Objective
We sought to develop a gestational age–independent sonographic parameter to characterize lung growth.
Study Design
Reported descriptors of lung growth, including lung-to-head circumference (HC) ratio (LHR) and observed/expected LHR, were examined. A new index, the quantitative lung index (QLI) was derived using published data on HC and the area of the base of the right lung.
Results
Neither the LHR nor the observed/expected LHR proved to be gestational age independent. Right lung growth can be expressed using the following formula: QLI = lung area/(HC/10)^2. The 50th percentile of the QLI remained constant at approximately 1.0 for the gestational age between 16-32 weeks. A small lung (<1st percentile) was defined as a QLI <0.6.
Conclusion
Fetal right lung growth can be adequately described using the QLI, independent of gestational age. Further studies are needed to assess the clinical accuracy of the QLI in characterizing fetal right lung growth.
Congenital diaphragmatic hernia (CDH) remains one of the most challenging conditions in fetal therapy. In utero approaches through open fetal surgery were initially aimed at repairing the defect but gave way to palliation of the condition in utero via tracheal occlusion (TO). Soon, open fetal surgery TO was itself replaced by percutaneous TO via direct laryngoscopic methods. In 2003, a randomized clinical trial conducted in the United States on TO via open fetal surgery vs expectant management for CDH did not show a benefit of therapy vs expectant management, with therapy-associated premature rupture of membranes in 100% of patients. Despite these perceived negative results, which suggested that expectant management was no different than in utero surgery, subsequent studies have shown a high incidence of neurological morbidity in both groups, suggesting that expectant management is not as advantageous as assumed. Thus, efforts to improve the outcome of CDH fetuses have continued. Attention has focused on identifying those fetuses for which in utero therapy would be of potential benefit.
See Journal Club, page 577
In 1996, Metkus et al proposed the use of the lung-to-head circumference (HC) ratio (LHR) as a sonographic measure to identify fetuses with CDH that had a poor prognosis. The LHR uses an assessment of right lung area (LA), measured at the level of the 4-chamber view of the heart. The longest diameter and the longest perpendicular diameter are multiplied and the product is divided by the HC. The LHR was assumed to be gestational age independent. The LHR was used as the basis for the 2003 US randomized clinical trial on TO via open fetal surgery vs expectant management for CDH. The criterion for entry in that trial was an LHR <1.4. In retrospect, the data suggested that a more restrictive LHR of <1.0 might have been more appropriate, since survival in this subgroup of CDH fetuses was only 33% compared to virtually 100% of both surgical and expectantly managed groups with an LHR >1. In a recent study, 210 CDH fetuses with an LHR <1.0 that underwent TO with a detachable balloon had a 49% survival, compared to an expected survival rate of 25% estimated from a regression model.
Notwithstanding the link between the LHR and neonatal survival, the use of the LHR as a sonographic criterion for surgical intervention criteria for CDH has come into question. Peralta et al, in a study of 650 normal fetuses from 12-32 weeks, demonstrated that the LHR increases exponentially with gestational age. As such, they suggested instead using percentiles of LA to discriminate between normal and small lungs. Jani et al proposed the concept of observed/expected (o/e) LHR to predict mortality in CDH, believing this ratio to correct for gestational age. However, the o/e LHR had only a 46% sensitivity in predicting perinatal mortality from CDH, with an attendant 10% false-positive rate. Other approaches, including 3-dimensional ultrasound and fetal magnetic resonance imaging have also failed to discriminate the at-risk populations.
Our group has worked on alternative sonographic methods to assess fetal lung growth.
The purpose of this paper is to describe the derivation of a sonographic mathematical index to quantify fetal lung growth independent of gestational age.
Materials and Methods
First, we examined the relationship of the LHR and the o/e LHR with gestational age. Percentiles of right LA ( Table 1 ) and for the LHR ( Table 2 ) were derived from the article of Peralta et al and Chitty et al. The LA, Z scores, and the corresponding percentiles for an LHR of 1.0 as well as for a 60% o/e LHR (which corresponds to an LHR of 1.0 at 19 weeks) were constructed between 16-32 weeks ( Table 3 ).
Percentiles | |||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Wk | 0.01 | 0.015 | 0.027 | 0.05 | 1 | 2 | 2.5 | 5 | 10 | 15 | 20 | 25 | 30 | 35 | 40 | 45 | 50 |
16 | 23 | 23 | 29 | 34 | 67 | 77 | 79 | 91 | 104 | 112 | 119 | 125 | 130 | 134 | 139 | 143 | 148 |
17 | 36 | 37 | 43 | 50 | 90 | 101 | 103 | 118 | 133 | 143 | 151 | 158 | 164 | 170 | 175 | 180 | 186 |
18 | 54 | 55 | 62 | 70 | 116 | 130 | 132 | 150 | 167 | 179 | 188 | 196 | 204 | 210 | 217 | 222 | 229 |
19 | 76 | 77 | 85 | 94 | 147 | 163 | 165 | 185 | 205 | 218 | 229 | 239 | 247 | 254 | 262 | 268 | 275 |
20 | 101 | 102 | 111 | 122 | 181 | 199 | 202 | 224 | 246 | 261 | 273 | 284 | 293 | 301 | 310 | 317 | 325 |
21 | 129 | 130 | 140 | 152 | 218 | 237 | 240 | 265 | 290 | 306 | 320 | 332 | 342 | 351 | 360 | 369 | 378 |
22 | 158 | 159 | 170 | 183 | 255 | 277 | 280 | 308 | 335 | 353 | 368 | 381 | 392 | 402 | 413 | 422 | 432 |
23 | 188 | 188 | 201 | 215 | 294 | 317 | 321 | 351 | 381 | 400 | 417 | 431 | 443 | 454 | 466 | 475 | 486 |
24 | 217 | 218 | 232 | 247 | 333 | 358 | 362 | 394 | 427 | 448 | 466 | 481 | 494 | 506 | 519 | 529 | 541 |
25 | 247 | 247 | 262 | 278 | 371 | 398 | 402 | 437 | 472 | 495 | 514 | 530 | 545 | 557 | 571 | 582 | 595 |
26 | 274 | 275 | 290 | 308 | 407 | 436 | 441 | 478 | 515 | 540 | 561 | 578 | 594 | 607 | 621 | 634 | 647 |
27 | 299 | 300 | 317 | 335 | 441 | 472 | 477 | 517 | 556 | 583 | 605 | 623 | 640 | 654 | 670 | 683 | 697 |
28 | 321 | 322 | 340 | 360 | 472 | 505 | 510 | 552 | 594 | 622 | 646 | 666 | 683 | 698 | 715 | 729 | 744 |
29 | 339 | 340 | 359 | 380 | 499 | 533 | 540 | 584 | 629 | 658 | 683 | 704 | 723 | 739 | 756 | 771 | 787 |
30 | 353 | 354 | 374 | 396 | 521 | 558 | 564 | 611 | 658 | 689 | 716 | 738 | 757 | 774 | 793 | 808 | 825 |
31 | 361 | 362 | 383 | 406 | 538 | 576 | 583 | 633 | 682 | 715 | 743 | 766 | 787 | 804 | 824 | 840 | 858 |
32 | 362 | 364 | 385 | 410 | 548 | 589 | 596 | 648 | 700 | 735 | 763 | 788 | 810 | 828 | 848 | 866 | 885 |
GA/Z score | Percentiles | ||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
0.01 | 0.015 | 0.027 | 0.05 | 1 | 2 | 2.5 | 5 | 10 | 15 | 20 | 25 | 30 | 35 | 40 | 45 | 50 | |
−3.62 | −3.61 | −3.46 | −3.29 | −2.33 | −2.05 | −2 | −1.64 | −1.28 | −1.04 | −0.84 | −0.67 | −0.52 | −0.39 | −0.25 | −0.13 | ||
16 | 0.40 | 0.40 | 0.44 | 0.48 | 0.70 | 0.77 | 0.78 | 0.86 | 0.95 | 1.00 | 1.05 | 1.09 | 1.12 | 1.16 | 1.19 | 1.22 | 1.25 |
17 | 0.50 | 0.50 | 0.54 | 0.58 | 0.82 | 0.89 | 0.91 | 1.00 | 1.09 | 1.15 | 1.20 | 1.24 | 1.28 | 1.31 | 1.35 | 1.38 | 1.41 |
18 | 0.59 | 0.59 | 0.63 | 0.68 | 0.94 | 1.01 | 1.03 | 1.12 | 1.22 | 1.28 | 1.34 | 1.38 | 1.42 | 1.46 | 1.50 | 1.53 | 1.56 |
19 | 0.67 | 0.68 | 0.72 | 0.77 | 1.04 | 1.12 | 1.14 | 1.24 | 1.35 | 1.41 | 1.47 | 1.52 | 1.56 | 1.60 | 1.64 | 1.68 | 1.71 |
20 | 0.75 | 0.75 | 0.80 | 0.85 | 1.15 | 1.23 | 1.25 | 1.36 | 1.47 | 1.54 | 1.60 | 1.65 | 1.70 | 1.74 | 1.78 | 1.82 | 1.86 |
21 | 0.82 | 0.83 | 0.87 | 0.93 | 1.24 | 1.33 | 1.35 | 1.46 | 1.58 | 1.66 | 1.72 | 1.78 | 1.82 | 1.87 | 1.91 | 1.95 | 1.99 |
22 | 0.89 | 0.89 | 0.94 | 1.00 | 1.33 | 1.42 | 1.44 | 1.56 | 1.69 | 1.77 | 1.83 | 1.89 | 1.94 | 1.99 | 2.04 | 2.08 | 2.12 |
23 | 0.95 | 0.95 | 1.00 | 1.06 | 1.41 | 1.51 | 1.53 | 1.66 | 1.78 | 1.87 | 1.94 | 2.00 | 2.06 | 2.10 | 2.15 | 2.20 | 2.24 |
24 | 1.00 | 1.00 | 1.06 | 1.12 | 1.48 | 1.59 | 1.61 | 1.74 | 1.88 | 1.97 | 2.04 | 2.11 | 2.16 | 2.21 | 2.27 | 2.31 | 2.36 |
25 | 1.04 | 1.05 | 1.11 | 1.17 | 1.55 | 1.66 | 1.68 | 1.82 | 1.96 | 2.06 | 2.14 | 2.21 | 2.26 | 2.32 | 2.37 | 2.42 | 2.47 |
26 | 1.08 | 1.09 | 1.15 | 1.22 | 1.61 | 1.73 | 1.75 | 1.90 | 2.05 | 2.14 | 2.23 | 2.30 | 2.36 | 2.41 | 2.47 | 2.52 | 2.57 |
27 | 1.11 | 1.12 | 1.18 | 1.25 | 1.67 | 1.79 | 1.81 | 1.96 | 2.12 | 2.22 | 2.31 | 2.38 | 2.45 | 2.50 | 2.56 | 2.61 | 2.67 |
28 | 1.14 | 1.14 | 1.21 | 1.29 | 1.72 | 1.84 | 1.86 | 2.02 | 2.19 | 2.29 | 2.38 | 2.46 | 2.53 | 2.58 | 2.65 | 2.70 | 2.76 |
29 | 1.16 | 1.16 | 1.23 | 1.31 | 1.76 | 1.89 | 1.91 | 2.08 | 2.25 | 2.36 | 2.45 | 2.53 | 2.60 | 2.66 | 2.73 | 2.78 | 2.84 |
30 | 1.17 | 1.17 | 1.25 | 1.33 | 1.79 | 1.93 | 1.95 | 2.13 | 2.30 | 2.42 | 2.51 | 2.59 | 2.67 | 2.73 | 2.80 | 2.86 | 2.92 |
31 | 1.17 | 1.18 | 1.25 | 1.34 | 1.82 | 1.96 | 1.99 | 2.17 | 2.35 | 2.47 | 2.57 | 2.65 | 2.73 | 2.79 | 2.86 | 2.92 | 2.99 |
32 | 1.17 | 1.18 | 1.26 | 1.34 | 1.84 | 1.99 | 2.01 | 2.20 | 2.39 | 2.51 | 2.62 | 2.70 | 2.78 | 2.85 | 2.92 | 2.98 | 3.05 |
Gestational age, wk | LA (mm 2 ) corresponding to LHR of 1 ( Table 1 ) | Percent LA associated with LHR of 1 | Percentile of LA associated with LHR of 1 ( Table 2 ) | 60% Of expected LHR | LA (mm 2 ) corresponding to 60% expected LHR | Percent LA associated with 60% expected LHR | Percentile of LA associated with 60% expected LHR |
---|---|---|---|---|---|---|---|
16 | 125 | 85% | 14.68 | 0.75 | 74.28 | 50.33 | 1.66 |
17 | 138 | 74% | 5.26 | 0.85 | 93.39 | 50.28 | 1.25 |
18 | 151 | 66% | 1.81 | 0.94 | 116.89 | 51.13 | 1.02 |
19 | 164 | 60% | 0.65 | 1.03 | 144.24 | 52.37 | 0.84 |
20 | 177 | 54% | 0.25 | 1.11 | 174.85 | 53.74 | 0.75 |
21 | 189 | 50% | 0.106 | 1.20 | 208.08 | 55.10 | 0.68 |
22 | 201 | 47% | 0.05 | 1.27 | 243.28 | 56.37 | 0.64 |
23 | 213 | 44% | 0.027 | 1.35 | 279.74 | 57.54 | 0.62 |
24 | 224 | 41% | 0.0153 | 1.42 | 316.77 | 58.57 | 0.60 |
25 | 235 | 40% | 0.007 | 1.48 | 353.65 | 59.46 | 0.60 |
26 | 246 | 38% | 0.0068 | 1.54 | 389.64 | 60.21 | 0.62 |
27 | 256 | 37% | 0.0052 | 1.60 | 424.00 | 60.82 | 0.66 |
28 | 266 | 36% | 0.0043 | 1.65 | 455.99 | 61.29 | 0.68 |
29 | 276 | 35% | 0.0038 | 1.70 | 484.85 | 61.61 | 0.73 |
30 | 285 | 34% | 0.0036 | 1.75 | 509.83 | 61.78 | 0.78 |
31 | 293 | 34% | 0.0036 | 1.79 | 530.17 | 61.79 | 0.84 |
32 | 301 | 34% | 0.0038 | 1.83 | 545.10 | 61.62 | 0.94 |
The mathematical relationship between LA and HC was then analyzed. A new parameter of right lung growth was derived from this analysis.
No human subjects were involved in this research, therefore 45 CFR 46 (institutional review board approval) does not apply.
Results
Association of LHR and o/e LHR with gestational age
Table 1 displays the percentiles of right LA by gestational age (16-32 weeks). Table 2 shows the LHR percentile distributions for the gestational ages from 16-32 weeks. For each fixed percentile, there is a clear increasing trend in LHR values with advancing gestational age. Table 3 demonstrates that a fixed LHR of 1.0 ranges from the 14th percentile at 16 weeks to the .006th percentile at 26 weeks. Similarly, a fixed o/e LHR of 60% corresponds to the 5th percentile of right LA at 16 weeks, but to < .01st percentile of right LA at 26 weeks.
Derivation of the quantitative lung index (QLI)
The mathematical reason why the LHR is not independent of gestational age is the following: the lung measurement is an area (mm 2 ), whereas the HC measurement is linear (mm). Expressed mathematically, the LA follows a quadratic formula of the form:
where u , v , and w are appropriate constants, and f(t) is a function of time.Similarly, the HC is a linear function of the form:
where m and b are appropriate constants, and g(t ) is a function of time.If we then assume that the f(t) is very similar to g(t) , and rename f(t) as t′ :
Therefore, the LHR is a division of 2 polynomials of different order. If we divide a polynomial of second order by a polynomial of first order, as shown below:
For very large values of t′ :
Therefore, LHR behaves as a polynomial of first order when t′ is large, ie:
where p and q are the slope and the intercept of a linear equation. Since we know that f(t) and g(t) are monotonically growing functions, then p is a positive integer, and LHR is a monotonically growing function.When t′ approaches 0, then:
![](https://freepngimg.com/download/social_media/63059-media-icons-telegram-twitter-blog-computer-social.png)
Stay updated, free articles. Join our Telegram channel
![](https://clinicalpub.com/wp-content/uploads/2023/09/256.png)
Full access? Get Clinical Tree
![](https://videdental.com/wp-content/uploads/2023/09/appstore.png)
![](https://videdental.com/wp-content/uploads/2023/09/google-play.png)