Relationship among anogenital distance, adrenal gland volume, and penile length and width at 22-36 weeks of pregnancy.

OBJECTIVES: The subject of current work was to determine the relationship of fetal ultrasonographic biomarkers, including anogenital distance (AGD), adrenal gland volume, and penile length and width in mothers with male fetuses at 22-36 weeks of gestation for the assessment of the effect of fetal adrenal gland producing androgens on the male anogenital structures that are exposed to androgen effects as anogenital region and penis. METHODS: This study is a prospective cross-sectional study conducted in our hospital's outpatient perinatal care unit. One hundred and seventy pregnant women with a male fetus aged 22-36 weeks of gestation were included in the study. The fetal adrenal gland length, width, and depth for the calculation of adrenal volume, AGD, and penile length and width were measured for each participant. The Pearson coefficients were calculated to assess the correlation among these parameters. RESULTS: The adrenal gland volume had a meaningful, positive moderate relationship with both the AGD (r=0.60) and penile length and width (r=0.57 and r=0.59, respectively; p<0.001). The AGD had a positive, strong correlation with the penile length and width (r=0.74 and r=0.76, respectively; p<0.001). CONCLUSIONS: The fetal adrenal gland as one of the androgen sources of the fetus is an influencer of the development of the anogenital and penile region. The findings of the current study support that the adrenal gland considerably affects the masculinization of male fetuses, since there were remarkable correlations among the AGD, adrenal gland volume, and penile length and width.

Evaluation of fetal adrenal artery Doppler velocimetry and fetal adrenal gland size in pregnancies after recovery from COVID-19.

AIM: Assessment of the fetal adrenal gland (FAG) size and middle adrenal artery (MAA) Doppler parameters in pregnancy recovered from Coronavirus Disease (COVID-19) and comparison of the values with the healthy control group. METHODS: Thirty-eight pregnant women who had recovered from COVID-19 infection and 76 healthy control group between 33 and 35 weeks of gestation were involved in this case-control study. Fetuses were examined for fetal biometry, fetal well-being, adrenal gland dimensions, and Doppler parameters 4-6 weeks after the diagnosis of COVID 19 infection. FAG dimensions were measured in two planes and MAA blood flow velocity was evaluated with pulsed Doppler. Pregnant women with COVID-19 infection were grouped according to the National Institutes of Health for the severity of the disease, and those with mild and moderate infections were examined in the study. RESULTS: The total adrenal gland (TAG) height, fetal zone (FZ) length and width, and MAA-Peak Systolic Velocity (MAA-PSV) were significantly higher, and the MAA-Pulsatility Index (MAA-PI) was significantly lower in the COVID-19 group (p < 0.05). The lower in MAA-PI and the higher in MAA-PSV, the width of the FZ, and width of the TAG were found to be significant in the moderate group compared to the mild groups (p < 0.05). CONCLUSION: COVID-19 pregnancies might cause early maturation of the FAG and its vasculature depends on the intrauterine stress due to the hyper-inflammation, so fetuses exposed to maternal COVID-19 suggested to have an increase in blood flow to the adrenal gland and fetal adrenal size.

Longitudinal adrenal gland measurements and growth trajectories as risk markers for late preterm delivery.

BACKGROUND: The fetal adrenal gland receives rising awareness as a predictor of spontaneous preterm birth. We hereby provide longitudinal growth assessments of the fetal adrenal gland in a low risk population with an additional focus on trajectories in fetuses born preterm. METHODS: Fetal adrenal gland was assessed via transabdominal ultrasound at gestational weeks (gw) 24-26, 28-30, and 34-36 in a low-risk pregnancy cohort. Longitudinal trajectories of the total gland and the mark (so called fetal zone) as well as ratio of fetal zone width/ total widths (w/W) were analyzed using repeated ANOVA analyses. To compare trajectories of the ratio w/W for preterm and term fetuses respectively, as well as women with and without clinical signs of preterm labor, the propensity score method was applied. RESULTS: Fetal zone width increased over the course of pregnancy (p < 0.0001), while the ratio w/W decreased (p < 0.0001) (n = 327). Comparing the trajectories of the ratio w/W in fetuses born preterm (n = 11) with propensity-score matched term born fetuses (n = 22), a decrease between gw 24-26 and 28-30 was observed in both groups, which continued to decrease for the term born fetuses. However, in preterm born fetuses, the ratio increased above the term born values at gw 34-36. CONCLUSION: Our study provides for the first time longitudinal growth data on the fetal adrenal gland and supports the hypothesis that fetal zone enlargement is associated with preterm birth which could play an important role in risk-prediction.

Fetal adrenal gland: Total gland volume and fetal zone to total gland ratio as markers of small for gestational age.

PURPOSE: Fetal adrenal gland changes have previously been investigated as novel markers of preterm labor and small for gestational age (SGA) fetuses. We aimed to compare the fetal adrenal gland parameters in SGA and appropriate for gestational age (AGA) fetuses. METHODS: A prospective cohort study was conducted on SGA fetuses with estimated fetal weight (EFW) ≤10th centile and AGA (EFW >10th centile) at 17 to 34 weeks gestation. Fetal adrenal total gland volume (TGV), TGV corrected for EFW (cTGV), fetal zone volume (FZV), FZV corrected for EFW (cFZV), and FZV:TGV ratio were compared and correlated with gestational age and EFW. Receiver operator curves assessed FZV:TGV ratio, cTGV, and cFZV in detecting SGA. RESULTS: Ultrasound examinations from 103 AGA and 50 SGA fetuses showed that (a) SGA fetuses had higher TGV (P = .002), FZV (P = .001), and FZV:TGV (P = .036) compared to AGA fetuses; (b) fetal adrenal TGV, FZV, cFZV, and FZV:TGV increase with advancing gestational age and EFW while cTGV does not; (c) Fetal adrenal changes in cTGV, cFZV, and FZV:TGV have ability to differentiate SGA; (d) FZV:TGV ratio 10 and 25 may be used to identify or exclude SGA in antenatally suspected SGA. CONCLUSIONS: We investigated the concept that SGA fetuses have measurable changes to the adrenal gland. We have shown that fetal TGV, TGV, and FZV:TGV ratio show differences between AGA and SGA with TGV remaining significant after accounting for GA at scan. These findings may be useful as potential biomarkers for diagnosing or excluding SGA.

Sonographic Evaluation of Fetal Adrenal Gland in Gestational Diabetes: Relation to Fetal Growth and Maternal Biochemical Markers.

OBJECTIVES: To relate measurements and volume of the fetal adrenal gland in third trimester ultrasound in diabetic pregnancies (1) to birth weight; (2) to other sonographic markers of diabetic fetopathy (expected fetal weight, sectional area, and fractional volume in fetal limbs); and (3) to maternal biochemical markers of diabetes (HbA1c, leptin). METHODS: Fetal adrenal gland measurements were obtained between 32 and 34 weeks. The gland length, width, depth, and volume (by Virtual Organ Computer-Aided Analysis [VOCAL]) were measured for total gland and fetal zone. Fetal total and fat sectional area and fractional volume were obtained in arm and thigh. A maternal blood sample was obtained. Univariate and multivariate models were used to assess the associations. RESULTS: Thirty-nine diabetic pregnancies were included. Birth weight related significantly to total and fetal zone adrenal depth, and total adrenal volume in third trimester. Total adrenal length and corrected adrenal gland volume also showed a significant correlation to birth weight percentile in univariate and multivariate models. Total adrenal volume associated significantly to total and fat areas and volumes in fetal limbs. Both maternal leptin and HbA1c levels found a significant positive relation to fetal total adrenal volume and corrected adrenal gland volume. Total adrenal gland volume showed a significant association to maternal HbA1c level in multivariate model. CONCLUSIONS: An enlargement of the fetal adrenal gland may be observed in gestational diabetes, not only related to birth weight, but also to distinctive features of diabetic pregnancies, such as fat tissue fetal deposits or maternal biochemical markers.

Ultrasonographic approach to diagnosis of fetal inflammatory response syndrome: a tool for at-risk fetuses?

Preterm parturition is a syndrome that may result from many underlying mechanisms. Infection and inflammation are the prominent ones. Intrauterine infection and inflammation have an effect akin to sepsis, and that is similar to systemic inflammatory response in adults. Indeed, there is evidence to support the association of a fetal inflammatory response syndrome (FIRS) to systemic infection and inflammation. The utilization of invasive procedures for the prenatal diagnosis of FIRS is associated with a risk for complications resulting from the invasive method. The progress in the imaging quality of obstetrical ultrasound and the development of novel methods for functional anatomical assessment of the fetal organs may help to identify, noninvasively, fetuses at risk for FIRS in patients presenting with preterm labor. We review the studies describing advanced sonographic modalities and the imaging findings in the heart, thymus, kidney, adrenal glands, and spleen of these fetuses.

The Impact of Fetal Growth Restriction on Prenatal 2D Ultrasound and Doppler Study of the Fetal Adrenal Gland.

Background: Uteroplacental insufficiency in fetuses with growth restriction (FGR) leads to chronic hypoxia and stress, predominantly affecting the adrenal glands. However, the mechanisms of impact remain unclear. Objectives: This study is aimed at comparing the Doppler indices of the adrenal artery and the adrenal gland sizes between FGR and those with normal growth. Materials and Methods: A multicenter, cross-sectional study was conducted from February to December 2023. We compared 34 FGR to 34 with normal growth in terms of inferior adrenal artery (IAA) Doppler indices and adrenal gland volumes. Results: The IAA peak systolic velocity (PSV) in the FGR group was 14.9 ± 2.9 cm/s compared to 13.5 ± 2.0 cm/s in the normal group, with a mean difference of 1.4 cm/s (95% confidence interval [CI]: 0.27-2.65; p value = 0.017). There were no significant differences between groups in terms of IAA pulsatility index (PI), resistance index (RI), or systolic/diastolic (S/D), with p values of 0.438, 0.441, and 0.658, respectively. The volumes of the corrected whole adrenal gland and the corrected neocortex were significantly larger in the FGR group, with p values of 0.031 and 0.020, respectively. Conclusion: Both increased IAA PSV and enlarged volumes of the corrected whole adrenal gland and neocortex were found in fetuses with FGR, suggesting significant adrenal gland adaptation in response to chronic intrauterine stress.

Ultrasonographic Measurement of Fetal Adrenal Gland Size for the Prediction of Success of Induction of Labor Among Primigravida Beyond 40 Weeks Gestation.

Introduction: As the pregnancy advances beyond term, the risk of perinatal morbidity and mortality increases. Hence to prevent these complications associated with postterm pregnancy, induction of labor is done, as per our institution protocol between 40 and 41 weeks of gestation. Induction has its own drawback, so it is essential to identify the women with high chances of failure of induction of labor, to prevent the morbidities associated with induction failure. Aim: To study the role of ultrasonographic fetal adrenal gland enlargement for the prediction of success of labor induction among primigravida beyond 40 weeks gestation. Material and Methods: Low-risk primigravidas beyond 40 weeks gestation, scheduled for induction of labor, were enrolled for the study. Fetal adrenal gland dimensions were measured by using abdominal probe Philips HD 7XE and general electronics logiq P6 pro or any ultrasound machine equipped with 7.5-10 MHz linear array probe and 3.5-5 MHz curved array probe. Results: The fetal adrenal gland length, width and ratio were statistically significant between the successful versus failed induction groups. The cutoff fetal zone ratio > 0.36 for the prediction of successful induction of labor had 90% sensitivity, 89% specificity, 93% PPV and 75% NPV. Conclusion: Fetal zone enlargement (fetal zone ratio > 0.36) is a strong predictor of successful induction of labor as compared to TVL and Bishop's score. It can be used for screening the women, who are destined for induction failure, so that adverse effects of induction of labor can be avoided.

Maternal adverse childhood experiences impact fetal adrenal volume in a sex-specific manner.

BACKGROUND: The mechanisms by which parental early life stress can be transmitted to the next generation, in some cases in a sex-specific manner, are unclear. Maternal preconception stress may increase susceptibility to suboptimal health outcomes via in utero programming of the fetal hypothalamic-pituitary-adrenal (HPA) axis. METHODS: We recruited healthy pregnant women (N = 147), dichotomized into low (0 or 1) and high (2+) adverse childhood experience (ACE) groups based on the ACE Questionnaire, to test the hypothesis that maternal ACE history influences fetal adrenal development in a sex-specific manner. At a mean (standard deviation) of 21.5 (1.4) and 29.5 (1.4) weeks gestation, participants underwent three-dimensional ultrasounds to measure fetal adrenal volume, adjusting for fetal body weight (waFAV). RESULTS: At ultrasound 1, waFAV was smaller in high versus low ACE males (b = - 0.17; z = - 3.75; p < .001), but females did not differ significantly by maternal ACE group (b = 0.09; z = 1.72; p = .086). Compared to low ACE males, waFAV was smaller for low (b = - 0.20; z = - 4.10; p < .001) and high ACE females (b = - 0.11; z = 2.16; p = .031); however, high ACE males did not differ from low (b = 0.03; z = .57; p = .570) or high ACE females (b = - 0.06; z = - 1.29; p = .196). At ultrasound 2, waFAV did not differ significantly between any maternal ACE/offspring sex subgroups (ps ≥ .055). Perceived stress did not differ between maternal ACE groups at baseline, ultrasound 1, or ultrasound 2 (ps ≥ .148). CONCLUSIONS: We observed a significant impact of high maternal ACE history on waFAV, a proxy for fetal adrenal development, but only in males. Our observation that the waFAV in males of mothers with a high ACE history did not differ from the waFAV of females extends preclinical research demonstrating a dysmasculinizing effect of gestational stress on a range of offspring outcomes. Future studies investigating intergenerational transmission of stress should consider the influence of maternal preconception stress on offspring outcomes.

The Correlation Between Three-Dimensional Ultrasound Measurement of Fetal Adrenal Gland and Maternal Serum Fructosamine Level in Gestational Diabetes Mellitus: Prospective Cohort Study.

Objective: Gestational diabetes mellitus (GDM) has an impact on fetal adrenal gland size and volume, which are greater in the GDM population. This study used 2D and 3D ultrasound scanning to determine the correlation of fetal adrenal gland size and volume with fructosamine levels, HbA1c levels, estimated fetal weight (EFW), and neonatal birth weight in GDM patients. Methods: This study included eighty singleton pregnant women diagnosed with GDM between 24-28 weeks of gestation. During weeks 32-34 of gestation, the length, width, and depth of the fetal zone and total adrenal gland were measured using transabdominal 2D ultrasound. Virtual organ computer-aided analysis (VOCAL) software was used to evaluate fetal zone and total adrenal gland volume in 3D ultrasound. All the participants were followed until delivery. Pearson's correlation analysis was conducted to examine the correlation between fetal adrenal gland ultrasound measurements and the factors of interest. Results: The study consisted of sixty-six (82.5%) pregnant women with diet-controlled GDM (GDMA1) and fourteen (17.5%) pregnant women with insulin-managed GDM (GDMA2). There was no difference in fetal adrenal gland measurements between the diet-controlled (GDMA1) and the insulin-managed (GDMA2) groups. All the participants had achieved optimal glucose levels at the time of ultrasound acquisition. The total adrenal gland length and fetal zone volume had statistically significant positive correlations with EFW (r = 0.69, p = 0.02 and r = 0.84, p = 0.01, respectively). After adjusting for EFW, only the fetal zone volume was significantly correlated with fructosamine levels (adjusted-OR = 2.4, 95% CI: 1.5, 3.9, p = 0.01) and HbA1c levels (adjusted-OR = 2.5, 95% CI: 1.6, 4.3, p = 0.01). Conclusion: The fetal zone volume is correlated with EFW, fructosamine levels, and HbA1c levels. This non-invasive technique may be beneficial as an indirect marker for glycemic monitoring in GDM.

Possible Relevance of Soluble Luteinizing Hormone Receptor during Development and Adulthood in Boys and Men.

Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) are agonists for the luteinizing hormone receptor (LHCGR) which regulates male reproductive function. LHCGR may be released into body fluids. We wish to determine whether soluble LHCGR is a marker for gonadal function. Cross-sectional, longitudinal, and intervention studies on 195 healthy boys and men and 396 men with infertility, anorchia, or Klinefelter Syndrome (KS) were used to correlate LHCGR measured in serum, seminal fluid, urine, and hepatic/renal artery and vein with gonadal function. LHCGR was determined in fluids from in vitro and in vivo models of human testicular tissue and cell lines, xenograft mouse models, and human fetal kidney and adrenal glands. Western blot showed LHCGR fragments in serum and gonadal tissue of similar size using three different antibodies. The LHCGR-ELISA had no species cross-reactivity or unspecific reaction in mouse serum even after human xenografting. Instead, sLHCGR was released into the media after the culture of a human fetal kidney and adrenal glands. Serum sLHCGR decreased markedly during puberty in healthy boys (p = 0.0001). In healthy men, serum sLHCGR was inversely associated with the Inhibin B/FSH ratio (ß -0.004, p = 0.027). In infertile men, seminal fluid sLHCGR was inversely associated with serum FSH (ß 0.006, p = 0.009), sperm concentration (ß -3.5, p = 0.003) and total sperm count (ß -3.2, p = 0.007). The injection of hCG lowered sLHCGR in serum and urine of healthy men (p < 0.01). In conclusion, sLHCGR is released into body-fluids and linked with pubertal development and gonadal function. Circulating sLHCGR in anorchid men suggests that sLHCGR in serum may originate from and possibly exert actions in non-gonadal tissues. (ClinicalTrials: NTC01411527, NCT01304927, NCT03418896).

Fetal Adrenal Gland Volume a Novel Predictor of Onset of Labor.

INTRODUCTION: There is a definite need to find a highly sensitive and specific, noninvasive, and cost-effective marker for prediction of preterm labor. We hypothesize that a measurement of adrenal gland volume can predict a preterm as well as a term labor. MATERIALS AND METHODS: Two hundred and sixty-eight pregnant women were enrolled in the study at 28-34 weeks' antenatal visit. Final analysis was done in 204. All of them were subjected to 2D ultrasonographic measurement of the corrected fetal adrenal gland volume (cFAGV) and fetal adrenal zone parameters including the width ratio and depth ratio. The cohort was followed up to term, and a reassessment of cFAGV and fetal adrenal zone parameters was repeated between 37 and 39 weeks. Women who presented with features of preterm labor had a scan at the time of presentation to record cFAGV and fetal adrenal zone parameters. RESULTS: Women, who developed features of preterm labor eventually, had a significantly high cFAGV (404.70 mm3/kg body weight) during the first scan compared to those who reached term asymptomatically (241.35 mm3/kg body weight). A cutoff value of 271.16 mm3/kg body weight showed 90% sensitivity and 81.9% specificity. Fetal adrenal gland width ratio had the best efficacy (sensitivity 96.67%, specificity 86.2%) followed by cFAGV (sensitivity 96.67%, specificity 83%) for predicting preterm delivery. CONCLUSION: 2D ultrasound measurement of fetal adrenal gland parameters can be used as a marker for prediction of preterm delivery. cFAGV at term can also be used to predict the possibility of spontaneous onset of labor.

Fetal adrenal gland size and the ability to predict spontaneous term labor.

OBJECTIVE: The objective of this study was to evaluate whether ultrasound measured fetal adrenal gland size can be a predictor of spontaneous term labor. STUDY DESIGN: This study was a diagnostic test accuracy study using a prospective cohort design evaluating the ability of 2-dimensional ultrasound measurement of fetal adrenal gland total length, total width, fetal zone length and fetal zone width in women in the third trimester to predict the primary outcome of spontaneous term labor. Secondary outcomes were vaginal delivery, length of labor, and maternal and neonatal morbidities. RESULTS: Of 43 patients recruited, 3 were excluded. 11 (25.6%) presented in spontaneous labor and 29 (67.4%) underwent induction of labor. Patient demographics were similar for all included except for admission cervical exam and oxytocin use. A receiver operative curve was created to assess test predictability. Weighted width of fetal adrenal gland was the best predictor of spontaneous labor amongst variables measured with an area under the curve of 0.674, p = 0.93. w/W ≥ 0.41 had a sensitivity of 91.0%, specificity of 44.8%, positive predictive value of 38.5% and a negative predictive value of 92.3%. Maternal and neonatal morbidities were not different between the spontaneous labor group and the induction of labor group. CONCLUSION: Ultrasound measured fetal w/W was moderately predictive of spontaneous labor.

Reference ranges of fetal adrenal gland and fetal zone volumes between 24 and 37 + 6 weeks of gestation by three-dimensional ultrasound.

OBJECTIVE: To establish reference ranges of the fetal adrenal gland (AG) and fetal zone (FZ) volumes using three-dimensional ultrasound (3DUS). METHODS: We performed a prospective cross-sectional study with 204 normal singleton pregnancies between 24 and 37 + 6 weeks of gestation. The fetal AG and FZ volumes were obtained using the virtual organ computer-aided analysis method with a 30° rotation. To establish reference ranges as the function of gestational age (GA), quantile regression was performed with the adjusted coefficient of determination (R2). Intra- and inter-observer repeatability was performed using the intraclass correlation coefficient (ICC). RESULTS: The mean results of fetal AG and FZ values were 0.42 cm3 (0.04-1.22) and 0.10 cm3 (0.02-0.47), respectively. The best-fit quantile regression models for fetal AG and FZ volumes as the function of GA were in first-degree models: AG = -0.937 + 0.041 × GA (R2 = 0.124) and FZ = -0.201 + 0.009 × GA (R2 = 0.127), respectively. We observed good intra-observer repeatability of fetal AG and FZ volumes, with an ICC of 0.996 and 0.989, respectively. We also observed good inter-observer repeatability, with an ICC of 0.972 and 0.966 for AG and FZ, respectively. CONCLUSION: The reference ranges of AG and FZ volumes using 3DUS between 24 and 37 + 6 weeks of gestation were established and exhibited good repeatability.

Fetal adrenal gland volume and preterm birth: a prospective third-trimester screening evaluation.

OBJECTIVE: Given the importance of the fetal adrenal gland in producing hormones critical to labor, we sought to evaluate whether sonographic three-dimensional measurements of the adrenal gland are a useful screening tool for spontaneous preterm birth (SPTB). METHOD: We prospectively screened 128 non-anomalous singletons from 24 to 36 weeks' gestation with volumetric measurements of the fetal adrenal gland at their indicated antenatal sonogram. Labor and delivery outcomes were assessed and compared with respect to adrenal volume. RESULTS: When corrected for estimated fetal weight, the 11 women (9%) who delivered following SPTB had smaller adrenals than those who did not, 0.33 cm(3)/kg compared with 0.57 cm(3)/kg, respectively (p = 0.006). There was no difference in volumes between those who delivered by SPTB within 7 days or greater than 14 days from measurement (0.34 cm(3)/kg versus 0.33 cm(3)/kg, p = 0.79). Among women at increased risk of SPTB, those with SPTB had smaller adrenals than those who did not: 0.32 cm(3)/kg versus 0.53 cm(3)/kg, p = 0.06. CONCLUSION: We found fetal adrenal glands significantly smaller for those delivering preterm. Given the prior literature and our asymptomatic population, our data support multiple pathways leading to SPTB.

Monitoring fetal immune development in human pregnancies: current concepts and future goals.

The vast majority of the current knowledge on immune development in the fetal period has been gained from animal studies, particularly from mouse models. This has led to a great improvement in our current understanding of immune ontogeny. However, it has also become clear that in many ways the mouse model of pregnancy differs from the situation in human pregnancy, such as the degree and importance of trophoblast invasion, the kind of MHC class repertoire of the extravillous trophoblast cells, and differences concerning the development and regulation of T-cells. It will be of paramount importance to develop non-invasive screening methods to assess fetal immune development in humans. The focus of this mini-review is to discuss how prenatal ultrasound evaluation can be used as a tool to monitor fetal immune development in human pregnancies. To identify the fetuses at risk of immune disorders could be the first step to developing prevention strategies in the future.