Timing of magnetic resonance imaging in pregnancy for congenital diaphragmatic hernia

Timing of magnetic resonance imaging in pregnancy for congenital diaphragmatic hernia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Timing of magnetic resonance imaging in pregnancy for congenital diaphragmatic hernia Vivien Dütemeyer, Mieke Cannie, Thomas Schaible, Meike Weis, Nicola Persico, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4117685/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Purpose : To evaluate the impact of the timing of MRI on the prediction of survival and morbidity in patients with CDH, and whether serial measurements have a beneficial value. Methods: This retrospective cohort study was conducted in two perinatal centers, in Germany and Italy. It included 354 patients with isolated CDH having at least one fetal MRI. The severity was assessed with the observed to expected total fetal lung volume (o/e TFLV) measured by two experienced double-blinded operators. The cohort was divided into three groups according to the gestational age (GA) at which the MRI was performed (32 weeks gestation [WG]). The accuracy for the prediction of survival at discharge and morbidity was analyzed with receiver operating characteristic (ROC) curves. Multiple logistic regression analyses and propensity score matching examined the population for balance. The effect of repeated MRI was evaluated in ninety-seven cases. Results: There were no significant differences in prediction of survival when the o/e TFLV was measured before 27, between 27 and 32, and after 32 WG (area under the curve [AUC]: 0.77, 0.79, and 0.77, respectively). After adjustment for confounding factors, it was seen, that GA at MRI was not associated with survival at discharge, but the risk of mortality was higher with an intrathoracic liver position (adjusted odds ratio [aOR]: 0.30, 95% confidence interval [95%CI]: 0.12-0.78), lower GA at birth (aOR 1.48, 95%CI: 1.24-1.78) and lower o/e TFLV (aOR 1.13, 95%CI: 1.06-1.20). ROC curves showed comparable prediction accuracy for the different timepoints in pregnancy for pulmonary hypertension, the need of extracorporeal membrane oxygenation, and feeding aids. Serial measurements revealed no difference in change rate of the o/e TFLV according to survival. Conclusion: The timing of MRI does not affect the prediction of survival rate or morbidity as the o/e TFLV does not change during pregnancy. Clinicians could choose any gestational age starting mid second trimester for the assessment of severity and counseling. fetal magnetic resonance imaging congenital diaphragmatic hernia total fetal lung volume timing prenatal prognosis survival Figures Figure 1 Figure 2 Figure 3 Figure 4 What does this study adds to the clinical work In fetuses with congenital diaphragmatic hernia the assessment of survival rate and morbidity with fetal MRI can be done from mid second trimester until the end of the pregnancy. The o/e TFLV does not change with advancing gestational age, thus there is no benefit of repeated imaging. INTRODUCTION The assessment of congenital diaphragmatic hernia (CDH) during pregnancy by genetic testing and advanced imaging is crucial to discuss the individual estimated rate of mortality and morbidity [ 1 ] with future parents and to counsel them about various prenatal interventions, such as fetal endoscopic tracheal occlusion (FETO) [ 2 – 5 ], termination of pregnancy for fetal anomaly (TOPFA), or antenatal expectant management plus delivery in a tertiary center. Fetal ultrasound is the gold standard to screen patients for CDH. The detection rate is about 60% at a mean gestational age (GA) of 24 weeks. It becomes higher and at earlier GA in the presence of associated abnormalities compared to that of isolated CDH [ 6 , 7 ]. The rate of prenatal diagnosis varies among the European regions, and it can be up to 95% in highly experienced prenatal centers [ 7 , 8 ]. Cases with a postnatal diagnosis of CDH present lower mortality rates [ 9 ], probably due to a lesser severity. The degree of severity can be identified by various sonographic methods like the identification of an intrathoracic position of the liver [ 10 ], the stomach position [ 11 ] or the measurement of the lung-to-head ratio (LHR) and the calculation of the observed over the expected ratio at each GA (o/e LHR) [ 12 ]. The latest mentioned quantification of the lung volume obtained with the tracing method, seems to be the most precise to predict survival [ 13 ]. However, fetal magnetic resonance imaging (MRI) has gained by now a worldwide approval for the extensive evaluation of CDH [ 14 ]. The prediction of outcome and the measurement of the observed to expected total fetal lung volume ratio (o/e TFLV) is more precise compared to a sonographic approach [ 15 , 16 ]. As CDH patients should be referred to prenatal centers with access to this type of imaging studies and with the expertise in the examination and treatment of this rare malformation, the question raises about the best timing to assess the severity and to address pregnant women accordingly to perform MRI. Thus, the aim of the study was to determine the accuracy of MRI at different periods of pregnancy in the prediction of survival and morbidity, and to examine whether serial measurements of the lung volume would have an additional value regarding postnatal prognosis. METHODS Study participants and design This retrospective study was conducted in two perinatal referral centers (University Hospital in Mannheim, Germany and Hospital 'L. Mangiagalli', Italy). We included all fetuses with isolated congenital diaphragmatic hernia having at least one MRI during pregnancy between 2001 and 2019. Exclusion criteria were twin pregnancies, patients undergoing fetoscopic endoluminal tracheal occlusion (FETO), inappropriate images, incompleteness of data, fetuses with major associated congenital/genetic malformations pre- or postnatally diagnosed, eventrations and bilateral hernia. Patients with mild heart defects (atrio- or ventricular-septal defects), scoliosis or gastro-intestinal anomalies (bowel duplication) associated with CDH and not influencing prognosis were not excluded. Data of 213 patients included in this study have been reported in another context previously [ 17 ]. Three groups were formed according to the GA at which the MRI was done (before 27 WG, between 27 and 32 WG and after 32 WG). These two timepoints were selected because they represent the limits to perform FETO [ 18 ]. Severity was assessed with the measurement of the TFLV by two experienced operators (M.M.C. and V.D.), who were blinded to the antenatal and postnatal data, and the o/e TFLV was calculated by the formula first described by Rypens et al. [ 19 ] In the case of multiple MRI, the first exam performed during gestation was taken for analysis. Fetal lung growth was evaluated with the interval change rate of the o/e TFLV of two exams at different moments in pregnancy. The study was approved by the local ethics committee and the requirement for written informed consent was waived. Data collection The two participating centers provided the requested data of eligible patients, which were merged into a single database. It included the following variables: (1) type of CDH; (2) GA and o/e TFLV at MRI; (3) GA at delivery; (4) fetal gender; (5) birthweight at birth (Z-score using the web accessible Fenton growth chart) [ 20 ]; (6) extracorporeal membrane oxygenation (ECMO) use; (7) corrective surgery for CDH during the postnatal period; (8) patch use during surgery; (9) survival at hospital discharge; (10) bronchopulmonary dysplasia (BPD) described as oxygen dependency by day 28 and classified into mild, moderate and severe according to the definition of Jobe and Bancalari [ 21 ]; (11) persistent pulmonary hypertension (PPHN) requiring medication; (12) oxygen therapy by nasal canula or tracheostomy and (13) feeding support by naso-gastric tube or gastro/jejunostomy. Outcomes Primary outcomes included prediction of survival at discharge from hospital with the o/e TFLV measured at different moments during pregnancy and with serial measurements, whereas secondary outcomes comprised predictions of BPD, PPHN, need for oxygen and feeding support. Statistical analysis Statistical analysis was performed using R software version 4.2.2 ( www.r-project.org ). Continuous variables were summarized as mean ± standard deviation (SD) unless stated otherwise, while categorical variables were expressed as numbers (frequency). Baseline characteristics among the three study groups (MRI at 32 WG) were compared with either analysis of variance or Pearson’s chi-squared test, and a post-hoc comparison was performed using Tukey’s test. Receiver operating characteristic (ROC) curves were constructed for the prediction of survival at discharge and for the different morbidities by the o/e TFLV 32 WG. Afterwards, a propensity score that included possible confounding variables was created for the three groups to calculate an average treatment effect (ATE) by the inverse probability of treatment weighting (IPTW). The balance of covariates among the groups was assessed by the standardized mean difference (SMD) according to the Euclidean distance (ES) mean statistic. An SMD below 0.10–0.15 is expected to ensure a good balance. Afterwards, a logistic regression model that included the ATE weights was performed to examine the effect size (odds ratio [OR]) of the timing of MRI in the prediction of mortality at discharge. The package “twang” was used. Finally, in a subgroup analysis of patients who underwent two consecutive MRIs, the percentage of o/e TFLV per week in patients who survived at discharge was compared to patients who died before discharge. The following formula was used to calculate this parameter: o/e TFLV change (%/week) = (o/e TFLV MRI2 – o/e TFLV MRI1) / (GA at MRI2 – GA at MRI1). Statistical significance was set at p < 0.05. RESULTS A total of 467 fetuses with CDH were identified. We excluded 48 FETO patients, 12 twin pregnancies, 19 with associated malformations, 7 with bilateral CDH, 22 had no MR imaging and 5 had an MRI of bad quality. For the final analysis, 354 (75,8%) participants were included. Of these, MRI was done before 27 WG in 107 (30.2%), between 27 and 32 WG in 96 (27.1%), and after 32 WG in 151 (42.7%) (Fig. 1 ). There was a statistically significant difference among the 3 groups for the referral center (p < 0.001), o/e TFLV (p < 0.001), and male gender (p = 0.003). Nevertheless, the survival rate at discharge was comparable among the groups (p = 0.288) (Table 1 ). Table 1 Baseline characteristics of the study population according to the gestational age at the magnetic resonance imaging was performed. GA at MRI < 27 WG N = 107 GA at MRI 27–32 WG N = 96 GA at MRI ≥ 32 WG N = 151 p-value Center < 0.001* Germany 95 (88.8%) 84 (87.5%) 150 (99.3%) Italy 12 (11.2%) 12 (12.5%) 1 (0.7%) Right-sided CDH 13 (12.1%) 10 (10.4%) 19 (12.6%) 0.871 Intrathoracic liver 69 (64.5%) 58 (60.4%) 89 (58.9%) 0.660 O/E TFLV 29.42 (11.79) 29.20 (12.57) 23.78 (13.60) < 0.001* GA at birth, WG 37.02 (1.97) 37.04 (1.92) 37.34 (1.48) 0.262 Birthweight Z-score 0.06 (0.95) -0.20 (1.01) -0.13 (0.94) 0.124 Male gender 75 (70.1%) 50 (52.1%) 75 (49.7%) 0.003** ECMO 37 (34.6%) 27 (28.1%) 53 (35.1%) 0.484 Survival at discharge 92 (86.0%) 76 (79.2%) 130 (86.1%) 0.288 *Significant statistical difference between group 3 and group 1, and between group 3 and group 2. ** Significant statistical difference between group 2 and group 1, and between group 3 and group 1. There was no statistically significant difference for the prediction of survival at discharge when the o/e TFLV was calculated at 32 WG (area under the curve [AUC]: 0.77, 95% confidence interval [95%CI]: 0.65–0.89; AUC: 0.79 [95%CI: 0.66–0.92]; and AUC: 0.77 [95%CI: 0.68–0.86], respectively) (Fig. 2 ). After balancing the possible confounders among the three groups (Fig. 3 ), the calculation of o/e TFLV at 32 WG was not an independent predictor for survival. Only intrathoracic liver, GA at birth and o/e TFLV independent predictors of survival (adjusted OR: 0.3 [95%CI 0.12–0.78]; 1.48 [1.24–1.78]; and 1.13 [1.06–1.20], respectively) (Table 2 ). Table 2 Independent factors associated with survival at discharge. Mortality at discharge N = 56 Survival at discharge N = 298 Adjusted OR (95%CI) GA at MRI, WG < 27 15 (26.8%) 92 (30.9%) Ref 27–32 20 (35.7%) 76 (25.5%) 0.53 (0.22–1.27) ≥ 32 21 (37.5%) 130 (43.6%) 1.52 (0.59–3.90) Center Germany 53 (94.6%) 276 (92.6%) Ref Italy 3 (5.4%) 22 (7.4%) 0.45 (0.09–2.31) ECMO 30 (53.6%) 87 (29.2%) 0.54 (0.24–1.21) Intrathoracic liver 48 (85.7%) 168 (56.4%) 0.30 (0.12–0.78) Male gender 31 (55.4%) 169 (56.7%) 0.96 (0.47–1.97) Right-sided CDH 5 (8.9%) 37 (12.4%) 2.23 (0.72–6.89) GA at birth, WG 36.31 (2.29) 37.32 (1.60) 1.48 (1.24–1.78) O/E TFLV, % 18.36 (8.13) 28.57 (13.18) 1.13 (1.06–1.20) Birthweight Z-score -0.39 (0.96) -0.04 (0.96) 1.21 (0.86–1.79) Abbreviations : 95%CI: 95% confidence interval; CDH: congenital diaphragmatic hernia; ECMO: extracorporeal membrane oxygenation; GA: gestational age; o/e TFLV: observed over expected total fetal lung volume; OR: odds ratio; WG: weeks of gestation. Similar analysis was replicated in 350 patients with a known status about the use of ECMO, 257 with known status about feeding support, 278 with known status about PPHN, 282 with known status about BPD, and 256 with known status about oxygen therapy. Only the prediction of BPD was significantly better after 32 WG in comparison with < 27 WG (p = 0.011), and the prediction of oxygen therapy was significantly better between 27 and 32 WG in comparison with < 27 WG (p = 0.009) (Supplementary Figs. 1–5). In a subgroup analysis, 97 fetuses benefited from two consecutive MRI. Ten of them (10.3%) had right sided CDH and 65 (67.0%) had intrathoracic liver. The mean GA at the first MRI was 25.75 WG and at the second MRI was 32.51 WG. The survival rate was 86.6% (Table 3 ). There was no significant difference for the o/e TFLV change rate between fetuses who survived and those who did not at discharge (p = 0.390) (Fig. 4 ). Table 3 Characteristics of patients who underwent two consecutive magnetic resonance imaging examinations. N = 97 Right-sided CDH 10 (10.3%) Intrathoracic liver 65 (67.0%) GA at 1st MRI, WG 25.75 (3.25) GA at 2nd MRI, WG 32.51 (2.48) Survival at discharge 84 (86.6%) Abbreviations : CDH: congenital diaphragmatic hernia; GA: gestational age; MRI: magnetic resonance imaging; WG: weeks of gestation. DISCUSSION Principal findings In this study, we examined the effect of the calculation of o/e TFLV at different periods of pregnancy in the prediction of the survival at discharge in fetuses with CDH. The analysis was performed by two approaches: single measurement and serial measurements. We showed that the prediction of survival is not affected by the timing of MRI. Hence, the assessment of o/e TFLV in patients with CDH can be done during the whole pregnancy starting late second trimester. Comparison with results of previous studies A smaller retrospective single center study with 57 patients who had two MRIs, one in the second and the second in the third trimester, reported similar results regarding the prediction of ECMO and PPHN [ 22 ]. Nonetheless, the group in Houston suggested that second trimester MRI strongly correlated with mortality. They included all types of CDH in their population (left-sided, right-sided, and bilateral), and the mean severity was not mentioned. Walleyo et al. required almost the same inclusion criteria as our study except that they excluded CDH patients born before 34 WG [ 23 ], which is a confounding factor and not representative for the general CDH population as the incidence of prematurity, even without the invasive procedure FETO, is around 30% [ 24 ]. Nevertheless, concerning the survival, need for ECMO and development of chronic lung disease (CLD), they also showed the same prognostic strength of o/e TFLV measured at different periods in the second or third trimester [ 23 ]. We showed that the o/e TFLV does not change during pregnancy, thus, multiple MRI examinations have no benefit regarding the accuracy of the established prognosis. This was already demonstrated in a prospective study of Cannie et al. with 18 expectantly managed fetuses [ 25 ]. They found no increase of the o/e TFLV during the second half of pregnancy irrespective of the position of the liver. The survival rate in our study (86.6%) was comparable to that of Cannie et al. (83,3%), despite that the fetuses who had serial MRI in our cohort were more severely affected. Similar conclusion was drawn by the group in Houston, who observed that patients with severe PPHN had a significant lower mean rate of lung growth over time, but the change rate of the o/e TFLV was not altered [ 22 ]. The study showed that routine repeat imaging is not necessary within the general CDH population. Comparable results were also obtained by Coleman et al. , who analyzed retrospectively 47 cases of left sided CDH with two MRI examinations, one between 22 to 30 WG and the second after 30 WG [ 26 ]. Non-survivors had lower rate of lung growth than survivors, but again the o/e TFLV remained stable during pregnancy so that its change rate was not significantly different between the groups. The lung-volume ratio obtained either early or late throughout the pregnancy was predictive of neonatal survival, whereas the crude MRI derived lung-volume was only associated with adverse outcomes when assessed close to term. This highlights the value of adjustment for gestational age. A previous study by Hagelstein et al. including patients who received two MRIs at around 26 WG and 34 WG, showed that first and last o/e TFLV were associated with mortality and neonatal ECMO requirement [ 27 ]. Comparing the AUC respectively, they stated a higher prognostic accuracy of measurements done near delivery, without mentioning a statistical significance. However, the study was based only on 89 fetuses, whereas in the current study we included 354 fetuses, from 2 centers and we performed comparisons based on different statistical methods. Furthermore, they noted a lower weekly lung growth rate of non-survivors compared to survivors, but this value in addition to the o/e TFLV did not improve significantly the prognostic accuracy. Clinical implications The fact that the assessment of CDH severity has the same prediction accuracy independently of the gestational age at which the MRI examination is done, is of great interest in view of possible prenatal interventions. FETO in severe CDH patients is generally performed at 27 to 29 WG and the most difficult decision of termination of pregnancy in more sinister cases is better to handle before the third trimester – emotionally [ 28 ], physically and in terms of feasibility in countries with a term limit of abortion. This result should encourage clinicians to refer their patients early in pregnancy to a specialized prenatal care center in order to assess the prognosis, discuss the management options and organize subsequent treatment strategy. In addition, knowing that serial MRI comprise no benefit for the prediction of survival could spare the future mother and her partner from undergoing through a procedure, which is probably more stressful than ultrasound [ 29 ]. Furthermore, this finding has a great impact on the economical level. Research implications The observed to expected lung area to head circumference ratio (o/e LHR) at ultrasound comports similar [ 30 ]. The prediction of survival is independent on the timing of assessment during pregnancy. However, the performance of the o/e TFLV seems to be better [ 15 , 16 ]. Further studies comparing both methods, ultrasound and MRI measurements of the lung volume, at several timepoints during pregnancy on the same fetus are required. Strengths and limitations This was a retrospective study with a significant sample size coming from two different perinatal care centers. The lung volume assessment was exclusively performed by two experienced blinded operators not working in the participating centers in order to guarantee an objective investigation and to reduce interobserver errors [ 31 ]. The gestational age stratification of when the MRI was performed was deliberately set at < 27 WG, because FETO, when indicated, should be done between 27 and 29 WG [ 18 ]. In order to analyze a representative cohort, we did not exclude preterm birth, but instead we balanced GA at delivery in the different groups of the study. A potential limitation of the current study could be the determination of survival at discharge, even though we observed in a previous study only a small decrease of survival between discharge and two years of life (about 2%) [ 17 ]. Similar was seen after analyzing the morbidity parameters. Nevertheless, future studies with a longer follow up are required. Conclusion The MR assessment of severity and the prediction of survival and morbidity in fetuses with CDH can be done at any time of gestation starting mid second trimester. The substantial counseling of concerned parents can already take place in the second trimester without the need of an additional MRI during pregnancy. Moreover, patients presenting late with advanced gestational age could benefit from this diagnostic tool. Declarations AUTHOR CONTRIBUTIONS: All authors read and approved the final manuscript V Dütemeyer: Project development, Data collection and management, Measurement of the o/e TFLV, Manuscript writing MM Cannie: Project development, Measurement of the o/e TFLV T Schaible: Project development, Data management M Weis: Data collection N Persico: Project development, Data management I Borzani: Data collection DA Badr: Project development, Data management, Data analysis, Manuscript writing JC Jani: Project development, Data management, Data analysis, Manuscript writing Funding: The Fetal Medicine Foundation Belgium partly funded this study, but had no role in the study design, data gathering, data analysis, data interpretation, or writing of the report Competing Interests: The authors report no conflict of interest. Ethics approval: This is a retrospective observational study. The local ethics committee has confirmed that no ethical approval is required. 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J Matern Fetal Neonatal Med 35:1036–1044. https://doi:10.1080/14767058.2020.1740982 STATEMENTS & DECLARATIONS Supplementary Files SupplementaryFigures.pptx Supplementary figure legends: Supplementary figure 1: Comparison of the receiver operating characteristic (ROC) curves for the prediction of extracorporeal membrane oxygenation (ECMO) when the observed over expected total fetal lung volume was measured before 27 weeks of gestation (WG) (in red), between 27 and 32 WG (in blue), and after 32 WG (in green). There was no statistically significant difference among the three curves. Supplementary figure 2: Comparison of the receiver operating characteristic (ROC) curves for the prediction of feeding support when the observed over expected total fetal lung volume was measured before 27 weeks of gestation (WG) (in red), between 27 and 32 WG (in blue), and after 32 WG (in green). There was no statistically significant difference among the three curves. Supplementary figure 3: Comparison of the receiver operating characteristic (ROC) curves for the prediction of persistent pulmonary hypertension when the observed over expected total fetal lung volume was measured before 27 weeks of gestation (WG) (in red), between 27 and 32 WG (in blue), and after 32 WG (in green). There was no statistically significant difference among the three curves. Supplementary figure 4: Comparison of the receiver operating characteristic (ROC) curves for the prediction of bronchopulmonary dysplasia when the observed over expected total fetal lung volume was measured before 27 weeks of gestation (WG) (in red), between 27 and 32 WG (in blue), and after 32 WG (in green). The prediction of CLD in the third group was significantly better than in first group (p = 0.011). Supplementary figure 5: Comparison of the receiver operating characteristic (ROC) curves for the prediction of oxygen therapy when the observed over expected total fetal lung volume was measured before 27 weeks of gestation (WG) (in red), between 27 and 32 WG (in blue), and after 32 WG (in green). The prediction of OXYGEN in the second group was significantly better than in the first group (p = 0.009). Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Minor revisions 23 Apr, 2024 Reviewers agreed at journal 07 Apr, 2024 Reviewers invited by journal 25 Mar, 2024 Editor assigned by journal 18 Mar, 2024 First submitted to journal 17 Mar, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4117685","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":283806762,"identity":"87c491f6-8f30-461e-95bc-9c07d3b3bbd3","order_by":0,"name":"Vivien Dütemeyer","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-6374-2843","institution":"Hannover Medical School: Medizinische Hochschule Hannover","correspondingAuthor":true,"prefix":"","firstName":"Vivien","middleName":"","lastName":"Dütemeyer","suffix":""},{"id":283806763,"identity":"5cd65ac9-7b07-431b-a63b-cce8befbd15a","order_by":1,"name":"Mieke Cannie","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Mieke","middleName":"","lastName":"Cannie","suffix":""},{"id":283806764,"identity":"f2b0644b-9a66-4505-8687-0a25443dc4bc","order_by":2,"name":"Thomas Schaible","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Schaible","suffix":""},{"id":283806765,"identity":"1d49c4a6-055e-4dc0-b4c0-7982b52c02c4","order_by":3,"name":"Meike Weis","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Meike","middleName":"","lastName":"Weis","suffix":""},{"id":283806766,"identity":"63b9cb86-9826-4f16-8134-1dd50072a6c5","order_by":4,"name":"Nicola Persico","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Nicola","middleName":"","lastName":"Persico","suffix":""},{"id":283806767,"identity":"77a9082c-8827-404f-b203-a64e4537db71","order_by":5,"name":"Irene Borzani","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Irene","middleName":"","lastName":"Borzani","suffix":""},{"id":283806768,"identity":"33405350-6769-4d23-9a1c-a0f2879d2b0b","order_by":6,"name":"Dominique Badr","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Dominique","middleName":"","lastName":"Badr","suffix":""},{"id":283806769,"identity":"9e49507b-0357-480a-94a0-88afa371931a","order_by":7,"name":"Jacques JANI","email":"","orcid":"https://orcid.org/0000-0003-2252-342X","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Jacques","middleName":"","lastName":"JANI","suffix":""}],"badges":[],"createdAt":"2024-03-17 15:16:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4117685/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4117685/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53749626,"identity":"798fee16-44b5-41b3-b983-2cd6ec6ee90b","added_by":"auto","created_at":"2024-03-29 18:34:28","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":48265,"visible":true,"origin":"","legend":"\u003cp\u003eflowchart of the study population.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e CDH: congenital diaphragmatic hernia; FETO: fetoscopic endoluminal tracheal occlusion; MRI: magnetic resonance imaging; WG: weeks of gestation.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4117685/v1/d696e73b439a34b928d11ea0.jpg"},{"id":53749624,"identity":"43b5820d-74b6-4d65-8f90-6e7eeb265a3f","added_by":"auto","created_at":"2024-03-29 18:34:28","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":40164,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of the receiver operating characteristic (ROC) curves for the prediction of survival at discharge when the observed over expected total fetal lung volume was measured before 27 weeks of gestation (WG) (in red), between 27 and 32 WG (in blue), and after 32 WG (in green). There was no statistically significant difference among the three curves.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e WG: weeks of gestation; AUC: Area under the curve\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4117685/v1/1437515a2d1fd0d00d007060.jpg"},{"id":53749625,"identity":"739ec35d-7ac9-4f12-a327-27038c0c09b9","added_by":"auto","created_at":"2024-03-29 18:34:28","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":45119,"visible":true,"origin":"","legend":"\u003cp\u003eAbsolute standardized difference (ASD) of variables before and after propensity score matching by the average treatment effect (ATE) according to the Euclidean distance (ES) mean statistic. An ASD below 0.10-0.15 indicates a good balance among the 3 groups.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4117685/v1/ccbd26290e03efa2e2957c92.jpg"},{"id":53749627,"identity":"3e504b19-5dff-473c-b495-531401fa26e3","added_by":"auto","created_at":"2024-03-29 18:34:28","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":47957,"visible":true,"origin":"","legend":"\u003cp\u003eViolin plot for the comparison of the change of observed to expected total fetal lung volume on serial magnetic resonance imaging according to survival at discharge. There was no significant difference in either group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e O/E TFLV: observed to expected total fetal lung volume\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4117685/v1/a78ccdad66fdb5b5ef170bf1.jpg"},{"id":53750920,"identity":"ba419a44-ed81-41b1-963f-9a9854bbf9b3","added_by":"auto","created_at":"2024-03-29 18:42:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":504810,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4117685/v1/a8ada97f-9bff-4e69-92eb-e5b29b073b86.pdf"},{"id":53749628,"identity":"214cd361-d08a-421e-b269-352f814a7cb4","added_by":"auto","created_at":"2024-03-29 18:34:28","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":272770,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary figure legends:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary figure 1:\u003c/strong\u003e Comparison of the receiver operating characteristic (ROC) curves for the prediction of extracorporeal membrane oxygenation (ECMO) when the observed over expected total fetal lung volume was measured before 27 weeks of gestation (WG) (in red), between 27 and 32 WG (in blue), and after 32 WG (in green). There was no statistically significant difference among the three curves.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary figure 2:\u003c/strong\u003e Comparison of the receiver operating characteristic (ROC) curves for the prediction of feeding support when the observed over expected total fetal lung volume was measured before 27 weeks of gestation (WG) (in red), between 27 and 32 WG (in blue), and after 32 WG (in green). There was no statistically significant difference among the three curves.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary figure 3:\u003c/strong\u003e Comparison of the receiver operating characteristic (ROC) curves for the prediction of persistent pulmonary hypertension when the observed over expected total fetal lung volume was measured before 27 weeks of gestation (WG) (in red), between 27 and 32 WG (in blue), and after 32 WG (in green). There was no statistically significant difference among the three curves.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary figure 4:\u003c/strong\u003e Comparison of the receiver operating characteristic (ROC) curves for the prediction of bronchopulmonary dysplasia when the observed over expected total fetal lung volume was measured before 27 weeks of gestation (WG) (in red), between 27 and 32 WG (in blue), and after 32 WG (in green). The prediction of CLD in the third group was significantly better than in first group (p = 0.011).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary figure 5:\u003c/strong\u003e Comparison of the receiver operating characteristic (ROC) curves for the prediction of oxygen therapy when the observed over expected total fetal lung volume was measured before 27 weeks of gestation (WG) (in red), between 27 and 32 WG (in blue), and after 32 WG (in green). The prediction of OXYGEN in the second group was significantly better than in the first group (p = 0.009).\u003c/p\u003e","description":"","filename":"SupplementaryFigures.pptx","url":"https://assets-eu.researchsquare.com/files/rs-4117685/v1/eb964bc092dd5c9f3628c446.pptx"}],"financialInterests":"","formattedTitle":"Timing of magnetic resonance imaging in pregnancy for congenital diaphragmatic hernia","fulltext":[{"header":"What does this study adds to the clinical work","content":"\u003cp\u003eIn fetuses with congenital diaphragmatic hernia the assessment of survival rate and morbidity with fetal MRI can be done from mid second trimester until the end of the pregnancy. The o/e TFLV does not change with advancing gestational age, thus there is no benefit of repeated imaging.\u003c/p\u003e"},{"header":"INTRODUCTION","content":"\u003cp\u003eThe assessment of congenital diaphragmatic hernia (CDH) during pregnancy by genetic testing and advanced imaging is crucial to discuss the individual estimated rate of mortality and morbidity [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] with future parents and to counsel them about various prenatal interventions, such as fetal endoscopic tracheal occlusion (FETO) [\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], termination of pregnancy for fetal anomaly (TOPFA), or antenatal expectant management plus delivery in a tertiary center.\u003c/p\u003e \u003cp\u003eFetal ultrasound is the gold standard to screen patients for CDH. The detection rate is about 60% at a mean gestational age (GA) of 24 weeks. It becomes higher and at earlier GA in the presence of associated abnormalities compared to that of isolated CDH [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The rate of prenatal diagnosis varies among the European regions, and it can be up to 95% in highly experienced prenatal centers [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Cases with a postnatal diagnosis of CDH present lower mortality rates [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], probably due to a lesser severity.\u003c/p\u003e \u003cp\u003eThe degree of severity can be identified by various sonographic methods like the identification of an intrathoracic position of the liver [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], the stomach position [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] or the measurement of the lung-to-head ratio (LHR) and the calculation of the observed over the expected ratio at each GA (o/e LHR) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The latest mentioned quantification of the lung volume obtained with the tracing method, seems to be the most precise to predict survival [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, fetal magnetic resonance imaging (MRI) has gained by now a worldwide approval for the extensive evaluation of CDH [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The prediction of outcome and the measurement of the observed to expected total fetal lung volume ratio (o/e TFLV) is more precise compared to a sonographic approach [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. As CDH patients should be referred to prenatal centers with access to this type of imaging studies and with the expertise in the examination and treatment of this rare malformation, the question raises about the best timing to assess the severity and to address pregnant women accordingly to perform MRI. Thus, the aim of the study was to determine the accuracy of MRI at different periods of pregnancy in the prediction of survival and morbidity, and to examine whether serial measurements of the lung volume would have an additional value regarding postnatal prognosis.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy participants and design\u003c/h2\u003e \u003cp\u003eThis retrospective study was conducted in two perinatal referral centers (University Hospital in Mannheim, Germany and Hospital 'L. Mangiagalli', Italy). We included all fetuses with isolated congenital diaphragmatic hernia having at least one MRI during pregnancy between 2001 and 2019. Exclusion criteria were twin pregnancies, patients undergoing fetoscopic endoluminal tracheal occlusion (FETO), inappropriate images, incompleteness of data, fetuses with major associated congenital/genetic malformations pre- or postnatally diagnosed, eventrations and bilateral hernia. Patients with mild heart defects (atrio- or ventricular-septal defects), scoliosis or gastro-intestinal anomalies (bowel duplication) associated with CDH and not influencing prognosis were not excluded. Data of 213 patients included in this study have been reported in another context previously [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThree groups were formed according to the GA at which the MRI was done (before 27 WG, between 27 and 32 WG and after 32 WG). These two timepoints were selected because they represent the limits to perform FETO [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSeverity was assessed with the measurement of the TFLV by two experienced operators (M.M.C. and V.D.), who were blinded to the antenatal and postnatal data, and the o/e TFLV was calculated by the formula first described by Rypens \u003cem\u003eet al.\u003c/em\u003e [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] In the case of multiple MRI, the first exam performed during gestation was taken for analysis. Fetal lung growth was evaluated with the interval change rate of the o/e TFLV of two exams at different moments in pregnancy.\u003c/p\u003e \u003cp\u003e The study was approved by the local ethics committee and the requirement for written informed consent was waived.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003e The two participating centers provided the requested data of eligible patients, which were merged into a single database. It included the following variables: (1) type of CDH; (2) GA and o/e TFLV at MRI; (3) GA at delivery; (4) fetal gender; (5) birthweight at birth (Z-score using the web accessible Fenton growth chart) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]; (6) extracorporeal membrane oxygenation (ECMO) use; (7) corrective surgery for CDH during the postnatal period; (8) patch use during surgery; (9) survival at hospital discharge; (10) bronchopulmonary dysplasia (BPD) described as oxygen dependency by day 28 and classified into mild, moderate and severe according to the definition of Jobe and Bancalari [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]; (11) persistent pulmonary hypertension (PPHN) requiring medication; (12) oxygen therapy by nasal canula or tracheostomy and (13) feeding support by naso-gastric tube or gastro/jejunostomy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes\u003c/h2\u003e \u003cp\u003ePrimary outcomes included prediction of survival at discharge from hospital with the o/e TFLV measured at different moments during pregnancy and with serial measurements, whereas secondary outcomes comprised predictions of BPD, PPHN, need for oxygen and feeding support.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was performed using R software version 4.2.2 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"http://www.r-project.org\" target=\"_blank\"\u003ewww.r-project.org\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.r-project.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Continuous variables were summarized as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) unless stated otherwise, while categorical variables were expressed as numbers (frequency). Baseline characteristics among the three study groups (MRI at \u0026lt;\u0026thinsp;27 WG, 27\u0026ndash;32 WG, and \u0026gt;\u0026thinsp;32 WG) were compared with either analysis of variance or Pearson\u0026rsquo;s chi-squared test, and a post-hoc comparison was performed using Tukey\u0026rsquo;s test.\u003c/p\u003e \u003cp\u003eReceiver operating characteristic (ROC) curves were constructed for the prediction of survival at discharge and for the different morbidities by the o/e TFLV\u0026thinsp;\u0026lt;\u0026thinsp;27 WG, between 27 and 32 WG, and \u0026gt;\u0026thinsp;32 WG.\u003c/p\u003e \u003cp\u003eAfterwards, a propensity score that included possible confounding variables was created for the three groups to calculate an average treatment effect (ATE) by the inverse probability of treatment weighting (IPTW). The balance of covariates among the groups was assessed by the standardized mean difference (SMD) according to the Euclidean distance (ES) mean statistic. An SMD below 0.10\u0026ndash;0.15 is expected to ensure a good balance. Afterwards, a logistic regression model that included the ATE weights was performed to examine the effect size (odds ratio [OR]) of the timing of MRI in the prediction of mortality at discharge. The package \u0026ldquo;twang\u0026rdquo; was used.\u003c/p\u003e \u003cp\u003eFinally, in a subgroup analysis of patients who underwent two consecutive MRIs, the percentage of o/e TFLV per week in patients who survived at discharge was compared to patients who died before discharge. The following formula was used to calculate this parameter: o/e TFLV change (%/week) = (o/e TFLV MRI2 \u0026ndash; o/e TFLV MRI1) / (GA at MRI2 \u0026ndash; GA at MRI1). Statistical significance was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eA total of 467 fetuses with CDH were identified. We excluded 48 FETO patients, 12 twin pregnancies, 19 with associated malformations, 7 with bilateral CDH, 22 had no MR imaging and 5 had an MRI of bad quality. For the final analysis, 354 (75,8%) participants were included. Of these, MRI was done before 27 WG in 107 (30.2%), between 27 and 32 WG in 96 (27.1%), and after 32 WG in 151 (42.7%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). There was a statistically significant difference among the 3 groups for the referral center (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), o/e TFLV (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and male gender (p\u0026thinsp;=\u0026thinsp;0.003). Nevertheless, the survival rate at discharge was comparable among the groups (p\u0026thinsp;=\u0026thinsp;0.288) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of the study population according to the gestational age at the magnetic resonance imaging was performed.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGA at MRI\u0026thinsp;\u0026lt;\u0026thinsp;27 WG\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;107\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGA at MRI 27\u0026ndash;32 WG\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;96\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGA at MRI\u0026thinsp;\u0026ge;\u0026thinsp;32 WG\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;151\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCenter\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGermany\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e95 (88.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e84 (87.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e150 (99.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eItaly\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12 (11.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12 (12.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1 (0.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRight-sided CDH\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13 (12.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10 (10.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e19 (12.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.871\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIntrathoracic liver\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e69 (64.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e58 (60.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e89 (58.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.660\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eO/E TFLV\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29.42 (11.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e29.20 (12.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23.78 (13.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGA at birth, WG\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e37.02 (1.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e37.04 (1.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e37.34 (1.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.262\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBirthweight Z-score\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.06 (0.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.20 (1.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.13 (0.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.124\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMale gender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e75 (70.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e50 (52.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e75 (49.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.003**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eECMO\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e37 (34.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e27 (28.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e53 (35.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.484\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSurvival at discharge\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e92 (86.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e76 (79.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e130 (86.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.288\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e*Significant statistical difference between group 3 and group 1, and between group 3 and group 2.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e** Significant statistical difference between group 2 and group 1, and between group 3 and group 1.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThere was no statistically significant difference for the prediction of survival at discharge when the o/e TFLV was calculated at \u0026lt;\u0026thinsp;27 WG, between 27 and 32 WG, or \u0026gt;\u0026thinsp;32 WG (area under the curve [AUC]: 0.77, 95% confidence interval [95%CI]: 0.65\u0026ndash;0.89; AUC: 0.79 [95%CI: 0.66\u0026ndash;0.92]; and AUC: 0.77 [95%CI: 0.68\u0026ndash;0.86], respectively) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAfter balancing the possible confounders among the three groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), the calculation of o/e TFLV at \u0026lt;\u0026thinsp;27 WG, between 27\u0026ndash;32 WG, or \u0026gt;\u0026thinsp;32 WG was not an independent predictor for survival. Only intrathoracic liver, GA at birth and o/e TFLV independent predictors of survival (adjusted OR: 0.3 [95%CI 0.12\u0026ndash;0.78]; 1.48 [1.24\u0026ndash;1.78]; and 1.13 [1.06\u0026ndash;1.20], respectively) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eIndependent factors associated with survival at discharge.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMortality at discharge\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;56\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSurvival at discharge\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;298\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdjusted OR (95%CI)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGA at MRI, WG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (26.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e92 (30.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e27\u0026ndash;32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (35.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76 (25.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.53 (0.22\u0026ndash;1.27)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (37.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e130 (43.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.52 (0.59\u0026ndash;3.90)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCenter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGermany\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53 (94.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e276 (92.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRef\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eItaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (5.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (7.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.45 (0.09\u0026ndash;2.31)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECMO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (53.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e87 (29.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.54 (0.24\u0026ndash;1.21)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntrathoracic liver\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48 (85.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e168 (56.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.30 (0.12\u0026ndash;0.78)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale gender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (55.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e169 (56.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.96 (0.47\u0026ndash;1.97)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRight-sided CDH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (8.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (12.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.23 (0.72\u0026ndash;6.89)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGA at birth, WG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36.31 (2.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37.32 (1.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.48 (1.24\u0026ndash;1.78)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eO/E TFLV, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.36 (8.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.57 (13.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.13 (1.06\u0026ndash;1.20)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirthweight Z-score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.39 (0.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.04 (0.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.21 (0.86\u0026ndash;1.79)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cb\u003eAbbreviations\u003c/b\u003e: 95%CI: 95% confidence interval; CDH: congenital diaphragmatic hernia; ECMO: extracorporeal membrane oxygenation; GA: gestational age; o/e TFLV: observed over expected total fetal lung volume; OR: odds ratio; WG: weeks of gestation.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eSimilar analysis was replicated in 350 patients with a known status about the use of ECMO, 257 with known status about feeding support, 278 with known status about PPHN, 282 with known status about BPD, and 256 with known status about oxygen therapy. Only the prediction of BPD was significantly better after 32 WG in comparison with \u0026lt;\u0026thinsp;27 WG (p\u0026thinsp;=\u0026thinsp;0.011), and the prediction of oxygen therapy was significantly better between 27 and 32 WG in comparison with \u0026lt;\u0026thinsp;27 WG (p\u0026thinsp;=\u0026thinsp;0.009) (Supplementary Figs.\u0026nbsp;1\u0026ndash;5).\u003c/p\u003e \u003cp\u003eIn a subgroup analysis, 97 fetuses benefited from two consecutive MRI. Ten of them (10.3%) had right sided CDH and 65 (67.0%) had intrathoracic liver. The mean GA at the first MRI was 25.75 WG and at the second MRI was 32.51 WG. The survival rate was 86.6% (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). There was no significant difference for the o/e TFLV change rate between fetuses who survived and those who did not at discharge (p\u0026thinsp;=\u0026thinsp;0.390) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of patients who underwent two consecutive magnetic resonance imaging examinations.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;97\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRight-sided CDH\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10 (10.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIntrathoracic liver\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e65 (67.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGA at 1st MRI, WG\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25.75 (3.25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGA at 2nd MRI, WG\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e32.51 (2.48)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSurvival at discharge\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e84 (86.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003cb\u003eAbbreviations\u003c/b\u003e: CDH: congenital diaphragmatic hernia; GA: gestational age; MRI: magnetic resonance imaging; WG: weeks of gestation.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePrincipal findings\u003c/h2\u003e \u003cp\u003eIn this study, we examined the effect of the calculation of o/e TFLV at different periods of pregnancy in the prediction of the survival at discharge in fetuses with CDH. The analysis was performed by two approaches: single measurement and serial measurements. We showed that the prediction of survival is not affected by the timing of MRI. Hence, the assessment of o/e TFLV in patients with CDH can be done during the whole pregnancy starting late second trimester.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eComparison with results of previous studies\u003c/h2\u003e \u003cp\u003eA smaller retrospective single center study with 57 patients who had two MRIs, one in the second and the second in the third trimester, reported similar results regarding the prediction of ECMO and PPHN [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Nonetheless, the group in Houston suggested that second trimester MRI strongly correlated with mortality. They included all types of CDH in their population (left-sided, right-sided, and bilateral), and the mean severity was not mentioned.\u003c/p\u003e \u003cp\u003eWalleyo \u003cem\u003eet al.\u003c/em\u003e required almost the same inclusion criteria as our study except that they excluded CDH patients born before 34 WG [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], which is a confounding factor and not representative for the general CDH population as the incidence of prematurity, even without the invasive procedure FETO, is around 30% [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Nevertheless, concerning the survival, need for ECMO and development of chronic lung disease (CLD), they also showed the same prognostic strength of o/e TFLV measured at different periods in the second or third trimester [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe showed that the o/e TFLV does not change during pregnancy, thus, multiple MRI examinations have no benefit regarding the accuracy of the established prognosis. This was already demonstrated in a prospective study of Cannie \u003cem\u003eet al.\u003c/em\u003e with 18 expectantly managed fetuses [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. They found no increase of the o/e TFLV during the second half of pregnancy irrespective of the position of the liver. The survival rate in our study (86.6%) was comparable to that of Cannie \u003cem\u003eet al.\u003c/em\u003e (83,3%), despite that the fetuses who had serial MRI in our cohort were more severely affected. Similar conclusion was drawn by the group in Houston, who observed that patients with severe PPHN had a significant lower mean rate of lung growth over time, but the change rate of the o/e TFLV was not altered [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The study showed that routine repeat imaging is not necessary within the general CDH population. Comparable results were also obtained by Coleman \u003cem\u003eet al.\u003c/em\u003e, who analyzed retrospectively 47 cases of left sided CDH with two MRI examinations, one between 22 to 30 WG and the second after 30 WG [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Non-survivors had lower rate of lung growth than survivors, but again the o/e TFLV remained stable during pregnancy so that its change rate was not significantly different between the groups. The lung-volume ratio obtained either early or late throughout the pregnancy was predictive of neonatal survival, whereas the crude MRI derived lung-volume was only associated with adverse outcomes when assessed close to term. This highlights the value of adjustment for gestational age.\u003c/p\u003e \u003cp\u003eA previous study by Hagelstein \u003cem\u003eet al.\u003c/em\u003e including patients who received two MRIs at around 26 WG and 34 WG, showed that first and last o/e TFLV were associated with mortality and neonatal ECMO requirement [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Comparing the AUC respectively, they stated a higher prognostic accuracy of measurements done near delivery, without mentioning a statistical significance. However, the study was based only on 89 fetuses, whereas in the current study we included 354 fetuses, from 2 centers and we performed comparisons based on different statistical methods. Furthermore, they noted a lower weekly lung growth rate of non-survivors compared to survivors, but this value in addition to the o/e TFLV did not improve significantly the prognostic accuracy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eClinical implications\u003c/h2\u003e \u003cp\u003eThe fact that the assessment of CDH severity has the same prediction accuracy independently of the gestational age at which the MRI examination is done, is of great interest in view of possible prenatal interventions. FETO in severe CDH patients is generally performed at 27 to 29 WG and the most difficult decision of termination of pregnancy in more sinister cases is better to handle before the third trimester \u0026ndash; emotionally [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], physically and in terms of feasibility in countries with a term limit of abortion. This result should encourage clinicians to refer their patients early in pregnancy to a specialized prenatal care center in order to assess the prognosis, discuss the management options and organize subsequent treatment strategy.\u003c/p\u003e \u003cp\u003eIn addition, knowing that serial MRI comprise no benefit for the prediction of survival could spare the future mother and her partner from undergoing through a procedure, which is probably more stressful than ultrasound [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Furthermore, this finding has a great impact on the economical level.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eResearch implications\u003c/h2\u003e \u003cp\u003eThe observed to expected lung area to head circumference ratio (o/e LHR) at ultrasound comports similar [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. The prediction of survival is independent on the timing of assessment during pregnancy. However, the performance of the o/e TFLV seems to be better [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Further studies comparing both methods, ultrasound and MRI measurements of the lung volume, at several timepoints during pregnancy on the same fetus are required.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and limitations\u003c/h2\u003e \u003cp\u003e This was a retrospective study with a significant sample size coming from two different perinatal care centers. The lung volume assessment was exclusively performed by two experienced blinded operators not working in the participating centers in order to guarantee an objective investigation and to reduce interobserver errors [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe gestational age stratification of when the MRI was performed was deliberately set at \u0026lt;\u0026thinsp;27 WG, because FETO, when indicated, should be done between 27 and 29 WG [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In order to analyze a representative cohort, we did not exclude preterm birth, but instead we balanced GA at delivery in the different groups of the study.\u003c/p\u003e \u003cp\u003eA potential limitation of the current study could be the determination of survival at discharge, even though we observed in a previous study only a small decrease of survival between discharge and two years of life (about 2%) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Similar was seen after analyzing the morbidity parameters. Nevertheless, future studies with a longer follow up are required.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe MR assessment of severity and the prediction of survival and morbidity in fetuses with CDH can be done at any time of gestation starting mid second trimester. The substantial counseling of concerned parents can already take place in the second trimester without the need of an additional MRI during pregnancy. Moreover, patients presenting late with advanced gestational age could benefit from this diagnostic tool.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS:\u003c/strong\u003e All authors read and approved the final manuscript\u003c/p\u003e\n\u003cp\u003eV D\u0026uuml;temeyer: Project development, Data collection and management, Measurement of the o/e TFLV, Manuscript writing\u003c/p\u003e\n\u003cp\u003eMM Cannie: Project development, Measurement of the o/e TFLV\u003c/p\u003e\n\u003cp\u003eT Schaible: Project development, Data management\u003c/p\u003e\n\u003cp\u003eM Weis: Data collection\u003c/p\u003e\n\u003cp\u003eN Persico: Project development, Data management\u003c/p\u003e\n\u003cp\u003eI Borzani: Data collection\u003c/p\u003e\n\u003cp\u003eDA Badr: Project development, Data management, Data analysis, Manuscript writing\u003c/p\u003e\n\u003cp\u003eJC Jani: Project development, Data management, Data analysis, Manuscript writing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e The Fetal Medicine Foundation Belgium partly funded this study, but had no role in the study design, data gathering, data analysis, data interpretation, or writing of the report\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u0026nbsp;\u003c/strong\u003eThe authors report no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e This is a retrospective observational study. The local ethics committee has confirmed that no ethical approval is required.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u003c/strong\u003e Due to the retrospective observational design of the study informed consent was not required.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCordier A-G, Russo FM, Deprest J, Benachi A (2020) Prenatal diagnosis, imaging, and prognosis in Congenital Diaphragmatic Hernia. Semin Perinatol 44:51163. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi:10.1053/j.semperi.2019.07.002\u003c/span\u003e\u003cspan address=\"https://doi:10.1053/j.semperi.2019.07.002\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJani JC, Nicolaides KH, Gratac\u0026oacute;s E et al (2009) Severe diaphragmatic hernia treated by fetal endoscopic tracheal occlusion. 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N Engl J Med 385:107\u0026ndash;118. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi:10.1056/NEJMoa2027030\u003c/span\u003e\u003cspan address=\"https://doi:10.1056/NEJMoa2027030\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCordier AG, Badr DA, Basurto D et al (2023) Effect of cannula insertion site in fetal endoscopic tracheal occlusion for congenital diaphragmatic hernia on preterm premature rupture of membranes. 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J Matern Fetal Neonatal Med 35:1036\u0026ndash;1044. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi:10.1080/14767058.2020.1740982\u003c/span\u003e\u003cspan address=\"https://doi:10.1080/14767058.2020.1740982\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSTATEMENTS \u0026amp; DECLARATIONS\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"archives-of-gynecology-and-obstetrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arch","sideBox":"Learn more about [Archives of Gynecology and Obstetrics](https://www.springer.com/journal/404)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/arch/default.aspx","title":"Archives of Gynecology and Obstetrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"fetal magnetic resonance imaging, congenital diaphragmatic hernia, total fetal lung volume, timing, prenatal prognosis, survival","lastPublishedDoi":"10.21203/rs.3.rs-4117685/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4117685/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e: To evaluate the impact of the timing of MRI on the prediction of survival and morbidity in patients with CDH, and whether serial measurements have a beneficial value.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThis retrospective cohort study was conducted in two perinatal centers, in Germany and Italy. It included 354 patients with isolated CDH having at least one fetal MRI. The severity was assessed with the observed to expected total fetal lung volume (o/e TFLV) measured by two experienced double-blinded operators. The cohort was divided into three groups according to the gestational age (GA) at which the MRI was performed (\u0026lt;27, 27-32 and \u0026gt;32 weeks gestation [WG]). The accuracy for the prediction of survival at discharge and morbidity was analyzed with receiver operating characteristic (ROC) curves. Multiple logistic regression analyses and propensity score matching examined the population for balance. The effect of repeated MRI was evaluated in ninety-seven cases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThere were\u003cstrong\u003e \u003c/strong\u003eno significant differences in prediction of survival when the o/e TFLV was measured before 27, between 27 and 32, and after 32 WG (area under the curve [AUC]: 0.77, 0.79, and 0.77, respectively). After adjustment for confounding factors, it was seen, that GA at MRI was not associated with survival at discharge, but the risk of mortality was higher with an intrathoracic liver position (adjusted odds ratio [aOR]: 0.30, 95% confidence interval [95%CI]: 0.12-0.78), lower GA at birth (aOR 1.48, 95%CI: 1.24-1.78) and lower o/e TFLV (aOR 1.13, 95%CI: 1.06-1.20). ROC curves showed comparable prediction accuracy for the different timepoints in pregnancy for pulmonary hypertension, the need of extracorporeal membrane oxygenation, and feeding aids. Serial measurements revealed no difference in change rate of the o/e TFLV according to survival.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eThe timing of MRI does not affect the prediction of survival rate or morbidity as the o/e TFLV does not change during pregnancy. Clinicians could choose any gestational age starting mid second trimester for the assessment of severity and counseling.\u003c/p\u003e","manuscriptTitle":"Timing of magnetic resonance imaging in pregnancy for congenital diaphragmatic hernia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-29 18:34:23","doi":"10.21203/rs.3.rs-4117685/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revisions","date":"2024-04-24T02:39:48+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-04-07T12:14:22+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-03-25T22:26:23+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-18T12:14:35+00:00","index":"","fulltext":""},{"type":"submitted","content":"Archives of Gynecology and Obstetrics","date":"2024-03-17T11:15:16+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"archives-of-gynecology-and-obstetrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arch","sideBox":"Learn more about [Archives of Gynecology and Obstetrics](https://www.springer.com/journal/404)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/arch/default.aspx","title":"Archives of Gynecology and Obstetrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"b675f889-166d-4a40-ac5f-a4957302e86f","owner":[],"postedDate":"March 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-04-29T18:55:24+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-29 18:34:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4117685","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4117685","identity":"rs-4117685","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}