Hs-CRP and TNF-α effects on postnatal umbilical coiling: impact assessment of the gestational diabetes mellitus in a prospective cohort study

doi:10.21203/rs.3.rs-1982262/v1

Download PDF

Research Article

Hs-CRP and TNF-α effects on postnatal umbilical coiling: impact assessment of the gestational diabetes mellitus in a prospective cohort study

https://doi.org/10.21203/rs.3.rs-1982262/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 11 Feb, 2023

Read the published version in Medical Journal of The Islamic Republic of Iran →

Version 1

posted

You are reading this latest preprint version

Background

Hence, no study has been conducted to demonstrate specifically the relationship between gestational diabetes mellitus (GDM) status, inflammatory factors, and postnatal umbilical coiling index (pUCI), as understanding this relation could help to select the best appropriate interventions to save the fetus.

Method

To assess the impact of high sensitivity C-reactive protein (hs-CRP) and Tumor necrosis factor-Alpha (TNF-α) (in maternal venous and umbilical cord (UC) blood) on pUCI, comparing GDM and non-GDM groups.This prospective observational study contained 40 parturients in each of GDM and non-GDM groups, matched for maternal age, ethnicity, and parity. GDM diagnosis was confirmed by 24–28 weeks of gestation (WOG) and two-step strategy. The covariates of interest were maternal hs-CRP and TNF-α, measured at 37-41th WOG, and their UC analogous, measured during delivery. The gross morphologies were assessed immediately after delivery. The UC coiling was quantitatively assessed by the postnatal umbilical coiling index (pUCI)..

Results

No significant difference of hs-CRP and TNF-α, in maternal venous blood or UC blood, was found between GDM/non-GDM groups. The mean (SD) of pUCI in GDM and non-GDM groups were 0.28 (0.15) and 0.24 (0.21) (p-value = 0.441), respectively. In GDM group, none of the four covariates of interest had significant effects on pUCI. Among the non-GDM patients, merely the UC hs-CRP had a direct association with pUCI, a Pearson correlation of r = 0.54 (p-value < .01).

Conclusions

In GDM group, no apparent relationship was observed between inflammatory factors and pUCI, although a direct association was detected between UC hs-CRP and pUCI in the non-GDM.

Tweetable abstract

The umbilical cord high sensitivity C-reactive protein is directly correlated with postnatal umbilical coiling.

Gestational diabetes mellitus

Hs-CRP

TNF-α

Postnatal umbilical coiling index

Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance presenting in variable severity of hyperglycemia, firstly diagnosed during pregnancy, and is associated with an increased risk of fetal morbidity and mortality(1). The metabolic impairments in GDM status create an abnormal environment in peripheral blood, and subsequently vascular structure alterations may occur which affect the function and development of placenta (2). GDM persuades excessive chronic hypoxia stress and inflammatory response in placenta(2), and this inflammatory cascade and vascular endothelial dysfunction plays an important role in the progression and pathogenesis of GDM (3).

Conversely, mild but significant inflammatory activity is involved in the development of normal pregnancy, which might have important physiological roles(4), and pregnancy is a pro-inflammatory and anti-inflammatory condition, depending upon the stage of gestation (5).

Accordingly, genetics, maternal characteristics, placental and umbilical cord structure and functions are the most important health factors that influence the fetus. In the umbilical cord as the vigorous lifeline of the fetus (6), we could watch coiling, as a unique feature of the human umbilical cord and can be evaluated by the umbilical coiling index (UCI) (7). UCI is quantified macroscopically after delivery by dividing the total number of complete vascular coils by the umbilical cord length in centimeters (postnatal UCI (pUCI)) (7, 8), and the changes of UCI is individualized (9).

The mechanisms underlying the changes in cord coiling are not fully understood (10). The importance of UCI abnormalities could be due to adverse prenatal outcomes caused by abnormal flow, constriction or thrombosis in the umbilical cord (10). Adverse perinatal outcomes in UCI abnormalities especially represent in pregnancies complicated by diabetes (7, 10–13).

GDM is one of the most important risk factors for abnormal coiling(14) which has an injurious effect on umbilical vessels and the connective tissue(15). The augmented perinatal fatality and morbidity associated with GDM may be the result of a vascular etiology (15).

Vascular endothelial dysfunction and elevated serum levels of inflammatory and endothelial markers have also been observed in women with GDM (3).

Simple differences in mechanical properties of the cord, growth response of the cord to metabolic and pharmacological abnormalities as well as intrinsic vascular structural changes and variations in placental morphology affecting placental blood flow and maternal-fetal gas exchange are the reasons for the correlation between GDM status, coiling abnormalities and adverse perinatal outcomes (16, 17).

Thus far, no study has been conducted to demonstrate specifically the relationship between GDM status, inflammatory factors, and pUCI, as understanding this relation could help to select the best appropriate interventions to save the fetus. Therefore, the inflammatory biomarkers were assessed as predictors of coiling abnormalities. This seems to be beneficial to select pregnancies for intensified fetal monitoring.

We hypothesized that GDM generates inflammatory changes in maternal and umbilical cord (UC) samples, which could affect the pUCI value. The aim of the current study was to assess the effect of high sensitivity C-reactive protein (hs-CRP) and Tumor necrosis factor- Alpha (TNF-α) (maternal venous blood and UC blood) on postnatal umbilical coiling in GDM and non-GDM.

Subjects

This prospective observational study recruited 80 singleton parturients (mother-infant pairs), during April 2018 until September 2019. This study was performed in the Sayad Shirazi hospital (tertiary perinatal center), located in Gorgan, Golestan, Iran.

The parturients were recruited at the 37th week of gestation (WOG) (determined by the first day of the last menstrual period or 1st trimester ultrasound scan using crown-rump length) and followed until delivery and postpartum period. The sample size was calculated by G power software (version 3.1), power= 90%, α =5%, d= 0.15, prevalence macrosomia =7%, 10% probable drop rate (6).

The outcomes and covariates of interest were fully measured for these parturients, who comprised of two groups of GDM and non-GDM (40 parturients in each group), and matched for maternal age, ethnicity, and parity.

The exclusion criteria included unavailable demographic, maternal, laboratory, neonatal and gross morphological data, or being afflicted by overt diabetes, presence of gross fetal anomalies, history of chronic hypertension, smoking or substance abuse, systemic disease, use of medications other than routine pregnancy supplements, single-artery UC, chorioamnionitis, placenta previa, placenta abruption, fever, and multifetal pregnancy.

Face to face interviews were performed in the first and the following prenatal visits by a single trained physician. Maternal and fetal detailed history, anthropometric variables, obstetrical, physical examination, and paraclinical parameters were collected from the patient’s files.

GDM was diagnosed according to the American Diabetes Association criteria at 24 to 28 weeks of gestation (WOG) using two-step strategy (100 grams Oral Glucose Tolerance Test (100-g OGTT)) (18-20). The non-GDM group included the parturients who were not complicated by GDM.

The medical nutrition therapy was prescribed for all GDM patients, and after 2 weeks, insulin therapies were assigned, due to ethical considerations. The appropriate insulin therapy was selected for the parturients, due to their self-monitoring blood glucose, and their socioeconomic status.

Blood pressure (BP) was measured in a standard condition (sitting position, after 5 minutes of resting, and ceasing smoking, drinking tea or coffee, and eating food for at least half an hour).

Blood glucose was measured by the Enzymatic Calorimeter method using a standard kit (EliTech kit) supplied by EliTech Group (France).

The maternal serum samples were collected and evaluated according to the hs-CRP and TNF-α during 37-41th WOG in the aforementioned hospital’s lab and immediately after delivery the same tests were performed for the UC’s blood samples of 80 neonates. The hs-CRP and TNF-α were analyzed by ELISA method, using Monobind kit (Germany) (ng/ml) and Manual kit (America) (ng/L), respectively.

Then infantile evaluation was performed and entered into the checklist. All of the gross morphologic assessments were performed for all of the parturients immediately after delivery. To avoid diagnostic error, all of the evaluations were performed in the same physical conditions, and by same instruments and procedures.

Definition of terms

The umbilical cord coiling is quantitatively assessed by the UCI, the pUCI was determined by dividing the total number of complete UC twists by the total UC length in centimeters after delivery, resulting in range variability (0-1) (21, 22). One coil was defined as complete 360 degrees of umbilical artery around umbilical vein (7, 10, 14, 23, 24).

Gross morphology assessment

The following gross morphologies were assessed in this study: presence of UC coiling, existing complete vascular coils by 5 centimeters cord length (UCI), UC length, UC diameter, and number of vascular coils.

Macroscopic examination of placenta and UC was carried out in accordance with previously published protocols (25). A true pUCI was grossly evaluated within 24 hours after delivery and cord clamping in the fresh state, and the specimen was handled with great care, avoiding lacerations by a trained single physician who was blinded to the parturients’ clinical characteristics, laboratory data and pregnancy outcomes. Immediately after birth both placental and fetal ends of the cord was clamped and cut straight at five cm from the fetal insertion taking care not to milk and stretch the cord (which may affect the UCI) (26). Five centimeters was added to the length of each cord, to account for the portion of the cord that remained attached to the fetal umbilicus (27). The length and diameter of the UC were measured against a non-elastic tape graduated in centimeters, from its insertion into the placenta up to neonatal clamp. The placenta was allowed to separate spontaneously. Immediately after delivery, the placenta and the UC were preserved in a labeled, clean and dry plastic container full of normal saline (28) with an airtight lid. They were kept in a dry, clean laboratory with constant temperature maintained at 5 ̊C and were washed clean of blood before examination.

Intrapartum and neonatal outcomes

Intrapartum outcomes included gestational age (GA) at delivery, emergency cesarean delivery, preeclampsia, premature rupture of membranes (PROM), polyhydramnios, and meconium stained amniotic fluid. Neonatal outcomes were inspected by a blinded pediatrician after delivery. Neonatal outcomes included neonatal sex, height, weight, and head circumference, first and fifth minute Apgar score, respiratory distress syndrome, cardiopulmonary resuscitation (CPR) and O2 consumption after CPR, neonatal intensive care unit admission, duration of hospital admission, fetal complications, large for GA (LGA), small for GA (SGA) and preterm delivery.

Statistical analysis

The independent sample t-test was used to compare the GDM and non-GDM groups, in terms of the continuous variables with normal distributions, and for the non-normal ones, non-parametric Mann-Whitney U test was utilized. Moreover, for comparing the discrete variables between two groups, chi-squared test was the tool.

To assess the effect of each one of the covariates of interest; maternal hs-CRP, UC hs-CRP, maternal TNF-α, and UC TNF-α on the pUCI, multivariate regression models containing the assessed covariate plus systolic BP, body mass index (BMI), Family history of diabetes mellitus (DM), and a binary variable comparing GDM/non-GDM patients were fitted. Since the response variable (pUCI) was a rate, the Poisson regression model was fitted, which provided the incidence-rate ratios, as the inferential tool.

Statistical analysis was performed using SPSS (version 16, SPSS Inc., Chicago, IL, USA).

In this study, the average of GA at delivery time was 37.8 (1.1) vs. 37.8 (1.4) weeks (p-value = 0.09), for GDM and non-GDM groups, respectively. Demographic and reproductive characteristics of parturients are summarized in Table 1.

Table 1

Demographic and reproductive characteristics of parturients.
Variables	GDM (N = 40)	Non-GDM (N = 40)	p-value
Maternal age (yrs., mean(SD))	29.9 (5.5)	28.7 (5.6)	0.327
Relativity (n (%))	6 (15.0)	6 (15.4)	0.962
Gravidity (median (IQ))	2 (1–3)	2 (1–3)	0.694
Parity (median (IQ))	0 (0–1)	1 (0–2)	0.080
History of Abortion (n (%))	2 (1–3)	1 (0–2)	0.041
History of stillbirth (n (%))	1 (2.5)	3 (7.5)	0.615
History of macrosomia (n (%))	0 (0.0)	1 (2.5)	0.506
History of GDM (n (%))	5 (12.5)	1 (2.5)	0.201
Family history of DM (n (%))	17 (42.5)	3 (7.5)	0.001
Pre-pregnancy BMI (mean(SD))	29.5 (5.1)	25.6 (4.7)	< 0.001
Maternal systolic BP (mean(SD))	117.9 (11.7)	109.5 (10.0)	0.001
Maternal diastolic BP (mean(SD))	74.9 (6.8)	71.4 (9.5)	0.066
GDM: Gestational diabetes mellitus. DM: Diabetes mellitus, BMI: Body mass index. BP: Blood Pressure.

The mean (SD) of GA of GDM diagnosis was 22.3(9.3) and the mean (SD) of GDM duration was 15.4(9.3) weeks, all of the GDM group received insulin therapy, and the type of insulin therapy was combination of short and long acting insulin in 52.5% of cases, 25% long acting, and 22.5%short acting insulin. The mean (SD) of insulin duration was 13.3(8.9) weeks.

The laboratory findings are compared between GDM and non-GDM groups, in Table 2, implying no significant differences in hs-CRP and TNF-α (maternal or UC), between two groups.

Table 2

Laboratory findings of two GDM and non-GDM groups.
	GDM^†(N = 40)	Non-GDM(N = 40)	p-value
Maternal Hs-CRP (median (IQR))	4633.5 (2277.6-8519.3)	6579.2 (2409.1-13235.1)	0.40
UC Hs-CRP (median (IQR))	27.1 (7.3–55.2)	13.5 (0-89.6)	0.50
Maternal TNF-α (median (IQR))	105.3 (85.1-277.9)	130.4 (93.9-226.3)	0.31
UC TNF-α (median (IQR))	163.3 (140.7-297.9)	186.1 (158.3-373.9)	0.10
GDM: Gestational diabetes mellitus. Hs-CRP: high-sensitivity C-reactive protein.
UC: Umbilical Cord. TNF-α: tumor necrosis factor alpha.

All neonates were alive; and delivered by cesarean section in 85% of GDM and 39.5% of non-GDM parturients (p-value = < 0.001). Comparing the intrapartum and neonatal outcomes, no significant statistical difference was detected. No PROM, SGA and preterm delivery was reported. Although polyhydramnios and neonatal intestinal atresia was detected in one of the GDM parturients, and in another a LGA neonate was distinguished.

The gross morphology findings were compared between GDM and non-GDM groups, implying no significant difference regarding the presence of UC coiling, number of vascular coils, UC length and diameter. The mean (SD) of pUCI in GDM and non-GDM groups was 0.28 (0.15) and 0.24 (0.21) (p-value = 0.441), respectively.

According to Fig. 1, among the GDM parturients, none of the four covariates of interest, i.e. hs-CRP and TNF-α in maternal venous blood or UC blood, showed an apparent relationship with the pUCI, and among the non-GDM parturients, merely the UC hs-CRP had a direct association with pUCI. The Pearson correlation analysis also confirmed it, where the only significant correlation was found between UC hs-CRP and pUCI (r = 0.54, p-value < .01). Although no statistically significant correlations were detected, there seemed to be reverse relations between (maternal and UC) TNF- α and pUCI, in both GDM and non-GDM groups.

The multivariate regression models were fitted taking the pUCI as dependent variable, using the covariates of interest hs-CRP and TNF-α in both forms of maternal venous blood and umbilical cord blood, and adjusted for the confounders systolic BP, BMI, family history of diabetes and GDM/non-GDM status. The findings are reported in Table 3. None of the four assessed covariates showed any significant effect on pUCI.

Table 3

The multivariate Poisson regression models evaluating the effects of the covariates hs-CRP and TNF-α (maternal and UC forms) on pUCI, adjusted for confounders.
Covariates	IRR	p-value	Confidence interval (95%)
Maternal hs-CRP	1.000001	0.98	0.99992	1.00007
UC hs-CRP	1.0001	0.18	0.99993	1.0003
Maternal TNF-α	0.9998	0.63	0.9989	1.0006
UC TNF-α	0.9998	0.64	0.9989	1.0006
IRR: Incidence-rate ratio, pUCI: Postnatal umbilical coiling index
Hs-CRP: high-sensitivity C-reactive protein. UC: Umbilical Cord.
TNF-α: tumor necrosis factor alpha.
Adjusted for the confounders; systolic blood pressure, BMI, family history of diabetes, and GDM/non-GDM status.

This prospective observational study investigated the effect of hs-CRP and TNF-α (maternal and UC) on postnatal umbilical coiling in GDM and non-GDM pregnancy.

The present study’s investigators have not found any previous publications correlating the GDM status, postnatal umbilical coiling and inflammatory factors.

We found no significant difference of hs-CRP and TNF-α, in maternal venous blood or UC blood, between two groups. The same result was detected by Gomes et al. for TNF-α, between GDM and non-GDM groups (29). The same non-significant difference in UC hs-CRP was demonstrated between GDM and non-GDM groups by other studies (30, 31). In addition, no significant difference of pUCI in both groups were detected, the same as other studies (6, 21, 32).

In GDM group, the maternal and UC hs-CRP had no apparent effects on pUCI, although no significant association was observed, there seemed to be direct relations. Among the non-GDM parturients, merely the UC hs-CRP had a direct and significant association with pUCI, in contrast with maternal hs-CRP.

No statistically significant correlations were detected between maternal/UC TNF-α and pUCI in both groups, though there seemed to be reverse relations.

In the multivariate regression models, adjusted for the confounders systolic BP, BMI and family history of diabetes, none of the four assessed covariates showed any significant effect on pUCI.

For normal pregnancy development, significant inflammatory activity is needed which might have important physiological roles (4).

In the prepartum period; the metabolic and immunological disorders besides the inflammatory status alterations, could affect the fetal developing environment (4). The inflammation is an important determinant of adverse fetal and perinatal outcomes (33). The fetal response to inflammation is considered by increased levels of pro-inflammatory cytokines in the amniotic fluid and UC blood (33, 34); which induces inflammation of chorionic plate, placental and UC vessels (fetal vasculitis) (35). However, the association between perinatal inflammation and biochemical inflammatory indicators in UC blood and maternal circulation are not completely understood. TNF-α and CRP have been mentioned for their role in the inflammatory process and are most commonly assessed in relation to insulin resistance and obesity (36, 37). TNF-α have been recognized as being responsible for hepatic production of the acute phase reactants such as cytokines and CRP (38). Hs-CRP is an acute phase reactant biomarker and is produced by liver in response to pro-inflammatory cytokines, which may be used as adjunctive test in the diagnosis of inflammation (33). The plasma levels of hs-CRP will be increased within a day after the onset of inflammation and tissue injury, when diagnostic clinical signs and other laboratory tests may be non-specific, and remains elevated until after stimulus resolves (39). Elevation of serum and UC hs-CRP in the neonate is due to endogenous hepatic synthesis, since very low quantities of hs-CRP cross the placenta (33, 40). Perinatal inflammation is associated with increased UC inflammatory cytokines including hs-CRP (41), but the impact on inflammatory markers in the early neonatal period is less well-described (33).

TNF-α is mainly produced by activated macrophages and monocytes (42), it affects insulin secretion and sensitivity through influencing B-cell function and insulin signaling pathways, which possibly induces GDM (43). It’s level is controversial in this way, no changes was observed during pregnancy vs. postpartum (4) in contrast with Germain’s (44) study which demonstrated more in normal pregnancy, vice versa Graham presented that most pro-inflammatory cytokine expression, including TNF-α was reduced during normal pregnancy(45).

The prepartum pro-inflammatory and anti-inflammatory condition is depended to the severity of comorbidities, the trimesters that were evaluated (5), and also pregnancy duration (46) and the mode of delivery may affect the concentrations (47).

Hs-CRP, TNF-α and other adipokines were found to be highly correlated with obesity which contributes to insulin resistance and this correlation leads to many diseases, notably GDM and preeclampsia during pregnancy (48). TNF-α and hs-CRP are mostly raised at the end of pregnancy (37).

GDM diagnosis was performed during second trimester, which probably exposed the infant to intrauterine metabolic changes, inflammatory process and epigenetic programming for nearly 24 to 28 WOG, which predispose infants to long-term abnormality (49). The hyperglycemia is contributed to produce reactive oxygen species which concluded oxidative tresses, and so pro-inflammatory cytokines and TNF-α is produced (50). So, according to elevation of serum inflammatory biomarkers and endothelial markers in GDM, the vascular endothelial dysfunction and placental angiogenesis is observed (3, 50). In another view, the metabolic impairments in GDM status cause vascular structure alterations, so consequently affect the morphology, function and development of placenta and UC (2, 50). GDM induces chronic hypoxia and inflammatory response in placental and UC vascular endothelial cells (2). A hypoxic placenta may release cytokines and inflammatory factors (TNF-α and CRP) which could induce vascular endothelial dysfunction (51, 52). This inflammatory cascade and vascular endothelial dysfunction plays an important role in the progression and pathogenesis of GDM (3).

Cvitic et al. and the other studies presented more expression of TNF-α in placenta in GDM parturients (53–55), in contrast with UC that low TNF-α level was detected (50, 55, 56). Increment of TNF-α levels in GDM may according to increased oxidative stress and imbalance in the expression of pro-inflammatory and anti-inflammatory cytokines which may contribute to impaired glucose metabolism (55, 57).

In prepartum period, hs-CRP is correlated with maternal serum glucose of GDM parturients, when measured at the 3rd trimester as a standard screening time (58, 59), which is similar with the present study. According to the adverse perinatal outcomes in GDM parturients, a vascular etiology is seems as an important cause (15, 60), and also metabolic and pharmacological abnormalities are the other causes. Additionally; the mentioned adverse fetal morbidities in UCI abnormalities, especially represent in pregnancies complicated by GDM (7, 10–13). GDM as one of the most important etiologies for coiling abnormalities(14) has an deleterious effect on umbilical vessels and the connective tissue(15).

The influence of UCI on perfusion pressure is unknown, it is hypothesized that the pressure reduction caused as a weaker stimulus to angiogenesis with failure to form vasculo-syncytial membranes (13). Consequently, a raised pressure in the coiling abnormalities also seen more frequently detected in diabetes, which leads to terminal villi congestion and consequently angiogenesis increment (13). Besides the effect of insulin on placental vascularity, the other factors such as angiogenic factors and inflammatory/ oxidative stress factors also induce angiogenesis (61, 62). Adverse fetal outcomes were attributed to abnormal UCI (63), which predisposed the vessels of the umbilical to stenosis, thrombosis, constriction, occlusion, torsion of umbilical vessels, cord entanglement (10). These abnormal mechanisms lead to compress the fetoplacental blood flow, maternal-fetal gas exchange abnormality and fetal hypoxia (7, 16, 17), which may strengthen and exaggerated in GDM parturients because of the reduction of the Wharton’s jelly content, decrement of mucopolysaccharide synthesis and the collagen molecules changes(15). The fetal hypoxia leads to more oxidative and nitrative stresses (64). Conclusively, all these conditions induced placental blood supply decrement(16, 17); which may affect the number of coils was an important etiology to all mentioned conditions (14).

All the above-mentioned changes were noticed in nearly one third of diabetic parturients and it seems that the poor glycemic control is significantly related to these changes, these changes are prominently described in pre-gestational diabetes not in GDM and occult form(13).

In similar way, Mayhew et al. defined normal vascular function in GDM parturients with good glycemic control (65) in contrast with Leach, which described vascular insufficiency with appropriate glycemic control (66). The mentioned inflammatory activity may affect from intra-partum GDM treatment (by life style changes, medical nutrition therapy, glycemic control) according to ethical consideration, decrement of GDM severity, on-time diagnosis and appropriate follow-ups, in GDM group. We suggested the aforementioned considerations; as confounding factors that affect our results.

In the literature review, no study has been conducted to demonstrate specifically the relationship of biochemical inflammatory biomarkers, and pUCI in parturients complicated by GDM.

The strengths of this study were that all evaluations were demonstrated in a referral obstetric hospital (tertiary perinatal center). In this prospective observational study, the authors could follow the late prenatal, perinatal and postnatal period. The study population comprised GDM and normal pregnancy, providing valid comparison between groups. Additionally, for UCI calculation, the total length of the cord was considered and rapid bilateral clamping of the cord was performed to avoid urgent blood drainage. Using merely “two-step strategy” (100-g OGTT) for GDM diagnosis of all cases to prevent over diagnosis by “one-step strategy”.

These are the first data to show that in GDM group, no apparent relationship was detected between inflammatory biomarkers with pUCI although a direct association was detected between UC hs-CRP and pUCI in non-GDM.

The limitation of the present study could be mentioned as the small sample size, according to that the impact assessment of some variables could not be achieved. Consequently; further investigations in larger populations with serial and early evaluation of inflammatory biomarkers to understand the correlations between the aforementioned and other inflammatory indicators with UCI; as screening tests for detection of coiling abnormalities and prediction of pUCI in different comorbidities such as GDM, preeclampsia and so on.

BMI

CPR

GDM

Hs-CRP

LGA

OGTT

PROM

SGA

TNF-α

pUCI

UCI

WOG

Body mass index

Blood pressure

Cardiopulmonary resuscitation

Diabetes mellitus

Gestational Age

Gestational Diabetes Mellitus

High sensitivity C-reactive protein

Large for gestational age

Oral glucose tolerance test

Premature rupture of membranes

Small for gestational age

Tumor necrosis factor- Alpha

Postnatal Umbilical Coiling Index

Umbilical cord

Umbilical Coiling Index

Weeks of gestation

Ethics approval and consent to participate

The ethics committee of Golestan University of medical sciences approved the study protocol (IR.GOUMS.REC.1397.273, IR.GOUMS.REC.1397.272) and all participants signed the written informed consent. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent to participate was obtained by all subjects. We confrm that all methods were performed in accordance with the relevant guidelines and regulations

Consent for publication

Not applicable.

Availability of data and material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interest

The authors declare that they have no competing interests.

Funding

This study was funded and supported by Golestan University of Medical Sciences (GOUMS); Grant No. 110401-23, 110417-23.

Authors’ contributions

HA and LN designed the study. LN and AK contributed to the analysis and interpretation of data. LN and AK drafted the manuscript. FM, AN, and FA critically revised the manuscript. All authors approved the final draft.

Acknowledgements: The authors would like to acknowledge the Golestan University of Medical Sciences (GOUMS) for funding and supporting the research. The authors wish to thank the staff who greatly helped us to complete the project. In addition, we are grateful to all the people who contributed to this study.

Author details

^{^[1]} Clinical Research Development Center, Sayad Shirazi hospital, Golestan University of Medical Sciences, Gorgan, Iran.

² Student Research Committee, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran. [email protected]

³ Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran.

Disclosure of interests

The authors declare that there are no financial and non-financial conflicts of interest that could be perceived as prejudicing the impartiality of the research reported.

Jafari-Shobeiri M, Ghojazadeh M, Azami-Aghdash S, Naghavi-Behzad M, Piri R, Pourali-Akbar Y, et al. Prevalence and risk factors of gestational diabetes in Iran: a systematic review and meta-analysis. Iranian journal of public health. 2015;44(8):1036.
Li H-P, Chen X, Li M-Q. Gestational diabetes induces chronic hypoxia stress and excessive inflammatory response in murine placenta. International journal of clinical and experimental pathology. 2013;6(4):650.
Bo S, Valpreda S, Menato G, Bardelli C, Botto C, Gambino R, et al. Should we consider gestational diabetes a vascular risk factor? Atherosclerosis. 2007;194(2):e72-e9.
Palm M, Axelsson O, Wernroth L, Larsson A, Basu S. Involvement of inflammation in normal pregnancy. Acta obstetricia et gynecologica Scandinavica. 2013;92(5):601–5.
Mor G, Cardenas I, Abrahams V, Guller S. Inflammation and pregnancy: the role of the immune system at the implantation site. Annals of the New York Academy of Sciences. 2011;1221(1):80.
de Laat MW, Franx A, Bots ML, Visser GH, Nikkels PG. Umbilical coiling index in normal and complicated pregnancies. Obstetrics & Gynecology. 2006;107(5):1049–55.
Strong TH, Jarles DL, Vega JS, Feldman DB. The umbilical coiling index. American journal of obstetrics and gynecology. 1994;170(1):29–32.
Jessop F, Lees C, Pathak S, Hook C, Sebire N. Umbilical cord coiling: clinical outcomes in an unselected population and systematic review. Virchows Archiv. 2014;464(1):105–12.
Jo YS, Jang DK, Lee G. The sonographic umbilical cord coiling in late second trimester of gestation and perinatal outcomes. International journal of medical sciences. 2011;8(7):594.
Machin GA, Ackerman J, Gilbert-Barness E. Abnormal umbilical cord coiling is associated with adverse perinatal outcomes. Pediatric and Developmental Pathology. 2000;3(5):462–71.
Degani S, Leibovich Z, Shapiro I, Gonen R, Ohel G. Early second-trimester low umbilical coiling index predicts small‐for‐gestational‐age fetuses. Journal of ultrasound in medicine. 2001;20(11):1183–8.
De Laat M, Franx A, Nikkels P, Visser G. Prenatal ultrasonographic prediction of the umbilical coiling index at birth and adverse pregnancy outcome. Ultrasound in obstetrics & gynecology. 2006;28(5):704–9.
Evans MJ. Review: Diabetes and pregnancy: a review of pathology. The British Journal of Diabetes & Vascular Disease. 2009;9(5):201–6.
Ezimokhai M, Rizk DE, Thomas L. Maternal risk factors for abnormal vascular coiling of the umbilical cord. American journal of perinatology. 2000;17(08):441–6.
Singh SD. Gestational diabetes and its effect on the umbilical cord. Early human development. 1986;14(2):89–98.
Ezimokhai M, Rizk D, Thomas L. Abnormal vascular coiling of the umbilical cord in gestational diabetes mellitus. Archives of physiology and biochemistry. 2001;109(3):209–14.
Atalla RK, Abrams K, Bell SC, Taylor DJ. Newborn acid-base status and umbilical cord morphology. Obstetrics & Gynecology. 1998;92(5):865–8.
American Diabetes Association. 2. Classification and diagnosis of diabetes. Diabetes care. 2015;38(Supplement 1):S8-S16.
Metzger BE, Buchanan TA, Coustan DR, De Leiva A, Dunger DB, Hadden DR, et al. Summary and recommendations of the fifth international workshop-conference on gestational diabetes mellitus. Diabetes care. 2007;30(Supplement 2):S251-S60.
Center Joslin Diabetes. Guideline for Detection and Management of Diabetes in Pregnancy. Revised 1/17/11). Retrieved from https://www.joslin.org/Preg_guideline_5_10_11_ (2)-0615-11. pdf; 2011.
Pathak S, Hook E, Hackett G, Murdoch E, Sebire N, Jessop F, et al. Cord coiling, umbilical cord insertion and placental shape in an unselected cohort delivering at term: relationship with common obstetric outcomes. Placenta. 2010;31(11):963–8.
Chitra T, Sushanth Y, Raghavan S. Umbilical coiling index as a marker of perinatal outcome: an analytical study. Obstetrics and gynecology international. 2012;2012.
de Laat M, Franx A, van Alderen E, Nikkels P, Visser G. The umbilical coiling index, a review of the literature. The Journal of Maternal-Fetal & Neonatal Medicine. 2005;17(2):93–100.
Laily Najafi, Mohammad E. Khamseh, Maryam Kashanian, Ladan Younesi, Azadeh Abedini, Ameneh Ebrahim Valojerdi, et al. Antenatal umbilical coiling index in gestational diabetes mellitus and non-gestational diabetes pregnancy. Taiwanese Journal of Obstetrics and Gynecology. 2018;In Press.
Hargitai B, Marton T, Cox P. BEST PRACTICE NO 178: Examination of the human placenta. Journal of clinical pathology. 2004;57(8):785–92.
Malpas P, Symonds E. Observations on the structure of the human umbilical cord. Surgery, gynecology & obstetrics. 1966;123(4):746.
Ogunlaja I, Aiyeyemi J, Fasoranti O, Ogunlaja O, Adegoke A. Correlation between placenta and umbilical cord morphplogy and perinatal outcome in singleton deliveries at term in a Nigerian tertiary health centre. Tropical Journal of Obstetrics and Gynaecology. 2015;32(1):96–103.
Qin Y, Lau T, Rogers M. Second-trimester ultrasonographic assessment of the umbilical coiling index. Ultrasound in Obstetrics and Gynecology. 2002;20(5):458–63.
Gomes CP, Torloni MR, Gueuvoghlanian-Silva BY, Alexandre SM, Mattar R, Daher S. Cytokine levels in gestational diabetes mellitus: a systematic review of the literature. American Journal of Reproductive Immunology. 2013;69(6):545–57.
Aramesh MR, Dehdashtian M, Malekian A, ShahAli S, Shojaei K. Relation between fetal anthropometric parameters and cord blood adiponectin and high-sensitivity C-reactive protein in gestational diabetes mellitus. Archives of endocrinology and metabolism. 2017;61(3):228–32.
Mordwinkin NM, Ouzounian JG, Yedigarova L, Montoro MN, Louie SG, Rodgers KE. Alteration of endothelial function markers in women with gestational diabetes and their fetuses. The Journal of Maternal-Fetal & Neonatal Medicine. 2013;26(5):507–12.
Najafi L, Malek M, Abedini A, Kadivar M, Ebrahim Valojerdi A, Zahmatkesh E, et al. Prediction of postnatal abnormal coiling of the umbilical cord in gestational diabetes mellitus: a diagnostic accuracy study. The Journal of Maternal-Fetal & Neonatal Medicine. 2018:1–7.
Howman RA, Charles AK, Jacques A, Doherty DA, Simmer K, Strunk T, et al. Inflammatory and haematological markers in the maternal, umbilical cord and infant circulation in histological chorioamnionitis. PloS one. 2012;7(12):e51836.
Park C-W, Moon KC, Park JS, Jun JK, Romero R, Yoon BH. The involvement of human amnion in histologic chorioamnionitis is an indicator that a fetal and an intra-amniotic inflammatory response is more likely and severe: clinical implications. Placenta. 2009;30(1):56–61.
Tita AT, Andrews WW. Diagnosis and management of clinical chorioamnionitis. Clinics in perinatology. 2010;37(2):339–54.
Khan A, Ali Z. Normal ranges for acute phase reactants (Interleukin-6, tumour necrosis factor-alpha and c-reactive protein) in umbilical cord blood of healthy term neonates at the Mount Hope Women's Hospital, Trinidad. The West Indian Medical Journal. 2014;63(5):465.
Pantham P, Aye ILH, Powell TL. Inflammation in maternal obesity and gestational diabetes mellitus. Placenta. 2015;36(7):709–15.
Mishra U, Jacobs S, Doyle L, Garland S. Newer approaches to the diagnosis of early onset neonatal sepsis. Archives of Disease in Childhood-Fetal and Neonatal Edition. 2006;91(3):F208-F12.
Marnell L, Mold C, Du Clos TW. C-reactive protein: ligands, receptors and role in inflammation. Clinical immunology. 2005;117(2):104–11.
Kirwan JP, Hauguel-De Mouzon S, Lepercq J, Challier J-C, Huston-Presley L, Friedman JE, et al. TNF-α is a predictor of insulin resistance in human pregnancy. Diabetes. 2002;51(7):2207–13.
Kordek A, Hałasa M, Podraza W. Early detection of an early onset infection in the neonate based on measurements of procalcitonin and C-reactive protein concentrations in cord blood. Clinical Chemistry and Laboratory Medicine (CCLM). 2008;46(8):1143–8.
Bette M, Schäfer M, Van Rooijen N, Weihe E, Fleischer B. Distribution and kinetics of superantigen-induced cytokine gene expression in mouse spleen. The Journal of experimental medicine. 1993;178(5):1531–9.
Cawthorn WP, Sethi JK. TNF-α and adipocyte biology. FEBS letters. 2008;582(1):117–31.
Germain SJ, Sacks GP, Soorana SR, Sargent IL, Redman CW. Systemic inflammatory priming in normal pregnancy and preeclampsia: the role of circulating syncytiotrophoblast microparticles. The Journal of Immunology. 2007;178(9):5949–56.
Graham C, Chooniedass R, Stefura WP, Becker AB, Sears MR, Turvey SE, et al. In vivo immune signatures of healthy human pregnancy: Inherently inflammatory or anti-inflammatory? PloS one. 2017;12(6):e0177813.
Logan CA, Thiel L, Bornemann R, Koenig W, Reister F, Brenner H, et al. Delivery mode, duration of labor, and cord blood adiponectin, leptin, and C-reactive protein: results of the population-based Ulm birth cohort studies. PLoS One. 2016;11(2):e0149918.
Treviño-Garza C, Villarreal-Martínez L, Estrada-Zúñiga CM, Leal-Treviño M, Rodríguez-Balderrama I, Nieto-Sanjuanero A, et al. Leptin, IL-6 and TNF-α levels in umbilical cord blood of healthy term newborns in relation to mode of delivery. Journal of Obstetrics and Gynaecology. 2016;36(6):719–21.
Kocak A, Kutlu R, Civi S, Kilinc I. The relationship between insulin resistance and leptin, interleukin-6, hs-CRP and fibrinogen in obesity. TURKISH JOURNAL OF BIOCHEMISTRY-TURK BIYOKIMYA DERGISI. 2014;39(3):373 – 82.
Brink HS, van der Lely AJ, van der Linden J. The potential role of biomarkers in predicting gestational diabetes. Endocrine connections. 2016;5(5):R26-R34.
Cvitic S, Desoye G, Hiden U. Glucose, insulin, and oxygen interplay in placental hypervascularisation in diabetes mellitus. BioMed research international. 2014;2014.
Borna S, Abdollahi A, Mirzaei F. Predictive value of mid-trimester amniotic fluid high-sensitive C-reactive protein, ferritin, and lactate dehydrogenase for fetal growth restriction. Indian Journal of Pathology and Microbiology. 2009;52(4):498.
Retnakaran R, Qi Y, Connelly P, Sermer M, Hanley A, Zinman B. Low adiponectin concentration during pregnancy predicts postpartum insulin resistance, beta cell dysfunction and fasting glycaemia. Diabetologia. 2010;53(2):268.
Radaelli T, Varastehpour A, Catalano P, Hauguel-de Mouzon S. Gestational diabetes induces placental genes for chronic stress and inflammatory pathways. Diabetes. 2003;52(12):2951–8.
Moreli JB, Morceli G, De Luca AKC, Magalhães CG, Costa RA, Damasceno DC, et al. Influence of maternal hyperglycemia on IL-10 and TNF-α production: the relationship with perinatal outcomes. Journal of Clinical Immunology. 2012;32(3):604–10.
Xu J, Zhao YH, Chen YP, Yuan XL, Wang J, Zhu H, et al. Maternal circulating concentrations of tumor necrosis factor-alpha, leptin, and adiponectin in gestational diabetes mellitus: a systematic review and meta-analysis. The Scientific World Journal. 2014;2014.
Atègbo J-M, Grissa O, Yessoufou A, Hichami A, Dramane K, Moutairou K, et al. Modulation of adipokines and cytokines in gestational diabetes and macrosomia. The Journal of Clinical Endocrinology & Metabolism. 2006;91(10):4137–43.
Briana DD, Malamitsi-Puchner A. Reviews: adipocytokines in normal and complicated pregnancies. Reproductive Sciences. 2009;16(10):921–37.
Berggren EK, Roeder HA, Boggess KA, Moss K, Offenbacher S, Campbell E, et al. First-trimester maternal serum C-reactive protein as a predictor of third-trimester impaired glucose tolerance. Reproductive sciences. 2015;22(1):90–3.
Lowe LP, Metzger BE, Lowe Jr WL, Dyer AR, McDade TW, McIntyre HD, et al. Inflammatory mediators and glucose in pregnancy: results from a subset of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. The Journal of Clinical Endocrinology & Metabolism. 2010;95(12):5427–34.
Najafi L, Abedini A, Kadivar M, Khajavi A, Bordbar A, Noohi AH, et al. Gestational diabetes mellitus: the correlation between umbilical coiling index, and intrapartum as well as neonatal outcomes. Journal of Diabetes & Metabolic Disorders. 2019:1–7.
Reynolds LP, Redmer DA. Angiogenesis in the placenta. Biology of reproduction. 2001;64(4):1033–40.
Jarmuzek P, Wielgos M, Bomba-Opon DA. Placental pathologic changes in gestational diabetes mellitus. Neuroendocrinology Letters. 2015;36(2):101–5.
de Laat MW, van Alderen ED, Franx A, Visser GH, Bots ML, Nikkels PG. The umbilical coiling index in complicated pregnancy. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2007;130(1):66–72.
Elsennawy T. Effect of gestational diabetes on gross morphology, histology and histochemistry of human placenta. Endocrinol Metab Syndr. 2016;5(5):1–13.
MAYHEW TM, JAIRAM IC. Stereological comparison of 3D spatial relationships involving villi and intervillous pores in human placentas from control and diabetic pregnancies. The Journal of Anatomy. 2000;197(2):263–74.
Leach L, Taylor A, Sciota F. Vascular dysfunction in the diabetic placenta: causes and consequences. Journal of Anatomy. 2009;215(1):69–76.

No competing interests reported.

Download PDF

Journal Publication

published 11 Feb, 2023

Read the published version in Medical Journal of The Islamic Republic of Iran →

Version 1

posted

You are reading this latest preprint version

Hs-CRP and TNF-α effects on postnatal umbilical coiling: impact assessment of the gestational diabetes mellitus in a prospective cohort study

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Methods

Results

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Associated Publications

Status:

Journal Publication

Version 1