Advertisement

Assessment of the fetal lungs in utero

Open AccessPublished:July 16, 2022DOI:https://doi.org/10.1016/j.ajogmf.2022.100693
      Antenatal diagnosis of abnormal pulmonary development has improved significantly over recent years because of progress in imaging techniques. Two-dimensional ultrasound is the mainstay of investigation of pulmonary pathology during pregnancy, providing good prognostication in conditions such as congenital diaphragmatic hernia; however, it is less validated in other high-risk groups such as those with congenital pulmonary airway malformation or preterm premature rupture of membranes. Three-dimensional assessment of lung volume and size is now possible using ultrasound or magnetic resonance imaging; however, the use of these techniques is still limited because of unpredictable fetal motion, and such tools have also been inadequately validated in high-risk populations other than those with congenital diaphragmatic hernia. The advent of advanced, functional magnetic resonance imaging techniques such as diffusion and T2* imaging, and the development of postprocessing pipelines that facilitate motion correction, have enabled not only more accurate evaluation of pulmonary size, but also assessment of tissue microstructure and perfusion. In the future, fetal magnetic resonance imaging may have an increasing role in the prognostication of pulmonary abnormalities and in monitoring current and future antenatal therapies to enhance lung development. This review aims to examine the current imaging methods available for assessment of antenatal lung development and to outline possible future directions.

      Key words

      Introduction

      Fetal lung abnormalities are a heterogeneous group of disorders accounting for approximately 18% of all congenital abnormalities.
      • Andrade CF
      • Ferreira HPdC
      • Fischer GB.
      Congenital lung malformations.
      They encompass both primary lung abnormalities and extrapulmonary conditions that detrimentally affect pulmonary growth and subsequent function. The latter group includes disorders of the renal, cardiovascular, or neurologic systems and acquired pregnancy complications such as preterm premature rupture of membranes (PPROM). Accurate antenatal diagnosis is imperative to provide appropriate counseling and perinatal care planning. The mainstay of fetal lung assessment in clinical practice is the evaluation of pulmonary size using 2D ultrasound. Although ultrasound measurements have been extensively assessed as prognostic markers in fetuses with congenital diaphragmatic hernia (CDH),
      • Hedrick HL
      • Danzer E
      • Merchant AM
      • et al.
      Liver position and lung-to-head ratio for prediction of extracorporeal membrane oxygenation and survival in isolated left congenital diaphragmatic hernia.
      ,
      • Senat MV
      • Bouchghoul H
      • Stirnemann J
      • et al.
      Prognosis of isolated congenital diaphragmatic hernia using lung-area-to-head-circumference ratio: variability across centers in a national perinatal network.
      their utility in other high-risk groups (ie, congenital pulmonary airway malformation [CPAM]) is less certain. Fetal magnetic resonance imaging (MRI) is used in clinical practice in the evaluation of specific conditions such as CDH, and although lung volumes can be assessed alongside other prognostic features such as the position of the fetal liver, image acquisition is often disrupted by fetal movement. Motion-correction approaches such as deformable slice-to-volume reconstruction (DSVR) have the potential to provide a more accurate evaluation of overall lung size. Antenatal MRI can also provide an indirect assessment of tissue perfusion and microstructure via T2* and diffusion sequences, which could yield information about alveolar development.
      The current review examines the most common prenatal methodologies used in antenatal assessment of some lung abnormalities both in the clinical and research setting.

      Background: normal lung development

      Lung development comprises a number of stages commencing in utero and continuing into the neonatal period and beyond. Around embryologic week 3, the respiratory diverticulum emerges from the ventral wall of the foregut into the adjacent mesenchyme. Five characteristic stages of growth and maturation are described (Table 1

      Sadler TW, Langman J. Langman's medical embryology (12th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. 2012. https://www.ncbi.nlm.nih.gov/nlmcatalog/101562744.

      ). Disruption of these stages in pulmonary development can result in long-term sequelae.
      Table 1Key points of the 5 stages of lung development
      Avena-Zampieri. Assessment of the fetal lungs in utero. Am J Obstet Gynecol MFM 2022.

      Evaluation of the fetal lung

      Ultrasound

      2D ultrasound is currently the predominant imaging modality used for assessment of the fetus in clinical practice because of its widespread availability and relative low cost. The normally developing lung is of moderate echogenicity in comparison with the adjacent liver. Abnormalities can present as hypo- or hyperechogenic areas. Primary thoracic masses should be differentiated from extrapulmonary masses, such as the bowel, stomach, or liver, which can also occupy the thoracic cavity. Ultrasound findings of primary lung hypoplasia can include reduced fetal chest circumference and fetal lung-to-head ratio,
      • Ohlsson A
      • Fong K
      • Rose T
      • et al.
      Prenatal ultrasonic prediction of autopsy-proven pulmonary hypoplasia.
      and major mediastinal shift can also be observed when hypoplastic right lung is diagnosed. Assessment of the position and size of the heart is therefore imperative.
      Lung size is often used as a prognostic marker for pulmonary hypoplasia and adverse neonatal outcome. Multiple 2D assessments have been evaluated (some of the most relevant are summarized in Table 2) as an indirect estimation of lung size and as a predictor of postnatal respiratory outcome. Although extensively validated in CDH, their role and feasibility in evaluating adverse outcomes in other pulmonary conditions, such as CPAM, are less clear. In addition, machine learning techniques have the potential to be clinically valuable: using algorithms such as quantusFLM, quantitative texture analysis was achieved by processing 2D ultrasound images obtained within 48 hours of delivery. Indeed, this technique helped with the antenatal prediction of neonatal respiratory morbidity because quantusFLM was able to automatically identify and segment a region of interest in the fetal lung from 790 ultrasound images obtained from patients enrolled in specific ultrasound protocols, one of which involved the evaluation of fetal lung maturity. From this, a neonatal respiratory morbidity risk score was derived with an accuracy of 91.5% compared with using a manual delineation of the lung or only using gestational age as a predictor of adverse outcomes.
      • Burgos-Artizzu XP
      • Perez-Moreno Á
      • Coronado-Gutierrez D
      • Gratacos E
      • Palacio M.
      Evaluation of an improved tool for non-invasive prediction of neonatal respiratory morbidity based on fully automated fetal lung ultrasound analysis.
      Table 2Ultrasound parameters used as indirect evaluation of lung hypoplasia and outcomes in congenital diaphragmatic hernia and their details of measurements
      Avena-Zampieri. Assessment of the fetal lungs in utero. Am J Obstet Gynecol MFM 2022.
      Ultrasound methodsDetails of measurementsTrends and associated outcomes
      Lung area (2D)• 3 different techniques:

      ◦ Tracing method of the limits of the lungs
      • Schittny JC.
      Development of the lung.
      • Narayanan M
      • Owers-Bradley J
      • Beardsmore CS
      • et al.
      Alveolarization continues during childhood and adolescence: new evidence from helium-3 magnetic resonance.
      • Peralta CFA
      • Cavoretto P
      • Csapo B
      • Vandecruys H
      • Nicolaides KH.
      Assessment of lung area in normal fetuses at 12-32 weeks.
      • Boonvisudhi K
      • Wanitpongpan P
      • Changnoi A.
      Nomogram of the lungs area by tracing method to head circumference ratio in normal Thai fetuses at 20-40 weeks of gestation.
      • Jani J
      • Peralta CF
      • Benachi A
      • Deprest J
      • Nicolaides KH.
      Assessment of lung area in fetuses with congenital diaphragmatic hernia.


      ◦ Longest diameter × longest perpendicular diameter
      • Peralta CFA
      • Cavoretto P
      • Csapo B
      • Vandecruys H
      • Nicolaides KH.
      Assessment of lung area in normal fetuses at 12-32 weeks.
      • Boonvisudhi K
      • Wanitpongpan P
      • Changnoi A.
      Nomogram of the lungs area by tracing method to head circumference ratio in normal Thai fetuses at 20-40 weeks of gestation.
      • Jani J
      • Peralta CF
      • Benachi A
      • Deprest J
      • Nicolaides KH.
      Assessment of lung area in fetuses with congenital diaphragmatic hernia.


      ◦ Anteroposterior diameter of the lung at the midclavicular line × perpendicular diameter at the midpoint of the anteroposterior diameter
      • Peralta CFA
      • Cavoretto P
      • Csapo B
      • Vandecruys H
      • Nicolaides KH.
      Assessment of lung area in normal fetuses at 12-32 weeks.
      • Boonvisudhi K
      • Wanitpongpan P
      • Changnoi A.
      Nomogram of the lungs area by tracing method to head circumference ratio in normal Thai fetuses at 20-40 weeks of gestation.
      • Jani J
      • Peralta CF
      • Benachi A
      • Deprest J
      • Nicolaides KH.
      Assessment of lung area in fetuses with congenital diaphragmatic hernia.
      Lung area overall shown to increase over gestation regardless of the technique used in normal fetuses.
      • Peralta CFA
      • Cavoretto P
      • Csapo B
      • Vandecruys H
      • Nicolaides KH.
      Assessment of lung area in normal fetuses at 12-32 weeks.


      In 650 normal fetuses, a linear 16-fold increase over gestation was observed from 12–32 wk, with the manual tracing method being the most reproducible method.
      • Peralta CFA
      • Cavoretto P
      • Csapo B
      • Vandecruys H
      • Nicolaides KH.
      Assessment of lung area in normal fetuses at 12-32 weeks.


      A slight decrease in lung area can be observed after 40 wk when recorded from 60 normal singleton pregnancies at 20–40 wk of gestation using the tracing method.
      • Boonvisudhi K
      • Wanitpongpan P
      • Changnoi A.
      Nomogram of the lungs area by tracing method to head circumference ratio in normal Thai fetuses at 20-40 weeks of gestation.
      .

      In fetuses with CDH, the most reproducible measurement of fetal lung area was found to be manual tracing96over the other 2 methods.
      CC• Several measurements have been evaluated:

      ◦ Transverse section of the fetal chest at right angles to the fetal spine compared with the width of the heart at the 4-chamber view
      • Nimrod C
      • Davies D
      • Iwanicki S
      • Harder J
      • Persaud D
      • Nicholson S.
      Ultrasound prediction of pulmonary hypoplasia.


      ◦ Tracing method along the diaphragm and inner chest walls to the apex of the lung in parasagittal section of the left chest in the midclavicular line
      • Nimrod C
      • Davies D
      • Iwanicki S
      • Harder J
      • Persaud D
      • Nicholson S.
      Ultrasound prediction of pulmonary hypoplasia.
      ,
      • Lian X
      • Xu Z
      • Zheng L
      • et al.
      Reference range of fetal thorax using two-dimensional and three-dimensional ultrasound VOCAL technique and application in fetal thoracic malformations.


      ◦ Width of 1 rib calculated from average distance of 4 ribs and interspaces in section perpendicular to the long axis of the lowest 5 ribs
      • Nimrod C
      • Davies D
      • Iwanicki S
      • Harder J
      • Persaud D
      • Nicholson S.
      Ultrasound prediction of pulmonary hypoplasia.
      A linear relationship was observed from scattergrams developed for each measurement between chest growth and GA between 24 and 39 wk in 83 normal fetuses.
      • Nimrod C
      • Davies D
      • Iwanicki S
      • Harder J
      • Persaud D
      • Nicholson S.
      Ultrasound prediction of pulmonary hypoplasia.


      Using the transverse-section method, a flattening growth in the third trimester was observed when recorded from 610 heathy fetuses between 12 and 41 wk gestation.
      • Merz E
      • Wellek S
      • Bahlmann F
      • Weber G.
      [Normal ultrasound curves of the fetal osseous thorax and fetal lung].


      If CC is recorded as within the 95th percentile confidence interval, it is associated with higher chances of survival.

      The other methods were not described in detail.

      CVR• The congenital pulmonary airway malformation volume is estimated using the formula for a prolate ellipse

      ◦ CVR=(length × height × width × 0.52)/head circumference
      • Crombleholme TM
      • Coleman B
      • Hedrick H
      • et al.
      Cystic adenomatoid malformation volume ratio predicts outcome in prenatally diagnosed cystic adenomatoid malformation of the lung.
      A significant growth in mean CVR in fetuses (20–35 wk) with no hydrops was recorded between 20 and 25 wk gestation, after which a progressive decrease was observed with advancing GA. Fetuses with a higher CVR are at higher risk of developing hydrops and adverse outcomes.
      • Crombleholme TM
      • Coleman B
      • Hedrick H
      • et al.
      Cystic adenomatoid malformation volume ratio predicts outcome in prenatally diagnosed cystic adenomatoid malformation of the lung.


      CVR ≥1.6: early predictor of fetal hydrops

      Lung span to hemithorax diameter ratio• Lung span to fetal hemithorax ratio determined in transverse or longitudinal views:

      ◦ From the hilum of the lung to its outermost edge or from the hilum of the lung to the thoracic wall
      • Castillo RA
      • Devoe LD
      • Hadi HA
      • Martin S
      • Geist D.
      Nonimmune hydrops fetalis: clinical experience and factors related to a poor outcome.
      ,
      • Castillo RA
      • Devoe LD
      • Falls G
      • Holzman GB
      • Hadi HA
      • Fadel HE.
      Pleural effusions and pulmonary hypoplasia.
      The ratio obtained from 9 fetuses with significant pleural effusions at 18–30 wk gestation seemed to decrease with GA. The ratios established were predictive of adverse outcomes, including hypoplastic lungs and severe hydrops.
      • Castillo RA
      • Devoe LD
      • Falls G
      • Holzman GB
      • Hadi HA
      • Fadel HE.
      Pleural effusions and pulmonary hypoplasia.


      Lung-thoracic ratio:

      44% to 77%: associated with severe hydrops and hypoplastic lungs, pleural effusions

      Not assessed in healthy fetuses.

      CA minus HA◦ Transverse section of the chest at level of 4-chamber view, with the heart in ventricular diastole
      • Vintzileos AM
      • Campbell WA
      • Rodis JF
      • Nochimson DJ
      • Pinette MG
      • Petrikovsky BM.
      Comparison of six different ultrasonographic methods for predicting lethal fetal pulmonary hypoplasia.
      :

      9Ratios were also established from these measurements
      • Vintzileos AM
      • Campbell WA
      • Rodis JF
      • Nochimson DJ
      • Pinette MG
      • Petrikovsky BM.
      Comparison of six different ultrasonographic methods for predicting lethal fetal pulmonary hypoplasia.
      :

      ◦ CA/HA

      (CA-HA) × 100/CA
      181 uncomplicated pregnancies between 16 and 40 wk of gestation were evaluated for both ratios
      • Vintzileos AM
      • Campbell WA
      • Rodis JF
      • Nochimson DJ
      • Pinette MG
      • Petrikovsky BM.
      Comparison of six different ultrasonographic methods for predicting lethal fetal pulmonary hypoplasia.
      :

      CA/HA displayed a linear relationship with GA

      (CA-HA) × 100/CA displayed a slight decrease over GA

      Patients with preterm premature rupture of membranes exhibited lower mean ratios than controls, which were predictive of lethal pulmonary hypoplasia when below the fifth percentile.
      • Vintzileos AM
      • Campbell WA
      • Rodis JF
      • Nochimson DJ
      • Pinette MG
      • Petrikovsky BM.
      Comparison of six different ultrasonographic methods for predicting lethal fetal pulmonary hypoplasia.
      CC-to-AC ratio• CC measured in the transverse plane of the fetus at the level of the 4-chamber view of the heart
      • Callan NA
      • Colmorgen GH
      • Weiner S.
      Lung hypoplasia and prolonged preterm ruptured membranes: a case report with implications for possible prenatal ultrasonic diagnosis.


      • AC measured in the transverse plane at the level of the stomach
      • Johnson A
      • Callan NA
      • Bhutani VK
      • Colmorgen GH
      • Weiner S
      • Bolognese RJ.
      Ultrasonic ratio of fetal thoracic to abdominal circumference: an association with fetal pulmonary hypoplasia.
      ,
      • Chitty LS
      • Altman DG
      • Henderson A
      • Campbell S.
      Charts of fetal size: 3. Abdominal measurements.
      In healthy fetuses the ratio has been reported to remain constant throughout pregnancy

      Johnson A, Callan NA, Bhutani VK, Colmorgen GHC, Weiner S, Bolognese RJ. Ultrasonic ratio of fetal thoracic to abdominal circumference: An association with fetal pulmonary hypoplasia. 1987;157:764-769. https://doi.org/10.1016/S0002-9378(87)80046-7.

      and accurate in predicting fetal lung growth.

      A progressive decline of the ratio over GA was recorded, preceding the development of pulmonary hypoplasia.
      • Callan NA
      • Colmorgen GH
      • Weiner S.
      Lung hypoplasia and prolonged preterm ruptured membranes: a case report with implications for possible prenatal ultrasonic diagnosis.
      The fetuses that later developed pulmonary hypoplasia were also confirmed to have lower CC/AC ratios than healthy fetuses.
      • Johnson A
      • Callan NA
      • Bhutani VK
      • Colmorgen GH
      • Weiner S
      • Bolognese RJ.
      Ultrasonic ratio of fetal thoracic to abdominal circumference: an association with fetal pulmonary hypoplasia.


      A ratio <0.6 suggests a perinatal lethal disorder.
      LHR• LHR

      ◦ Longest diameter method: product of the longest 2 perpendicular linear measurements of the lung, measured at the level of the 4-chamber view of the heart
      • Peralta CFA
      • Cavoretto P
      • Csapo B
      • Vandecruys H
      • Nicolaides KH.
      Assessment of lung area in normal fetuses at 12-32 weeks.
      ,
      • Metkus AP
      • Filly RA
      • Stringer MD
      • Harrison MR
      • Adzick NS.
      Sonographic predictors of survival in fetal diaphragmatic hernia.


      ◦ Tracing method: tracing the limits of the contralateral lung
      • Boonvisudhi K
      • Wanitpongpan P
      • Changnoi A.
      Nomogram of the lungs area by tracing method to head circumference ratio in normal Thai fetuses at 20-40 weeks of gestation.


      divided by the head circumference to obtain the LHR
      1. a) The longest diameter method displayed an LHR increase over GA in healthy fetuses imaged from 12–32 weeks, but was deemed least reproducible and as overestimating the lung areas.
      • Peralta CFA
      • Cavoretto P
      • Csapo B
      • Vandecruys H
      • Nicolaides KH.
      Assessment of lung area in normal fetuses at 12-32 weeks.


      b) When evaluated in fetuses with CDH, the ratio was significantly lower in nonsurvivors than in survivors.
      • Metkus AP
      • Filly RA
      • Stringer MD
      • Harrison MR
      • Adzick NS.
      Sonographic predictors of survival in fetal diaphragmatic hernia.


      2. a) Using the tracing method, left and right LHRs were established for 60 normal singleton pregnancies at 20–40 wk of gestation, both displaying an increase until 20 wk and a slight decrease at 40 wk
      • Boonvisudhi K
      • Wanitpongpan P
      • Changnoi A.
      Nomogram of the lungs area by tracing method to head circumference ratio in normal Thai fetuses at 20-40 weeks of gestation.


      b) When evaluated in fetuses with CDH at 22–28 wk gestation, the tracing method was the most reproducible measurement, and the LHR was significantly lower than in normal lung development and was one of the most significant predictors of survival.
      • Jani J
      • Peralta CF
      • Van Schoubroeck D
      • Deprest J
      • Nicolaides KH.
      Relationship between lung-to-head ratio and lung volume in normal fetuses and fetuses with diaphragmatic hernia.
      ,
      • Jani J
      • Keller RL
      • Benachi A
      • et al.
      Prenatal prediction of survival in isolated left-sided diaphragmatic hernia.


      • <25%: disease classified as severe

      • 26%–45%: disease classified as moderate

      • >45%: disease classified as mild
      Observed to expected LHR (o/e LHR)• o/e LHR × 100

      ◦ Measured LHR expressed as a percentage of the expected normal mean for GA
      • Jani J
      • Nicolaides KH
      • Keller RL
      • et al.
      Observed to expected lung area to head circumference ratio in the prediction of survival in fetuses with isolated diaphragmatic hernia.
      ,
      • Jani JC
      • Peralta CF
      • Nicolaides KH.
      Lung-to-head ratio: a need to unify the technique.
      o/e LHR is expressed as a percentage of the expected mean for GA (ultimately determined to be dependent on GA
      • Quintero RA
      • Kontopoulos EV
      • Quintero LF
      • Landy DC
      • Gonzalez R
      • Chmait RH.
      The observed vs. expected lung-to-head ratio does not correct for the effect of gestational age on the lung-to-head ratio.
      ) and was found to be a useful predictor of subsequent survival, with higher values correlating with an increased rate of survival.
      • Ruano R
      • Takashi E
      • da Silva MM
      • Campos JADB
      • Tannuri U
      • Zugaib M.
      Prediction and probability of neonatal outcome in isolated congenital diaphragmatic hernia using multiple ultrasound parameters.


      Conversely, very low values were associated with extreme pulmonary hypoplasia and low survival rates.
      • Jani J
      • Nicolaides KH
      • Keller RL
      • et al.
      Observed to expected lung area to head circumference ratio in the prediction of survival in fetuses with isolated diaphragmatic hernia.


      • <15%: virtually no chance of survival: extreme pulmonary hypoplasia

      • 15%–25%: predicted survival ≈ 15%: severe pulmonary hypoplasia

      • 26%–45%: predicted survival 30%–75%: moderate pulmonary hypoplasia

      • >45%: very likely to survive: mild pulmonary hypoplasia

      QLI• QLI41=lung area/(head circumference/10)
      • Hedrick HL
      • Danzer E
      • Merchant AM
      • et al.
      Liver position and lung-to-head ratio for prediction of extracorporeal membrane oxygenation and survival in isolated left congenital diaphragmatic hernia.
      This index seems to be more stable throughout gestation (can be assessed independently from GA) and might predict neonatal survival more accurately than LHR.
      • Illescas T
      • Rodó C
      • Arévalo S
      • Giné C
      • Peiró JL
      • Carreras E.
      The quantitative lung index and the prediction of survival in fetuses with congenital diaphragmatic hernia.


      From retrospective data, QLI seems to have a relatively constant value between 16 and 32 wk.
      • Quintero RA
      • Quintero LF
      • Chmait R
      • et al.
      The quantitative lung index (QLI): a gestational age–independent sonographic predictor of fetal lung growth.


      This index also has the potential to quantitatively determine which CDH fetuses would benefit the most from surgery (ie, tracheal occlusion).
      • Illescas T
      • Rodó C
      • Arévalo S
      • Giné C
      • Peiró JL
      • Carreras E.
      The quantitative lung index and the prediction of survival in fetuses with congenital diaphragmatic hernia.


      • <0.3: virtually no chance of survival

      • 0.6: poor outcome and associated with small lungs

      • >0.89: higher chance of survival

      Lung to thorax transverse area ratio• Area of bilateral lung profiles divided by the profile area of thorax at the level of the 4-chamber view of the heart
      • Hasegawa T
      • Kamata S
      • Imura K
      • et al.
      Use of lung-thorax transverse area ratio in the antenatal evaluation of lung hypoplasia in congenital diaphragmatic hernia.
      No significant relationship was found between the ratio and GA in normal fetuses and CDH cases.
      • Hasegawa T
      • Kamata S
      • Imura K
      • et al.
      Use of lung-thorax transverse area ratio in the antenatal evaluation of lung hypoplasia in congenital diaphragmatic hernia.


      The ratio was lower in cases with CDH than in normal fetuses, and was found to accurately characterize respiratory outcome and to be well related to the postoperative respiratory condition.
      • Hasegawa T
      • Kamata S
      • Imura K
      • et al.
      Use of lung-thorax transverse area ratio in the antenatal evaluation of lung hypoplasia in congenital diaphragmatic hernia.


      • Normal range: mean ratio 0.52±0.04

      • Cases with CDH: mean ratio 0.24±0.08

      AC, abdominal circumference; CA, chest area; CC, chest circumference; CDH, congenital diaphragmatic hernia; CVR, congenital pulmonary airway malformation volume ratio; GA, gestational age; HA, heart area; LHR, lung-to-head ratio; QLI, Quantitative lung index.
      Although 3D sonography has been assessed in research settings to evaluate lung volumetry, it is not used routinely in clinical practice because it is too time-consuming and has not been shown to be an accurate predictive tool. Using the conventional multiplanar mode allows simultaneous display of 3 perpendicular views of the lung. Pulmonary volume calculated using this technique has been found to be reproducible in both normal pregnancies and in fetuses at high risk of pulmonary hypoplasia (including in cases of PPROM), fetuses with suspected intrauterine growth restriction, and those with congenital anomalies.
      • Kalache KD
      • Espinoza J
      • Chaiworapongsa T
      • et al.
      Three-dimensional ultrasound fetal lung volume measurement: a systematic study comparing the multiplanar method with the rotational (VOCAL) technique.
      The evolution of a virtual organ computer‐aided analysis (VOCAL) has allowed the fetal lung volume to be calculated as a rotational measurement around a fixed axis, and reference values of both lungs have been established.
      • Moeglin D
      • Talmant C
      • Duyme M
      • Lopez AC
      CFEF
      Fetal lung volumetry using two- and three-dimensional ultrasound.
      VOCAL has a shorter acquisition time than the multiplanar technique when performed between 20 and 37 weeks of pregnancy,
      • Ruano R
      • Joubin L
      • Aubry MC
      • et al.
      A nomogram of fetal lung volumes estimated by 3-dimensional ultrasonography using the rotational technique (virtual organ computer-aided analysis).
      and provides good prediction of pulmonary hypoplasia severity when compared with postmortem volumes.
      • Ruano R
      • Martinovic J
      • Dommergues M
      • Aubry MC
      • Dumez Y
      • Benachi A.
      Accuracy of fetal lung volume assessed by three-dimensional sonography.
      However, VOCAL is not commonly used in clinical practice because it is highly dependent on fetal position, is sensitive to both motion and acoustic shadows, and requires significant training. Although some studies have demonstrated good intra- and interobserver variability (mean difference for right lung/left lung, respectively: VOCAL, −2.09/−2.09 and multiplanar, −0.93/−0.59) using the 2 techniques,
      • Kalache KD
      • Espinoza J
      • Chaiworapongsa T
      • et al.
      Three-dimensional ultrasound fetal lung volume measurement: a systematic study comparing the multiplanar method with the rotational (VOCAL) technique.
      others have indicated that VOCAL has higher interobserver variability and lower interobserver agreement compared with the multiplanar technique.

      Magnetic resonance imaging

      MRI has been increasingly used for assessment of fetal anatomy since the advent of ultrafast sequences in the 1990s. It is noninvasive and provides excellent soft-tissue contrast and high spatial resolution with a large field of view. It is also less restricted by factors such as maternal habitus, fetal lie, and oligohydramnios compared with ultrasound. The fetal lungs, trachea, and bronchial tree have a high water content in utero and high signal intensity on T2-weighted images, facilitating both morphologic and volumetric assessment. In a series of 74 fetuses with ultrasound-suspected thoracic abnormalities, MRI assessment led to a change in management in 8% of cases, namely either termination of pregnancy or altered care or birthing plans. MRI was indeed able to provide precise additional information in those cases, such as clearer delineation of ultrasound-detected masses for example, which helped establish the severity of the diagnosis.
      • Levine D
      • Barnewolt CE
      • Mehta TS
      • Trop I
      • Estroff J
      • Wong G.
      Fetal thoracic abnormalities: MR imaging.
      Other MRI parameters have also been evaluated, including the lung-to-liver signal intensity ratio as a predictor of neonatal survival, but this has been restricted to conditions resulting in hypoplastic lungs and is lacking significant results in other high-risk groups.
      • Yamoto M
      • Iwazaki T
      • Takeuchi K
      • et al.
      The fetal lung-to-liver signal intensity ratio on magnetic resonance imaging as a predictor of outcomes from isolated congenital diaphragmatic hernia.
      3D MRI-derived lung volumes have been evaluated as a prognostic marker for pulmonary hypoplasia in CDH
      • Shieh HF
      • Barnewolt CE
      • Wilson JM
      • et al.
      Percent predicted lung volume changes on fetal magnetic resonance imaging throughout gestation in congenital diaphragmatic hernia.
      ,
      • Weidner M
      • Hagelstein C
      • Debus A
      • et al.
      MRI-based ratio of fetal lung volume to fetal body volume as a new prognostic marker in congenital diaphragmatic hernia.
      and are used in clinical practice; however, validation in other high-risk groups is limited and confined to the research setting.
      • Messerschmidt A
      • Pataraia A
      • Helmer H
      • et al.
      Fetal MRI for prediction of neonatal mortality following preterm premature rupture of the fetal membranes.
      ,
      • Zamora IJ
      • Sheikh F
      • Cassady CI
      • et al.
      Fetal MRI lung volumes are predictive of perinatal outcomes in fetuses with congenital lung masses.
      Recent advances in image acquisition such as fast single-shot, accelerated MRI sequences and postprocessing techniques such as DSVR
      • Davidson J
      • Uus A
      • Egloff A
      • et al.
      Motion corrected fetal body magnetic resonance imaging provides reliable 3D lung volumes in normal and abnormal fetuses.
      now yield reconstructed high-resolution motion-corrected 3D volumes from multiple stacks of slices affected by nonrigid motion (Figure 1). DSVR oversamples the region of interest in which a single stack is selected as a template and iteratively aligns the reconstructed volume to each individual slice in a common coordinate space thereby accounting for unpredictable motion. It can potentially be applied to several types of images with different protocol acquisition and help determine lung volumes in any high-risk group.

      Uus A, Steinweg JK, Ho A, et al. Deformable slice-to-volume registration for reconstruction of quantitative, vol. T2* Placental and Fetal MRI. Cham, Germany: Springer International Publishing; 2020. https://www.scopus.com/record/display.uri?eid=2-s2.0-85092706860&origin=inward&txGid=8458f33936a3444c878984d93fb1a9c0&featureToggles=FEATURE_NEW_DOC_DETAILS_EXPORT:1,FEATURE_ EXPORT_REDESIGN:0.

      Patch-to-volume reconstruction has also been developed for use in more mobile structures and has proven successful for reconstructions of the fetal body and placenta; however, it has not been fully assessed for lung reconstruction to date.
      • Alansary A
      • Rajchl M
      • McDonagh SG
      • et al.
      PVR: patch-to-volume reconstruction for large area motion correction of fetal MRI.
      Fetal body volumes have also been calculated from MRI data to create lung-to-body volume ratios to account for the overall size of the fetus. Indeed, at later gestational age there is a wider variability in lung size correlating with the total volume of the fetus. This technique has been used in uncomplicated pregnancies,
      • Cannie MM
      • Jani JC
      • Van Kerkhove F
      • et al.
      Fetal body volume at MR imaging to quantify total fetal lung volume: normal ranges.
      those at high risk of preterm birth,
      • Story L
      • Zhang T
      • Steinweg JK
      • et al.
      Foetal lung volumes in pregnant women who deliver very preterm: a pilot study.
      and fetuses with CDH.
      • Weidner M
      • Hagelstein C
      • Debus A
      • et al.
      MRI-based ratio of fetal lung volume to fetal body volume as a new prognostic marker in congenital diaphragmatic hernia.
      Figure 1
      Figure 13T images of low-risk fetus at 30 weeks before and after applying DSVR
      • Davidson J
      • Uus A
      • Egloff A
      • et al.
      Motion corrected fetal body magnetic resonance imaging provides reliable 3D lung volumes in normal and abnormal fetuses.

      Uus A, Steinweg JK, Ho A, et al. Deformable slice-to-volume registration for reconstruction of quantitative, vol. T2* Placental and Fetal MRI. Cham, Germany: Springer International Publishing; 2020. https://www.scopus.com/record/display.uri?eid=2-s2.0-85092706860&origin=inward&txGid=8458f33936a3444c878984d93fb1a9c0&featureToggles=FEATURE_NEW_DOC_DETAILS_EXPORT:1,FEATURE_ EXPORT_REDESIGN:0.

      Avena-Zampieri. Assessment of the fetal lungs in utero. Am J Obstet Gynecol MFM 2022.
      DSVR: Deformabale slice-to-volume registration.
      In addition to anatomic postprocessing pipelines, the use of multiparametric MRI techniques, including combined diffusion and relaxometry,
      • Hutter J
      • Slator PJ
      • Christiaens D
      • et al.
      Integrated and efficient diffusion-relaxometry using ZEBRA.
      is a rapidly evolving field in the research setting and has the potential to simultaneously describe intrinsic lung characteristics such as microstructure and tissue perfusion, which may provide an indirect assessment of lung maturity. Diffusion MRI evaluates the microstructure of tissue and extracellular fluid spaces on the basis of signal loss because of molecular motion of water. This has the potential to provide information on alveolar and parenchymal development. Quantitative assessment can be achieved by obtaining several derived measurements including the apparent diffusion coefficient (ADC) (this is reduced in the presence of increased cellular complexity). ADC values have been shown to increase in the lungs of healthy fetuses
      • Afacan O
      • Gholipour A
      • Mulkern RV
      • et al.
      Fetal lung apparent diffusion coefficient measurement using diffusion-weighted MRI at 3 Tesla: correlation with gestational age.
      as gestation continues, which may reflect development. T2* imaging has the potential to identify alterations in tissue oxygenation. T2* relaxation exploits the blood oxygen level–dependent effect, which works on the different paramagnetic properties of oxygenated and deoxygenated hemoglobin. Quantitative T2* maps can be obtained using gradient-echo imaging with several echo times (Figure 2). Although limited, T2* relaxation times have been quantified in several fetal organs. In the fetal lungs, it seems that T2* values increase with gestation until 30 weeks, but a clear trend was hard to establish given the small number of cases studied and limited gestational age range.
      • Sethi S
      • Giza SA
      • Goldberg E
      • et al.
      Quantification of 1.5 T T1 and T2* relaxation times of fetal tissues in uncomplicated pregnancies.
      The increase observed may be attributable to an increase in metabolic activity across maturation. In addition, other functional MRI techniques, such as perfusion MRI, where the circulation in the vascular bed per unit volume can be recorded by evaluating indirect markers of tissue perfusion, or T1 relaxometry, assessing the relaxation of the longitudinal magnetization, have been assessed in previous studies and may play a role in pulmonary characterization in the future.
      Figure 2
      Figure 2T2 (top) and T2* (bottom) aligned maps of a healthy fetus at 35 weeks’ gestation scanned on a 3T MRI scanner
      Avena-Zampieri. Assessment of the fetal lungs in utero. Am J Obstet Gynecol MFM 2022.
      3T MRI, 3 Tesla magnetic resonance imaging.

      Other technologies

      Artificial intelligence (AI) techniques have for example been used to automate biometric measurements such as head circumference or biparietal diameter measurement. Therefore, fully convolutional neural networks combined with a regression network have been employed using multiscale information to pinpoint the edge of the skull. This results in more accurate estimation of the measurements (evaluated with 3 metrics and ranked first on the basis of absolute head circumference vs Thomas et al's
      • van den Heuvel TLA
      • de Bruijn D
      • de Korte CL
      • Ginneken BV
      Automated measurement of fetal head circumference using 2D ultrasound images.
      automated evaluation ranked 25th) compared with that of the previous network that used a single scale to segment the head region of a fetus, and compared with current 2D ultrasound fetal head measurements.
      • Li P
      • Zhao H
      • Liu P
      • Cao F.
      Automated measurement network for accurate segmentation and parameter modification in fetal head ultrasound images.
      From these encouraging results, an ongoing retrospective data study is developing a software system for automatic fetal lung volume segmentation in MRI. This is based on the deep-learning 3D U-NET, a semantic segmentation network based on the convolutional neural network. Using this approach, the aim is to ultimately build an AI system able to identify patients in the antenatal period at high risk of developing CDH-associated pulmonary hypoplasia.
      • Amodeo I
      • De Nunzio G
      • Raffaeli G
      • et al.
      A maChine and deep Learning Approach to predict pulmoNary hypertension in newbornS with congenital diaphragmatic Hernia (CLANNISH): protocol for a retrospective study.
      Multimodal fusion imaging, which allows superimposition of real-time ultrasound images and multiplanar reconstruction images of MRI, is another promising technique, which has been assessed to date in multiple conditions including CDH and pulmonary sequestration.
      • Millischer AE
      • Brasseur-Daudruy M
      • Mahallati H
      • Salomon LJ.
      The use of image fusion in prenatal medicine.

      Abnormal lung development and associated lung pathologies

      Normal fetal lung development can be disrupted at any stage of development (Table 1). Prognosis is dependent on the underlying condition and gestation of the insult. Congenital abnormalities of the lung can be primary such as CPAM or secondary to a reduction in thoracic space, adversely affecting pulmonary development, such as CDH or lethal skeletal dysplasia.

      Primary pulmonary conditions

      • 1.
        CPAM occurs because of underdevelopment of the terminal bronchiolar structures from which multiple lung cysts arise. It accounts for 30% to 40% of congenital lung malformations. A significant proportion of cases regress in the third trimester. Poor prognosis is associated with the presence of hydrops (10% of cases) and large masses.
        • Pelizzo G
        • Costanzo S
        • Selvaggio GGO
        • et al.
        Non-casual association between congenital pulmonary airway malformations/primary lung hypoplasia and congenital diaphragmatic hernia (CDH).
        Antenatal diagnosis can be made during routine second-trimester ultrasound evaluation. Hyperechogenic lesions in the fetal chest are divided into solid or microcystic, macrocystic with ≥1 large cysts (>2 cm), and mixed with areas that are solid intermixed with areas containing multiple cysts <2 cm in diameter
        • Stocker JT
        • Madewell JE
        • Drake RM.
        Congenital cystic adenomatoid malformation of the lung. Classification and morphologic spectrum.
        (Figure 3).
        Figure 3
        Figure 3Ultrasound and MR images comparison with measurement diagrams of CDH, CPAM, and pleural effusion cases
        Avena-Zampieri. Assessment of the fetal lungs in utero. Am J Obstet Gynecol MFM 2022.
        CDH, congenital diaphragmatic hernia; CPAM, congenital pulmonary airway malformation; CVR, congenital pulmonary airway malformation volume ratio; FETO, fetoscopic endoluminal tracheal occlusion; MRI, magnetic resonance imaging.
      • 2.
        Bronchopulmonary sequestration (BPS) is a nonfunctional mass of lung tissue that does not communicate with the normal tracheobronchial tree. It accounts for 0.15% to 6.4% of congenital lung malformations
        • Corbett HJ
        • Humphrey GM.
        Pulmonary sequestration.
        and can be subcategorized into intralobar or extralobar sequestration. The latter is found in <25% of cases but is more commonly associated with pleural effusion. Fetal pulsed-wave Doppler during ultrasound evaluation is often used to assess for the presence of an aortic feeding vessel, the size of which can affect hemodynamic status and potentially lead to high-output cardiac failure and life-threatening perioperative hemorrhages.
        • Yoshitake S
        • Hayashi H
        • Osada H
        • Kawahara M.
        Emergency laparotomy helped the resection of an intralobar pulmonary sequestration with haemorrhagic shock.
        In several case reports, MRI has accurately diagnosed complex thoracic lesions, distinguishing CPAMs from BPS by accurately characterizing the anatomy of the feeding vessels in BPS.
        • Kline-Fath B
        • Bitters C.
        Prenatal imaging of fetal lung lesions: magnetic resonance imaging complements ultrasound.
        MRI had a higher sensitivity (71%) in determining whether a systemic feeding vessel was present, demonstrating the arterial supply and delineating the mass more clearly than ultrasound (49%).
        • Mon RA
        • Johnson KN
        • Ladino-Torres M
        • et al.
        Diagnostic accuracy of imaging studies in congenital lung malformations.
        On T2-weighted MR images, high signal intensity of the lungs relative to that of normal lung tissue has been observed in sequestration lesions, and changes in vascularity in these T2-hyperintense lesions.
        • Levine D
        • Barnewolt CE
        • Mehta TS
        • Trop I
        • Estroff J
        • Wong G.
        Fetal thoracic abnormalities: MR imaging.
        Accurate diagnosis of CPAM and its distinction from BPS are crucial in optimizing postnatal management plans in complex cases of anomalous vessels. Laser ablation of the feeding artery can be performed antenatally using Doppler ultrasound with the aim to improve prognosis in severe forms associated with massive pleural effusions and hydrops.
        • Cruz-Martínez R
        • Nieto-Castro B
        • Martínez-Rodríguez M
        • et al.
        Thoracic changes after full laser ablation of the feeding artery in fetuses with bronchopulmonary sequestration.

      Congenital abnormalities resulting in a reduction in thoracic space

      • 1.
        CDH is an anomaly with a prevalence of 1 in 4000 births.
        • Skari H
        • Bjornland K
        • Haugen G
        • Egeland T
        • Emblem R.
        Congenital diaphragmatic hernia: a meta-analysis of mortality factors.
        It is characterized by malformation of the diaphragm causing part of the abdominal viscera to herniate into the thorax (Figure 3). Compression of the ipsilateral lung can displace the heart and mediastinum while also affecting the contralateral lung. This compression affects lung development and can culminate in pulmonary hypoplasia. Prognosis is dependent on the severity, type, and laterality of the hernia.
      On ultrasound, features may include absence or partial absence of the pleural line that represents the parietal pleura (ie, the layer of pleura associated with the walls of the pleural cavity).
      • Corsini I
      • Parri N
      • Coviello C
      • Leonardi V
      • Dani C.
      Lung ultrasound findings in congenital diaphragmatic hernia.
      Other findings can include polyhydramnios, liver herniation, mediastinal shift, abnormal cardiac axis, and inability to demonstrate the normal stomach bubble.
      • Cruz-Martínez R
      • Etchegaray A
      • Molina-Giraldo S
      • et al.
      A multicentre study to predict neonatal survival according to lung-to-head ratio and liver herniation in fetuses with left congenital diaphragmatic hernia (CDH): hidden mortality from the Latin American CDH Study Group Registry.
      However, most of these parameters have been deemed to have insufficient sensitivity and specificity to assist clinical decision-making and are mostly applicable to fetuses with left-sided CDH.
      • Kandil RA
      • El shahawy AsZ
      • El Shafiey MH
      • Alarabawy RA
      Values and validity of fetal parameters by ultrasound and Doppler as markers of fetal lung maturity.
      As previously discussed, it is essential to determine the location and size of abdominal organs in the thoracic cavity to confirm the diagnosis of CDH and to stratify the severity of the lesion. Various scores have been developed to support clinicians in predicting the degree of subsequent pulmonary hypoplasia using an ultrasound approach (Table 2). These include the lung-to-head ratio (LHR), which provides an estimate of the size of the lung contralateral to the lesion, normalized by the head circumference. Because the LHR changes over gestation, with the lung growing at a faster rate compared with the head, the observed/expected ratio has been introduced (o/e LHR). Here the LHR is normalized for the expected score measured in healthy fetuses at the same gestational age. The above scores based on ultrasound assessment of lung volumes have been found to offer good prediction value of neonatal outcome in CDH fetuses.
      • Jani J
      • Nicolaides KH
      • Keller RL
      • et al.
      Observed to expected lung area to head circumference ratio in the prediction of survival in fetuses with isolated diaphragmatic hernia.
      Quintero et al introduced another parameter that stays constant throughout pregnancy for the assessment of lung volume, the quantitative lung index (QLI) (Table 2). In their study, a QLI <0.6 was predictive of small lungs and confirmed its accuracy in anticipating adverse neonatal outcome, especially in the CDH groups presenting an index between 0.4 and 0.6.
      • Quintero RA
      • Quintero LF
      • Chmait R
      • et al.
      The quantitative lung index (QLI): a gestational age–independent sonographic predictor of fetal lung growth.
      Other parameters have been evaluated, such as the lung-to-liver signal intensity ratio studied by Yamoto et al
      • Yamoto M
      • Iwazaki T
      • Takeuchi K
      • et al.
      The fetal lung-to-liver signal intensity ratio on magnetic resonance imaging as a predictor of outcomes from isolated congenital diaphragmatic hernia.
      as a marker for fetal lung maturity where correlation between increasing lung-to-liver signal intensity ratio and gestation in control fetuses was further confirmed in the 47 fetuses with CDH; however, there is limited applicability to this technique, with around one-third of diagnoses missed. Only small cohort studies have tried to quantify the degree of liver herniation to evaluate antenatal fetal lung maturity in isolated CDH cases and to predict postnatal outcome.
      • Yamoto M
      • Iwazaki T
      • Takeuchi K
      • et al.
      The fetal lung-to-liver signal intensity ratio on magnetic resonance imaging as a predictor of outcomes from isolated congenital diaphragmatic hernia.
      ,
      • Cruz-Martínez R
      • Etchegaray A
      • Molina-Giraldo S
      • et al.
      A multicentre study to predict neonatal survival according to lung-to-head ratio and liver herniation in fetuses with left congenital diaphragmatic hernia (CDH): hidden mortality from the Latin American CDH Study Group Registry.
      To standardize the use of the aforementioned methods, a guideline has been developed by the European Reference Network for rare Inherited and Congenital Anomalies, providing a more practical guide for the assessment of isolated CDH (Table 2). Several studies have evaluated the feasibility of pulmonary vascular Doppler in predicting survival in fetuses with CDH; however, these studies vary significantly with regard to their methodology and number of participants evaluated, and all came to the conclusion of progressive reduction in intrapulmonary blood flow independently of lung size.
      • Basurto D
      • Fuenzalida J
      • Martinez-Portilla RJ
      • et al.
      Intrapulmonary artery Doppler to predict mortality and morbidity in fetuses with mild or moderate left-sided congenital diaphragmatic hernia.
      ,
      • Cruz-Martinez R
      • Martínez-Rodríguez M
      • Nieto-Castro B
      • et al.
      Longitudinal changes in lung size and intrapulmonary-artery Doppler during the second half of pregnancy in fetuses with congenital diaphragmatic hernia.
      MRI is increasingly being used to evaluate CDH in clinical practice because the available higher resolution, 3D continuity, and soft-tissue contrast allows for the hernia to be characterized with regard to its location, type (ie, posterolateral Bochdalek hernia, anterior Morgagni hernia, or hiatus hernia), and the position of other structures such as the liver, stomach, and bowel.
      • Balassy C
      • Kasprian G
      • Brugger PC
      • et al.
      Assessment of lung development in isolated congenital diaphragmatic hernia using signal intensity ratios on fetal MR imaging.
      In uncomplicated pregnancies there is good agreement between ultrasound and MRI-derived lung volumes (mean of difference for right lung volume/left lung volume: −2.13/−0.86)
      • Gerards FA
      • Twisk JW
      • Bakker M
      • Barkhof F
      • van Vugt JM.
      Fetal lung volume: three-dimensional ultrasonography compared with magnetic resonance imaging.
      ; however, in cases of CDH, ultrasound underestimates the volume of the contralateral lung by 25%. This might be attributable to the smaller number of sections and planes obtained in ultrasound compared with MRI.
      • Jani JC
      • Cannie M
      • Peralta CFA
      • Deprest JA
      • Nicolaides KH
      • Dymarkowski S.
      Lung volumes in fetuses with congenital diaphragmatic hernia: comparison of 3D US and MR imaging assessments.
      The ipsilateral lung has been reported across several other studies to be visible in only 55% to 64% of cases using 3D ultrasound,
      • Ruano R
      • Joubin L
      • Sonigo P
      • et al.
      Fetal lung volume estimated by 3-dimensional ultrasonography and magnetic resonance imaging in cases with isolated congenital diaphragmatic hernia.
      which thus does not yield reliable measurements, whereas MRI-determined observed/expected total lung volume (o/e TLV) in 85 fetuses with an isolated left CDH with a range of 18 to 39 weeks functioned better than ultrasound in predicting survival antenatally.
      • Bebbington M
      • Victoria T
      • Danzer E
      • et al.
      Comparison of ultrasound and magnetic resonance imaging parameters in predicting survival in isolated left-sided congenital diaphragmatic hernia.
      ,
      • Tsuda H
      • Kotani T
      • Miura M
      • et al.
      Observed-to-expected MRI fetal lung volume can predict long-term lung morbidity in infants with congenital diaphragmatic hernia.
      MRI also provides good prediction for the requirement of extracorporeal membrane oxygenation, and for the development of chronic lung disease in surviving infants.
      • Walleyo A
      • Debus A
      • Kehl S
      • et al.
      Periodic MRI lung volume assessment in fetuses with congenital diaphragmatic hernia: prediction of survival, need for ECMO, and development of chronic lung disease.
      ,
      • Debus A
      • Hagelstein C
      • Kilian AK
      • et al.
      Fetal lung volume in congenital diaphragmatic hernia: association of prenatal MR imaging findings with postnatal chronic lung disease.
      MRI also has an increasing role in assessing suitability of pregnancies complicated by CDH for surgical antenatal treatments such as fetoscopic endoluminal tracheal occlusion.
      • Van der Veeken L
      • Russo FM
      • De Catte L
      • et al.
      Fetoscopic endoluminal tracheal occlusion and reestablishment of fetal airways for congenital diaphragmatic hernia.
      In the research setting, ADC values were also found to be significantly different at both low and high b-values (reflecting the strength and timing of the gradients used to generate diffusion-weighted images) between the normal developing lungs and the ones affected by CDH, but unrelated to lung volume.
      • Cannie M
      • Jani J
      • De Keyzer F
      • Roebben I
      • Dymarkowski S
      • Deprest J
      Diffusion-weighted MRI in lungs of normal fetuses and those with congenital diaphragmatic hernia.
      This a promising technique and needs evaluation in further studies: the effect of capillary perfusion and water diffusion in the extracellular extravascular space could potentially be quantitatively obtained (reflected in those ADC values) to differentiate normal from abnormal tissue structures and be evaluated in CDH cases with different severities to predict adverse outcomes and/or need or timing for surgical intervention.
      • 1.
        Skeletal dysplasia encompasses a series of >400 heterogeneous disorders affecting any or a combination of bone or cartilage development, growth, and structure.
        • İpek MS
        • Akgul Ozmen C
        Skeletal dysplasias that cause thoracic insufficiency in neonates: illustrative case reports.
        ,
        • Bonafe L
        • Cormier-Daire V
        • Hall C
        • et al.
        Nosology and classification of genetic skeletal disorders: 2015 revision.
        Many of these abnormalities result in a small or deformed thorax, increasing the risk of airway malformation and pulmonary hypoplasia, which is significantly associated with lethality.
        • Mogayzel PJ
        • Marcus CL.
        Skeletal dysplasias and their effect on the respiratory system.
        Diagnosis and subsequent pulmonary consequences have been evaluated using ultrasound parameters of thoracic-to-abdominal or thoracic-to-head-circumference ratios. The diagnostic rate of specific skeletal dysplasia subtypes was only 65% to 68%,
        • Parilla BV
        • Leeth EA
        • Kambich MP
        • Chilis P
        • MacGregor SN.
        Antenatal detection of skeletal dysplasias.
        but prediction of lethality using these parameters is very effective. Limited studies have specifically evaluated 3D ultrasound–derived lung volumes and their correlation with outcomes, one of which was able to accurately predict lethality from pulmonary hypoplasia in fetuses between 20 and 32 weeks of gestation with skeletal dysplasia by using the VOCAL 3D ultrasound method.
        • Barros CA
        • Rezende Gde C
        • Araujo Júnior E
        • Tonni G
        • Pereira AK
        Prediction of lethal pulmonary hypoplasia by means fetal lung volume in skeletal dysplasias: a three-dimensional ultrasound assessment.
        Other 2D sonographic parameters, including chest circumference (CC) and chest circumference to abdominal circumference (AC) ratio, were assessed simultaneously with these 3D lung measurements, and were found to have lower sensitivities and specificities than total lung volume.
        • Barros CA
        • Rezende Gde C
        • Araujo Júnior E
        • Tonni G
        • Pereira AK
        Prediction of lethal pulmonary hypoplasia by means fetal lung volume in skeletal dysplasias: a three-dimensional ultrasound assessment.
        ,
        • Vintzileos AM
        • Campbell WA
        • Rodis JF
        • Nochimson DJ
        • Pinette MG
        • Petrikovsky BM.
        Comparison of six different ultrasonographic methods for predicting lethal fetal pulmonary hypoplasia.
        Lung volumes in fetuses with skeletal dysplasia have also been assessed using MRI. In 36 fetuses with suspected skeletal dysplasia, this measurement proved superior to ultrasound by demonstrating an association with a reduction in o/e TLV, with values of 47.9% and 0.124 in FL/AC determined to be potentially useful clinical cutoffs in the prediction of lethality.
        • Weaver KN
        • Johnson J
        • Kline-Fath B
        • et al.
        Predictive value of fetal lung volume in prenatally diagnosed skeletal dysplasia.
        MRI was also found to provide clear depiction of soft tissue, allowing the analysis of the fetal spine and differentiation between the various subphenotypes of skeletal dysplasia.
        • Gilligan LA
        • Calvo-Garcia MA
        • Weaver KN
        • Kline-Fath BM.
        Fetal magnetic resonance imaging of skeletal dysplasias.
      • 2.
        Significant cardiomegaly puts the fetus at increased risk of impaired lung growth because of a reduction in thoracic space.
        • Tanaka T
        • Yamaki S
        • Ohno T
        • Ozawa A
        • Kakizawa H
        • Iinuma K.
        The histology of the lung in neonates with tricuspid valve disease and gross cardiomegaly due to severe regurgitation.
        In CDH fetuses, smaller branch pulmonary arteries (PAs) compared with those of control fetuses of the same gestational age have also been recorded on cross-sectional imaging through the fetal chest using ultrasound, establishing a potential correlation between PA diameter and extent of hypoplasia.
        • Mlczoch E
        • Schmidt L
        • Schmid M
        • et al.
        Fetal cardiac disease and fetal lung volume: an in utero MRI investigation.
        ,
        • Ruchonnet-Metrailler I
        • Bessieres B
        • Bonnet D
        • Vibhushan S
        • Delacourt C.
        Pulmonary hypoplasia associated with congenital heart diseases: a fetal study.
        Fetal cardiac abnormalities that can be associated with cardiomegaly include tricuspid valve regurgitation, particularly Ebstein's anomaly. There is evidence that in fetuses with right outflow obstruction, early disruption of pulmonary vascular growth alters the branching morphogenesis of the airways,
        • Akeson AL
        • Greenberg JM
        • Cameron JE
        • et al.
        Temporal and spatial regulation of VEGF-A controls vascular patterning in the embryonic lung.
        as assessed using ultrasound parameters, whereas reduced pulmonary flow at a later stage of gestation alters alveolarization.
        • Filby CE
        • Hooper SB
        • Wallace MJ.
        Partial pulmonary embolization disrupts alveolarization in fetal sheep.
      Clinical diagnosis of congenital heart disease is established through routine cardiac screening using ultrasound, which rose from 40% of cases being accurately detected in England in 2013 to 52% in March 2021 following the COVID-19 pandemic.
      Research NIfCO
      National Congenital Heart Disease Audit Summary Report 2020/1 data).
      Very few studies have explored the impact of fetal cardiac malformations on neonatal respiratory outcomes because of multiple confounding variables in the perinatal period and the lack of accurate diagnostic tools to differentiate between cardiac and pulmonary etiology. One study reviewed the echocardiograms of CDH fetuses and suggested that an enlarged contralateral PA diameter in the midtrimester correlates with postnatal death, which can be attributed to the possible overworking redistribution of blood flow from the left to the right part (contralateral) of the heart, and discrepancy between fetal branch PA diameters correlated directly with postnatal respiratory morbidity.
      • Sokol J
      • Bohn D
      • Lacro RV
      • et al.
      Fetal pulmonary artery diameters and their association with lung hypoplasia and postnatal outcome in congenital diaphragmatic hernia.
      Fetal cardiovascular magnetic resonance (CMR) sequences have an additional value in simultaneously assessing cardiac abnormalities and providing invaluable information about the fetal lungs. Fetal CMR has efficiently been used to study fetal circulatory physiology in fetuses with CDH, providing new insights on blood flow distribution in the fetal circulation. Providing supplementary maternal oxygen during fetal CMR can physiologically test the vessels and vasoactive responses of certain fetal organs, and could be used in the future to determine the relationship between absolute volumes of the lungs and the maturity of the arterial tree in terms of size and physiological characteristics.
      • 1.
        Pleural effusion is defined as an accumulation of fluid within the pleural space (Figure 3), and is estimated to occur in 1 of 15,000 pregnancies.
        • Longaker MT
        • Laberge JM
        • Dansereau J
        • et al.
        Primary fetal hydrothorax: natural history and management.
        It can arise because of a number of different conditions such as infection or CHD, all with the potential to culminate in abnormalities in lung growth. A large pleural effusion can act as a space-occupying lesion, compressing the lungs. Effusions have additionally been found to be associated with a decreased number of cells, alveoli, and overall lung size.
        • Castillo RA
        • Devoe LD
        • Falls G
        • Holzman GB
        • Hadi HA
        • Fadel HE.
        Pleural effusions and pulmonary hypoplasia.
        Diagnosis is reliably made using ultrasound, with the effusion appearing as an anechoic area surrounding the lungs.
        • Adams H
        • Jones A
        • Hayward C.
        The sonographic features and implications of fetal pleural effusions.
        Effusions may also be associated with hydrops or mediastinal shift, which may require in utero interventions. Treatment options include drainage with pleurodesis, thoracentesis, and thoracoamniotic shunting,
        • Rustico MA
        • Lanna M
        • Coviello D
        • Smoleniec J
        • Nicolini U.
        Fetal pleural effusion.
        the last being the most effective in improving perinatal outcomes.
        • Jeong BD
        • Won HS
        • Lee MY
        • Shim JY
        • Lee PR
        • Kim A.
        Perinatal outcomes of fetal pleural effusion following thoracoamniotic shunting.
        Limited studies have used fetal MRI to assess hydrothorax and its effect on pulmonary development.
        • Coleman AM
        • Merrow AC
        • Crombleholme TM
        • Jaekle R
        • Lim FY.
        Fetal MRI of torsed bronchopulmonary sequestration with tension hydrothorax and hydrops in a twin gestation.
        ,
        • Recio Rodríguez M
        • Martínez de Vega V
        • Cano Alonso R
        • Carrascoso Arranz J
        • Martínez Ten P
        • Pérez Pedregosa J
        MR imaging of thoracic abnormalities in the fetus.
        These have however highlighted the value of MRI in better defining the underlying etiology, as demonstrated in one retrospective study conducted on 76 fetuses in which postnatal diagnosis confirmed the prenatal diagnosis in 51 of the 56 lung lesions (91%), including CPAM, BPS, and bronchopulmonary cysts.
        • Pacharn P
        • Kline-Fath B
        • Calvo-Garcia M
        • et al.
        Congenital lung lesions: prenatal MRI and postnatal findings.

      Conditions resulting in oligohydramnios/anhydramnios

      Conditions that result in second-trimester oligohydramnios may restrict fetal lung growth and result in pulmonary hypoplasia, as shown in both animal models and human fetuses.
      • Chien LN
      • Chiou HY
      • Wang CW
      • Yeh TF
      • Chen CM.
      Oligohydramnios increases the risk of respiratory hospitalization in childhood: a population-based study.
      ,
      • Moessinger AC
      • Collins MH
      • Blanc WA
      • Rey HR
      • James LS.
      Oligohydramnios-induced lung hypoplasia: the influence of timing and duration in gestation.
      This may be because of congenital abnormalities such as bilateral renal agenesis or acquired abnormalities such as PPROM.
      • 1.
        Renal tract abnormalities and early-onset oligohydramnios are associated. Pulmonary hypoplasia in these cases is thought to be attributable to low urine production that results in a decrease in intraamniotic pressure and increase in the alveolar–amniotic pressure gradient. A population-based study suggested a positive correlation between pulmonary hypoplasia and oligohydramnios, in which oligohydramnios-exposed children presented an 8% higher increased admissions rate with respiratory illness than nonexposed children.
        • Chien LN
        • Chiou HY
        • Wang CW
        • Yeh TF
        • Chen CM.
        Oligohydramnios increases the risk of respiratory hospitalization in childhood: a population-based study.
        The exact mechanism by which lung hypoplasia ensues is unclear, but animal models suggest that oligohydramnios at the pseudoglandular stage reduces elastin deposition, alveolarization, and the amount of collagen in the fetal lung.
        • Chen CM
        • Chou HC
        • Wang LF
        • Lang YD.
        Experimental oligohydramnios decreases collagen in hypoplastic fetal rat lungs.
        There are limited data specifically evaluating lung development antenatally in cases of renal agenesis, but postnatal quantitative analysis has demonstrated a reduction in size of the pulmonary airways and growth within the acinar region, with resulting hypoplastic lungs.
        • Hislop A
        • Hey E
        • Reid L.
        The lungs in congenital bilateral renal agenesis and dysplasia.
        MRI images are less affected by oligo- and anhydramnios than ultrasound images.
        • Behairy NHED
        • El Din LAS
        • Hanoun NMF
        • Abd El Raof M
        • Ali MAEK
        Diagnostic value of fetal MRI in evaluating fetal urinary anomalies.
        The role of MRI in assessing pulmonary development in urinary tract abnormalities in these cases of oligo- and anhydramnios has been assessed through several studies. One study yielded images from fast gradient-echo sequences and true fast imaging analyzed by an experienced observer for valuating signal intensity of the lungs to diagnose pulmonary hypoplasia. Low signal intensity in the lungs was thus identified in a fetus with Meckel–Gruber syndrome. Overall, MRI was deemed superior in detecting the bilateralism and severity of the renal diseases, and denoted better visualization of the fetal whole body in a single cut compared with ultrasound. Reaching a diagnostic accuracy of 96% for urinary tract anomalies in this study, MRI demonstrated its potential in characterizing the associated extrarenal fetal anomalies, such as pulmonary anomalies, with high accuracy.
        • Behairy NHED
        • El Din LAS
        • Hanoun NMF
        • Abd El Raof M
        • Ali MAEK
        Diagnostic value of fetal MRI in evaluating fetal urinary anomalies.
      Neonates with second-trimester PPROM have an increased risk of pulmonary hypoplasia (≥47%)
      • Grisaru-Granovsky S
      • Eitan R
      • Kaplan M
      • Samueloff A.
      Expectant management of midtrimester premature rupture of membranes: a plea for limits.
      and other respiratory morbidity, including pulmonary hypertension and pneumothoraces.
      • Pharande P
      • Mohamed AL
      • Bajuk B
      • Lui K
      • Bolisetty S.
      Preterm infant outcomes in relation to the gestational age of onset and duration of prelabour rupture of membranes: a retrospective cohort study.
      Gestational age at the time of membrane rupture was found to be the best predictor of pulmonary hypoplasia (superior to the duration and degree of oligohydramnios
      • Rotschild A
      • Ling EW
      • Puterman ML
      • Farquharson D.
      Neonatal outcome after prolonged preterm rupture of the membranes.
      ).
      Ultrasound-derived CC, CC-to-AC ratios,
      • Johnson A
      • Callan NA
      • Bhutani VK
      • Colmorgen GH
      • Weiner S
      • Bolognese RJ.
      Ultrasonic ratio of fetal thoracic to abdominal circumference: an association with fetal pulmonary hypoplasia.
      and CC-to-femur-length ratios
      • Ohlsson A
      • Fong K
      • Rose T
      • et al.
      Prenatal ultrasonic prediction of autopsy-proven pulmonary hypoplasia.
      have low sensitivity in predicting adverse outcome in PPROM. Fetal breathing, fetal movements, and thoracic-circumference-to-abdominal-circumference ratios were not found to be predictive of respiratory outcome.
      • Kilbride HW
      • Yeast J
      • Thibeault DW.
      Defining limits of survival: lethal pulmonary hypoplasia after midtrimester premature rupture of membranes.
      Overall, there is limited accuracy of imaging biometric parameters in the prediction of pulmonary hypoplasia in midtrimester PPROM,
      • van Teeffelen AS
      • Van Der Heijden J
      • Oei SG
      • et al.
      Accuracy of imaging parameters in the prediction of lethal pulmonary hypoplasia secondary to mid-trimester prelabor rupture of fetal membranes: a systematic review and meta-analysis.
      but some recent evaluations of o/e LHR and QLI in live birth with PPROM occurring before 24 weeks of gestation proved valuable in predicting lethality.
      • Jozan C
      • Huissoud C
      • Labaune JM
      • Fichez A
      • Sesques A
      • Cortet M.
      Contribution of ultrasound pulmonary ratio in pre-viable premature ruptures of membranes.
      Moreover, lower-chest-area-to-heart-area mean ratios were established to be lower than those of controls, and predictive of lethal pulmonary hypoplasia when below the fifth percentile.
      • Vintzileos AM
      • Campbell WA
      • Rodis JF
      • Nochimson DJ
      • Pinette MG
      • Petrikovsky BM.
      Comparison of six different ultrasonographic methods for predicting lethal fetal pulmonary hypoplasia.
      MRI has been used to evaluate lung volumetry and its correlation with postnatal outcome in fetuses with second-trimester PPROM. Lung volumes <60% of that predicted from normal ranges were found to be incompatible with postnatal survival.
      • Messerschmidt A
      • Pataraia A
      • Helmer H
      • et al.
      Fetal MRI for prediction of neonatal mortality following preterm premature rupture of the fetal membranes.
      Our group has also demonstrated that fetuses with high risk of preterm birth (both with and without membrane rupture) have smaller MRI-assessed lung volumes after adjustment for overall fetal size.
      • Story L
      • Zhang T
      • Steinweg JK
      • et al.
      Foetal lung volumes in pregnant women who deliver very preterm: a pilot study.
      A period of prolonged oligohydramnios during mid-gestation leads to a decrease in radial alveolar in the fetal lung, potentially mirrored by the significantly reduced signal intensities of the fetal lung tissue recorded across several studies on T2-weighted sequences. MRI therefore also has the potential to provide additional information pulmonary hypoplasia due to prolonged exposure of oligohydramnios induced by PPROM.

      Conclusions

      Ultrasound provides a cost-effective, widely available tool that is effective in detecting a high percentage of lung lesions. MRI, with its ability to display multiple planes and greater tissue differentiation, can provide additional information in a number of pulmonary conditions. Although already used in the clinical setting, rapid advances in the field, particularly with regard to motion correction and functional tissue assessment, indicate its potential to provide significantly more information on lung development in the future. This may enhance not only prognostication and antenatal counseling but also monitoring of existing and future therapies.

      References

        • Andrade CF
        • Ferreira HPdC
        • Fischer GB.
        Congenital lung malformations.
        J Bras Pneumol. 2011; 37: 259-271
        • Hedrick HL
        • Danzer E
        • Merchant AM
        • et al.
        Liver position and lung-to-head ratio for prediction of extracorporeal membrane oxygenation and survival in isolated left congenital diaphragmatic hernia.
        Am J Obstet Gynecol. 2007; 197 (422.e1–4)
        • Senat MV
        • Bouchghoul H
        • Stirnemann J
        • et al.
        Prognosis of isolated congenital diaphragmatic hernia using lung-area-to-head-circumference ratio: variability across centers in a national perinatal network.
        Ultrasound Obstet Gynecol. 2018; 51: 208-213
      1. Sadler TW, Langman J. Langman's medical embryology (12th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. 2012. https://www.ncbi.nlm.nih.gov/nlmcatalog/101562744.

        • Ohlsson A
        • Fong K
        • Rose T
        • et al.
        Prenatal ultrasonic prediction of autopsy-proven pulmonary hypoplasia.
        Am J Perinatol. 1992; 9: 334-337
        • Burgos-Artizzu XP
        • Perez-Moreno Á
        • Coronado-Gutierrez D
        • Gratacos E
        • Palacio M.
        Evaluation of an improved tool for non-invasive prediction of neonatal respiratory morbidity based on fully automated fetal lung ultrasound analysis.
        Sci Rep. 2019; 9: 1950
        • Kalache KD
        • Espinoza J
        • Chaiworapongsa T
        • et al.
        Three-dimensional ultrasound fetal lung volume measurement: a systematic study comparing the multiplanar method with the rotational (VOCAL) technique.
        Ultrasound Obstet Gynecol. 2003; 21: 111-118
        • Moeglin D
        • Talmant C
        • Duyme M
        • Lopez AC
        • CFEF
        Fetal lung volumetry using two- and three-dimensional ultrasound.
        Ultrasound Obstet Gynecol. 2005; 25: 119-127
        • Ruano R
        • Joubin L
        • Aubry MC
        • et al.
        A nomogram of fetal lung volumes estimated by 3-dimensional ultrasonography using the rotational technique (virtual organ computer-aided analysis).
        J Ultrasound Med. 2006; 25: 701-709
        • Ruano R
        • Martinovic J
        • Dommergues M
        • Aubry MC
        • Dumez Y
        • Benachi A.
        Accuracy of fetal lung volume assessed by three-dimensional sonography.
        Ultrasound Obstet Gynecol. 2005; 26: 725-730
        • Levine D
        • Barnewolt CE
        • Mehta TS
        • Trop I
        • Estroff J
        • Wong G.
        Fetal thoracic abnormalities: MR imaging.
        Radiology. 2003; 228: 379-388
        • Yamoto M
        • Iwazaki T
        • Takeuchi K
        • et al.
        The fetal lung-to-liver signal intensity ratio on magnetic resonance imaging as a predictor of outcomes from isolated congenital diaphragmatic hernia.
        Pediatr Surg Int. 2018; 34: 161-168
        • Shieh HF
        • Barnewolt CE
        • Wilson JM
        • et al.
        Percent predicted lung volume changes on fetal magnetic resonance imaging throughout gestation in congenital diaphragmatic hernia.
        J Pediatr Surg. 2017; 52: 933-937
        • Weidner M
        • Hagelstein C
        • Debus A
        • et al.
        MRI-based ratio of fetal lung volume to fetal body volume as a new prognostic marker in congenital diaphragmatic hernia.
        AJR Am J Roentgenol. 2014; 202: 1330-1336
        • Messerschmidt A
        • Pataraia A
        • Helmer H
        • et al.
        Fetal MRI for prediction of neonatal mortality following preterm premature rupture of the fetal membranes.
        Pediatr Radiol. 2011; 41: 1416-1420
        • Zamora IJ
        • Sheikh F
        • Cassady CI
        • et al.
        Fetal MRI lung volumes are predictive of perinatal outcomes in fetuses with congenital lung masses.
        J Pediatr Surg. 2014; 49: 853-858
        • Davidson J
        • Uus A
        • Egloff A
        • et al.
        Motion corrected fetal body magnetic resonance imaging provides reliable 3D lung volumes in normal and abnormal fetuses.
        Prenat Diagn. 2022; 42: 628-635
      2. Uus A, Steinweg JK, Ho A, et al. Deformable slice-to-volume registration for reconstruction of quantitative, vol. T2* Placental and Fetal MRI. Cham, Germany: Springer International Publishing; 2020. https://www.scopus.com/record/display.uri?eid=2-s2.0-85092706860&origin=inward&txGid=8458f33936a3444c878984d93fb1a9c0&featureToggles=FEATURE_NEW_DOC_DETAILS_EXPORT:1,FEATURE_ EXPORT_REDESIGN:0.

        • Alansary A
        • Rajchl M
        • McDonagh SG
        • et al.
        PVR: patch-to-volume reconstruction for large area motion correction of fetal MRI.
        IEEE Trans Med Imaging. 2017; 36: 2031-2044
        • Cannie MM
        • Jani JC
        • Van Kerkhove F
        • et al.
        Fetal body volume at MR imaging to quantify total fetal lung volume: normal ranges.
        Radiology. 2008; 247: 197-203
        • Story L
        • Zhang T
        • Steinweg JK
        • et al.
        Foetal lung volumes in pregnant women who deliver very preterm: a pilot study.
        Pediatr Res. 2020; 87: 1066-1071
        • Hutter J
        • Slator PJ
        • Christiaens D
        • et al.
        Integrated and efficient diffusion-relaxometry using ZEBRA.
        Sci Rep. 2018; 8: 15138
        • Afacan O
        • Gholipour A
        • Mulkern RV
        • et al.
        Fetal lung apparent diffusion coefficient measurement using diffusion-weighted MRI at 3 Tesla: correlation with gestational age.
        J Magn Reson Imaging. 2016; 44: 1650-1655
        • Sethi S
        • Giza SA
        • Goldberg E
        • et al.
        Quantification of 1.5 T T1 and T2* relaxation times of fetal tissues in uncomplicated pregnancies.
        J Magn Reson Imaging. 2021; 54: 113-121
        • van den Heuvel TLA
        • de Bruijn D
        • de Korte CL
        • Ginneken BV
        Automated measurement of fetal head circumference using 2D ultrasound images.
        PLoS One. 2018; 13e0200412
        • Li P
        • Zhao H
        • Liu P
        • Cao F.
        Automated measurement network for accurate segmentation and parameter modification in fetal head ultrasound images.
        Med Biol Eng Comput. 2020; 58: 2879-2892
        • Amodeo I
        • De Nunzio G
        • Raffaeli G
        • et al.
        A maChine and deep Learning Approach to predict pulmoNary hypertension in newbornS with congenital diaphragmatic Hernia (CLANNISH): protocol for a retrospective study.
        PLoS One. 2021; 16e0259724
        • Millischer AE
        • Brasseur-Daudruy M
        • Mahallati H
        • Salomon LJ.
        The use of image fusion in prenatal medicine.
        Prenat Diagn. 2020; 40: 18-27
        • Pelizzo G
        • Costanzo S
        • Selvaggio GGO
        • et al.
        Non-casual association between congenital pulmonary airway malformations/primary lung hypoplasia and congenital diaphragmatic hernia (CDH).
        Front Pediatr. 2020; 8 (446–6)
        • Stocker JT
        • Madewell JE
        • Drake RM.
        Congenital cystic adenomatoid malformation of the lung. Classification and morphologic spectrum.
        Hum Pathol. 1977; 8: 155-171
        • Corbett HJ
        • Humphrey GM.
        Pulmonary sequestration.
        Paediatr Respir Rev. 2004; 5: 59-68
        • Yoshitake S
        • Hayashi H
        • Osada H
        • Kawahara M.
        Emergency laparotomy helped the resection of an intralobar pulmonary sequestration with haemorrhagic shock.
        Eur J Cardiothorac Surg. 2013; 43: 190-192
        • Kline-Fath B
        • Bitters C.
        Prenatal imaging of fetal lung lesions: magnetic resonance imaging complements ultrasound.
        J Rad Nurs. 2010; 29: 3-9
        • Mon RA
        • Johnson KN
        • Ladino-Torres M
        • et al.
        Diagnostic accuracy of imaging studies in congenital lung malformations.
        Arch Dis Child Fetal Neonatal Ed. 2019; 104: F372-F377
        • Cruz-Martínez R
        • Nieto-Castro B
        • Martínez-Rodríguez M
        • et al.
        Thoracic changes after full laser ablation of the feeding artery in fetuses with bronchopulmonary sequestration.
        Fetal Diagn Ther. 2018; 44: 166-172
        • Skari H
        • Bjornland K
        • Haugen G
        • Egeland T
        • Emblem R.
        Congenital diaphragmatic hernia: a meta-analysis of mortality factors.
        J Pediatr Surg. 2000; 35: 1187-1197
        • Corsini I
        • Parri N
        • Coviello C
        • Leonardi V
        • Dani C.
        Lung ultrasound findings in congenital diaphragmatic hernia.
        Eur J Pediatr. 2019; 178: 491-495
        • Cruz-Martínez R
        • Etchegaray A
        • Molina-Giraldo S
        • et al.
        A multicentre study to predict neonatal survival according to lung-to-head ratio and liver herniation in fetuses with left congenital diaphragmatic hernia (CDH): hidden mortality from the Latin American CDH Study Group Registry.
        Prenat Diagn. 2019; 39: 519-526
        • Kandil RA
        • El shahawy AsZ
        • El Shafiey MH
        • Alarabawy RA
        Values and validity of fetal parameters by ultrasound and Doppler as markers of fetal lung maturity.
        Egypt J Rad Nucl Med. 2021; 52: 76
        • Jani J
        • Nicolaides KH
        • Keller RL
        • et al.
        Observed to expected lung area to head circumference ratio in the prediction of survival in fetuses with isolated diaphragmatic hernia.
        Ultrasound Obstet Gynecol. 2007; 30: 67-71
        • Quintero RA
        • Quintero LF
        • Chmait R
        • et al.
        The quantitative lung index (QLI): a gestational age–independent sonographic predictor of fetal lung growth.
        Am J Obstet Gynecol. 2011; 205 (544.e1–8)
        • Basurto D
        • Fuenzalida J
        • Martinez-Portilla RJ
        • et al.
        Intrapulmonary artery Doppler to predict mortality and morbidity in fetuses with mild or moderate left-sided congenital diaphragmatic hernia.
        Ultrasound Obstet Gynecol. 2021; 58: 590-596
        • Cruz-Martinez R
        • Martínez-Rodríguez M
        • Nieto-Castro B
        • et al.
        Longitudinal changes in lung size and intrapulmonary-artery Doppler during the second half of pregnancy in fetuses with congenital diaphragmatic hernia.
        Prenat Diagn. 2019; 39: 45-51
        • Balassy C
        • Kasprian G
        • Brugger PC
        • et al.
        Assessment of lung development in isolated congenital diaphragmatic hernia using signal intensity ratios on fetal MR imaging.
        Eur Radiol. 2010; 20: 829-837
        • Gerards FA
        • Twisk JW
        • Bakker M
        • Barkhof F
        • van Vugt JM.
        Fetal lung volume: three-dimensional ultrasonography compared with magnetic resonance imaging.
        Ultrasound Obstet Gynecol. 2007; 29: 533-536
        • Jani JC
        • Cannie M
        • Peralta CFA
        • Deprest JA
        • Nicolaides KH
        • Dymarkowski S.
        Lung volumes in fetuses with congenital diaphragmatic hernia: comparison of 3D US and MR imaging assessments.
        Radiology. 2007; 244: 575-582
        • Ruano R
        • Joubin L
        • Sonigo P
        • et al.
        Fetal lung volume estimated by 3-dimensional ultrasonography and magnetic resonance imaging in cases with isolated congenital diaphragmatic hernia.
        J Ultrasound Med. 2004; 23: 353-358
        • Bebbington M
        • Victoria T
        • Danzer E
        • et al.
        Comparison of ultrasound and magnetic resonance imaging parameters in predicting survival in isolated left-sided congenital diaphragmatic hernia.
        Ultrasound Obstet Gynecol. 2014; 43: 670-674
        • Tsuda H
        • Kotani T
        • Miura M
        • et al.
        Observed-to-expected MRI fetal lung volume can predict long-term lung morbidity in infants with congenital diaphragmatic hernia.
        J Matern Fetal Neonatal Med. 2017; 30: 1509-1513
        • Walleyo A
        • Debus A
        • Kehl S
        • et al.
        Periodic MRI lung volume assessment in fetuses with congenital diaphragmatic hernia: prediction of survival, need for ECMO, and development of chronic lung disease.
        AJR Am J Roentgenol. 2013; 201: 419-426
        • Debus A
        • Hagelstein C
        • Kilian AK
        • et al.
        Fetal lung volume in congenital diaphragmatic hernia: association of prenatal MR imaging findings with postnatal chronic lung disease.
        Radiology. 2013; 266: 887-895
        • Van der Veeken L
        • Russo FM
        • De Catte L
        • et al.
        Fetoscopic endoluminal tracheal occlusion and reestablishment of fetal airways for congenital diaphragmatic hernia.
        Gynecol Surg. 2018; 15: 9
        • Cannie M
        • Jani J
        • De Keyzer F
        • Roebben I
        • Dymarkowski S
        • Deprest J
        Diffusion-weighted MRI in lungs of normal fetuses and those with congenital diaphragmatic hernia.
        Ultrasound Obstet Gynecol. 2009; 34: 678-686
        • İpek MS
        • Akgul Ozmen C
        Skeletal dysplasias that cause thoracic insufficiency in neonates: illustrative case reports.
        Medicine (Baltimore). 2016; 95: e3298
        • Bonafe L
        • Cormier-Daire V
        • Hall C
        • et al.
        Nosology and classification of genetic skeletal disorders: 2015 revision.
        Am J Med Genet A. 2015; 167A: 2869-2892
        • Mogayzel PJ
        • Marcus CL.
        Skeletal dysplasias and their effect on the respiratory system.
        Paediatr Respir Rev. 2001; 2: 365-371
        • Parilla BV
        • Leeth EA
        • Kambich MP
        • Chilis P
        • MacGregor SN.
        Antenatal detection of skeletal dysplasias.
        J Ultrasound Med. 2003; 22: 255-258
        • Barros CA
        • Rezende Gde C
        • Araujo Júnior E
        • Tonni G
        • Pereira AK
        Prediction of lethal pulmonary hypoplasia by means fetal lung volume in skeletal dysplasias: a three-dimensional ultrasound assessment.
        J Matern Fetal Neonatal Med. 2016; 29: 1725-1730
        • Vintzileos AM
        • Campbell WA
        • Rodis JF
        • Nochimson DJ
        • Pinette MG
        • Petrikovsky BM.
        Comparison of six different ultrasonographic methods for predicting lethal fetal pulmonary hypoplasia.
        Am J Obstet Gynecol. 1989; 161: 606-612
        • Weaver KN
        • Johnson J
        • Kline-Fath B
        • et al.
        Predictive value of fetal lung volume in prenatally diagnosed skeletal dysplasia.
        Prenat Diagn. 2014; 34: 1326-1331
        • Gilligan LA
        • Calvo-Garcia MA
        • Weaver KN
        • Kline-Fath BM.
        Fetal magnetic resonance imaging of skeletal dysplasias.
        Pediatr Radiol. 2020; 50: 224-233
        • Tanaka T
        • Yamaki S
        • Ohno T
        • Ozawa A
        • Kakizawa H
        • Iinuma K.
        The histology of the lung in neonates with tricuspid valve disease and gross cardiomegaly due to severe regurgitation.
        Pediatr Cardiol. 1998; 19: 133-138
        • Mlczoch E
        • Schmidt L
        • Schmid M
        • et al.
        Fetal cardiac disease and fetal lung volume: an in utero MRI investigation.
        Prenat Diagn. 2014; 34: 273-278
        • Ruchonnet-Metrailler I
        • Bessieres B
        • Bonnet D
        • Vibhushan S
        • Delacourt C.
        Pulmonary hypoplasia associated with congenital heart diseases: a fetal study.
        PLoS One. 2014; 9: e93557
        • Akeson AL
        • Greenberg JM
        • Cameron JE
        • et al.
        Temporal and spatial regulation of VEGF-A controls vascular patterning in the embryonic lung.
        Dev Biol. 2003; 264: 443-455
        • Filby CE
        • Hooper SB
        • Wallace MJ.
        Partial pulmonary embolization disrupts alveolarization in fetal sheep.
        Respir Res. 2010; 11: 42
        • Research NIfCO
        National congenital heart disease audit report 2010–2013.
        UCL Press, 2014 (Annual Public Report)
        • Research NIfCO
        National Congenital Heart Disease Audit Summary Report 2020/1 data).
        Annual public report. 2022
        • Sokol J
        • Bohn D
        • Lacro RV
        • et al.
        Fetal pulmonary artery diameters and their association with lung hypoplasia and postnatal outcome in congenital diaphragmatic hernia.
        Am J Obstet Gynecol. 2002; 186: 1085-1090
        • Longaker MT
        • Laberge JM
        • Dansereau J
        • et al.
        Primary fetal hydrothorax: natural history and management.
        J Pediatr Surg. 1989; 24: 573-576
        • Castillo RA
        • Devoe LD
        • Falls G
        • Holzman GB
        • Hadi HA
        • Fadel HE.
        Pleural effusions and pulmonary hypoplasia.
        Am J Obstet Gynecol. 1987; 157: 1252-1255
        • Adams H
        • Jones A
        • Hayward C.
        The sonographic features and implications of fetal pleural effusions.
        Clin Radiol. 1988; 39: 398-401
        • Rustico MA
        • Lanna M
        • Coviello D
        • Smoleniec J
        • Nicolini U.
        Fetal pleural effusion.
        Prenat Diagn. 2007; 27: 793-799
        • Jeong BD
        • Won HS
        • Lee MY
        • Shim JY
        • Lee PR
        • Kim A.
        Perinatal outcomes of fetal pleural effusion following thoracoamniotic shunting.
        Prenat Diagn. 2015; 35: 1365-1370
        • Coleman AM
        • Merrow AC
        • Crombleholme TM
        • Jaekle R
        • Lim FY.
        Fetal MRI of torsed bronchopulmonary sequestration with tension hydrothorax and hydrops in a twin gestation.
        Fetal Diagn Ther. 2016; 40: 156-160
        • Recio Rodríguez M
        • Martínez de Vega V
        • Cano Alonso R
        • Carrascoso Arranz J
        • Martínez Ten P
        • Pérez Pedregosa J
        MR imaging of thoracic abnormalities in the fetus.
        RadioGraphics. 2012; 32: E305-E321
        • Pacharn P
        • Kline-Fath B
        • Calvo-Garcia M
        • et al.
        Congenital lung lesions: prenatal MRI and postnatal findings.
        Pediatr Radiol. 2013; 43: 1136-1143
        • Chien LN
        • Chiou HY
        • Wang CW
        • Yeh TF
        • Chen CM.
        Oligohydramnios increases the risk of respiratory hospitalization in childhood: a population-based study.
        Pediatr Res. 2014; 75: 576-581
        • Moessinger AC
        • Collins MH
        • Blanc WA
        • Rey HR
        • James LS.
        Oligohydramnios-induced lung hypoplasia: the influence of timing and duration in gestation.
        Pediatr Res. 1986; 20: 951-954
        • Chen CM
        • Chou HC
        • Wang LF
        • Lang YD.
        Experimental oligohydramnios decreases collagen in hypoplastic fetal rat lungs.
        Exp Biol Med (Maywood). 2008; 233: 1334-1340
        • Hislop A
        • Hey E
        • Reid L.
        The lungs in congenital bilateral renal agenesis and dysplasia.
        Arch Dis Child. 1979; 54: 32-38
        • Behairy NHED
        • El Din LAS
        • Hanoun NMF
        • Abd El Raof M
        • Ali MAEK
        Diagnostic value of fetal MRI in evaluating fetal urinary anomalies.
        Egypt J Rad Nucl Med. 2015; 46: 521-528
        • Grisaru-Granovsky S
        • Eitan R
        • Kaplan M
        • Samueloff A.
        Expectant management of midtrimester premature rupture of membranes: a plea for limits.
        J Perinatol. 2003; 23: 235-239
        • Pharande P
        • Mohamed AL
        • Bajuk B
        • Lui K
        • Bolisetty S.
        Preterm infant outcomes in relation to the gestational age of onset and duration of prelabour rupture of membranes: a retrospective cohort study.
        BMJ Paediatr Open. 2017; 1e000216
        • Rotschild A
        • Ling EW
        • Puterman ML
        • Farquharson D.
        Neonatal outcome after prolonged preterm rupture of the membranes.
        Am J Obstet Gynecol. 1990; 162: 46-52
        • Johnson A
        • Callan NA
        • Bhutani VK
        • Colmorgen GH
        • Weiner S
        • Bolognese RJ.
        Ultrasonic ratio of fetal thoracic to abdominal circumference: an association with fetal pulmonary hypoplasia.
        Am J Obstet Gynecol. 1987; 157: 764-769
        • Kilbride HW
        • Yeast J
        • Thibeault DW.
        Defining limits of survival: lethal pulmonary hypoplasia after midtrimester premature rupture of membranes.
        Am J Obstet Gynecol. 1996; 175: 675-681
        • van Teeffelen AS
        • Van Der Heijden J
        • Oei SG
        • et al.
        Accuracy of imaging parameters in the prediction of lethal pulmonary hypoplasia secondary to mid-trimester prelabor rupture of fetal membranes: a systematic review and meta-analysis.
        Ultrasound Obstet Gynecol. 2012; 39: 495-499
        • Jozan C
        • Huissoud C
        • Labaune JM
        • Fichez A
        • Sesques A
        • Cortet M.
        Contribution of ultrasound pulmonary ratio in pre-viable premature ruptures of membranes.
        Gynecol Obstet Fertil Senol. 2018; 46: 78-85
        • Schittny JC.
        Development of the lung.
        Cell Tissue Res. 2017; 367: 427-444
        • Narayanan M
        • Owers-Bradley J
        • Beardsmore CS
        • et al.
        Alveolarization continues during childhood and adolescence: new evidence from helium-3 magnetic resonance.
        Am J Respir Crit Care Med. 2012; 185: 186-191
        • Peralta CFA
        • Cavoretto P
        • Csapo B
        • Vandecruys H
        • Nicolaides KH.
        Assessment of lung area in normal fetuses at 12-32 weeks.
        Ultrasound Obstet Gynecol. 2005; 26: 718-724
        • Boonvisudhi K
        • Wanitpongpan P
        • Changnoi A.
        Nomogram of the lungs area by tracing method to head circumference ratio in normal Thai fetuses at 20-40 weeks of gestation.
        Siriraj Med J. 2014; 66: 75-78
        • Jani J
        • Peralta CF
        • Benachi A
        • Deprest J
        • Nicolaides KH.
        Assessment of lung area in fetuses with congenital diaphragmatic hernia.
        Ultrasound Obstet Gynecol. 2007; 30: 72-76
        • Nimrod C
        • Davies D
        • Iwanicki S
        • Harder J
        • Persaud D
        • Nicholson S.
        Ultrasound prediction of pulmonary hypoplasia.
        Obstet Gynecol. 1986; 68: 495-498
        • Lian X
        • Xu Z
        • Zheng L
        • et al.
        Reference range of fetal thorax using two-dimensional and three-dimensional ultrasound VOCAL technique and application in fetal thoracic malformations.
        BMC Med Imaging. 2021; 21: 34
        • Merz E
        • Wellek S
        • Bahlmann F
        • Weber G.
        [Normal ultrasound curves of the fetal osseous thorax and fetal lung].
        Geburtshilfe Frauenheilkd. 1995; 55: 77-82
        • Crombleholme TM
        • Coleman B
        • Hedrick H
        • et al.
        Cystic adenomatoid malformation volume ratio predicts outcome in prenatally diagnosed cystic adenomatoid malformation of the lung.
        J Pediatr Surg. 2002; 37: 331-338
        • Castillo RA
        • Devoe LD
        • Hadi HA
        • Martin S
        • Geist D.
        Nonimmune hydrops fetalis: clinical experience and factors related to a poor outcome.
        Am J Obstet Gynecol. 1986; 155: 812-816
        • Callan NA
        • Colmorgen GH
        • Weiner S.
        Lung hypoplasia and prolonged preterm ruptured membranes: a case report with implications for possible prenatal ultrasonic diagnosis.
        Am J Obstet Gynecol. 1985; 151: 756-757
        • Chitty LS
        • Altman DG
        • Henderson A
        • Campbell S.
        Charts of fetal size: 3. Abdominal measurements.
        Br J Obstet Gynaecol. 1994; 101: 125-131
      3. Johnson A, Callan NA, Bhutani VK, Colmorgen GHC, Weiner S, Bolognese RJ. Ultrasonic ratio of fetal thoracic to abdominal circumference: An association with fetal pulmonary hypoplasia. 1987;157:764-769. https://doi.org/10.1016/S0002-9378(87)80046-7.

        • Metkus AP
        • Filly RA
        • Stringer MD
        • Harrison MR
        • Adzick NS.
        Sonographic predictors of survival in fetal diaphragmatic hernia.
        J Pediatr Surg. 1996; 31: 148-151
        • Jani J
        • Peralta CF
        • Van Schoubroeck D
        • Deprest J
        • Nicolaides KH.
        Relationship between lung-to-head ratio and lung volume in normal fetuses and fetuses with diaphragmatic hernia.
        Ultrasound Obstet Gynecol. 2006; 27: 545-550
        • Jani J
        • Keller RL
        • Benachi A
        • et al.
        Prenatal prediction of survival in isolated left-sided diaphragmatic hernia.
        Ultrasound Obstet Gynecol. 2006; 27: 18-22
        • Jani JC
        • Peralta CF
        • Nicolaides KH.
        Lung-to-head ratio: a need to unify the technique.
        Ultrasound Obstet Gynecol. 2012; 39: 2-6
        • Quintero RA
        • Kontopoulos EV
        • Quintero LF
        • Landy DC
        • Gonzalez R
        • Chmait RH.
        The observed vs. expected lung-to-head ratio does not correct for the effect of gestational age on the lung-to-head ratio.
        J Matern Fetal Neonatal Med. 2013; 26: 552-557
        • Ruano R
        • Takashi E
        • da Silva MM
        • Campos JADB
        • Tannuri U
        • Zugaib M.
        Prediction and probability of neonatal outcome in isolated congenital diaphragmatic hernia using multiple ultrasound parameters.
        Ultrasound Obstet Gynecol. 2012; 39: 42-49
        • Illescas T
        • Rodó C
        • Arévalo S
        • Giné C
        • Peiró JL
        • Carreras E.
        The quantitative lung index and the prediction of survival in fetuses with congenital diaphragmatic hernia.
        Eur J Obstet Gynecol Reprod Biol. 2016; 198: 145-148
        • Hasegawa T
        • Kamata S
        • Imura K
        • et al.
        Use of lung-thorax transverse area ratio in the antenatal evaluation of lung hypoplasia in congenital diaphragmatic hernia.
        J Clin Ultrasound. 1990; 18: 705-709