Preterm labour (PTL), defined as the onset of labour before 37 completed weeks of gestation, is a leading cause of neonatal morbidity and mortality worldwide. According to the World Health Organization (WHO), preterm birth affects approximately 15 million infants annually, accounting for 10% of all live births globally (1). The consequences of preterm labour (PTL) extend beyond neonatal mortality, as surviving preterm infants are at higher risk for chronic health issues such as neurodevelopmental disabilities, respiratory complications, and impaired cognitive function (2). Despite advances in obstetric care, preterm birth remains the leading cause of death in children under five years of age, contributing to nearly one million deaths annually (3) India, bears the highest burden of preterm births, with an estimated 3.5 million preterm deliveries annually (4). This accounts for nearly a quarter of the global preterm birth burden. The prevalence of PTL in India is estimated to be around 13%, (5). In these settings, early prediction of PTL can facilitate timely referral, appropriate interventions, and better neonatal outcomes.

However, current methods of predicting PTL, including cervical length measurements and biochemical markers, have limitations in sensitivity and specificity, underscoring the need for innovative, reliable, and non-invasive predictive tools (6). The fetal adrenal gland has recently emerged as a potential marker for predicting PTL. The adrenal gland plays a critical role in the initiation of labour by producing cortisol, which are pivotal in the parturition process (7).

The placental clock hypothesis suggests that the fetus determines the timing of parturition through the release of CRH, which activates the maternal and fetal hypothalamic-pituitary-adrenal (HPA) axes (8). This hormonal cascade stimulates fetal adrenal gland enlargement and increased production of cortisol, estrogen and progesterone, and prostaglandins, ultimately resulting in labour initiation (9).

Current diagnostic methods primarily rely on clinical assessment, ultrasonographic evaluation, and biochemical markers. The clinical criteria for PTL diagnosis include regular uterine contractions accompanied by cervical changes, such as effacement and dilation, before 37 weeks of gestation (10). Transvaginal ultrasonography (TVS) is widely used to measure cervical length, with a shorter cervical length being a strong predictor of PTL risk (11). Additionally, fetal fibronectin (fFN) testing, which detects the presence of fFN in vaginal secretions, has emerged as a valuable biochemical marker for PTL. The role of FAGV as a diagnostic tool for PTL is gaining attention due to its non-invasive nature and high predictive value. Ultrasonographic measurement of FAGV and adrenal zone parameters, such as the width-to-depth ratio, has been shown to be more sensitive and specific than traditional markers like cervical length ( 4)

Aim:

To assess the role of fetal adrenal gland volume and fetal adrenal zone parameter measurement in predicting preterm labour.

METHODS

This study is a cross-sectional observational study conducted at a tertiary care hospital in Hyderabad. The study was approved by the Institutional Ethics Committee. Written informed consent was got from all the subjects. Confidentiality of patient data was maintained throughout the study, and participation was voluntary.

Convenience sampling was employed to recruit patients from the obstetric outpatient department and emergency units based on their eligibility and willingness to participate. A total of 100 participants meeting the inclusion and exclusion criteria were enrolled in the study.

The Inclusion criteria were:

• Pregnant women above years age.
• Singleton pregnancies at 32 weeks of gestation or
• Women presenting with symptoms of preterm
• Women who gave consent and agreed to follow-

The Exclusion criteria were:

• Pregnant women with suspected fetal growth
• Those with medical complications, like hypertension, preeclampsia, diabetes, and thyroid diseases.
• Women with preterm premature rupture of membranes .
• Pregnancies with fetal anomalies or placenta

After obtaining informed consent, eligible participants underwent 2D ultrasonographic evaluation to measure the corrected fetal adrenal gland volume (cFAGV) and related parameters. The fetal adrenal zone width ratio (w/W) and depth ratio (d/D) were calculated. Ultrasound was performed at the time of presentation and repeated at regular intervals if the participants remained undelivered. Participants were followed up until delivery, and the outcomes were recorded.

Data were collected through structured proformas that included demographic details, clinical history, ultrasound measurements, and delivery outcomes.

The primary study tool was a 2D ultrasound machine equipped with high-resolution probes to measure fetal adrenal gland and zone dimensions. The fetal adrenal zone was identified as a well defined echogenic area within the gland. For the whole fetal adrenal gland the length(L), width(W) and depth(D) were recorded and for the fetal zone the corresponding parameters (l, w and d) were obtained. Length (L and l) was assessed in transverse or sagittal sections, width (W and w) in transverse or coronal sections and depth (D and d) in sagittal or coronal sections. (5)

Table / Figure 1: Methodology of measurement of the whole adrenal gland and the fetal zone (5)

Statistical Analysis

Data were entered into Microsoft Excel and analyzed using SPSS software (version 22). Descriptive statistics, including means and standard deviations, were calculated for continuous variables. Categorical variables were summarized as frequencies and percentages. Chi-square tests and independent t-tests were used to compare groups. Receiver operating characteristic (ROC) curve analysis was performed to determine the predictive accuracy of cFAGV, with sensitivity and specificity values calculated. A p-value of <0.05 was considered statistically significant.

RESULTS

MATERNAL AGE: The most frequent age categories were 21-25 years and 26-30 years, each comprising 39% of the total participants. Participants aged below 20 years and above 30 years accounted for 11% each, indicating a relatively young cohort.

GESTATIONAL AGE: The majority of participants (79%) were recruited before 33 weeks of gestation, while only 21% each were recruited at 34weeks.

SYMPTOMS OF PRETERM LABOUR: The distribution of symptoms of preterm labor shows that 45% of participants reported symptoms, whereas 55% did not. Most participants (86%) had no history of preterm labor, while 14% reported such a history. Cervical length was another variable of interest, with a mean of 23.32 mm in our cohort.

Table / Figure 2: Preterm Birth (<37 weeks)

Table / Figure 3: Comparison of Fetal Adrenal Gland Volume (mm3/kg)

*Chi-square test †Independent t-test

The difference was statistically significant

Table / Figure 4: Comparison of Adrenal Zone Width Ratio (w/W) between the Groups

*Chi-square test †Independent t-test             

 The difference was not statistically significant .

Table / Figure 5: Comparison of Adrenal Zone Depth Ratio (d/D)

*Chi-square test †Independent t-test

The difference was not statistically significant

Table / Figure 6: Comparison of Delivery Interval (days)

*Chi-square test †Independent t-test

The difference was statistically significant

Table / Figure 7: Comparison of Fetal Zone Enlargement (%)

*Chi-square test †Independent t-test.

The difference was not significant (p=0.866).

Table / Figure 8: ROC Analysis of predictive accuracy for Fetal Adrenal Gland Volume, Adrenal Zone Width Ratio and Adrenal Zone Depth Ratio

CI = Confidence Interval

ROC Curve analysis of Foetal adrenal gland volume

Area under curve (AUC) of 0.7321 indicates Excellent predictive accuracy with high sensitivity and specificity .

ROC curve analysis of Fetal adrenal zone width ratio

Area under curve (AUC ) of 0.5914 indicates Moderate prediction accuracy

ROC curve analysis of Fetal adrenal zone depth ratio

Area under curve ( AUC ) of 0.4519 indicates Weak prediction accuracy

Table / Figure 9: ROC Curve analysis of Foetal adrenal gland volume, Fetal adrenal zone width ratio and Fetal adrenal zone depth ratio in predicting preterm labour

Table / Figure 10: Sensitivity, Specificity, and Predictive Values

CI=Confidence Interval

DISCUSSION

The association of fetal adrenal gland volume (FAGV) with preterm birth in our study highlights its predictive potential, as evidenced by a significantly higher mean volume in the preterm group compared to the term group (p<0.001). This finding aligns with previous studies by Turan et al. and Bhat et al., which demonstrated that an increased FAGV correlates with imminent labor, supporting the hypothesis that hormonal changes in the fetal adrenal gland trigger labor onset (12, 13, 14). Similarly, studies by Ali et al. and Gimovsky et al. noted that FAGV could differentiate between preterm and term deliveries with high specificity, further validating our results (15, 16). However, the strong sensitivity observed in our study (71.79%) suggests that FAGV should be considered alongside other markers to predict the pre term labour.

Our findings on adrenal zone width (w/W) showed moderate predictor of preterm labour with P- value 0.069 and adrenal zone depth (d/D) ratios revealed no significant difference between preterm and term births, with p-value of 0.229 respectively. These results differ from Kim et al., who reported limited utility of w/W ratios in predicting preterm labor and Eltantawy et al., who found a significant association with the depth ratio in high-risk pregnancies (17, 18). The lack of consistent findings across studies may be due to variations in sample populations and measurement techniques.

The delivery interval analysis in our study revealed significant difference between groups (p<0.001). This contrasts with Sharma et al., who reported similar intervals in women undergoing induction of labor but aligns with Hall’s findings, where a shorter delivery interval was significantly associated with increased FAGV (19, 20). Differences in study design and population characteristics might explain these discrepancies, emphasizing the need for further research on this parameter.

Our ROC analysis revealed that FAGV had the highest area under the curve (AUC=0.7321), followed by w/W and d/D ratios. While the AUC for FAGV indicates excellent predictive accuracy, its performance was lower than reported by Sage et al. and Turan et al., who achieved higher AUC values by integrating FAGV with biochemical markers such as corticotropin-releasing hormone (21, 22). This highlights the potential for combining sonographic and biochemical tools to enhance predictive capabilities.

Fetal zone enlargement (FZE) was comparable between groups, with no significant differences (p=0.866). Similar findings were reported by Weiss et al., who concluded that FZE alone might not reliably predict preterm birth (9). However, combining FZE with other sonographic markers could improve its diagnostic utility.

The significant association between high FAGV and preterm birth observed in our study (p<0.001) aligns with Chandana et al. and Agarwal et al., who emphasized the hormonal changes within the adrenal gland as key triggers for labor (14, 7). The Cramér’s V value (0.4211) suggests a meaningful association, indicating room for further investigation into additional contributing factors.

This study supports the growing evidence that FAGV is a strong predictor of preterm birth. However, its sensitivity and specificity highlight the need for combined models incorporating other biomarkers and clinical factors. Future research should focus on longitudinal studies with larger sample sizes to validate these findings and refine predictive models. Cervical length was another variable of interest, with a mean of 23.32 mm in our cohort. Shortened cervical length (<25 mm) has long been associated with preterm birth risk. Our results support the findings of Gomez et al. and Romero et al., who highlighted the role of cervical shortening as an early indicator of labor initiation (23, 11). However, integrating cervical length with FAGV may enhance predictive accuracy, as demonstrated by Goletzke et al., who combined both parameters to identify high-risk cases (8).

The integration of sonographic and biochemical tools holds promise for improving early identification and management of preterm birth, ultimately reducing its associated morbidity and mortality.

Strengths:

• The study provides valuable insights into the predictive accuracy of fetal adrenal gland volume for identifying preterm birth, using a non-invasive and widely accessible ultrasonographic technique.
• It includes a comprehensive analysis of multiple predictors, such as adrenal zone width and depth ratios, along with clinical variables like cervical length , enhancing the robustness of the findings.
• The study's cross-sectional design and sample size of 100 participants offer a sufficient dataset for initial exploration, laying the groundwork for future longitudinal studies.

Limitations:

• The cross-sectional design limits the ability to establish causal relationships between fetal adrenal gland volume and preterm birth outcomes.
• The study was conducted in a single tertiary care center, which may restrict the generalizability of the findings to other populations or healthcare settings.
• The study did not account for potential confounding factors, such as maternal stress levels or nutritional status, which could influence adrenal gland development and preterm labor outcomes.

CONCLUSION

This study highlights the potential of fetal adrenal gland volume as a reliable predictor of preterm labor, with significant differences observed between preterm and term birth groups. The ROC analysis supports its utility, showing an excellent predictive accuracy. These findings suggest that fetal adrenal gland measurements, along with other markers such as cervical length, cervicovaginal fibronectin, can aid in early risk assessment and clinical decision-making for preterm births. Implementing routine fetal adrenal gland volume measurement in high-risk pregnancies could improve early detection and management of preterm labor, reducing adverse neonatal outcomes. Further large-scale studies and the integration of these findings into clinical guidelines could enhance obstetric care and contribute to better maternal and neonatal health outcomes.

REFERENCES

1. World Health Preterm birth. Geneva: WHO; 2022.
2. Levels and trends in child mortality. New York: UNICEF; 2021.
3. Blencowe H, Cousens S, Oestergaard MZ, et Preterm birth associated with neonatal death: systematic review. Lancet. 2013;381(9862):2239-46.
4. Lawn JE, Kinney MV, Black RE, et Newborn survival: a decade of change. Lancet. 2013;382(9906):452-77.
5. Turan OM, Buhimschi IA, Funai EF, et al. Ultrasound measurement of fetal adrenal gland enlargement: an accurate predictor of preterm birth. Am J Obstet Gynecol. 2011;204(4):311.e1-10.
6. National Family Health Survey (NFHS-5). Mumbai: International Institute for Population Sciences; 2021
7. Agarwal S, Chandak Fetal adrenal gland biometry as a predictor of preterm birth. Int J Gynecol Obstet. 2018;26(1):54-62.
8. Goletzke J, Pagenkemper M, Wiessner C, et al. Longitudinal adrenal gland measurements as risk markers for late preterm delivery. BMC Pregnancy Childbirth. 2020;20(1):1-9.
9. Weiss E, Bartz C, Fischer T, et Guideline: Management of late-term pregnancy.Geburtshilfe Frauenheilkd. 2014;74(12):1099-1103.
10. Goldenberg RL, Culhane JF, Iams JD, et al. Epidemiology and causes of preterm birth. Lancet. 2008;371:75-84.
11. Romero R, Espinoza J, Kusanovic JP, et al. Inflammation in preterm and term labor and delivery. Semin Fetal Neonatal Med. 2006;11:317-26.
12. Bhat CS, Amin SV, Adiga P, et al. Fetal adrenal gland volume: a novel predictor of labour onset. J Obstet Gynecol India. 2019;69(3):252-7.
13. Turan OM, Buhimschi IA, Funai EF, et al. Ultrasound measurement of fetal adrenal gland enlargement: an accurate predictor of preterm birth. Am J Obstet Gynecol. 2011;204(4):311.e1-10.
14. Chandana S, Bhat SV, Amin P, et al. Fetal adrenal gland volume: a novel predictor of onset of labor. J Obstet Gynecol India. 2019;69:252-257.
15. Ali AS, Hussein M, Fetih AN, Ahmed AM. Prediction of preterm birth by evaluating the fetal adrenal gland volume and blood flow: a pilot study. Int J Gynaecol Obstet. 2018;143(1):45-51.
16. Gimovsky AC, Pham A, Shlossman PA, Gyamfi-Bannerman C. Fetal adrenal gland size and the ability to predict spontaneous term labor. Eur J Obstet Gynecol Reprod Biol. 2019;236:94-99.
17. Kim D, Epperson CN, Wang E, et al. Using sonography to measure fetal adrenal gland volume in pregnancy. J Ultrasound Med. 2016;35(9):2029-37.
18. Eltantawy WHA, Mohyieldin MMN, El-Helw MAS, et al. Predictive accuracy of three-dimensional ultrasound measurement of fetal adrenal gland volume in preterm labor cases. QJM. 2020;113(11):793-800.
19. Sharma R, Kumari A, Tandon A, Suneja A. Ultrasonographic measurement of fetal adrenal gland size for the prediction of success of induction of labor among primigravida beyond 40 weeks J Obstet Gynaecol India. 2023;73(2):156-162.
20. Hall M. Assessment of the fetal immune and endocrine systems using MRI prior to preterm birth. Ann Acad Med Singapore. 2024;53(1):22-30
21. Sage YH, Benson CB, Shipp TD, et al. Fetal adrenal gland volume and preterm J Matern Fetal Neonatal Med. 2016;29(10):1552-5.
22. Turan OM, Buhimschi CS, Funai EF, et al. Comparative analysis of 2-D versus 3-D ultrasound estimation of the fetal adrenal gland volume and prediction of preterm birth. Am J Perinatol. 2012;29:673-80
23. Gomez R, Romero R, Nien JK, et A short cervix in women with preterm labor and intact membranes: a risk factor for microbial invasion of the amniotic cavity. Am J Obstet Gynecol. 2005;192:678-89