Manuscript accepted on :30-Sep-2020
Published online on: --
Plagiarism Check: Yes
Views:
PDF Downloads:
Hala A.Youssef1, Ayman F. Armaneous2, Hatem M. Hasan3, Eman R. Youness4* and Marwa W. Abouelnaga2
1Departments of Neonatology, El-Galaa Teaching Hospital.
2Departments of Neonatology Child Health.
3Departments of Neonatology Reproductive Health.
4Departments of Neonatology Medical Biochemistry, National Research Center, Egypt.
Corresponding author E-mail: hoctober2000@yahoo.com
DOI : https://dx.doi.org/10.13005/bpj/1989
Abstract
Endothelin -1 appears to be the predominant member of the family (endothelins ET-1, ET-2 and ET-3), which is exclusively produced by vascular endothelial cells and has the most potent vasoconstrictor activity of all naturally occurring press or substances. Our objective is to evaluate whether Endothelin -1 has a role in altered umbilical arterial blood flow velocity in pregnant mothers with IDDM and its relation to neonatal outcome. 60 pregnant women were recruited for this study and were divided into two groups: 30 IDDM pregnant women with abnormal umbilical Doppler flow velocity waveforms and 30 IDDM pregnant women with normal umbilical artery flow velocity waveform studies. Levels of glycosylated hemoglobin and plasma concentration of ET-1 were determined. Neonatal assessment using the 5 minutes Apgar score and birth weight were estimated; also, plasma level of ET-1 was done for all neonates. A highly significant statistical difference of ET-1 levels between newborns of diabetics with abnormal flow velocity Doppler waveforms and newborns of diabetics with normal Doppler waveforms (P<0.001). In addition, there was a highly significant statistical difference of Apgar score and birth weights between newborns of diabetics with abnormal flow velocity Doppler waveform and newborns of diabetics with normal Doppler waveform. We can conclude that although IDDM pregnant women have markedly elevated ET-1 levels, it is not responsible for the vascular changes associated with abnormal umbilical Doppler studies. Higher neonatal ET-1 levels were associated with low Apgar score in newborns of mothers with abnormal umbilical Doppler studies, suggesting that ET-1 could be a marker of perinatal asphyxia.
Keywords
Endothelin-1; Umbilical Doppler waveform; IDDM pregnant women
Download this article as:
| Copy the following to cite this article: Youssef H. A, Armaneous A. F, Hasan H. M, Youness E. R, Abouelnaga M. W. Relation of Endothelin-1 to Abnormal Umbilical Doppler Waveform Studies in Pregnancies Complicated by IDDM and its Relation to the Neonatal Outcome. Biomed Pharmacol J 2020;13(3). |
| Copy the following to cite this URL: Youssef H. A, Armaneous A. F, Hasan H. M, Youness E. R, Abouelnaga M. W. Relation of Endothelin-1 to Abnormal Umbilical Doppler Waveform Studies in Pregnancies Complicated by IDDM and its Relation to the Neonatal Outcome. Biomed Pharmacol J 2020;13(3). Available from: https://bit.ly/379XNwi |
Introduction
Endothelin-1 (ET-1) seems to act as a local paracrine signal rather than a circulating hormone. Its effects are mediated by specific, membrane- bound receptors, which are detectable in high concentrations in the fetoplacental tissue. ET-1 causes an initial transient fall in blood pressure, followed by a strong, long-lasting increase in peripheral resistance and blood pressure1. This complex opposing vascular effects mediated through vascular smooth muscle and a number of receptor sub-types for endothelines namely ET-A, ET-B1 and ET-B2. ET-A and ETB2 are known to be selective for ET-1 and may be responsible for the direct vasoconstrictor activity. The ET-B1 receptors are believed to mediate vasodilator activity through release of endothelium derived mediators (PGI2, PGE2 and EDRF)2.
The low placental vascular resistance is essential for efficient placental function; there by enabling it to meet the growing needs of the fetus right up until the end of pregnancy. Activation of vascular smooth muscle through generation of endogenous endothelin-1 appears to contribute to maintenance of blood pressure; basal vascular tone and regional blood flow3.
Reduced output of nitric acid and prostacyclin with increased production of endothelin-1 and thromboxane A2 are associated with placental insufficiency and fetal growth retardation .These changes promote platelet aggregation and intravascular coagulation, vasoconstriction, increased vascular sensitivity to vasoconstrictor stimuli, retarding blood flow and feto-placental growth. It was suggested that uteroplacental vascular bed, might be one of the sources for increased ET-1 production in women with pre-eclampsia4,5.
Doppler velocimetry can supply important information about the uterine and umbilical circulation. Vascular impedance can be detected using umbilical artery Doppler flow-velocity waveform analysis. High S/D ratio more than 3, absent and reversed end diastolic flow are indices of vascular impedance6. Emily (2015)7 showed that ET-1, and nor adrenalin related mechanisms could be involved in the abnormal umbilical artery velocity waveforms associated with pre-eclampsia.
Altered vascular responses to endogenous peptides such as endothelin-1 may be in part a cause of vascular dysfunction associated with diabetes. The decreased maternal peripheral resistance in pregnancy may be also a result of these alterations. Increased insulin resistance can activate the sympathetic nervous system and lead to an increased in expression of receptors for endothelin, both of which events lead to increased vasoconstriction8,9.
Endothelin-1 is involved in the circulatory adaptation and in the transition from fetal to extra uterine life10. Elevated plasma levels of ET-1 during the neonatal period have been reported in different neonatal diseases11.
Our objective is to study the maternal and neonatal plasma concentration of endothelin- 1 in relation to abnormal umbilical artery Doppler flow-velocity waveforms in pregnancies complicated with IDDM and its relation to the neonatal outcome.
Patients and Methods
The study was carried out at Antenatal Care Clinic, National Research Center and El-Galaa Teaching Hospital. After taking consent, 60 singleton term normotensive IDDM pregnant women were chosen to join this study according to Doppler waveform study results. All women were subjected to history taking, medical and obstetrical examinations and routine investigations were done. In addition, they were subjected to ultrasonic assessment of fetal biometry, biophysical profile, placental site and grading together with Doppler studies of the umbilical artery. All women were delivered by cesarean section. Women recruited for this study, were divided into two groups: Group 1 (study group): 30 IDDM pregnant women with abnormal umbilical artery waveforms. Flow in the umbilical artery waveforms are considered abnormal if S/D ratio >3, absent or reversed end diastolic flow. Group II (control group): 30 IDDM pregnant women with normal umbilical artery flow velocity waveform studies. All pregnant women were submitted to laboratory investigations including: Fasting and 2 hours postprandial blood glucose by enzymatic methods using kits from Biomerieux (69280 Marcy-L, Etoile, France). Determination of glycosylated hemoglobin by ion exchange chromatography using kits from Stanbio Lab, Inc. (2930 East Houston st., San Antonio, Texas). Plasma concentration of ET-1 were measured in maternal venous blood before induction of anaesthia and neonatal umbilical cord blood in the two groups using a Sandwich Enzymatic Immunoassay technique from American Diagnostic Inc. (P.O. Box 1165, Greenwich, CT 06836-1165) . The kit uses monoclonal antibodies directed against endothelin-1. The detection limit was 0.1 Pg/mL. Neonatal assessment using the 5 minutes Apgar score and birth weight were estimated.
Statistical Methods
The collected data were coded, presented as mean ± SD. Statistical analysis using students t-test and Pearson Correlation Coefficient. Results were considered statistically significant if P value < 0.05.
Results
Characteristics of mothers in both groups were represented in Table 1. No differences were found related to maternal age, gestational age or diabetic control using glycosylated hemoglobin.
Table 1: Characteristics of Mothers of Both Groups.
| Group I (N =30) |
Group II (N=30) |
P-value | |
| Maternal age (years) | 23.1 ± 2.51 | 21.6 ± 2.85 | 0.104 NS |
| Gestational age (weeks) | 37.55 ±0.94 | 37.9 ± 1.7 | 0.26 NS |
| Glycosylated HB (%) | 7.14 ± 0.81 | 6.83 ± 0.94 | 0.04 NS |
Table 2 shows that the ET-1 levels in group I was ranging from 12.8 to 16.4 Pg/mL with a mean ± SD 14.24 ± 1.18 and in group II ranging from 12.0 to 16.21 Pg/mL with a mean ± SD 14.02 ± 1.3. This shows that there is no significant statistical difference of ET-1 levels between diabetics with abnormal flow velocity Doppler waveform and those with normal Doppler waveform.
Table 2: Comparison of Maternal Endothelin-1 levels In Both groups.
| Group I (N =30) | Group II (N =30) | P-value | |
| ET-1 Mean (Pg/mL) | 14.24 | 14.02 | 0.37 NS |
| SD | 1.18 | 1.30 |
Table 3 shows that the ET-1 levels in newborns of group I was ranging from 25 to 31.9 Pg/mL with a mean ± SD 28.7 ± 1.77 and in newborns of group II ranging from 25.6 to 29.4 Pg/mL with a mean ± SD 27.44 ± 1.01. This shows a highly significant statistical difference of ET-1 levels between newborns of diabetics with abnormal flow velocity Doppler waveform and newborns of diabetics with normal Doppler waveform (P<0.001).
Table 3: Comparison of Neonatal Endothelin-1 levels In Both groups.
| Group I (N =30) | Group II (N =30) | P-value | |
| ET-1 Mean (Pg/mL) | 28.7 | 27.44 | 0.001 HS |
| SD | 1.77 | 1.01 |
Neonatal 5 minutes Apgar score and birth weight were compared in Table 4. The 5 minutes Apgar score of newborns of group I was ranging from 5 to 9 with a mean ± SD 7.03 ± 1.09, which was lower than that of newborns of group II that was ranging from 7 to 9 with a mean ± SD 8.03 ± 0.76. This shows that there is a highly significant statistical difference of Apgar score between newborns of diabetics with abnormal flow velocity Doppler waveform and newborns of diabetics with normal Doppler waveform.
Table 4: Comparison of Neonatal Outcome in Both Groups.
| Group I (N=30) | Group II (N=30) | P-value | |
| Apgar Score Mean | 7.03 | 8.03 | 0.001 HS |
| SD | 1.09 | 0.76 | |
| Birth weight Mean (gm) | 3460 | 3830 | |
| SD | 289.29 | 211.96 |
The birth weight of newborns of group I was ranging from 3100 to 4100 gm with a mean ± SD 3400 ± 289 which was lower in comparison to the birth weight of group II which ranged from 3350 to 4200 gm with a mean ± SD 3830 ± 211. So a highly significant statistical difference of birth weights between newborns of diabetics with abnormal flow velocity Doppler waveform and newborns of diabetics with normal Doppler waveform.
Table 5 shows the ET-1 levels in neonates of group I in relation to the Apgar score. The ET-1 levels in newborns delivered with Apgar score <7 was ranging from 27.5 to 31.9 Pg/mL with a mean ± SD 30.47 ± 1.63 which was higher than ET-1 levels of newborns delivered with Apgar score >7 which ranged from 25 to 31 Pg/mL with a mean ± SD 28.16 ± 1.45. So in IDDM with abnormal flow velocity Doppler waveform, it was found that a highly significant statistical difference of ET-1 level between newborns with Apgar score <7 and newborns with Apgar score >7.
In-group I there were significant negative correlations between neonatal ET-1 level and both 5 min Apgar score (r= -0.39, P= 0.03) and birth weight (r = -0.40, P = 0.02). Meanwhile, no correlation could be detected between maternal ET-1 level and either neonatal ET-1, Apgar score, or birth weight in group I and in group II.
Table 5: Comparison of ET-1 level in Relation to Apgar score in Neonates of group I
| Newborns with Apgar score < 7 (Group I) N=7 |
Newborns with Apgar score > 7 (Group I) N=23 |
P-value | |
| ET-1 Mean (Pg/mL) | 30.47 | 28.16 | 0.001 HS |
| SD | 1.63 | 1.45 |
Discussion
It is well established that women with diabetes had significantly higher levels of plasma ET-1 through pregnancy when compared to normal nondiabetic pregnant women12. Pregnant women with IDDM are known to be at a higher risk of developing uteroplacental vascular changes associated with placental insufficiency13. Diabetes is associated with vascular dysfunction, which may be due to altered vascular responses to endogenous peptides such as ET-1.
This study showed that there was no significant statistical difference of ET-1 levels between diabetics with abnormal flow-velocity Doppler waveform and those with normal Doppler waveform. This shows that ET-1 is not responsible for the placental vascular changes associated with diabetes. This may be explained by the abnormal vascular reactivity associated with diabetes in the form of reduced sensitivity to ET-1. This was also found by Elzbiet et al.14 whereas sensitivity of myometrial blood vessel to endothelin- 1 was reduced in the diabetic compared with the nondiabetic pregnant women. Francesco et al.15 found that there was no significant difference in plasma ET-1 levels between pregnant women with diabetes who had pre-existing diabetic retinopathy reflecting pre-existing endothelial damage and those without. They concluded that no association could be demonstrated between diabetic retinopathy and serum ET-1 levels. Also Furuya et al.,1 found that IDDM pregnant women had markedly elevated ET-1 levels. However diabetic women with and without preeclampsia did not differ with respect to ET-1 concentration.
In our study ET-1, levels in the umbilical cord were higher than in the maternal plasma. Gospodins et al.16 also found this. It is interesting to speculate that this increase in ET-1 concentration is fetal in origin.
In addition, we elicited a highly significant statistical difference of ET-1 levels and Apgar score between newborns of diabetics with abnormal flow velocity Doppler waveform and newborns of diabetics with normal Doppler waveform. Also we found a higher ET-1 levels in newborns with Apgar score < 7 compared to those > 7. A pathogenic role of perinatal asphyxia as a potent trigger for ET-1 synthesis and secretion could be confirmed by elevated ET-1 plasma levels in these neonates, which was also found by Laforgia et al.10 and Neslihan et al.17
Although there was no difference in the diabetic control proved by glycosylated hemoglobin, a highly significant statistical difference of birth weight between newborns of diabetics with abnormal flow-velocity Doppler waveform and newborns of diabetics with normal Doppler waveform was found. This could be attributed to decreased uteroplacental blood flow in neonates of mothers with placental insufficiency18,19,20.
Conclusion
Although IDDM pregnant women have markedly elevated ET-1 levels, it is not responsible for the vascular changes associated with abnormal umbilical Doppler studies. Higher neonatal ET-1 levels associated with low Apgar score were found in newborns of mothers with abnormal umbilical Doppler studies, suggesting that ET-1 could be a marker of perinatal asphyxia.
Acknowledgments
Many thanks to all our patients and all the staff of El-Galaa Teaching Hospital For their great help during the study.
References
- Furuya K, Kumasawa K, Nakamura H, Kimura T. Endothelin-1 profiles in advanced maternal age complicated with hypertensive disorders of pregnancy. Biochemical and Biophysical Research Communications, 2019 Aug 27; 516 (3): 941-944.
CrossRef - Cerrato R, Crabtree M, Antoniades C, Kublickiene K, Schiffrin EL, Channon KM, Bohm F. Effects of Endothelin-1 on intracellular tetrahydrobiopterin levels in vascular tissue. Scandinavian Cardiovascular Journal, 2018 June, 52(3): 163-169.
CrossRef - Ferre F. Regulation of fetal placental circulation. Gynecol., Obstet., Fertil., 2001 Jul-Aug; 29(7-8): 512-517.
CrossRef - Singh H, Abdul Rahman, Larmie E, Nila A. Endothelin-1 in feto-placental tissues from normotensive pregnant women and women with pre-eclampsia. Acta Obstet., Gynecol., Scandinavia, 2001, 80(2): 99-103.
CrossRef - Riu DS, Sunarno I, Lukas E, Wewengkang ET, Amalia R. The effect of pravastatin on endothelin-1 levels and pregnancy outcomes in women who have a high risk of preeclampsia: A randomized control trial. Enferm Clín, 2020 Mar; 30(2): 499-505.
CrossRef - Roy Kessous, Barak Aricha-Tamir, Adi Y Weintraub, Eyal Sheiner, Reli Hershkovitz. Umbilical Artery Peak Systolic Velocity Measurements for Predication of Perinatal Outcome among IUGR Fetuses. J Clin Ultrasound, 2014 Sep; 42 (7): 405-10.
CrossRef - Emily J Su. Role of Fetoplacental Endothelium in Fetal Growth Restriction with Abnormal Umbilical Artery Doppler velocimetry. Am J Obstet Gynecol, 2015 Oct; 213 (40): 5123-5130.
- Ang C, Hillier C, Cameron AD, Greer IA, Lumsden MA. The Effect of type 1 diabetes mellitus on vascular responses to endothelin-1 in pregnant women. J Clin Endocrinol Metab, 2001 Oct; 86(10): 4939-42.
CrossRef - Abdul Y, Jamil S, He L, Li W, Ergul A. Endothelin-1 promotes a proinflammatory microglia phenotypes in diabetic conditions. Can J Physiol Pharmacol, 2020 Mar 2. Obi: 10. 1139.
CrossRef - Laforgia N, Difonzo I, Altomare M, Mautone A. Cord blood endothelin-1 and perinatal asphyxia. Acta Ped, 2001; 90: 351-352.
CrossRef - Mohamed Al-Shahat, Azza M Abd El Baky, Othman Soliman, Hesham Abdel-Hady. Endothelin-1 and Leptin as markers of intrauterine growth restriction. The Indian Journal of Pediatrics, 2009 May; 76(5): 485-8.
CrossRef - Lu Y, Hasan A, Zeng S, Hocher B. Plasma ET-1 concentrations are elevated in pregnant women with hypertension- Meta – Analysis of clinical studies. Kidney Blood Pres Res, 2017; 42: 654-663.
CrossRef - Ebundou SN, Lee J, Wu D, Lei J, Feller MC, Ozen M, Zhu Y et al. Placental malperfusion in response to intrauterine inflammation and its connection to fetal sequelae. PLOS One, 2019; 14(4): e0214951.
CrossRef - Elzbieta P, Radzislaw M, Dariusz S, Bozenal, Jan O. Intracellular Adhesion Molecule and Endogenous Nos inhibitor: Asymmetric Dimethyl arginine in pregnant women with gestational diabetes mellitus. J. Diabetes Res, 2016 Feb. ID 1342643, 5 pages.
CrossRef - Francesco S, Silvia M, Claudio B, Adolfo S, Francesco P. Diabetic retinopathy and endothelin system: microangiopathy versus endothelial dysfunction. Eye (Lond), 2018 Jul; 32(7): 1157-1163.
CrossRef - Gospodin S, Seema B, Gwendolyn P, Bhagya P, Anil G . Relationship between oxidative stress markers and Endothelin-1 levels in newborns of different gestational ages. Front Pediatric, 2020 June.
- Neslihan T, Ener C, Mehmet A, Nurdan K, Kevser E. Plasma and urinary endothelin-1 concentration in asphyxiated newborns. Neuro Endocrinol lett, 2007 Jun; 28(3): 284-8.
- Yahia M Mizar, Ismael El-Garhy, Ashraf H Mohamed. Correlation between Hemoglobin A1c and umbilical artery Doppler as predictors of perinatal outcome in pregestational diabetic pregnancy and pregestational diabetic pregnancy complicated by pre-eclampsia in third trimester. The Egyptian Journal of Hospital Medicine, 2018 Apr; 71(7): 3601-3613.
- Kant A, Seth N, Rastogi D. Comparison of outcome of normal and high-risk pregnancies based upon cerebroplacental ratio assessed by Doppler studies. J Obstet Gynaecol India, 2017 Jun; 67(3): 173-177.
CrossRef - Khanduri S, Chhabra S, Yadav S, Sabharwal T, Chaudhary M, Usmani T, Goyal A, Sharma H. Role of color Doppler flowmetry in the prediction of intrauterine growth retardation in high –risk pregnancy. Cureus, 2017 Nov; 8, 9 (11): e1827.
