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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 12  |  Issue : 5  |  Page : 205-210

Evaluation of maternal cortisol-to-highly sensitive C-reactive protein ratio and glucocorticoid receptor resistance at 11–14 weeks of pregnancy to predict pre-eclampsia


Department of Physiology, Smt. BK Shah Medical Institute and Research Centre, Sumandeep Vidyapeeth Deemed to be University, Vadodara, Gujarat, India

Date of Submission30-May-2022
Date of Decision16-Aug-2022
Date of Acceptance25-Aug-2022
Date of Web Publication31-Oct-2022

Correspondence Address:
K Jhansi
PhD Scholar, Department of Physiology, Smt. BK Shah Medical Institute and Research Centre, Sumandeep Vidyapeeth Deemed to be University, Vadodara, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cmrp.cmrp_46_22

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  Abstract 


Background: Preeclampsia (PE) is a disorder of pregnancy with a worldwide prevalence of about 5-8% and 4.6% in India. It is the second leading cause of direct maternal and foetal adverse outcomes, resulting in about 50,000-60,000 deaths annually worldwide. Cortisol is a stress hormone, that suppresses the immune system and inhibits the production of pro-inflammatory substances to reduce inflammation. During pregnancy cortisol levels raise to three-fold of nonpregnant level by the third trimester, it is due to changes in HPA axis regulation, raised oestrogen levels and raised maternal CRH levels through placental secretion.
Aims: The objective of this study is to evaluate the cortisol (CORT)-to-highly sensitive C-reactive protein (HS-CRP) ratio and glucocorticoid receptor resistance (GCR) in early pregnancy to understand the pathophysiology of pre-eclampsia (PE) and to test whether these parameters have a role in the prediction of PE. CO + RT: HS-CRP ratio evaluates the interrelationship between the hypothalamic–pituitary–adrenal axis (HPA-axis) and the inflammatory response system. It is a new concept and an integrated approach to understand the pathophysiology of PE.
Materials and Methods: In this prospective case–control study, we recruited 250 healthy pregnant women at 11–14 weeks of pregnancy and followed them. Those who developed PE after the 20th week according to the American College of Obstetricians and Gynecologists guidelines were considered study participants and the remaining served as controls. CORT was estimated through the ELISA method and HS-CRP was measured by autoanalyser through the turbidimetric method. The CORT-to-HS-CRP ratio was calculated manually. GCR was measured indirectly through leucocytes subsets, neutrophil-to-lymphocyte ratio (NLR) and neutrophil-to-monocyte ratio (NMR); individual leucocytes were obtained from complete blood counts. Data were analysed using the SPSS version 20, Pearson's correlation test was used to correlate the results and receiver operator characteristic (ROC) was used to test the predictive capacity of parameters.
Results: Low CORT: HS-CRP was associated with PE, having a significance of P < 0.00, but it did not show any specificity and sensitivity under ROC. NLR and NMR were elevated in cases who developed PE, especially NMR with P < 0.008. NMR showed good specificity and sensitivity under ROC with the area under curve 0.74, cutoff value is 23.
Conclusion: Low CORT: HS-CRP ratio has an association with PE, the uncontrolled inflammation during early pregnancy in pregnant women who were destined to develop PE. This is due to low-CORT secretion due to dysregulation of the HPA-axis. GCR also has an association with PE, but it was not fully clarified. HS-CRP and NMR can be used to screen in early pregnancy for the prediction of PE.

Keywords: Glucocorticoid receptor resistance, hypothalamic–pituitary–adrenal axis, inflammation, pre-eclampsia


How to cite this article:
Jhansi K, Harsoda J M. Evaluation of maternal cortisol-to-highly sensitive C-reactive protein ratio and glucocorticoid receptor resistance at 11–14 weeks of pregnancy to predict pre-eclampsia. Curr Med Res Pract 2022;12:205-10

How to cite this URL:
Jhansi K, Harsoda J M. Evaluation of maternal cortisol-to-highly sensitive C-reactive protein ratio and glucocorticoid receptor resistance at 11–14 weeks of pregnancy to predict pre-eclampsia. Curr Med Res Pract [serial online] 2022 [cited 2022 Nov 27];12:205-10. Available from: http://www.cmrpjournal.org/text.asp?2022/12/5/205/359940




  Introduction Top


Pre-eclampsia (PE) is a disorder of pregnancy with a worldwide prevalence of about 5%–8% and 4.6% in India.[1] It is the second-leading cause of direct maternal and foetal adverse outcomes, resulting in about 50,000–60,000 deaths annually worldwide.[2] Recent advances in the research to understand the pathophysiology of PE concluded that oxidative stress in the placenta due to poor implantation is the major cause.[3],[4] The underperfused uteroplacental unit faces ischaemia reperfusion or hypoxia-reoxygenation type of injury, leading to oxidative stress.[5],[6] Oxidative stress triggers inflammation, both are interlinked and intensify each other.[7] The activated immune system produces the inflammation-associated cytokines which include interleukin-6 (IL-6), IL-1 β, tumour necrosis factor-α (TNF-α), interferon-γ and inflammatory growth factor-β.[8] It is a well-known fact that the inflammatory system and hypothalamic–pituitary–adrenal axis (HPA-axis) are intertwined in a reciprocal manner to maintain homeostasis in the body to prevent diseases.[9],[10] During pregnancy, cortisol (CORT) levels rise to three-fold of non-pregnant level by the third trimester, which is due to changes in HPA-axis regulation, raised oestrogen levels and raised maternal corticotropin-releasing hormone levels through placental secretion.[11],[12] Raised CORT levels coupled with various biochemical changes during pregnancy also play a major role in foetal development.[13],[14] In PE patients, the CORT levels are significantly decreased, it also has a strong negative association with the severity of PE.[15] Salvador-Moysén et al.'s study show that increased CORT levels before 20 weeks of gestation can be used for the prediction of PE,[16] which is contrary to the study conducted by Sikkema et al.[17] Salvador et al. concluded that the CORT levels and the anxiety in the first trimester showed no positive association with PE.[16]

Oancea et al.[18] and Devi et al.[19] have used inflammatory markers such as IL-6 and C-reactive protein (CRP). Kaur et al. used serum uric acid and CRP and[20] Narang et al.[21] used uterine artery Doppler and pregnancy-associated plasma protein-A in predicting PE. Stepan et al.[22] used the ratio of sFlt-1 and PLGF, Freitas et al.[23] and Nooh et al.[24] used the platelet indices, Kirbas et al.[25] used the white blood cell subtype ratios and PAPP-A, Sikkema et al.[17] and Salvador-Moysén et al.[16] used the salivary CORT and Jayasuriya et al.[26] used the ratio of CORT to cortisone for the prediction of PE.

Suarez et al. introduced the CORT/CRP ratio to evaluate the status of the feedback loop between the HPA-axis and the inflammatory system in people with the major depressive disorder;[27] he also found a negative relationship between stress and CORT/CRP ratio in chronically stressed individuals.[28] Demir et al. and Narváez et al. studied the CORT/CRP ratio in polymyalgia rheumatic; their studies showed a low CORT/CRP ratio in patients relative to controls, which indicates the hyporesponsivity of HPA-axis even though CRP levels were high.[29],[30]

The aim of the present study from the above evidence is to evaluate the interrelationship between the HPA-axis and immune system through CORT: CRP and glucocorticoid receptor (GR) sensitivity by the neutrophil-to-lymphocyte ratio (NLR), neutrophil-to-monocyte ratio (NMR) and also to understand the pathophysiology and their role in the prediction of PE. This is the first study giving an attempt on integrative approach to the understanding of PE pathology and its prediction.


  Materials and Methods Top


Study design

This was a prospective cohort study, conducted among 250 healthy pregnant women aged between 18 and 35 years, who attended the outpatient department of obstetrics and gynaecology, after obtaining ethical clearance. Written consent was taken from all the participants. This study was conducted from March 2021 to December 2021. All the data and blood samples were collected from participants who came for an antenatal checkup at 11–14 weeks of gestation according to ultrasound scanning. Participants were followed after the 20th week of gestation. Those who developed PE according to the American College of Obstetricians and Gynecologists guidelines, new-onset hypertension with systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg, proteinuria of >0.3 g/24 h or ≥1+ proteinuria, detected by urine dipstick test, in the absence of proteinuria, new-onset hypertension with thrombocytopenia, renal insufficiency, impaired liver function, pulmonary oedema or cerebral or visual problems were taken as study subject cases and remaining were labelled as controls. A total of 12 women developed PE (n = 12) out of the remaining 238, 1 had an abortion hence 237 served as controls.

Inclusion criteria

Healthy pregnant women at 11–14 weeks of gestation were included in the study.

Exclusion criteria

The women with pre-existing medical disorders such as diabetes before pregnancy, chronic hypertension, cardiovascular diseases, chronic renal diseases, gastroenterology diseases, thyroid, epilepsy, mental disorders, known foetal anomalies, polyhydramnios, oligohydramnios, placenta previa, abruption placenta, abortion, stillbirth, smokers and alcohol consumers were excluded from the study.

Sampling and analysis

Anthropometric measurements such as height in centimetres, weight in killograms and body mass index (BMI) were recorded.

Blood pressure was measured through a sphygmomanometer and 7 ml of non-fasting, diurnal random venous blood sample was collected.

Assessment of cortisol: Highly sensitive C-reactive protein ratio

Through the CORT-to-CRP ratio, the integration between HPA-axis and the immune system was assessed according to Suarez et al.[27] Five millilitres of blood was collected in clot-activating vials. After centrifugation, fresh serum was collected and used for CRP estimation immediately; the remaining was stored at −10°C untill sample collection was over for about 2 months to estimate the CORT.

Cortisol analysis

CORT was estimated by the ELISA method, using Erba LisaScan with the CORT ELISA kit (Diagnostic Biochem Canada Inc.). The reference range of cortisol is between 3.95–27.23 μg/dl with a mean value of 15.59 μg/dl.

Highly sensitive C-reactive protein estimation

Highly sensitive CRP (HS-CRP) was estimated through an autoanalyser using the latex turbid metric method, with normal values up to 5 mg/L.

The CORT-to-HS-CRP ratio was calculated manually.

Glucocorticoid receptor sensitivity

GR sensitivity is indirectly assessed through NLR and NMR according to Steve W Cole's study.[31]

About 2 ml of blood was collected in Ethylenediaminetetraacetic acid (EDTA) vials for complete blood count and analysed through Auto Haematology Analyser, ratios were calculated manually.

Statistical analysis

The data were analysed using the SPSS version 20 (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp), using the Pearson's correlation test to compare the results of controls and study participants; statistical significance was considered at P<0.05. The receiver operator characteristic (ROC) curve was used to test the sensitivity and specificity of parameters.


  Results Top


Study participants had significantly higher BMI as compared to controls.

Maternal age, gestational age and systolic and diastolic blood pressure at the time of recruitment were similar in both groups.

Serum CORT levels were lower in study participants as compared to controls but were not statistically significant [Table 1].
Table 1: Demographic and clinical characteristics of the pregnant women in cases and control groups (P≤0.05)

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Significant elevation of HS-CRP levels was seen in study participants (P < 0.02), whereas CORT: CRP values were lower as compared to controls (7 ± 3.4), (P < 0.00).

The study participants had increased neutrophils and decreased monocytes as compared to the control group, but there is no statistically significant difference. The rise in lymphocytes among the cases has been statistically significant (P < 0.02). NLR was increased in cases (26.3 ± 0.1) than in controls (16.6 ± 4.7), but there is no statistical significance. NMR was significantly elevated (P < 0.008) in cases (3.5 ± 1.5) than in controls (3 ± 0.9).

Pearson's correlation was done to know the interrelationship between the variables [Table 2]. Age and gestational age had no correlation with another variable. BMI had a weak negative correlation with CORT, CORT: CRP, monocytes and NLR. CORT showed a highly significant negative association with HS-CRP (P < 0.00); CORT also had a strong positive association with CORT: CRP (P < 0.00) but it had a negative association with neutrophils. CORT did not show any association with individual lymphocytes and monocytes but NLR (P < 0.03) and NMR (0.04) had a significant negative correlation [Table 3].
Table 2: Pearson's correlation among variables

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Table 3: Laboratory parameters of the pregnant women in cases and control groups (P≤0.05)

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CRP had a strong negative association with the CORT: CRP (P < 0.00), coming to individual leucocytes, CRP had no association with neutrophils, lymphocytes and monocytes (P < 0.01) but depicted a negative correlation. NLR (P < 0.04) and NMR (P < 0.00) have a strong correlation with the CRP.

Receiver operator curve analysis was performed and values are in [Table 4]; even though CORT and HS-CRP have a strong negative association, their ratio failed to predict the PE; it did not show any specificity and sensitivity under ROC. Alone HS-CRP showed sensitivity and specificity; the area under the curve is 1.0 and the cutoff value is 6.3. NMR showed good specificity and sensitivity with the area under the curve is 0.74 and the cutoff value being 23 [Figure 1].
Figure 1: ROC graph, ROC: Receiver operator characteristic

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Table 4: Receiver operator curve analysis

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  Discussion Top


The Cortisol: Highly sensitive C-reactive protein ratio

In normal healthy pregnancy, CORT levels start to increase in the first trimester, reach its peak in the second trimester and then decline in the third trimester,[13] due to activation of the maternal HPA-axis by various maternal and placental factors. Glucocorticoids play a key role in pregnancy, they promote the establishment of gestation, inhibit the immune rejection responses during implantation and also help in the induction of decidualisation in early pregnancy.[31],[32],[33],[34]

The present study also means CORT levels were higher in controls that are healthy pregnant women at 11–14 weeks of gestation but in cases that develop PE, their CORT levels were not raised. It reflects that CORT levels were lower in study participants than in controls; similar findings were observed in Sikkema et al., in their study.[17] This is in contrary to Jaime Salvador-Moysén et al.'s study. In the pathophysiology of PE, pro-inflammatory cytokines such as TNF-α, INF-γ and IL-6 are markedly elevated, especially IL-6 has a positive association with HS-CRP in the first trimester. Oancea et al., in their study, observed similar findings.[16]

Lower CORT: CRP mean value was observed in the study participant. It indicates less release of CORT despite raising inflammation. Cytokines activate the HPA-axis to suppress the exaggerated immune system through CORT,[35],[36],[37] by reducing the expression of pro-inflammatory cytokines such as TNF-α and IL-6 and enhancing the expression of anti-inflammatory cytokines.[10] Women with chronic stress have insufficient CORT releases relative to greater inflammation was observed due to the loss of normal HPA-axis activity.[27] Nijm et al. have stated that the disinhibited inflammatory activity in coronary artery disease patients is due to altered HPA-axis activity.[38] Hence, in the present study, lower CORT: CRP levels indicate oxidative stress, leading to inflammation in PE due to dysregulation of the HPA-axis.

Glucocorticoid receptor resistance

Glucocorticoid receptor resistance (GCR) refers to a decrease in the sensitivity of immune cells to CORT that normally inhibit inflammation. CORT is a stress hormone, which has immune suppressive and anti-inflammatory properties.[10] The raised CORT levels have a positive relationship with circulating neutrophil percentages and a negative relationship with percentages of circulating lymphocytes and monocytes; the NLR and NMR also have a positive correlation with CORT in normal healthy conditions.[31] Under chronic stress, CORT has no association with leucocyte subsets and also with NLR and NMR due to GCR.[31],[32],[33]

In healthy pregnancies, total leucocyte count was elevated, neutrophils contribute the major proportion (55%) and then monocytes (38%) and lymphocytes were reduced by 36%.[39] In the present study, neutrophils and NLR were elevated in cases without any statistical significance; similar findings were observed in Phaloprakaram et al.'s study,[40] which indicates CORT has lost its down-regulatory mechanisms over neutrophils. Individual lymphocytes and monocytes did not show any correlation with the CORT, which implies that there is an existence of GCR in lymphocytes and monocytes. Similar findings were observed in Clarke et al.'s study,[33] they concluded GCR existed in the first trimester of PE. Both NLR and NMR were increased in groups. Even though individual lymphocytes and monocytes had no association with the CORT, the ratios showed a significant negative correlation with the CORT, which indicates low levels of CORT maybe not enough to produce desirable changes in the immune system. From the NLR and NMR, we cannot conclude that there is an existence of GCR, but we can use them as inflammatory markers because they had a significant positive correlation with HS-CRP, especially with NMR showing a strong positive association. Vildirim et al. concluded the NMR can be used for screening to know the severity of infection and mortality in COVID-19 patients.[34]

Limitations

The major limitation of the study is that the diurnal variations were not followed and there are few residual confounding factors. Needed further large-scale studies by following diurnal variations and molecular studies are also needed to assess the GCR, especially to understand the pathophysiology of PE in early pregnancy.


  Conclusion Top


The outcome of the study is the HPA axis was dysregulated and there is GCR in pregnant women who are destined to develop PE. CORT: HS-CRP ratio is not a good biomarker to predict PE. NMR and HS-CRP can serve as inflammatory markers to screen PE in early pregnancy before it was developed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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