Highlighting early detection of thyroid pathology and gestational diabetes effects on oxidative stress that provokes preterm delivery in thyroidology: Does that ring a bell?

Abstract

Objectives:

Ad fontes, the status of the thyroid gland, and metabolic disturbance lead to the alteration of oxygenation. In pregnancy, it is particularly crucial to possess all predictive parameters.

Methods:

This cross-sectional study was conducted at the Clinic of Gynecology and Obstetrics, Clinical Center of Serbia, Belgrade, Serbia, between 2017 and 2021 which study included a total of 99 women who had been admitted for preterm delivery and had undergone thyroid analysis, detected Hashimoto thyroiditis, and Oral Glucose Tolerance Test (OGTT) 40 days after delivery and had pathological Homeostatic Model Assessment for Insulin Response (HOMA IR) indices. In the group of urgent patients with preterm delivery, we looked after not only routine Doppler of the umbilical artery, but we measured specific ratios such as the Cerebroplacental ratio (CP).

Results:

The mean maternal age was 32.23 ± 5.96 years and the mean gestational age was detected as 35.40 ± 2.39 weeks. The delivery was completed vaginally in 77 women (78%) and surgically in 22 (22%). The Mean APGAR score was 8.44 ± 1.18, the mean birth weight was 2666.87 ± 622.17g and the cases undergoing cesarean section had significantly higher values of pulsatility index (1.85 ± 0.27 vs. 1.34 ± 0.31) and CP (1.22 ± 0.26 vs. 0.47 ± 0.17).

Conclusions:

The introduction of Doppler sonography for blood flow assessment helps to form a complete clinical description of the patient, particularly in conditions where oxidative stress became provocative by the thyroid gland antibodies and gestational diabetes in Thyroidology.

Keywords:
Oxidative stress; Thyroid gland; Diabetes; Gestational; Thyroidology; Thyroidologists

HIGHLIGHTS

The status of the thyroid gland and metabolic disturbance leads to the alteration of oxygenation.

The cases undergoing cesarean section had significantly higher values of the pulsatility index.

The cases with cesarean section had significantly higher values of the cerebroplacental ratio.

Introduction

Oxidative stress in pregnancy is provoked by the pathology of the thyroid gland and glucose metabolism. Ordinary Angel-Independent Doppler Indices have been developed for the analysis of blood flow through umbilical blood vessels in order to avoid observation bias. To this end, the most common indices in use have been the Resistance Index (RI), Pulsatility Index (PI), and Cerebroplacental ratio (CP).¹ In most cases, those indices are measured in the Umbilical Artery (UA) and Medial Cerebral Artery (MCA) because they are the most available for measurements and are shown to be highly reproducible.²

The CP is calculated by using the pulsatility index, MCA, and UA. As such, the CP ratio is shown to be a more sensitive indicator of complications and poor pregnancy outcomes, compared to MCA and UA indices individually. In addition, a low CP ratio indicates blood redistribution toward cerebral circulation. Numerous studies all over the world have been purposed to determine reference values of CP for different gestational ages in different populations.³ Moreover, a negative correlation between RI, PI, and UA on one hand and gestational age between 18 and 40 weeks of gestation has been declared. The values of RI, PI, and MCA during pregnancy (18‒40 weeks of gestation) form parabola with a peak around 30 weeks of gestation which means that RI, PI, and MCA values will increase in the period of 18 to 30 gestational weeks, and then decrease until the end of pregnancy. Furthermore, the CP ratio also follows the parabola curve from 18 to 40 gestational weeks with a plateau from week 29 to week 31. It is suggested that these changes in hemodynamics are associated with the need for nutrients in the brain tissue in different gestational phases.¹, ², ³

It was previously hypothesized that the Doppler indices including PI, RI, and CP can be a marker of Gestational Diabetes Mellitus (GDM) and that changes in these indices might be associated with the disease development and progression⁴ which can indicate that the condition of the blood flow during pregnancy can reflect the pathophysiology of GDM. One of the hypotheses for this is that women with GDM, who have higher blood sugar levels, also have higher plasma viscosity, which is followed by higher resistance to the blood flow, lower flow speed, and abnormal blood perfusion, especially during early diastole.⁵ As such, the lower perfusion of the placenta can lead to poor or insufficient nutrient intake for the fetus, can negatively influence fetal development, delayed removal of the metabolites, and higher risk of fetal asphyxia.⁴ Of note, the use of Doppler indices can help establish the hemodynamic parameters, and timely diagnosis of abnormal perfusion and provide opportunities for the predictions of adverse pregnancy outcomes, having in mind that diabetes, including the GDM, is frequently associated with numerous, not only health but different psychological and social consequences.⁶

Combining the data from the Doppler indices with the gestational age, race, and ethnicity of pregnant women can allow clinicians to predict poor pregnancy outcomes.⁷ This article aimed to examine as least some of the parameters that can be associated with the possibility of adverse pregnancy outcomes.

Material and methods

Ethical aspects

The present study was conducted according to the declaration of Helsinki and approved by the Clinical Research and Ethics Committee linked to the School of Medicine University of Belgrade, under the 1322/IX-80 approval number.

Study design

This cross-sectional study was conducted at the Clinic of Gynecology and Obstetrics, Clinical Center of Serbia, Belgrade, Serbia in the period of 2017‒2021. The study incorporated a total of 99 women who were admitted for preterm delivery and who had undergone analysis in Thyroidology. The values of anti-Peroxisomal (antiTPO), and Antithyroglobulin (antiTg) antibodies, were from OGTT 40 days after delivery and had pathological Homeostatic Model Assessment for Insulin Response (HOMA IR) indices. The data was gathered from the patient’s records including the presence of an increased amount of amniotic fluid, accelerated fetal movements, disturbed circulation, Umbilical Cord Coding Index (UCCI), clinical and laboratory condition of the mother, BP (Blood Pressure) and CTG records (coded as normal and pathological). The cases for whom there were missing data were excluded from the study.

Preterm delivery was defined as the delivery before 37 weeks of gestation. HOMA IR is the score that is being used for the assessment of the presence of insulin resistance which utilizes the values of fasting blood glucose and fasting insulin using the formula: HOMA - IR (when glucose is in mmoL/L) = (fasting blood glucose × fasting insulin)/22.5.

Blood pressure was defined as in the pathological ranges above 140/90 mmHg⁸ and all the cases who were primiparas also suffered from hypertension during pregnancy, adequately regulated with small doses of antihypertensive medications. Blood pressure, several thrombocytes, creatinine, and transaminase levels had been recognized as normal in those on therapy. The Doppler indices were calculated using the ultrasound and the data on systolic peak (maximal velocity), which is the maximal velocity during the contraction of the fetal heart, the end-diastolic flow which represents the flow during the relaxation phase of the heartbeat, and mean velocity. The formulas used for calculations were as follows:

$\begin{array}{c}\text{RI}=\left(\text{Systolic velocity}-\text{Diastolic}\frac{\text{velocity}}{\text{Systolic}}\text{velocity}\right);\text{PI}\\ =\left(\text{Systolic velocity}-\text{Diastolic}\frac{\text{velocity}}{\text{mean}}\text{velocity}\right).\end{array}$

The cerebroplacental ratio is calculated as the ratio between the pulsatility index of the MCA and the pulsatility index of the UA, as the use of PI was determined to be the preferred method in recent studies.⁹ The CPR was calculated as follows:

$\text{CPR}=\text{PI}\frac{\text{mca}}{\text{PIua}}.$

Statistical analysis

Statistical analyses, per se, were performed using the methods of descriptive and analytical statistics. The differences between the categorical variables were examined using the χ2 test. In addition, the differences between the numerical variables with normal distribution were examined using the student t-test. Furthermore, the differences between the numerical variables without the normal distribution were examined utilizing the Mann-Whitney U test. In fine, the normality was examined using the Kolmogorov-Smirnov Test. All analyses were done using the Statistical Package for Social Sciences SPSS 22.0.

Results

All the women included in the study were primiparas and the mean maternal age was 32.23 ± 5.96 years and the mean gestational age was 35.40 ± 2.39 weeks. The mean BMI of pregnant women was 28.70 ± 7.35 kg/m² and the delivery had been completed vaginally in 77 women (78%) and surgically in 22 women (22%). The Mean Apgar score was 8.44 ± 1.18, and the mean birth weight was 2666.87 ± 622.17g (Table 1). Poor UCCI, pathological BP, and poor redistribution had been more frequent in patients undergoing cesarean section (63.6% vs. 4.1%, 100% vs. 0%, 49.9% vs. 0%, and 95.5% vs. 1.4%, respectively) compared to patients with vaginal delivery (Table 2). The cases undergoing cesarean section had significantly higher values of PI (1.85 ± 0.27 vs. 1.34 ± 0.31), PI Artery cerebri media (PI Acm) (2.19 ± 0.09 vs. 0.61 ± 0.24), and CPR (1.22 ± 0.26 vs. 0.47 ± 0.17) compared to patients with vaginal delivery (Table 3).

Table 1
Patient characteristics, mode of delivery, and offspring characteristics after delivery.

Characteristics	(X ± SD)
Maternal age	32.23 ± 5.96
Maternal BMI	28.70 ± 7.35
Gestational age	35.40 ± 2.39
Mode of delivery Vaginal	77(78%)
Cesarian section	22 (22%)
Apgar score	8.44 ± 1.18
Birth weight	2666.87 ± 622.17

Table 2
Differences in patients’ clinical characteristics depending on the delivery mode.

Characteristics	Vaginal delivery, n (%)	Cesarean delivery, n (%)	p-value
UCCI
1	70 (95.9)	8 (36.4)
2	3 (4.1)	14 (63.6)	< 0.001
CTG
Without disease	72 (100)	0 (0)
Pathological	0 (0)	22 (100)	< 0.001
BP
Without disease	72 (100)	13 (59.1)
Pathological	0 (0)	9 (49.9)	< 0.001
Redistribution
1	73 (98.6)	1 (4.5)
2	1 (1.4)	21 (95.5)	< 0.001

Table 3
Differences in total pulsatility index, pulsatility index in the middle cerebral artery, and the cerebroplacental ratio between groups.

Characteristics	Vaginal delivery, n (%)	Cesarean delivery, n (%)	p-value
PI (X±SD)	1.34 ± 0.31	1.85 ± 0.27	<0.001
PI MCA (X ± SD)	0.61 ± 0.24	2.19 ± 0.09	<0.001
CPR (X ± SD)	0.47 ± 0.17	1.22 ± 0.26	<0.001

Discussion

Patients who delivered in the period of theoretical preterm deliveries had been analyzed in the present study. No ordinary reason for preterm delivery (excluding anemia, hematological disorders, infection, and progesterone deficiency) has been noticed, but after looking after the primary condition and saving mother and baby, we recognized that the thyroid pathology and gestational diabetes were only pathological elements that have made oxidative stress in uteroplacental and fetoplacental circulation.

The present study revealed the significant differences between pregnant who had a vaginal delivery and pregnant who had delivery by the Caesarean section in frequencies of pathological Cardiotocography (CTGs), high blood pressure, Umbilical Cord Coding Index (UCCI), and presence of blood redistribution. Of note, significant differences in the Doppler examination for en-suite measurements in two groups (RI, PI, and CPR) have been detected indicating the higher possibility of necessity for operative delivery among women who had higher values of Doppler indices and stressing their importance in the preparation of the Obstetricians for this mode of delivery.

Previously, observation of classic parameters of fetal capacity, BP, and CTG did not give a clear prediction of possible complications or explanation of existing circumstances.¹⁰, ¹¹ The introduction of regular following of blood flow impedance in UA and CMA provided evidence that in those pregnancies in which the elements of preterm labor exist, the CPR ratio goes with the redistribution, that is, the fetus provides adequate circulation within the central nervous system for itself, even in the period of early gestation which is a consequence of poor circulation in UA and difficulties in blood supply in a fetal organism.¹² Previous studies have shown that oxidative stress during delivery and in the perinatal period may cause fetal complications, as well. One of those studies aimed to assess the role of oxidative stress in perinatal hypoxic-ischemic brain injury using the activity of Glutathione Peroxidase (GPX) in Cerebrospinal Fluid (CSF) as an indirect biomarker of free radical production in the hypoxic brain and its correlation with the level of Neuron-Specific Enolase (NSE)¹³ which is an enzyme and good biomarker of extended brain injury which happens due to hypoxia and ischemia in fetal brain tissue.¹⁴

A possible interpretation of preterm delivery is the so-called “fetal escape” from the environment where metabolic disorder disturbs further intrauterine fetal existence. This occurs in different endocrinological disorders.¹⁵ The phenomenon of stress - fetal adrenal awakening and trying in order to escape the “space” which is not adequate for further growth and development, could be an explanation for preterm delivery in these situations.¹⁶ The fetus tolerates hypoxemia as a consequence of disturbed metabolism, given the fact that attenuated concentration of blood oxygen represents the consequence of metabolic disturbance. That kind of disturbance leads to fetal adrenal activation, known as the stress phenomenon, activating the early fetal maturation axis.¹⁷ The lower nutrient intake in the fetuses of pregnant women with the pathological values of Doppler indices may be associated with a higher likelihood of preterm delivery.¹⁸ As the prevalence of the various risk factors for GDM, among which is polycystic ovarian syndrome, is rising world-wide¹⁹, there is necessary to anticipate the possible complications among these patients. The authors have not noticed any other morbidity risk as family malignant potential²⁰, ²¹, ²² or rather a frequent pathology in women as endometriosis.²³, ²⁴, ²⁵

Delivery is a stress phenomenon itself, and, repeated hypoxic events in the fetus. A fetus without a compensatory capacity for adequate vaginal delivery had been delivered surgically. Those fetuses who had been delivered surgically had adequate APGAR scores, although their circulation at the admission to the hospital was beyond the level of compensatory effect and entered at the beginning of decompensation.

Conclusion

The importance of early detection of the status of the thyroid gland in Thyroidology and metabolic disturbance changes the oxygenation. Introduction of Doppler sonography for blood flow assessment in UA and MCA, as well as CP index, along with UCCI is part which helps to form a complete clinical description of the patient, along with BP and CTG, especially in conditions like glucose metabolism disorder not detected in a timely manner that is the way to decrease the morbidity and mortality of neonates, get better APGAR scores, and attenuate the number of surgical deliveries. The authors postulate that the so-called analysis of thyroid-stimulating hormone, free fractions of thyroid hormones, and antibodies, in Thyroidology, as well as oral glucose tests, should be performed in all pregnancies, even physiological status. Bene diagnoscitur, bene curatur.

Acknowledgments

The authors thank all of the article participants.

Dataavailability

The clinical data used to support the findings of this study are available from the corresponding author upon request.

• Funding statement
  None declared.

References

• ¹
  Pérez-Martín SM, Quintero-Prado R. Fetal cerebral three-dimensional power Doppler vascularization indices and their relationships with maternal glucose levels in pregnancies complicated with gestational diabetes. Diab Vasc Dis Res 2022; 19(1):14791641221078109.
• ²
  Oros D, Ruiz-Martinez S. Reference ranges for Doppler indices of umbilical and fetal middle cerebral arteries and cerebroplacental ratio: systematic review. Ultrasound Obstet Gynecol 2019;53(4):454–64.
• ³
  Vollgraff Heidweiller-Schreurs CA, De Boer MA. Prognostic accuracy of cerebroplacental ratio and middle cerebral artery Doppler for adverse perinatal outcome: systematic review and meta-analysis. Ultrasound Obstet Gynecol 2018;51(3):313–22.
• ⁴
  Wei Z, Mu M, Li M, Li J, Cui Y. Color Doppler ultrasound detection of hemodynamic changes in pregnant women with GDM and analysis of their influence on pregnancy outcomes. Am J Transl Res 2021;13(4):3330–6.
• ⁵
  Chen H, Huang X, Kong X, Liang C, Qiu C. Correlation study of color Doppler Examination of deep veins of both lower extremities combined with fibrinolysis system in hypertension during pregnancy. Open J Obstet Gynecol 2020;10:981–9.
• ⁶
  Grujic-Vujmilovic D, Gavric Z. Quality of life of patients with diabetes mellitus - social domain of health. Sanamed 2014;9(2):151–9.
• ⁷
  Monteith C, Flood K, Mullers S, Unterscheider J, Breathnachet F, Daly S, et al. Evaluation of normalization of cerebro-placental ratio as a potential predictor for adverse outcome in SGA fetuses. Am J Obstet Gynecol 2017;216(3):285.e1–e6.
• ⁸
  Garovic VD, Dechend R, Easterling T, Karumanchi SA, McMurtry Baird S, Magee LA, et al. Hypertension in pregnancy: diagnosis, blood pressure goals, and pharmacotherapy: a scientific statement from the American heart association. Hypertension 2022;79(2):e21–41.
• ⁹
  Moreta D, Benzie R. Cerebro-placental ratio - Is it time to start putting it to use? Australas J Ultrasound Med 2017;20(4):139–40.
• ¹⁰
  Mayrink J, Souza RT, Feitosa FE, Rocha Filho EA, Leite DF, Vettorazzi J, et al. Mean arterial blood pressure: potential predictive tool for preeclampsia in a cohort of healthy nulliparous pregnant women. BMC Pregnancy Childbirth 2019;19(1):460.
• ¹¹
  Grivell RM, Alfirevic Z, Gyte GM, Devane D. Antenatal cardiotocography for fetal assessment. Cochrane Database Syst Rev 2015;2015(9):CD007863.
• ¹²
  Oros D, Ruiz-Martinez S, Staines-Urias E, Conde-Agudelo A, Villar J, Fabre E, et al. Reference ranges for Doppler indices of umbilical and fetal middle cerebral arteries and cerebroplacental ratio: systematic review. Ultrasound Obstet Gynecol 2019;53(4):454–64.
• ¹³
  Vasiljević B. Maglajlić-Djukić S. The Role of Oxidative Stress in Perinatal HypoxicIschemic Brain Injury. Srp Arh Celok Lek 2012;140(1-2):35–41.
• ¹⁴
  Abbasoglu A, Sarialioglu F, Yazici N, Bayraktar N, Haberal A, Erbay A. Serum neuron-specific enolase levels in preterm and term newborns and in infants 1–3 months of age. Pediatr Neonatol 2015;56(2):114–9.
• ¹⁵
  Sengul D, Sengul I, Soares JM. Repercussion of thyroid dysfunctions in thyroidology on the reproductive system: conditio sine qua non? Rev Assoc Med Bras (1992) 2022;68(6):721–2.
• ¹⁶
  Sandman CA. Mysteries of the human fetus revealed. Monogr Soc Res Child Dev 2015;80(3):124–37.
• ¹⁷
  Ishimoto H, Jaffe RB. Development and function of the human fetal adrenal cortex: a key component in the feto-placental unit. Endocr Rev 2011;32(3):317–55.
• ¹⁸
  Misra VK, Hobel CJ, Sing CF. Placental blood flow and the risk of preterm delivery. Placenta 2009;30(7):619–24.
• ¹⁹
  Karatas S, Hacʅoğlu B, Kalaycʅ G. Phenotypes of polycystic ovary syndrome and accompanying hormonal disturbances. Sanamed 2022;17(3):145–9.
• ²⁰
  Gutic B, Bozanovic T, Mandic A, Dugalic S, Todorovic J, Stanisavljevic D, et al. Programmed cell death-1 and its ligands: current knowledge and possibilities in immunotherapy. Clinics (Sao Paulo) 2023;78:100177.
• ²¹
  Sengul D, Altinay S, Oksuz H, Demirtürk H, Korkmazer E. Population-based cervical screening outcomes in Turkey over a period of approximately nine and a half years with emphasis on results for women aged 30-34. Asian Pac J Cancer Prev 2014;15(5):2069–74.
• ²²
  Perniconi SE, J Simões Mde, S Simões Rdos, Haidar MA, Baracat EC, Jr Soares JM. Proliferation of the superficial epithelium of ovaries in senile female rats following oral administration of conjugated equine estrogens. Clinics (Sao Paulo) 2008;63(3):381–8.
• ²³
  Sengul D, Sengul I, Soares Júnior JM. Caesarean section scar endometriosis: quo vadis? Rev Assoc Med Bras (1992) 2022;68(1):1–2.
• ²⁴
  Sengul I, Sengul D, Soares Júnior JM. Interpretations on a rare localization of endometriosis: labium minus. Rev Assoc Med Bras (1992) 2021;67(1):1–2.
• ²⁵
  Sengul I, Sengul D, Kahyaoğlu S, Kahyaoğlu I. Incisional endometriosis: a report of 3 cases. Can J Surg 2009;52(5):444–5.

Publication Dates

• Publication in this collection
  13 Nov 2023
• Date of issue
  2023

History

• Received
  29 Apr 2023
• Reviewed
  05 Aug 2023
• Accepted
  08 Aug 2023