Evaluation of the relationship of fetal lung elastography values with the development of postpartum respiratory distress in late preterm labor cases

Introduction

Preterm births are births that occur before 37 weeks of gestation. Although important information has been obtained about the risk factors and pathophysiological mechanisms associated with preterm birth, preterm birth rates are increasing in many industrialized countries. Preterm births account for approximately 75 % of perinatal mortality and a significant portion of long-term morbidity [1]. Prematurity is a major cause of death among children under 5 years of age worldwide. In underdeveloped countries, half of all premature babies born at 32 weeks and earlier die due to inadequate health services and various complications. In middle developed and developing countries, limited health resources increase the risk of long-term morbidity and mortality in premature infants. Although preterm infants have a high chance of survival, they are at high risk for neurodevelopmental disorders, respiratory system disorders and gastrointestinal complications [2]. One of the most important complications of preterm birth is respiratory distress syndrome (RDS).

The prevention and management of RDS in neonates reflects a significant achievement in neonatal care, but also an ongoing challenge. The incidence of RDS is inversely proportional to gestational age, with the disease occurring in almost all preterm neonates born between 22 and 28 estimated gestational weeks, approximately 3 % of late preterm neonates born between 34 and 36, and 0.12 % of term neonates born >37 gestational weeks [3], [4], [5]. Advances in pharmacotherapy, particularly the use of antenatal corticosteroids and postnatal surfactant therapy, have significantly reduced the incidence and severity of neonatal RDS. Antenatal corticosteroid therapy accelerates fetal lung development, increasing the activity of enzymes that promote surfactant biosynthesis. This mechanism improves lung elasticity and promotes maturation of lung function. Antenatal corticosteroid therapy has been shown to improve survival rates of preterm neonates and reduce the risk of brain injury. Postnatal administration of exogenous surfactant has been shown to improve lung compliance, resulting in increased oxygenation and reduced rates of pneumothorax and mortality. The efficacy of these treatment strategies is of great importance in terms of stabilization of respiratory functions and improvement of survival rates in preterm infants [6]. Today, early recognition of RDS and rapid planning of treatment in the neonatal period are critical to reduce morbidity and mortality, minimize long-term complications and increase survival. Therefore, evaluation of fetal lung development has long been on the agenda.

The first studies conducted in the 1970s focused on amniotic fluid analysis. In these studies, parameters such as lecithin-sphingomyelin ratio, phosphatidyl-inositol and phosphatidyl-glycerol levels in amniotic fluid and fluorescent light polarization of the fluid were proposed as potential indicators for determining fetal lung maturation [7], [8], [9]. In the following years, these approaches were extended with new analysis methods such as lamellar body counting, foam stability test and surfactant/albumin ratio in amniotic fluid [10], [11], [12]. The most obvious disadvantage of these techniques is that they require amniocentesis, an invasive procedure. Amniocentesis is known to carry potential complications such as membrane rupture, risk of infection and fetal loss. Therefore, the development of non-invasive methods to predict RDS may provide a safer and more effective option by eliminating the risks of amniocentesis.

Elastography is a cost-effective method for measuring the elasticity properties of tissue using existing ultrasound technology. This technique has recently been used in the functional evaluation and pathology examination of many organs. Motet et al. reported that 2D-Share wave elastography (SWE) can be successfully applied to fetal lung and liver and may be a new complementary tool for reliable estimation of pulmonary function based on biomechanical properties [13].

Fetal elastography ultrasonography is an area of research that is still in its infancy, and this method has potential importance for the early diagnosis of fetal respiratory complications and preparation for treatment. In the current literature, the methods used in the prediction of fetal respiratory complications are limited and we believe that fetal elastography evaluation may fill an important gap in this field. Therefore, we aimed to examine the potential of fetal lung elastography as a non-invasive approach to predict and treat respiratory complications in preterm neonates.

Materials and methods

The study included singleton pregnancies with maternal age between 18 and 45, diagnosed with preterm labor between 34 and 37 weeks of gestation, who were admitted to the maternity ward after presenting to the Perinatology Clinic at Etlik City Hospital between January 2024 and December 2024. Fetuses with no amniotic fluid pathology, congenital, or chromosomal abnormalities were included. A total of 88 patients without systemic maternal disease findings and diagnoses, without chronic drug use, who were measured at least 24 h after antenatal corticosteroids were administered during pregnancy and delivered within a maximum of 72 h were included in our study as two case groups with and without RDS diagnosis in neonatal follow-up. The 88 pregnant women enrolled in the study were divided into two groups according to their clinical findings during the postnatal neonatal follow-up period. Those who were diagnosed with respiratory distress syndrome (RDS) were classified as the RDS group, and those who were not were classified as the control group. The determination of the groups was not based on a pre-planned randomization method but retrospectively based on the clinical picture that developed after delivery. The proportion of fetuses diagnosed with RDS shows a distribution parallel to the prevalence of this syndrome in the late preterm period. The study was initiated after approval by the Ethics Committee of Ankara Etlik City Hospital with protocol number AEŞH-EK1-2023-641 on 08/11/2023.

For standardization of the study, measurements and examinations were performed by the same radiologists and using the same ultrasound device Logic^® E 10 S (General Electric Healthcare). Measurements were performed using an abdominal convex probe 1–6 MHz (C1-6-D probe). All measurements were performed with direct ultrasound on the target organ. Biometric measurements included biparietal diameter (BPD), occipital-frontal diameter (OFD), head circumference (HC), abdominal circumference (AC), femur length (FL), amniotic fluid (single vertical deepest pocket), presentation, placenta localization, estimated fetal weight (EFW) and shear wave elastography measurements of fetal lung and liver. Elastography measurements were performed in the sagittal plane and bilaterally in the inferior dorsal position six times each and the min, max and median values of these measurements were recorded.

The fetal lung liver elastography (LLE) ratio was initially defined as the ratio of the fetal lung elastography value to the fetal liver elastography value. To model the fetal LLE ratio, only reproducible and reproducible values of each region of interest (ROI) were considered. Measurements were performed on a homogeneous circular ROI with a diameter of 5 mm. Technical failure was defined as the inability to obtain a homogeneous elastogram in the sampling area. Measurements were considered invalid when the ROI did not overlap the desired region or when significant artifacts interfered with the ROI. The elasticity of the fetal lung was measured in the most proximal area, in the region behind the plane passing through the atria, after obtaining a four-chamber view of the fetal heart (Figure 1). The elasticity of the fetal liver was measured in the region within the hepatic portal sinus after obtaining an image of the abdominal circumference (Figure 1). After the measurements were performed, the patient’s age, height and weight, body mass index, obstetric history, presence of maternal systemic disease and drug use, gestational age according to the last menstrual date or gestational age according to the 1st trimester ultrasound (if there was more than 1 week difference between the gestational age according to the last menstrual date and the ultrasonographic gestational age, the gestational age according to the ultrasonographic gestational age was taken as the basis) were recorded on the follow-up form. After the birth of the cases, the results of the newborns were accessed from the database of our hospital. These data included APGAR scores, birth weight, mode of delivery, gender, neonatal respiratory problems such as respiratory distress syndrome, need for intensive care and length of stay in intensive care, and other conditions requiring intensive care and were recorded on the follow-up forms.

Figure 1:

Fetal lung and liver sections obtained by 2D-SWE and elastography measurement samples.

Power analysis was performed using the G-Power 3.0.0.0.1 program and the standard effect size was determined as 0.39 with a 5 % margin of error and 95 % power. According to these data, 88 cases (n=88) including the sum of both groups were included in the study. Multiple pregnancies, patients without antenatal corticosteroid administration, amniotic fluid pathologies, fetal lung and liver diseases, fetal genetic and structural anomalies, systemic maternal disease findings and diagnoses, advanced maternal obesity preventing measurement, patients hospitalized with a diagnosis of preterm labor and discharged before delivery, patients with comorbid diseases of pregnancy (gestational diabetes, hypertensive diseases of pregnancy, premature rupture of membranes, chorioamnionitis, etc.), patients over 45 years of age, and patients with comorbid diseases of pregnancy (gestational diabetes, hypertensive diseases of pregnancy, premature rupture of membranes, chorioamnionitis, etc.) were included. Patients with comorbid diseases of pregnancy (gestational diabetes, hypertensive diseases of pregnancy, premature rupture of membranes, premature rupture of membranes, chorioamnionitis, etc.), pregnant women aged 45 years and older, and pregnant women with a history of systemic diseases (chronic, mental, physical diseases; severe renal, hepatic, gastrointestinal acute/chronic inflammatory diseases; hyperthyroidism, hypothyroidism, hypertension, type 1/2 DM, history of malignancy, smoking and alcohol use) were not included in the study. In addition, patients who did not deliver within 72 h after the measurement was taken, delivered before 24 h after antenatal corticosteroid administration, discontinued follow-up or continued follow-up in another center and whose data could not be accessed were also excluded from the study.

Results

Maternal age (28.0 [24.5–29.5] years vs. 28.0 [23.5–32.0] years, p=0.492), body mass index (27.0 [26.0–29.0] kg/m² vs. 28.0 [26.5–29.0] kg/m², p=0.541), gravida (2.0 [2.00–3.0] vs. 2.0 [2.00–3.00], p=1.000), parity (1.0 [0.0–1.0] vs. 1. 0 [0.0–1.0], p=0.664) and nulliparity rate (63.6 vs. 43.2 %, p=0.087), while gestational week was similar in both groups (35.0 [35.0–36.0] vs. 35.0 [35.0–36.0], p=0.918).

There was no significant difference between the groups in terms of fetal ultrasonographic measurements, including biparietal diameter (85.5 [84.0–89.0] mm vs. 86.0 [84.0–90.0] mm, p=0.730), head circumference (298.0 [293.0–309.5] mm vs. 296.0 [291.0–307.5] mm, p=0.421), abdominal circumference (298.0 [292.0–307.0] mm vs. 299.0 [290.0–308.0] mm, p=0.857), femur length (65.0 [64.0–66.0] mm vs. 64.0 [64.0–66.0] mm, p=0.983), estimated fetal weight (2470.0 [2350.0–2640.0] g vs. 2480.0 [2350.0–2645.0] g, p=0.738), and deepest vertical pocket of amniotic fluid (50.0 [45.0–65.0] mm vs. 50.0 [45.0–60.0] mm, p=0.211) (Table 1) (p>0.05).

There was no significant association between the groups in terms of newborn gender (female: 45.5 vs. 52.3 %; male: 54.5 vs. 47.7 %, p=0.670). The duration between antenatal steroid (Celestone™) administration and delivery (2.0 [2.0–2.5] days vs. 2.0 [2.0–2.0] days, p=0.519) and newborn weight (2515.0 [2450.0–2665.0] g vs. 2545.0 [2500.0–2665.0] g, p=0.425) also showed no significant difference between the groups.

APGAR score was significantly lower in the RDS group at 1 min (5.0 [4.0–6.0] vs. 8.0 [6.0–9.0], p<0.001) and 5 min (6.0 [5.0–7.0] vs. 9.0 [7.0–10.0], p<0.001). In addition, the proportion of newborns with APGAR score<7 measured at both times was higher in the RDS group (50.0 vs. 12.1 %, p=0.001).

The rate of neonatal intensive care unit (NICU) hospitalization was 100 % in the RDS group and 13.6 % in the control group, and the difference was significant (p<0.001). The duration of ICU stay was found to be longer in the RDS group (13.0 [13.0–15.0] days vs. 9.0 [6.0–12.0] days, p=0.001).

The survival rate at discharge was 95.5 % in the RDS group and 100 % in the control group and the relationship was not significant (p=0.494) (Table 2).

The need for resuscitation was 34.1 % (n=15) in the RDS group and 4.5 % (n=2) in the control group, and the relationship was significant (p=0.001). Surfactant requirement was 84.1 % (n=37) in the RDS group and none in the control group (0.0 %, p<0.001). The need for inotrope support was 11.4 % (n=5) in the RDS group and 0.0 % in the control group and the relationship was found to be significant (p=0.028). Sepsis rate was 29.5 % (n=13) in the RDS group and 0.0 % in the control group and the relationship was found to be significant (p=0.005).

The incidence of intraventricular hemorrhage (IVH) was 18.2 % (n=8) in the RDS group and 2.3 % (n=1) in the control group and the relationship was significant (p=0.030). The incidence of necrotizing enterocolitis (NEC) was 13.6 % (n=6) in the RDS group and 0.0 % in the control group and the relationship was found to be significant (p=0.026). The incidence of pulmonary hypoplasia was 13.6 % (n=6) in the RDS group and 0.0 % in the control group and the relationship was found to be significant (p=0.026). The incidence of bronchopulmonary dysplasia (BPD) was 11.4 % (n=5) in the RDS group and 0.0 % in the control group and the relationship was found to be significant (p=0.028). Early neonatal death was not observed in either group (Table 3).

In lung elastography measurements, the minimum value (2.40 [2.10–2.75] vs. 2.10 [1.85–2.45], p=0.016), maximum value (3.20 [2.90–3.65] vs. 2.80 [2.60–3.55], p=0.025) and median measurement value (2.70 [2.50–3.25] vs. 2.40 [2.27–3.10], p=0.006) were significantly higher in the RDS group.

In liver elastography measurements, there was no significant difference between the groups in terms of minimum value (3.20 [2.95–3.80] vs. 3.40 [2.90–3.80], p=0.933), maximum value (4.10 [3.75–4.95] vs. 4.40 [3.90–5.15], p=0.547) and median measurement value (3.65 [3.35–4.35] vs. 3.85 [3.40–4.40], p=0.545).

The LLE ratio was significantly higher in the RDS group (0.76 [0.65–0.89] vs. 0.69 [0.59–0.78], p=0.014) (Table 4).

Discussion

As a result of our study, we concluded that the minimum, maximum, median lung elastography values and LLE ratio were significantly higher in the group with RDS compared to the control group, and liver elastography values were similar in both groups; therefore, prenatal fetal lung elastography evaluation may be a successful method to predict RDS.

Lung ultrasonography has been widely used in the diagnosis and follow-up of various lung diseases including pneumonia, fibrosis, edema and pneumothorax in adult patients [14], [15], [16], [17], [18]. Likewise, the use of ultrasound in the evaluation of the lung in newborn babies is becoming increasingly widespread. It has also been used in the diagnosis of pneumonia and RDS in newborns and to demonstrate the efficacy of surfactant treatment in the presence of RDS [19], 20]. Over time, the incorporation of ultrasonographic elastography into diagnostic methods has allowed quantitative assessment of tissue elasticity in respiratory system organs. In different studies, several examples of how ultrasonographic elastography can be used in the diagnosis of various respiratory diseases in adult patients have been presented [21]. In a study by Zhou et al., ultrasound elastography (US-E) was interpreted as a technique that evaluates the mechanical properties of lung diseases in a non-invasive, safe and cost-effective manner and has found potential use in the diagnosis of diseases such as COVID-19 pneumonia in recent years [22]. In our study, the evaluation of the fetal lung with ultrasound elastography can be interpreted as an indirect examination and may raise doubts about the reliability of the results. According to the analysis of our study, it is understood that elastography values can provide accurate results in fetuses in the womb. Therefore, it suggests that ultrasound elastography evaluations performed with the right equipment and experienced specialists may be a promising method to safely examine the mechanical properties of fetal lungs. Although fetal applications of intrauterine elastography measurements have been the focus of recent studies, there is a limited number of studies on this topic in the literature. In particular, the potential use of elastography techniques such as shear wave elastography, which can provide more objective data, in obstetric and fetal evaluations has raised safety concerns. In a systematic review of 25 articles, it was concluded that elastography showed similar thermal effects to Doppler ultrasound in obstetric clinical applications and no cavitation effect in fetal tissue [21], 23].

In a study by Nallet et al. in which fetal lung and liver elasticities were measured by elastography, it was emphasized that elasticity developed in different ways throughout pregnancy, and this may reflect tissue maturation of both organs [24]. In our study, lung elastography measurements of fetuses at a specific gestational week were evaluated. Since the gestational weeks of both groups were close to each other, the measurements can be expected to be similar, which is important for the validity and generalizability of elastography evaluation.

In a different study by Liu et al., it was emphasized that fetal lung elasticity values decreased as the gestational week progressed and 2D-share wave elastography showed maturation at different stages of fetal lung development [25]. In our study, it was observed that fetal lung elastography values were higher in the group that did not complete lung maturation and developed RDS. This suggests that high lung elastography values in fetuses with similar gestational weeks may pose a risk for RDS development in the postnatal period.

Mottet et al. first proposed the LLE ratio as a new parameter to reflect changes in both lung and liver elasticity values [13]. Therefore, we included the LLE ratio as a new parameter in this study. In our study, the LLE ratio was found to be higher in the group with RDS compared to the control group. The fact that the LLE ratio was found to be higher in the group with RDS suggests that this parameter may be associated with the development of RDS. On the other hand, liver elasticity was similar between the two groups.

In a study conducted in diabetic pregnant women, it was reported that fetal placental and lung stiffness increased, and high fetal lung stiffness was associated with increased neonatal respiratory morbidity [26]. In our study, high lung elastography values because of increased lung density were observed in the neonatal group with postnatal RDS.

Lio et al. utilized fetal Doppler velocimetry in preterm pregnancies under 30 weeks to predict the risk of bronchopulmonary dysplasia (BPD) and demonstrated that BPD risk significantly increases when placental dysfunction is the underlying cause of low birth weight [27]. In our study, we evaluated the potential use of fetal lung elastography in predicting respiratory distress syndrome (RDS) in late preterm labor. Both studies aim to explore different biophysical assessment methods with the potential to evaluate fetal lung function in the antenatal period, offering new approaches for predicting neonatal respiratory morbidity.

The fact that our study was prospectively designed, and measurements were taken after antenatal corticosteroid administration in all patients constituted one of the strengths of the study. In addition, the high standardization of the study was ensured by the fact that delivery occurred within 72 h after the measurements were performed, the groups were similar in terms of demographic characteristics, and the ultrasonographic measurements were performed in a single center by an experienced radiologist using the same device. These factors increased the reliability of the results and minimized potential errors. Our study is one of the first to examine the potential of fetal lung elastography in predicting respiratory complications in preterm neonates, filling an important gap in the literature and demonstrating the reliability and applicability of 2D-Shear Wave Elastography (SWE) in predicting the development of RDS.

Our study has some limitations. Firstly, being a single-center study may limit the generalizability of our findings to the broader population. One limitation of this study is the absence of intra- and inter-observer variability data, as all elastographic measurements were performed by a single radiologist. However, methodological consistency was ensured by using the same ultrasound device and standardized protocols for all measurements. Future studies should consider conducting intra- and inter-observer reliability analyses to further validate the findings. Additionally, studies with a larger sample size could provide more reliable and valid data. Another limitation is that the measurements and evaluations were only conducted in preterm infants within a specific gestational age range, which restricts these findings to this patient group. The characteristics of the device used for fetal lung and liver elastography measurements may have also influenced the results. Multicenter studies involving larger patient groups and preterm infants at different gestational weeks are needed.

In conclusion, elastography examination of fetal lungs in preterm infants, particularly in predicting respiratory complications such as RDS, may be a promising approach. This method has the potential to play a guiding role, especially in clinical situations where assessing the maturation of fetal lungs is critical. Additionally, the applicability and practicality of elastography ultrasound as a non-invasive method provide significant advantages that support the clinical use of this technique.