, et al. The lung-to head ratio and fetoscopic temporary tracheal occlusion: prediction of survival in severe left congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 2003;21:244-9. 12. Sbragia L, Paek BW, Filly RA, et al. Congenital diaphragmatic hernia without herniation of the liver: does the lung-to-head ratio predict survival? J Ultrasound Med 2000;19:845-8. 13. Harrison MR, Keller RL, Lee H, et al. A randomized trial of fetal endoscopic tracheal occlusion for severe fetal congenital diaphragmatic hernia. N Engl J Med 2003;349:1916-24. 14. Laudy JAM, Van Gucht M, Van Dooren MF, Wladimiroff JW, Tibboel. Congenital diaphragmatic hernia: an evaluation of the prognostic value of the lung-to-head ratio and other prenatal parameters. Prenat Diag 2003;23:634-9. 15. Wedegaertner U, Tchirikov M, Habermann C, et al. Fetal sheep with tracheal occlusion: monitoring lung development with MR imaging and B-mode US. Radiology 2004;230:353-8. 16. Chitkara U, Rosenberg J, Chervenak FA, et al. Prenatal sonographic assessment of the fetal thorax: normal value. Am J Obstet Gynecol 1987;156:1069-74.
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17. Romero R, Pilu G, Jeanty P, Ghidini A, Hobbins JC. The central nervous system. In: Romero R, Pilu G, Jeanty P, Ghidini A, Hobbins JC, eds. Prenatal diagnosis of congenital anomalies. Norwalk (CT): Appleton & Lange; 1988: 56 (Table I-15). 18. Lucas JS, Inskip HM, Godfrey KM, et al. Small size at birth and greater postnatal weight gain. Am J Respir Crit Care Med 2004;170:534-40. 19. Maritz GS, Cock ML, Louey S, Suzuki K, Harding R. Fetal growth restriction has long-
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www.AJOG.org term effects on postnatal lung structure in sheep. Pediatr Res 2004;55:287-95. 20. Hernandez-Andrade E, Thuring-Jonsson A, Jansson T, Lingman G, Marsal K. Lung fractional moving blood volume in normally grown and growth restricted fetuses. Clin Physiol Funct Imaging 2004;24:69-74. 21. Deprest J, Jani J, Cannie M, et al. Progress in intrauterine assessment of the fetal lung and prediction of neonatal function (opinion). Ultrasound Obstet Gynecol 2005;25:108-11.
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22. Heling KS, Wauer RR, Hammer H, Bollmann R, Chaoui R. Reliablity of the lung-tohead ratio in predicting outcome and neonatal ventilation parameters in fetuses with congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 2005;25:112-8. 23. Moeglin D, Talmant C, Duyme M, Lopez, AC, College Français d’Echographie Foetal (Paris, France). Fetal lung volumetry using twoand three-dimensional ultrasound. Ultrasound Obstet Gynecol 2005;25:244-9.
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OBSTETRICS
Reliability of the lung-to-head ratio as a predictor of outcome in fetuses with isolated left congenital diaphragmatic hernia at gestation outside 24-26 weeks Soon Ha Yang, MD, PhD; Kerilyn K. Nobuhara, MD; Roberta L. Keller, MD; Robert H. Ball, MD; Ruth B. Goldstein, MD; Vickie A. Feldstein, MD; Peter W. Callen, MD; Roy A. Filly, MD; Diana L. Farmer, MD; Michael R. Harrison, MD; Hanmin Lee, MD OBJECTIVE: The purpose of this study was to investigate the relationship between lung-to-head ratio (LHR) and gestational age (GA) in fetuses with isolated left congenital diaphragmatic hernia and to determine the applicability and reliability of LHR to predict postnatal outcome beyond 24-26 weeks of gestation. STUDY DESIGN: The institutional review board approved this retro-
spective review of the University of California, San Francisco, Fetal Treatment Center database for cases with left congenital diaphragmatic hernia who were referred between March 1995 and June 2004. LHR was determined at the initial evaluation. One hundred seven live-born fetuses at 20-34 weeks of gestation (excluding cases that were lost to follow-up, with factors that potentially could influence the LHR measurement or postnatal outcome, or that were terminated electively). RESULTS: The median GA at LHR measurement was 25.6 weeks; the
median LHR was 1.01; the median GA at birth was 37.7 weeks; and the overall survival rate was 59% (64/107). The median LHR of nonsurvivors was significantly lower than that of survivors, but neither GA at LHR measurement nor at delivery was significantly different between the groups. Multiple logistic regression analysis confirmed LHR to be an independent predictor of postnatal survival, and receiver-operator
characteristic curve analysis demonstrated that an LHR of ⱖ0.97 has the highest performance in predicting postnatal survival. When fetuses were grouped by GA at initial LHR measurement to determine reliability of LHR, specifically with respect to GA, in the 26-34 and 24-26 weeks of gestation groups, median LHR of survivors was significantly higher than that of nonsurvivors, and receiver-operator characteristic curve analysis confirmed LHR to be a reliable predictor of postnatal survival. However, for fetuses at 20-24 weeks of gestation, there was a trend toward a higher LHR in survivors, although this did not reach statistical significance. CONCLUSION: A significant positive linear relationship exists between LHR and GA at the time of measurement, such that LHR reliably predicts postnatal survival in fetuses with left congenital diaphragmatic hernia at 24-34 weeks of gestation and less reliable at 20-24 weeks. However, given the limitations of a retrospective, cross-sectional study, further prospective longitudinal studies that will investigate the change of LHR with GA and its association with fetal outcome are necessary.
Key words: Lung-to-head ratio, congenital diaphragmatic hernia, survival
Cite this article as: Yang SH, Nobuhara KK, Keller RL, et al. Reliability of the lung-to-head ratio as a predictor of outcome in fetuses with isolated left congenital diaphragmatic hernia at gestation outside 24-26 weeks. Am J Obstet Gynecol 2007;197:30.e1-30.e7.
D
espite advances in prenatal diagnosis, fetal intervention, and neonatal respiratory support, a recent metaanalysis reported that the median
mortality rate of neonates with congenital diaphragmatic hernia (CDH) still remains 48%.1 Postnatal outcome of isolated CDH is determined mainly by the
From the Fetal Treatment Center (all authors) and the Departments of Surgery (Drs Nobuhara, Farmer, Harrison, and Lee), Pediatrics (Dr Keller), Obstetrics, Gynecology and Reproductive Sciences (Dr Ball), and Radiology (Drs Goldstein, Feldstein, Callen, and Filly), University of California, San Francisco, San Francisco, CA. Received June 15, 2006; accepted Jan. 16, 2007. Reprints: Hanmin Lee, MD, Fetal Treatment Center, University of California, San Francisco, 513 Parnassus Ave, Suite HSW 1601, San Francisco, CA 94143-0570; [email protected]. 0002-9378/$32.00 © 2007 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2007.01.016
See Journal Club, page 110
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severity of pulmonary hypoplasia and subsequent pulmonary hypertension refractory to therapy.2 Over the years, various sonographic and clinical parameters that indicate the extent of pulmonary hypoplasia (the primary cause of death in neonates who are born with CDH) have been proposed as prenatal prognostic factors.3-8 We previously presented the sonographically measured lung-to-head ratio (LHR), which is a ratio of the contralateral lung size compared with the head circumference, as an indicator of the severity of pulmonary hypoplasia and a predictor of postnatal outcome in a fetus with CDH.9-13
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www.AJOG.org The LHR has been regarded as the most reliable predictor of outcome when determined between 24 and 26 weeks of gestation. However, there have been few studies that have investigated the reliability of LHR to predict fetal outcome outside of that period. In practice, many referrals for ultrasound assessment do not take place between 24 and 26 weeks of gestation, and the lack of a reliable predictor of postnatal survival can be a serious dilemma, with respect to the determination of prenatal treatment and counseling. Laudy et al14 recently reported that the LHR was independent of gestational age and that the same cut-off value for postnatal outcome would be applicable to cases at different gestation other than 24-26 weeks. However, we have observed that serial ultrasound evaluation for some fetuses with CDH demonstrated an increasing LHR as gestational age advances. Therefore, the objectives of this study were to investigate a relationship between the LHR and gestational age in fetuses with isolated left CDH and to determine the applicability and reliability of the LHR as a predictor of postnatal outcome outside the period of 24-26 weeks of gestation.
M ATERIALS AND M ETHODS We retrospectively reviewed the University of California, San Francisco (UCSF), Fetal Treatment Center database for all fetuses between 20 and 34 weeks of gestation and demonstrated a prenatally diagnosed left CDH. The patient cohort was confined to those patients who were referred for prenatal evaluation from March 1995 to June 2004. The LHR was determined at the initial evaluation, before decisions regarding treatment and fetal outcome were known. Fetal echocardiography and karyotyping were performed. Cases with factors that potentially could influence the LHR measurement or postnatal outcome (ie, major congenital anomaly, chromosomal abnormality, death in utero, growth restriction, severe oligohydramnios [amniotic fluid index, ⱕ2] and multiple gestation) were excluded. We also excluded cases that underwent termination of pregnancy and that were lost
to follow-up. Gestational age was estimated on the basis of the last menstrual period, when reliable, or preferably on sonography that had been performed in the first trimester. Fetal sonography was performed at UCSF by 1 of 4 experienced sonologists for the confirmation of left CDH, complete evaluation of fetal structures, and the determination of the LHR. The LHR was obtained by visualization of a 4-chamber view of the heart on a transverse image of fetal thorax, as described in a previous report.9 Briefly, the right lung area was the product of 2 measurements: a linear distance from the atria to the ribs posteriorly and the distance of a perpendicular line from the aorta to the ribs laterally. The LHR was calculated by a simple ratio of right lung area to head circumference (in millimeters). Postnatal care was either at UCSF or at an appropriate tertiary center that was capable of extracorporeal membrane oxygenation (ECMO). The primary outcome was postnatal survival that was defined as survival to hospital discharge. Data were analyzed with SPSS statistical software (SPSS Inc, Chicago, IL). Results among gestational age groups (group 1, 20-24 weeks; group 2, 24-26 weeks; group 3, 26⫹ weeks) were compared with the use of the chi-square test, Student t test, Mann-Whitney U test, Kruskal-Wallis test, and JonckheereTerpstra test and were compared as continuous variables, as appropriate. Multiple logistic regression analysis was performed to evaluate the relationships between LHR and postnatal survival, with adjustment for confounding variables. Correlation between the LHR and gestational age at the time of the LHR measurement was described by the Spearman rank correlation. Simple linear regression analysis was used to examine a relationship between the LHR as a dependent variable and gestational age at time of the LHR measurement as an independent variable. Receiver-operator characteristic (ROC) curves were constructed to describe the relationship between the sensitivity and the false-positive rate (1-specificity) for the LHR in the prediction of postnatal survival. We used analysis of covariance (ANCOVA) to
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determine whether the LHR is an independent predictor for neonatal survival, even after being controlled for gestational age at measurement. Two-tailed ␣ value of ⬍.05 was considered statistically significant.
R ESULTS One hundred seven fetuses were included in this study, all of whom were liveborn. The median gestational age at the LHR measurement was 25.6 weeks (range, 20.4 to 34.0 weeks); the median LHR was 1.01 (range, 0.50 to 2.60). Fetuses with an LHR of ⱕ1.40 and herniated liver were candidates for fetoscopic tracheal occlusion; 29 fetuses (27%) underwent this procedure. The median gestational age at birth was 37.7 weeks (range, 25.7-41.4 weeks); 28 infants (26%) required ECMO support. The overall survival rate was 59% (64/107 infants). Table 1 presents the comparisons of clinical characteristics and neonatal outcomes between postnatal survivors and nonsurvivors. The gestational ages at LHR measurement and at delivery were not significantly different between both groups. The proportion of fetuses with herniated liver and neonates who underwent ECMO therapy was greater in nonsurvivors than in survivors. The median LHR of nonsurvivors was significantly lower than that of survivors (median, 0.95; range, 0.50 to 1.50 vs median, 1.13; range, 0.60 to 2.60, respectively; P ⬍ .0001, by Mann-Whitney U test). The ROC curve that was constructed for analysis of the performance of the LHR as a predictor of postnatal survival indicated that there was a significant relationship between the LHR and neonatal survival (area under the curve, 0.74; standard error, 0.05; P ⬍ .0001; Figure 1). With an LHR of ⱖ0.97 as the cut-off value, the highest performance in the prediction of postnatal survival showed a sensitivity of 77% and a specificity of 63%. Of 14 fetuses with a LHR of ⬎1.40, 13 fetuses (81%) survived, whereas 10 of 13 fetuses (77%) with an LHR of ⬍0.80 did not. The survival rate for fetuses with LHRs between 1.00 and 1.40 was 66% (53/80 fetuses).3 Cut off value for 100%
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TABLE 1
Clinical characteristics and neonatal outcomes of postnatal survivors and nonsurvivors Variable
Survivors (n ⴝ 64)
Nonsurvivors (n ⴝ 43)
P value
Gestational age at LHR measurement (wk)*
25.7 (22.3-34.0)
25.6 (20.4-33.0)
NS
LHR*
1.13 (0.60-2.60)
0.95 (0.5-1.50)
⬍.0001
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
Liver herniation (n)
49 (77%)
⬍.02
39 (91%)
................................................................................................................................................................................................................................................................................................................................................................................
Early diagnosis ⬍25 weeks gestation (n)
21 (33%)
12 (28%)
NS
8/46 (17%)
7/31 (23%)
NS
17 (27%)
12 (28%)
NS
................................................................................................................................................................................................................................................................................................................................................................................
Polyhydramnios (n/N)
................................................................................................................................................................................................................................................................................................................................................................................
Fetal surgery (n)
................................................................................................................................................................................................................................................................................................................................................................................
Gestational age at birth (wk)*
38.0 (27.3-40.9)
37.1 (27.4-41.4)
NS
................................................................................................................................................................................................................................................................................................................................................................................
Preterm delivery ⬍34 weeks of gestation (n)
13 (20%)
13 (30%)
NS
................................................................................................................................................................................................................................................................................................................................................................................
ECMO (n)
8 (13%)
⬍.0001
20 (47%)
................................................................................................................................................................................................................................................................................................................................................................................
NS, not significant. * Data are given as median (range).
survival and 100% mortality were an LHR of ⬎1.50 (n ⫽ 8 fetuses) and ⬍ 0.60 (n ⫽ 3 fetuses), respectively. Multiple logistic regression analysis showed that the LHR was an independent predictor of postnatal survival, even after adjustment for confounding variables such as liver herniation, fetal surgery, gestational age at delivery, gestational age at LHR measurement, and ECMO therapy (odds ratio, 24.45 [95% CI, 2.26-264.27]; P ⫽ .008; Table 2). We divided the cohort into 3 groups with respect to gestational age at the time of initial LHR measurement at our center (Table 3). Group 1 included 30 fetuses with LHRs that were measured between 20 and 24 weeks of gestation. In group 2, 38 fetuses with LHRs that were measured between 24 and 26 weeks of FIGURE 1
ROC curve shows a significant relationship between LHR and postnatal survival
gestation were identified. Thirty-nine fetuses whose LHRs were evaluated at a gestational age of ⬎26 weeks were included in group 3. There were no statistically significant differences in clinical characteristics and neonatal survival among the 3 groups. The median LHR values of the 3 gestational age groups showed not only a significant difference (group 1, 0.96 [range, 0.60 to 1.40] vs group 2, 1.10 [range, 0.50 to 1.87] vs group 3, 1.11 [range, 0.50 to 2.60]; P ⫽ .028, by Kruskal-Wallis test; Figure 2) but also an increasing tendency with gestational age (P ⫽ .01, by JonckheereTerpstra test). When we compared median LHRs between survivors and nonsurvivors in respective groups (Figure 3), the nonsurvivors in groups 2 and 3 had significantly lower LHRs than survivors (group 2, 0.95 [range, 0.50-1.40] vs 1.20 [range, 0.80-1.87]; P ⫽ .005;
group 3, 0.96 [range, 0.50-1.50] vs 1.20 [range, 0.89-2.60]; P ⫽ .016). In group 1, the nonsurvivors appeared to have lower LHRs than the survivors but not with statistical significant (0.91 [range, 0.681.36] vs 1.07 [range, 0.60-1.40]; P ⫽ .065). Figure 4 shows the ROC curves of the 3 groups that show the performance of the LHR in the prediction of postnatal survival. The ROC curves that were constructed to compare groups 2 and 3 were both above the 45-degree line, which indicated that, in both groups, LHR is related significantly to neonatal survival (group 2: area under the curve, 0.76; standard error, 0.078; P ⫽ .005; group 3: area under the curve, 0.74; standard error, 0.086; P ⫽ .02). An LHR of ⱖ1.00 as the cut-off value by ROC curve analysis for group 2 showed the highest performance in the predic-
TABLE 2
Relationships between postnatal survival and confounding factors, analyzed by multiple logistic regression Odds ratio LHR
24.45
95% CI 2.26-164.27
P value ⬍.01
..............................................................................................................................................................................................................................................
Gestational age at LHR measurement
0.89
0.72-1.10
NS
Liver herniation
0.61
0.089-4.19
NS
Gestational age at birth
1.04
0.90-1.19
NS
Fetal surgery
1.04
0.34-3.24
NS
ECMO
0.17
0.055-0.53
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
⬍.005
..............................................................................................................................................................................................................................................
NS, not significant.
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TABLE 3
Comparisons of clinical characteristics and postnatal outcome among the 3 groups, according to gestational age Variable
Group 1 (n ⴝ 30)
Group 2 (n ⴝ 38)
Group 3 (n ⴝ 39)
P value
Gestational age at LHR measurement (wk)*
23.1 (20.4-24.0)
25.3 (24.1-26.0)
27.6 (26.1-34.0)
⬍.0001
LHR*
0.96 (0.60-1.40)
1.02 (0.50-1.87)
1.11 (0.50-2.60)
⬍.05
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
Liver herniation (n)
27 (90%)
31/37 (84%)
30/37 (81%)
NS
3/26 (12%)
10/28 (36%)
⬍.05
11 (29%)
7 (18%)
................................................................................................................................................................................................................................................................................................................................................................................
Polyhydramnios (n)
2/23 (9%)
................................................................................................................................................................................................................................................................................................................................................................................
Fetal surgery (n)
11 (36%)
NS
................................................................................................................................................................................................................................................................................................................................................................................
Gestational age at birth (wk)*
36.3 (27.3-39.6)
37.5 (27.4-41.4)
38.1 (29.9-40.9)
⬍.05
................................................................................................................................................................................................................................................................................................................................................................................
Preterm delivery ⬍34 week of gestation (n)
10 (32%)
ECMO (n)
12 (40%)
Survival (n)
18 (60%)
11 (29%)
5 (13%)
NS
8 (21%)
8 (21%)
NS
20 (53%)
26 (67%)
NS
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
NS, not significant. * Data are given as median (range).
tion of postnatal survival, with a sensitivity of 80% and a specificity of 68%. For group 3, an LHR of ⱖ1.06 was the best predictor, with a sensitivity of 65% and a specificity of 77%. However, the ROC curve for group 1 demonstrated only a marginal relationship between LHR and neonatal survival (area under the curve, 0.70; standard error, 0.099; P ⫽ .063). In group 2, no fetuses with an LHR of ⬍0.80 (n ⫽ 3 fetuses) survived, whereas all of those fetuses with an LHR of ⬎1.40 (n ⫽ 6 fetuses) did. In group 3, survival was 100% for the cases with an LHR of FIGURE 2
Median LHR values of the 3 different gestational age groups
Median LHR values of the 3 different gestational age groups demonstrate a significant difference among groups and an increasing tendency with gestational age. The shadowed box represents a 3-quartile range.
⬎1.50 (n ⫽ 6 fetuses), but none of the fetuses survived among those with an LHR of ⱕ0.80 (n ⫽ 4 fetuses). No cutoff values for 100% survival or 100% mortality could be determined for the fetuses in group 1. Spearman rank correlation between the LHR and gestational age at its measurement was found to be statistically significant (correlation coefficient, 0.26; P ⫽ .007). Before the curve estimation confirmed that the relationship between LHR and gestational age fitted the linear regression model, we performed linear regression analysis, which demonstrated a significant relationship between LHR as a dependent variable and gestational age at measurement as an independent variable (y ⫽ 0.034x ⫹ 0.22; r ⫽ 0.27; P ⫽ .006; Figure 5). Figure 6 shows the respective linear regression curves of postnatal survivors and nonsurvivors. The regression curve for survivors indicated that LHR significantly increased with advancing gestational age at its measurement (y ⫽ 0.047x – 0.018; r ⫽ 0.36; P ⬍ .005). On the contrary, no significant relationship was found between LHR and gestational age in nonsurvivors (y ⫽ 0.007x ⫹ 0.77; r ⫽ 0.071; P ⫽ .65). Survivors had significantly greater LHR than nonsurvivors, even after an adjustment for gestational age at measurement (P ⬍ .001 by ANCOVA).
C OMMENT In fetuses with CDH, a reliable prenatal evaluation for the severity of pulmonary hypoplasia can provide physicians and parents with valuable information for selecting appropriate treatment that ranges from termination of pregnancy to fetal surgery. We have found that LHR that is measured by sonography at 24-26 weeks of gestation is not only the best predictor of postnatal survival for fetuses with CDH but also is a good method of measurement in terms of reproducibility, including both inter- and intraobserver reliability.11 However, in cases that are diagnosed at ⬍24 or ⬎26 weeks of gestation, the applicability of the LHR has remained undetermined, primarily FIGURE 3
Median LHR values in survivors and nonsurvivors in 3 gestational age groups
Median LHR values show a significant difference between survivors (blank markers) and nonsurvivors (filled markers) in 3 different gestational age groups.
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FIGURE 4
ROC curves of LHR groups
ROC curves analyze the performance of the LHR as a predictor of postnatal survival in the 3 gestational age groups. There is a significant relationship between the LHR and survival in groups 2 and 3.
because of a lack of investigation. Therefore, we expanded on our previous work. This study demonstrates that LHR is a reliable predictor of postnatal outcome in fetuses with CDH at a gestational age between 24 and 34 weeks and is less reliable between 20 and 24 weeks. Our data show that the median LHR of nonsurvivors was significantly lower than that of survivors after 24 weeks of gestation and approaches significance at ⬍24 weeks of gestation. These findings suggest that the LHR has usefulness not only between 24 and 26 weeks of gestation but also between 26 and 34 weeks of gestation. The LHR measurement before 24 weeks of FIGURE 5
Simple linear regression analysis
Simple linear regression analysis demonstrates a significant positive linear relationship between the LHR and survival in groups 2 and 3.
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www.AJOG.org gestation appears to have a more limited predictability for postnatal survival. We hypothesize that the marginal significance in the group before 24 weeks of gestation could have been caused either by measurement variability, small size and immaturity of fetal organs, or a late manifestation of more pronounced pulmonary hypoplasia in some cases. Our results are consistent with those of a previous work by Laudy et al,14 which is the only published data that evaluate the prognostic value of LHR in fetuses with CDH at a gestational age outside the 24- to 26-week period to our knowledge. They examined a relationship between the LHR and outcomes of CDH cases between 28 and 37 weeks of gestation (mean, 34.8 weeks) and concluded that the LHR was a reliable independent predictor of fetal outcome, even when it was measured at a gestational age outside 24-26 weeks of gestation. Their cut-off values for 100% mortality and 100% survival were ⬍1.1 and ⬎1.4, which are slightly different from ours. We speculate that the difference in cutoff value is attributable either to a higher mean LHR (1.16) and the different characteristics of cases (eg, higher mean gestational age) in their study or to the variation in sonographic techniques in the measurement of the LHR between the 2 institutions. Those authors concluded that the LHR is unrelated to gestational age and that the LHR measurement can be extrapolated to different gestations (ie, the same cut-off of LHR can be used at different gestational ages). Our study demonstrates a significant relationship between LHR and gestational age at the time of its measurement, which is expressed as a primary equation by linear regression model (Figure 5) and which suggests that a fetus in later gestation has a higher LHR. As the relative head size decreases, one would expect the LHR to increase. In fact, LHR in normal fetuses has never been reported. In the report of Laudy et al,14 there was no statistically significant relation between the LHR and gestational age (P ⫽ .39). However, it seems that their study had some limitations because of the small sample size (n ⫽ 21 fetuses) and a relatively narrow range of gestation (32-37 weeks) at the
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FIGURE 6
Linear regression curves for survivors and nonsurvivors
Linear regression curves for survivors and nonsurvivors, respectively. The curve of survivors indicates an increasing LHR with gestational age at its measurement, whereas the curve of nonsurvivors shows no significant relationship between LHR and gestational age.
time of LHR measurement. We believe that those 2 factors may have contributed to a false-negative study result in the examination of a relationship between the LHR and gestational age. The positive linear relationship between LHR and gestational age that is shown in our results may suggest the following conclusions: First, it may simply reflect the linear growth pattern of 2-dimensional lung area,15,16 as compared with the quadratic growth of head circumference17 (ie, a relatively faster increase of a numerator than a denominator). On the other hand, of greater significance, it may indicate that the arrest of progression or even the regression of pulmonary hypoplasia may occur in a certain subgroup of fetuses as gestation advances. The latter speculation is supported, at least partly, by our data that show a positive linear relationship between the LHR and gestational age in survivors in contrast with no relation between the LHR and gestational age in nonsurvivors (Figure 6), which is perhaps the most intriguing observation of our study. In addition, ANCOVA clearly demonstrated that the difference of LHRs between survivors and nonsurvivors remained significant, even after an adjustment was made for gestational age at LHR measurement. These findings lead us to make 2 assumptions: (1) The LHR of normal fetuses and fetuses with CDH with a good postnatal prognosis increases as gestation advances. (2) Serial LHR evaluations could provide additional
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www.AJOG.org prognostic information among fetuses with CDH. In practice, we occasionally have observed an increasing LHR with gestation on serial sonography in fetuses with CDH who undergo expectant treatment and show favorable postnatal outcome. Providing that the LHR changes with gestational age, a nomogram for age-related LHR, different cut-off values of LHR for survival, and a protocol of prenatal ultrasonography for different gestations would be necessary for the more accurate prediction of postnatal outcome. According to our data, the cut-off value for 100% survival was 1.50 for fetuses at gestation of ⬎26 weeks at the time of LHR measurement, whereas an LHR of 1.40 indicated survivability for those fetuses between 24 and 26 weeks of gestation. On the other hand, our results suggest that the LHR in fetuses at a gestation of ⬍24 weeks seems to have a limited reliability; therefore, in the cases with CDH that were diagnosed at early gestation, an additional ultrasound examination after 24 weeks of gestation is necessary for a more predictive result from the LHR measurement. A possible weakness of this study relates to its retrospective nature. We also recognize that our study cannot exclude the possibility of selection bias. For instance, in cases with lower LHR at gestational ages of ⬍24 weeks, there is a much higher probability of early termination of pregnancy, hidden congenital defects, or lost follow-up examinations, which in turn might have contributed to the results that were not significant but approached significance in the group at 20-24 weeks of gestation. We attempted to overcome the weaknesses as a retrospective study and to avoid selection bias by excluding possible factors that affect the LHR measurement or fetal and neonatal outcome. For instance, intrauterine growth restriction, which frequently is associated with various congenital defects, can have effects on pre- and postnatal lung development and function; thus, these patients were excluded.18-20 We also excluded cases of termination of pregnancy that are likely to be the cases that were associated with the poorest prognostic factors, which had not been done in some studies, as a recent review
has pointed out.21 Heling et al22 published a prospective study that investigated the reliability of LHR as a predictor of outcome and neonatal ventilation parameters in fetuses with CDH. They concluded that LHR was not useful in the prediction of postnatal outcomes. However, their study had some significant limitations (eg, small sample size of 10 fetuses between 22 and 27 weeks of gestation), heterogeneity of the study group (left-sided and right-sided CDH were included), and inclusion of cases in which the pregnancy was terminated. In conclusion, this study demonstrates that the LHR is reliable as a predictor of postnatal survival in fetuses with left CDH between 20 and 34 weeks of gestation, particularly ⬎24 weeks. In addition, there is a positive linear relationship between LHR and gestational age; that is, LHR linearly increases as gestation advances. Significantly, the LHR in fetuses with poor postnatal outcome fails to show any relationship to gestational age. Given the limitations of this study as a retrospective cross-sectional study, we are unable to conclude whether the LHR changes as gestational age increases in normal fetuses or whether the increasing LHR with advancing gestation indicates favorable postnatal outcome. However, the advantage of LHR measurement by sonography as an easy, inexpensive, noninvasive, and reproducible method of fetal lung volume evaluation should not be ignored. Moeglin et al23 recently proposed 2-dimensional ultrasound as an alternative to magnetic resonance imaging or 3-dimensional ultrasound in clinical situations in which fetal prognosis depends on lung volume and its growth potential. Therefore, further prospective longitudinal studies that will investigate the change of LHR with gestational age and its association with fetal outcome are necessary. f REFERENCES 1. Beresford M, Shaw N. Outcome of congenital diaphragmatic hernia. Pediatr Pulmonol 2000;30:249-56. 2. Geary MP, Chitty LS, Morrison JJ, Wright V, Pierro A, Rodeck C. Perinatal outcome and prognostic factors in prenatally diagnosed congenital diaphragmatic hernia. Ultrasound Obstet Gynecology 1998;12:107-11.
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