Tamaño de la glándula suprarrenal fetal en diabetes mellitus gestacional.

Hetkamp, T .; Hammer, K .; Möllers, M .; Köster, H.A .; Falkenberg, M.K .; Kerschke, L .; Braun, J .; Oelmeier de

Murcia, K .; Klockenbusch, W .; Schmitz, R. Journal of Perinatal Medicine. Vol. 47 Nr. 9 Página: 941 – 946. Fecha

de publicación: 26/11/2019

Resumen:

Antecedentes:

El objetivo de este estudio fue comparar el tamaño de la glándula suprarrenal de los fetos de

mujeres con diabetes mellitus gestacional (DMG) con el de los fetos de control sanos.

Métodos:

Este estudio transversal prospectivo incluyó mediciones del tamaño de la glándula suprarrenal de

62 fetos GDM (grupo GDM) y 370 controles normales (grupo control) entre la semana 19 y 41 de

gestación. Se usó un plano transversal estandarizado para medir el ancho total y el ancho de la

médula. El ancho de la corteza y una relación de la glándula suprarrenal (ancho total / ancho de la

médula) se calcularon a partir de estos datos. Las medidas del tamaño de la glándula suprarrenal

se ajustaron a la semana de gestación y se compararon entre los dos grupos en un análisis de

regresión lineal multivariable. Se utilizó una métrica de descomposición de la varianza para

comparar la importancia relativa de los predictores de las diferentes mediciones del tamaño de la

glándula suprarrenal.

Resultados:

Para todos los parámetros investigados del tamaño de la glándula suprarrenal, se encontraron

valores aumentados en el caso de GDM (P <0.05), mientras se ajustaba por la semana de

gestación. La DMG parece tener un mayor impacto en el tamaño de la corteza que en el tamaño

de la médula.

Conclusión La glándula suprarrenal fetal se agranda en el embarazo complicado por DMG. El ancho

de la corteza parece verse particularmente afectado.

J. Perinat. Med. 2019; aop

Tim Hetkamp*, Kerstin Hammer, Mareike Möllers, Helen A. Köster, Maria K. Falkenberg, Laura Kerschke, Janina Braun, Kathrin Oelmeier de Murcia, Walter Klockenbusch and Ralf Schmitz*

Fetal adrenal gland size in gestational diabetes mellitushttps://doi.org/10.1515/jpm-2019-0146Received April 25, 2019; accepted August 22, 2019

Abstract

Background: The aim of this study was to compare the adrenal gland size of fetuses of women with gestational diabetes mellitus (GDM) with that of healthy control fetuses.Methods: This prospective cross-sectional study included measurements of the adrenal gland size of 62 GDM fetuses (GDM group) and 370 normal controls (control group) between the 19th and 41st week of gestation. A standard-ized transversal plane was used to measure the total width and the medulla width. The cortex width and an adrenal gland ratio (total width/medulla width) were calculated from these data. Adrenal gland size measurements were adjusted to the week of gestation and compared between the two groups in a multivariable linear regression analy-sis. A variance decomposition metric was used to compare the relative importance of predictors of the different adrenal gland size measurements.Results: For all the investigated parameters of the adrenal gland size, increased values were found in the case of GDM (P < 0.05), while adjusting for the week of gestation. GDM seems to have a greater impact on the size of the cortex than on the size of the medulla.Conclusion: The fetal adrenal gland is enlarged in preg-nancy complicated by GDM. The width of the cortex seems to be particularly affected.

Keywords: adrenal gland; gestational age; gestational diabetes mellitus; prenatal ultrasound.

Introduction

Gestational diabetes mellitus (GDM) is characterized by impaired glucose intolerance with first onset during pregnancy diagnosed with a 75-g oral glucose tolerance test (oGTT) [1, 2].

GDM is present in one of seven pregnancies [3] and is associated with numerous complications for both the child and the mother [4]. Due to increased expression of the glucose transporters GLUT-1 and GLUT-9 in the transporting epithelium of the human placenta (syncy-tiotrophoblast), maternal hyperglycemia results in fetal hyperglycemia [5–7]. Hence the fetal pancreas is stimu-lated in its production of insulin. This hyperinsulinemia may cause increased fetal liver size, increased adipogen-esis and thus macrosomia [4, 8, 9]. In addition, the risk of premature birth [10], pre-eclampsia or pregnancy-induced hypertension [11] and intrauterine fetal death is higher [12]. Long-term exposure to hyperinsulinism increases the likelihood of suffering from impaired glucose tolerance or a metabolic syndrome in adulthood [13].

The fetal adrenal gland is an active endocrine organ, showing a highly specialized zonation of its cortex. Current research is based on three zones: the outer definitive zone (DZ), the transitional zone (TZ) and the inner fetal zone (FZ) forming 80–90% of the fetal adrenal cortex [14]. Each one has its own unique enzyme composition. The FZ expresses cytochrome P450 cholesterol side-chain cleavage (CYP11A) and 17α-hydroxylase/17,20-lyase (CYP17) in the absence of 23β-hydroxysteroid dehydrogenase/Δ4−5 isomerase (HSD3B2). It mainly produces dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) throughout most of gestation [15–17]. By providing large amounts of these C19  steroids used for placental estrogen synthesis, the fetal adrenal gland is part of the feto-placental unit and plays a key role in the regulation of intrauterine homeostasis, fetogenesis and initiation of parturition [18].

*Corresponding authors: Tim Hetkamp and PD Dr. Ralf Schmitz, MD, Department of Gynecology and Obstetrics, University Hospital of Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany, Tel.: +49-17634109151, Fax: +49-2518348210, E-mail: hetkamp.tim@googlemail.com; schmitzr@ukmuenster.de Kerstin Hammer, Mareike Möllers, Helen A. Köster, Maria K. Falkenberg, Janina Braun, Kathrin Oelmeier de Murcia and Walter Klockenbusch: Department of Gynecology and Obstetrics, University Hospital of Münster, Albert-Schweitzer-Campus 1, 48149 Münster, GermanyLaura Kerschke: Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany

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2      Hetkamp et al.: Fetal adrenal gland size in gestational diabetes

GDM, as a metabolic disease leading to hyperinsu-linemia, might have a direct impact on the endocrine adrenal gland itself. We hypothesized an enlarged fetal adrenal gland in pregnancies complicated by maternal diabetes compared to healthy controls. Hence the aim of this study was to demonstrate an association between GDM and fetal adrenal gland size.

Patients and methodsThis prospective cross-sectional study included 432 unselected cases of pregnant women with gestational ages ranging from 19 to 41  weeks, who received a routine ultrasound examination at the Department of Gynecology and Obstetrics at the University Hospital Münster between 2012 and 2018. The gestational age was based on the crown-rump length.

Sixty-two women with either pre-gestational diabetes or GDM (GDM group) and 370 normal controls (control group) were deter-mined. Data from multiple pregnancies, gestational age below 19  weeks of gestation, maternal age below 18  years, pregnancies complicated by maternal disease (e.g. infection, etc.), growth-restricted fetuses or fetuses with malformations or aneuploidy were excluded.

The IU22 and EPIQ7 Philips Ultrasound System (Philips Medical Systems, Andover, MA, USA) was utilized by seven specialists in obstetric ultrasound (S.H., K.H., M.M., M.K.F., J.B., K.O., R.S.) for the measurements. As in a previous study, a new standardized transver-sal plane in the smallest section was used to measure the total width and the medulla width [19]. Figure 1 demonstrates this method. We used the stored data (View-point©, General Electric, Wessling, Ger-many) to calculate the values of the cortex (half of the total width minus the medulla width) and the adrenal gland ratio (ratio of the total width to the medulla width). The Institutional Review Board accepted our study and it was planned in accordance with the Declaration of Helsinki. Informed consent was obtained prior to each ultrasound examination.

Statistical analysisStatistical analyses were performed using SPSS version 24 (IBM Corp., Released 2016. IBM SPSS Statistics for Mac Armonk, NY, USA: IBM Corp.) and R version 3.4.3 (R Core Team, 2018).

Inferential statistics were intended to be exploratory and were interpreted accordingly, i.e. P-values were used only to generate new hypotheses and no adjustment for multiplicity was made. P-values ≤0.05  were considered statistically significant.

The study population was described by standard descriptive statistical measures. Continuous variables were reported as median, lower and upper quartile and were compared between both study groups using the Mann-Whitney-U test.

The association between fetal adrenal gland size meas-urements and gestational diabetes was assessed using multivariable linear regression analysis, adjusting for the covariate week of gestation at ultrasound (WG_US) as well as a potential interaction effect between the WG_US and the study group. The total width, medulla width, cortex width and the adrenal gland ratio were considered as the main outcome variables. Results were reported as regres-sion coefficient estimates, corresponding 95% confidence intervals (CIs) and P-values of the Wald test.

The relative variable importance was calculated for each regressor and model using a variance (i.e. coefficient of determination) decomposition metric [20]. 95% CIs were obtained by bootstrapping [21].

ResultsValues of the adrenal gland size were recorded in 432 cases (GDM group: n = 62; control group: n = 370).

Baseline characteristics of the GDM group and the control group are listed in Table 1. The median f week of gestation at delivery (WG_Partus) [39.3 weeks (38.5, 40.0) vs. 38.9 weeks (35.3, 39.9), P = 0.028], birth weight [3652 g (3204, 3870) vs. 3345 g (3055, 3679), P = 0.016] and birth weight percentile [63.0 (33.3, 81.0) vs. 46.0 (26.1, 66.0), P = 0.016] were higher in the GDM group when compared to the control group. In contrast, the median pH of the umbilical artery was slightly decreased in GDM patients [7.27 (7.21, 7.31) vs. 7.29 (7.24, 7.33), P = 0.015]. There was a statistically significant but clinically irrelevant difference between groups regarding APGAR after 5 min (P = 0.046).

Figure 2 shows the association between the adrenal gland size measurements and WG_US for each

Figure 1: Demonstration of the standardized transversal plane in the smallest section, fetal adrenal gland of a normal controlled fetus (control group) in the 27th week of gestation.

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Hetkamp et al.: Fetal adrenal gland size in gestational diabetes      3

study group. The total, medulla and cortex width were positively correlated with WG_US, whilst no obvious correlation could be found between the adrenal gland ratio and WG_US. All adrenal gland size measurements tended to be higher in GDM patients compared to the

controls. Accordingly, multivariable linear regression analysis (Table 2) identified the total, medulla and cortex width to be positively associated with WG_US (P < 0.001), e.g. showing an increase in the total width of the adrenal gland by 0.098 mm per unit increase in WG_US.

Table 1: Baseline characteristics of the GDM group and the control group.

Parameter GDM group (n = 62) Control group (n = 370) P-valuea

WG_Partus, weeks 39.3 (38.5, 40.0)(n = 62)

38.9 (35.6, 39.9)(n = 370)

0.028

Birth weight, g 3562 (3204, 3870)(n = 48)

3345 (3055, 3679)(n = 272)

0.016

Birth weight percentile 63.0 (33.3, 81.0)(n = 48)

46.0 (26.1, 66.0)(n = 272)

0.016

APGAR after 5 min 10 (9, 10)(n = 48)

10 (9, 10)(n = 270)

0.046

pH umbilical artery 7.27 (7.21, 7.31)(n = 48)

7.29 (7.24, 7.33)(n = 268)

0.015

Data presented as median and lower and upper quartile. GDM, gestational diabetes mellitus; WG_Partus, week of gestation at delivery. aP-values from the Mann-Whitney-U tests.

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Figure 2: Scatter plots showing the correlation of adrenal gland total width, medulla width, adrenal gland ratio and cortex width (y-axis) and week of gestation (x-axis) for the control group and the GDM group.

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4      Hetkamp et al.: Fetal adrenal gland size in gestational diabetes

A significant effect of WG_US on the adrenal gland ratio could not be demonstrated (P = 0.310). All outcome variables were positively correlated with the presence of gestational diabetes (total and cortex width: P < 0.001, medulla width: P = 0.004, adrenal gland ratio: P = 0.002).

Table 3 presents the relative variable importance for each regressor and model. The impact of GDM on the adrenal gland cortex is higher than that on the medulla [0.057 (0.020, 0.109) vs. 0.020 (0.001, 0.058)] in terms of its contribution to the coefficient of determination in the respective models.

The interaction effect between the WG_US and the study group was examined, but not included in the final models because of statistically non-significant results (P > 0.05).

DiscussionOur study is the first to compare the size of the fetal adrenal gland in pregnancies complicated by maternal diabetes to healthy controls using a two-dimensional (2D)-standard-ized transversal plane for ultrasound measurements. We found a positive correlation of the adrenal gland size (total width, cortex width and medulla width) with the presence of GDM. The effect of GDM on the adrenal cortex width was particularly pronounced. Results were adjusted for the week of gestation.

Several studies have reported GDM influencing fetal organogenesis. Increased fetal liver size was demonstrated by Anderson et al. [9], while Dörnemann et  al. found reduced values for the size of the fetal thymus in women with gestational and pre-gestational diabetes [22].

Due to its various complications, maternal hypergly-cemia has been of high academic and clinical interest. GDM is a well-known risk factor for pre-eclampsia and pregnancy-induced hypertension [11]. It is also related to a higher probability of intrauterine fetal death and pre-mature birth [10, 12]. Comparing these pathologies with complications described in relation to an enlarged adrenal gland, there is a similarity. Previous studies revealed an increased risk of premature birth in association with hypertrophy of the fetal adrenals [23, 24]. Turan et  al. emphasized the FZ of the adrenal gland as the single best predictor of premature birth [23]. This impaired clinical outcome may indicate a connection between GDM and the adrenal gland volume.

This hypothesis is strengthened by results from endocrinological research. The placenta is the primary source of estrogens during pregnancy. As part of the feto-placental unit, the placenta is an incomplete steroidogenic organ which requires interaction with the fetal adrenal gland to produce estrogen by conversion of the androgen precursors of the FZ [18]. The rate-limiting enzyme is the aromatase (p450arom) located in the placenta [25]. A downregulation of the aromatase (p450arom) due to insulin was investigated in a previ-ous study [26]. This suggests that hyperinsulinemia caused by GDM [5–7] results in suppression of aromatase (p450arom) and thus to decreased levels of plasma estro-gen [27, 28]. Albrecht et al. showed in their experimen-tal study on pregnant baboons that by suppressing the endogenous estrogen synthesis, the fetal adrenal gland significantly increases in size, i.e. volume. This increase in size is mainly due to hypertrophy of the FZ, whereas the volume of the DZ and TZ remain unchanged [29]. These findings are consistent with our data. A possible

Table 2: Multivariable linear regression analysis.

Estimate 95% CI P-valuea

Total width WG_US 0.098 0.085, 0.112 <0.001 GDM 0.639 0.394, 0.884 <0.001Medulla width WG_US 0.030 0.025, 0.035 <0.001 GDM 0.138 0.043, 0.233 0.004Cortex width WG_US 0.034 0.029, 0.039 <0.001 GDM 0.250 0.160, 0.341 <0.001Ratio (total width/medulla width) WG_US 0.005 −0.005, 0.015 0.310 GDM 0.274 0.100, 0.448 0.002

Data presented as estimated regression coefficient and corresponding confidence interval (CI). GDM, gestational diabetes mellitus; WG_US, week of gestation at ultrasound. aP-values from the Wald tests.

Table 3: Evaluation of variable importance.

Metric 95% CI P-valuea

Total width WG_US 0.309 0.234, 0.384 <0.001 GDM 0.051 0.018, 0.104 <0.001Medulla width WG_US 0.225 0.165, 0.299 <0.001 GDM 0.020 0.001, 0.058 0.004Cortex width WG_US 0.281 0.209, 0.352 <0.001 GDM 0.057 0.020, 0.109 <0.001Ratio (total width/medulla width) WG_US 0.003 0.000, 0.022 0.310 GDM 0.023 0.001, 0.076 0.002

Data presented as relative importance metric (Metric) and corresponding confidence interval (CI). GDM, gestational diabetes mellitus; WG_US, week of gestation at ultrasound. aP-values from the Wald tests.

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hypothesis could be that the enlarged FZ may lead to hyperandrogenism, for example.

To the best of our knowledge, there is only one study which places its main focus on the influence of GDM on the size of the adrenal gland. Garcia et al. used a multiplanar evaluation to measure the length, width and depth of the adrenal gland. VOCAL (Virtual Organ Computer-Aided Analyses) was used to calculate the volume resulting in an increased size of the fetal adrenal gland observed in pregnancies complicated by mater-nal hyperglycemia [30]. The study contained a relatively small number of cases, and the three-dimensional (3D) measurements were time-consuming and showed only acceptable inter- and intra-observer variability [30]. Thus, we used a new standardized and easy-to-obtain 2D transversal plane in the smallest section with excel-lent intra- and inter-observer variability as shown in a previous study [19]. Furthermore, we selected a prospec-tive cross-sectional study design with a comparatively large cohort (62 cases with either pre-gestational diabe-tes or GDM, and 370 normal controls).

Study limitations

A possible limitation of our study could be the number of cases. However, by selecting a measuring plane with excellent intra- and inter-observer variability, we opti-mized the collection of data [19]. In order to minimize inac-curacies, we used a quotient (fetal adrenal gland ratio). As no noticeable correlation between the adrenal gland ratio and WG_US could be found, the homogenously distrib-uted gestational age of the included cases covering a large time range presents as an advantage of our study design.

Clinical impact of relevance

It is evident that the endocrine activity of the fetal adrenal gland makes an important contribution to organogenesis and intrauterine homeostasis [18]. The FZ, as the main component of the cortex and as a producer of estrogen precursors, seems to play a major role [14–17]. Hence the understanding of the influences on the adrenal gland development is of the highest clinical interest. Our data confirm the hypothesis that pregnancies complicated by maternal diabetes have an increased adrenal gland size compared to healthy controls. Various complica-tions related to GDM and enlarged fetal adrenal glands may be explained by this insight. Whether good blood sugar control affects the adrenal gland size and how early in pregnancy a strict blood sugar control must be

implemented to show this effect are interesting questions which necessitate further research. On the other hand, an enlarged adrenal gland may be used as a soft marker to identify fetuses with high risk for hyperglycemia. There is a need for further research as well as the collection of reference values for the measurement of the adrenal gland to become a diagnostic tool.

ConclusionOur study validated an enlarged fetal adrenal gland in pregnancy complicated by maternal hyperglycemia. The increase in size is particularly noticeable in the cortex. Further investigation is needed.

Acknowledgments: We thank everyone who voluntarily dedicated their time and effort.

Author contributions: T. Hetkamp: data collection,  data management, data analysis, manuscript writing; K. Hammer: data collection, manuscript editing; L. Kerschke: data analysis, manuscript editing; M. Möllers: data collection, manuscript editing; H.A. Köster: manuscript editing; M.K. Falkenberg: data collection, manuscript editing; J. Braun: data collection, manuscript editing; K. Oelmeier de Murcia: data collection, manu-script editing; W. Klockenbusch: manuscript editing; R. Schmitz: conceptualization, data collection, manuscript editing. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.Research funding: None declared.Employment or leadership: None declared.Honorarium: None declared.Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

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