Adiponectin

Adiponectin is a protein with an inverse association with IR, metabolic syndrome, and CVD. It possibly has fetal origins as it presented a slight though not significant increase between birth and four days postpartum. ^{Reference Sivan, Mazaki-Tovi and Pariente9} Concerning the neonatal population, lower adiponectin levels were noticed in cord samples of IUGR, ^{Reference Aydin, Eser and Kaygusuz10} SGA (term and preterm), and ELBW-AGA newborns compared to control groups. ^{Reference Cekmez, Canpolat and Pirgon11} Adiponectin seems an important determinant of fetal growth and neonatal body composition and there is a possible interaction between adiponectin’s molecular weight isoforms and gender. Specifically, for female neonates, high-molecular-weight adiponectin appeared as one of the main determinants of adiposity and fetal growth velocity, whereas in males, fetal growth and adiposity appeared affected by low-molecular-weight adiponectin. ^{Reference Simón-Muela, Näf and Ballesteros12} Females also presented with significantly higher levels of total and high molecular-weight adiponectin compared to males. ^{Reference Minatoya, Araki and Miyashita13} Cord adiponectin presented a linear association with weight, length, and subscapular z-scores at 6 months of age, in offspring of obese mothers. Also, a decrease in cord adiponectin levels was found in infants of diabetic mothers (IDMs) ^{Reference Patel, Hellmuth and Uhl14} The reduced adiponectin levels in these groups could be an expression of fetal programming, possibly affected also by the maternal compartment, that is related to altered adiposity and IR in later life and of a possible contribution of adiponectin in the pathogenesis of IR. ^{Reference Aydin, Eser and Kaygusuz10-Reference Patel, Hellmuth and Uhl14}

Leptin

Leptin is a satiety factor with a central role in the regulation of appetite and metabolism. ^{Reference Aydin, Eser and Kaygusuz10,Reference Li, Rifas-Shiman and Aris15} In neonates it possibly correlates with GA and birth weight. Cord leptin displayed a significant decrease in neonatal samples during the first week of life. ^{Reference Sivan, Mazaki-Tovi and Pariente9,Reference Matsuda, Yokota and Iida16} Concerning intrauterine growth, leptin presented no significant differences between IUGR and controls. However, a negative correlation was observed between adropin, a liver-secreted factor involved in several metabolic pathways, and leptin in cord samples of IUGR neonates. ^{Reference Aydin, Eser and Kaygusuz10} Cord leptin levels were related to measures of neonatal growth, body composition, and catch-up growth. Also, they were negatively associated with infant mid-upper arm circumference z-scores and positively associated, with birth weight, with increased odds of catch-down growth at 6 months of age and with the Ponderal Index. ^{Reference Simón-Muela, Näf and Ballesteros12-Reference Patel, Hellmuth and Uhl14} Additionally, leptin also appeared as a strong predictor of decreased septal strain in infants of obese or diabetic mothers. ^{Reference Cade, Levy and Tinius17} Following the dynamic changes in leptin levels from birth to childhood, three distinct patterns were identified: “low stable,” “high-decreasing,” and “intermediate-increasing.” Most of the adiposity measures and biomarkers presented with their greatest values in the third group, while high-density lipoprotein cholesterol (HDL-C) was decreased in this group. Furthermore, the “intermediate-increasing” trajectory was related to altered parameters of obesity, such as BMI z-score, waist circumference, total fat mass index, higher insulin, inflammation, and lower HDL-C compared to the low-stable trajectory. Association with higher leptin levels at early adolescence, presented the intermediate-increasing and high-decreasing trajectories. ^{Reference Li, Rifas-Shiman and Aris15} Leptin levels appear to correlate with body composition, adiposity, and energy balance, and elevated leptin levels have been associated with obesity-related inflammation biomarkers. Thus, the alterations in leptin levels throughout the first years of life could predict subsequent cardiometabolic outcomes. ^{Reference Aydin, Eser and Kaygusuz10,Reference Li, Rifas-Shiman and Aris15}

Additional adipokines

Aliquot adipokines studied include visfatin and adropin, which play an important part in the regulation of glycemic homeostasis. Adropin also seems to be a novel regulator of endothelial function. It attenuates metabolic distress syndromes associated with obesity and contributes to energy homeostasis and lipid metabolism. Cord blood adropin was found significantly lower in IUGR neonates and presented a negative correlation with leptin and a positive correlation with endothelin-1 levels. ^{Reference Aydin, Eser and Kaygusuz10} Visfatin is an insulin-mimetic factor known to increase along with the development of obesity. Visfatin levels were found to increase along with hyperglycemia as well. Significant differences between preterm and ELBW infants were reported regarding visfatin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and insulin levels. Visfatin levels were found significantly increased in ELBW infants compared to term and preterm, and in preterm SGA and AGA infants. Thus, visfatin can be used as an early IR indicator also in ELBW infants. ^{Reference Cekmez, Canpolat and Pirgon11}

High sensitivity C-reactive protein (hs-CRP)

Recent pediatric research demonstrated that elevated CRP levels are related to CVD from the first years of life. Thus, researchers investigated the contribution of hs-CRP, a sensitive marker of systemic inflammation, in the first days of life among neonates at risk of developing CVD. Term healthy infants presented a significant increase in CRP in 24 and 36 hours postpartum, with a peak at 24 hours. ^{Reference Rallis, Balomenou and Kappatou18} SGA neonates presented significantly higher levels of hs-CRP compared to AGA. No gender-specific differences were noticed. Further studies propose an association between cord hs-CRP and systolic blood pressure in children born SGA and a higher, though not significant aortic thickening in children born SGA. ^{Reference Trevisanuto, Doglioni, Altinier, Zaninotto, Plebani and Zanardo19,Reference Trevisanuto, Avezzù and Cavallin20} Interestingly, chorioamnionitis was associated with a significant increase in hs-CRP in the immediate postnatal period. ^{Reference Rafferty, Mcgrory and Cheung21} In addition, no increase in hs-CRP was reported in IUGR fetuses or infants from gestational diabetes mellites (GDM) pregnancies. ^{Reference Crispi, Hernandez-Andrade and Pelsers22,Reference López Morales, Brito Zurita and González Heredia23} Lastly, hs-CRP levels were significantly higher in South Asian neonates compared to Caucasian, in a frame of a general impaired metabolic profile characterized by hyperinsulinemia, dyslipidemia, and higher E-selectin levels in South Asian subjects. ^{Reference Boon, Karamali and De Groot24} The results suggest a possible association of the inflammatory status across perinatal conditions already correlated to CVD.

Additional inflammation markers

Additional elements of the inflammatory process, such as the cytokines IL-6 and TNF-a, the selectins and intercellular adhesion molecule (ICAM) families, seem important in CVD though less investigated. Both IL-6 and TNF-a appear to associate with IR, adiposity, and other CVD risk factors. In term healthy newborns cord IL-6 levels were significantly lower than in 24 and 48 hours postpartum reaching a peak during the first 24 hours. ^{Reference Chiesa, Pacifico and Natale25} The levels of IL-6 and TNF-a were negatively associated with neonatal birth weight z-scores, and even though they may contribute to the development of neonatal adiposity in utero, an inverse association with neonatal body composition was found. ^{Reference Patel, Hellmuth and Uhl14} IL-6 and TNF-a tended to increase in a group of IUGR neonates, and IL-6 values were higher in SGA neonates and neonates from GDM pregnancies. ^{Reference López Morales, Brito Zurita and González Heredia23,Reference Kim, Lee and Kim26,Reference Leduc, Delvin and Ouellet27} These higher inflammatory cytokine concentrations are suggestive of triggering the proinflammatory response in these populations.

E-selectin, ICAM-1, vascular cell adhesion molecule-1 (VCAM-1)

Concerning markers of endothelial dysfunction, such as E-selectin, ICAM-1, and VCAM-1 in the pediatric population, the number of relevant studies is very limited. E-Selectin appeared significantly higher in South Asian neonates, whereas ICAM-1 and VCAM-1 did not differ compared to Caucasian ones. Hyperinsulinemia, dyslipidemia, and higher CRP levels were also present in South Asian subjects. ^{Reference Boon, Karamali and De Groot24} In children with a family history of premature coronary artery diseases, there were positive correlations between total cholesterol (TC) and VCAM-1 and TC and ICAM-1. ^{Reference Pac-Kozuchowska, Krawiec and Grywalska28} Additionally, when the levels of serum ICAM-1 were studied among twins one of which being IUGR no significant differences were noticed. ^{Reference Leduc, Delvin and Ouellet27} Yet, the levels of serum ICAM-1 were statistically higher in infants of GDM pregnancies and VCAM-1 was significantly higher in infants of GDM pregnancies and placental atherosclerosis. ^{Reference López Morales, Brito Zurita and González Heredia23} Consequently, alterations on specific markers of endothelial dysfunction demonstrate the early onset of vascular stress as a result of exposure to an atherogenic environment.

Homocysteine (tHcys)

Homocysteine is considered a cardiovascular risk biomarker in adults. It exerts several toxic effects, including injury on the vascular endothelial cells. ^{Reference Ophir, Dourleshter and Hirsh29,Reference Perez-Cruz, Crispi and Fernández30} It appeared at no significant differences among SGA, IUGR, and control fetuses. ^{Reference Perez-Cruz, Crispi and Fernández30} However, studies have shown that maternal alleles affect neonatal homocysteinemia and that maternal levels of tHcys seemed the most powerful independent predictor of cord tHcys. ^{Reference Ophir, Dourleshter and Hirsh29,Reference Gesteiro, Sánchez-Muniz, Ortega-Azorín, Guillén, Corella and Bastida31} Furthermore, significantly higher concentrations of tHcys and fibrinogen were noticed among newborns of pre-eclamptic pregnancies compared to controls, suggesting the intrauterine origin of CVD risk in this population. ^{Reference Ophir, Dourleshter and Hirsh29}

Insulin

In term neonates, there is a hormonal and metabolic adaptation in the perinatal period, whereas, in preterm, abnormalities of glucose homeostasis are customary. Insulin and HOMA-IR appeared increased in ELBW and SGA infants. Additionally, IR increased across rising levels of prematurity and SGA status. ^{Reference Cekmez, Canpolat and Pirgon11} Yet, among IUGR who made a catch-up growth and those who did not, no significant differences were noticed concerning insulin and HOMA-IR, ^{Reference Alonso-Larruscain, Ruibal Francisco and Granizo Martínez32} which appeared to increase in newborns of mothers with GDM or obesity and pregestational DM. ^{Reference Cade, Levy and Tinius17,Reference López Morales, Brito Zurita and González Heredia23} Additionally, infants of obese mothers with pregestational type 2 DM showed impaired cardiac function at one month of age in the absence of septal hypertrophy, which is associated with altered maternal and infant lipid and glucose metabolism. ^{Reference López Morales, Brito Zurita and González Heredia23} Cord insulin levels also associated with maternal fasting glucose, neonatal birth weight z-scores, measures of body composition, and cord lysophosphatidylcholines. Consequently, fetal growth in the first two trimesters possibly associates with insulin levels. ^{Reference Simón-Muela, Näf and Ballesteros12,Reference Pate, Hellmuth and Uhl33} Maternal and neonatal obesogenic alleles significantly affected neonatal insulin and HOMA-IR values, while there are polymorphisms that affect neonatal glucose homeostasis elements, such as insulin, in an opposite manner. ^{Reference Gesteiro, Sánchez-Muniz, Ortega-Azorín, Guillén, Corella and Bastida31} In addition, insulin levels were significantly higher in South Asian neonates compared to Caucasian. ^{Reference Boon, Karamali and De Groot24}

Glucose

Hyperglycemia is directly associated with vascular disease. It is the first mediator of diabetic endothelial dysfunction, leading to impaired vascular health. ^{Reference López Morales, Brito Zurita and González Heredia23} Glucose in term AGA neonates ranges from 3.9 to 6.7 mmol/l (70.2–120.6 mg/dl) (5^th–90^th percentile). ^{Reference Simental-Mendía, Castañeda-Chacón and Rodríguez-Morán34} Its concentrations rise at two days postpartum at approximately 70mg/dl. ^{Reference Gandhi35} In contrast with the previous parameters glucose levels did not significantly differ among term, preterm, ELBW infants or the SGA, AGA subgroups. Similarly, glucose levels did not significantly differ among South Asian and Caucasian neonates. No significant differences were noticed among newborns of obese diabetic mothers, newborns of obese non-diabetic mothers and controls as well. Additionally, glucose itself did not seem to be involved in the impaired cardiac function of newborns of obese diabetic mothers. ^{Reference Cekmez, Canpolat and Pirgon11,Reference Cade, Levy and Tinius17,Reference Boon, Karamali and De Groot24} Yet other studies demonstrated significantly elevated glucose levels in SGA neonates. ^{Reference Kim, Lee and Kim26} Glucose presented with significantly negative associations with birth weight z score, percentage of body fat and the state of LGA among children born to Indigenous and Non-Indigenous Australian women or obese pregnant women. ^{Reference Pate, Hellmuth and Uhl33,Reference Lee, Barr and Longmore36} Cord glucose levels were significantly lower in IUGR neonates who got a catch-up, however, no significant differences were observed regarding during the follow-up. Elevated glucose and triglyceride levels in cord and maternal samples are typical features of SGA used to predict type 2 diabetes and CVD. ^{Reference Alonso-Larruscain, Ruibal Francisco and Granizo Martínez32} Also glucose levels were significantly lower in GDM infants. Glucose along with other metabolic elements presented a direct association with the pathophysiology of GDM. ^{Reference López Morales, Brito Zurita and González Heredia23} Lastly, maternal fat mass and obesity alleles seemed to affect glucose much more than neonatal alleles and several parameters linked to glucose homeostasis did. ^{Reference Gesteiro, Sánchez-Muniz, Ortega-Azorín, Guillén, Corella and Bastida31}

C-peptide

The connecting peptide, or C-peptide, represents pancreatic beta-cell function. In the context of diabetes or hypoglycemia, C-peptide can be used to distinguish between different conditions with similar clinical features. Studies have demonstrated a positive association of cord C-peptide with maternal fasting glucose, cord lysophoshatidilocholines, neonatal birth weight z-scores, measures of body composition, LGA, and neonatal fat; however, there were no associations with infant anthropometry at six months of age. ^{Reference Pate, Hellmuth and Uhl33,Reference Lee, Barr and Longmore36} Significantly higher C-peptide concentrations were noticed in infants of obese diabetic mothers. Also, C-peptide belongs to those infant parameters that correlate with septal segmental longitudinal strain. ^{Reference Cade, Levy and Tinius17} Thus, C-peptide seems to be a strong mediator of the association between maternal BMI and each neonatal outcome across the glucose tolerance spectrum of normal glucose tolerance, GDM, and type 2 diabetes. ^{Reference Lee, Barr and Longmore36}

Insulin-like growth factors I, II (IGF-I, II)

Insulin-like growth factors are molecules with a possible role in DM in the adults. In neonates, their contribution to the development of CVD is a field quite underexplored. However, IGF-I was raised in cord blood of offspring born to obese women because of maternal dysglycemia. ^{Reference Pate, Hellmuth and Uhl33} IGF-1 and IGF-BP3 levels were found similar in the umbilical cord, at 9 months and 12 months in IUGR infants. It is stated that the normalization of insulin levels and IGF growth factor usually occurs during the first three months of postnatal life. ^{Reference Alonso-Larruscain, Ruibal Francisco and Granizo Martínez32} Studies also have shown that at six months of age cord IGF-I was linearly associated with Lysophoshatidilocholines, infant weight z-scores, BMI z-score, and mid-upper arm circumference z-score. Also, it was positively associated with increased odds of catch-down growth, suggesting possible participation in fetal glucose homeostasis and fetal growth. ^{Reference Pate, Hellmuth and Uhl33}

Protein convertase subtilisin/Kexin type-9

Protein convertase subtilisin/Kexin type-9 (PCSK9) plays a key role in lipoprotein metabolism. It is a targeted CVD biomarker in adults. It appeared as an independent predictor of LDL concentrations in IUGR and controls. ^{Reference Pecks, Rath and Maass42,Reference Araki, Suga and Miyake43} PCSK9 levels in IUGR were 35% lower than in the control group. This persisted when subgrouping into early and late-onset IUGR. Furthermore, LDL receptor was significantly upregulated in IUGR. Gender wise, highest PCSK9 levels presented in control males born before 34 weeks of gestation. ^{Reference Pecks, Rath and Maass42} Further data showed that PCSK9 levels of female infants were significantly higher than in males and they correlated with TC and LDL-C. These indicate that PCSK9 is an important regulator of LDL through fetal life. PCSK9 levels were found significantly lower in male SGA neonates than in male AGA, while PCSK9 levels between SGA and AGA female infants presented with no significant differences. Also, male SGA infants presented the lowest serum LDL-C values, among the four studied groups, suggesting a possible influence of PCSK9 on LDL levels concerning these populations. The evidence regarding the relationship between serum PCSK9 levels at birth and the development of dyslipidemia during adulthood is sparse and thus further research is required to assess the predictive power and clinical relevance of this upcoming CVD risk biomarker. ^{Reference Araki, Suga and Miyake43}

Troponins (Tns)

Three subunit proteins (troponin C, I, and T) are involved in the actin–myosin interaction in muscle cells. Tns are increased in several forms of cardiomyopathy, such as hypertrophic cardiomyopathy or left ventricular hypertrophy. ^{Reference Blohm, Arndt and Sandig44} High-sensitive TnI (hsTnI) and hsTnT follow a similar pattern reaching a peak during the first month of life, with a fast decrease during the first six months and a slow-paced decrease until achieving a plateau at adolescence. ^{Reference Clerico, Aimo and Cantinotti45}

Troponin I (TnI)

TnI is a biomarker of myocardial injury (Table 2). HsTnI, presented with no differences among maternal and fetal levels and there was an independent regulation of hsTnI between mother and fetus. ^{Reference Blohm, Arndt and Sandig44} Yet, Cardiac TnI (cTnI) was found significantly elevated in IDMs. In fact, IDMs group with respiratory distress had significantly higher levels of cTnI. CTnI also correlated positively with interventricular septum thickness, intraventricular dimensions, and posterior wall diameter in IDMs. No sex-based differences are reported for cTnI. ^{Reference Korraa, Ezzat and Bastawy46} Further data demonstrate higher levels of cTnI, in term IUGR and SGA fetuses, that presented with echocardiographic signs of systolic and diastolic dysfunction with increased myocardial performance index (MPI) and decreased mitral annular plane systolic excursion. ^{Reference Perez-Cruz, Crispi and Fernández30}

Table 2.

CVD biomarkers of myocardial function

TnI; Troponin I, IUGR; intrauterine growth restriction, SGA; small for gestation, DM; diabetes mellites, US; ultrasound, TnT; Troponin T, GDM; gestational diabetes mellites, BNP; brain natriuretic peptide, NTpBNP; N terminal pro BNP.

* References on biomarker’s correspond to the findings of the included studies.

Also, preeclamptic and/or fetal growth-restricted pregnancies presented with indications of fetal cardiac remodeling and cardiac dysfunction manifested by increased MPI and cord TnI concentrations. ^{Reference Youssef, Miranda and Paules47} Thus, cTnI constitutes a valuable predictor of hypertrophic cardiomyopathy and/or left ventricular dysfunction. ^{Reference Korraa, Ezzat and Bastawy46}

Troponin T (TnT)

Serum cardiac troponin T (cTnT) is considered as a good marker of myocardial injury in conditions such as perinatal asphyxia. CTnT levels are higher in premature infants with respiratory distress syndrome, in macrosomic infants, and infants from pregnancies with GDM and pregestational DM I, II. ^{Reference El-Khuffash, Davis and Walsh48,Reference Mert, Satar and Özbarlas49} At the same time, cTnT levels presented an inverse correlation between cTnT and echocardiographic markers of myocardial function and stroke volume. No gender-based influences were noticed. ^{Reference El-Khuffash, Davis and Walsh48} Elevated cTnT values were found in fetuses with a reversed end-diastolic flow (AREDV) in the umbilical artery. AREDV in the umbilical arteries and ductus venosus pulsatility index for veins were characterized as independent variables associated with abnormal cTnT levels. Severe cardiac compromise, with increased systemic venous pressure, and a rise in right ventricular afterload in the cases of the third group are demonstrated by myocardial damage and elevated fetal cTnT. ^{Reference Nomura, Cabar and Costa50} A possible diagnostic value of cTnT in young children with suspected myocardial injury is supported by studies that pointed out neonatal high levels of cTnT in accordance with congestive heart failure ^{Reference Panteghini, Agnoletti and Pagani51} (Table 2).

Natriuretic peptides

Vitamin D

Interestingly, there is a possible relationship between insufficient vitamin D concentrations and the pathogenesis of early atherosclerotic CVD. ^{Reference Sauder, Stamatoiu, Leshchinskaya, Ringham, Glueck and Dabelea53,Reference Arman and Çetiner54} 25-dihydroxy vitamin D (25OHD) concentrations range from 17 to 34 ng/ml. ^{Reference Adeli, Higgins, Trajcevski and White-Al Habeeb55} 25OHD levels in cord blood and are inversely associated with childhood systolic and diastolic blood pressure. Additionally, neonates with sufficient levels of 25OHD had a significantly lower aIMT than the other 25OHD deficiency groups, suggesting that vitamin D deficiency may induce atherosclerotic changes in vascular structure in term healthy infants. ^{Reference Sauder, Stamatoiu, Leshchinskaya, Ringham, Glueck and Dabelea53,Reference Arman and Çetiner54} These formulate a possible protective role of this molecule against CVD risk.

Other potential CVD biomarkers

Placental 11b-hydroxysteroid dehydrogenase 2 (11b-HSD2) has been negatively correlated with HOMA-IR and fasting insulin and presented a negative association with SBP in one year of age. At the same age, cord cortisol presented a single negative correlation with skinfold thickness which could positively contribute to metabolic health in postnatal life. Cord cortisol and 11b-HSD2 values were unaffected from male or female sex. ^{Reference Chen, Guilmette and Luo56} Further data revealed higher Osteoprotegerin and lower Receptor activator of nuclear factor kappa-B ligand levels in newborns of pre-eclamptic pregnancies. Preeclampsia appeared as an important determinant of osteoprotegerin levels and an independent predictor of increased neonatal blood pressure. Osteoprotegerin levels were also significantly associated with increased diastolic blood pressure. ^{Reference Oikonomou, Papadopoulou and Fouzas57} Concerning serum minerals, neonates within the highest quartile for Mg displayed higher levels of LDL and homocysteine. Newborns with a high Ca/Mg ratio showed low levels of insulin. ^{Reference Ziniewicz, Gesteiro and González-Muñoz58} Urinary proteomics revealed that among the most abundant proteins in preterm were retinol-binding protein, plasma protease C1 inhibitor, antithrombin-III, and angiotensinogen. These upregulated elements are suggestive of higher CVD risk. ^{Reference Cabral, Soares and Guimarães59} Prematurity was also associated with hypoproteinemia mediated impaired cardiovascular function and an “anti-angiogenic” status established by the downregulation of proangiogenic factors, angio-MiRs (inter alia MiR-125, MiR-126, MiR-145, MiR-150, or MiR155) and the upregulation of angiostatic factors endostatin and thrombospondin-2. ^{Reference Bonsante, Ramful and Samperiz60,Reference Gródecka-Szwajkiewicz, Ulańczyk and Zagrodnik61} Serum proteomics have shown that the state of IUGR alters the expression of proteins such as lysophospholipid acyltransferase MBOAT7, serotransferrins, apolipoprotein E, apolipoprotein A-I, SERPIN1, with a known contribution to CVD pathways such as apoptosis, diabetes, dyslipidemia, inflammation, and arterial hypertension. ^{Reference Ruis-González, Cañete, Gómez-Chaparro, Abril, Cañete and López-Barea62} Concerning IUGR, renin, and angiotensin I levels were significantly elevated as well as systolic blood pressure and prolonged mean left ventricular isovolumic relaxation time. ^{Reference Tsyvian, Markova, Mikhailova, Hop and Wladimiroff63} Concerning the peptidome profile of fetal GDM-induced macrosomia, various upregulated peptides play a key role in the regulation of lipids. ^{Reference Liu, Zhao, Liu, Ding, Huo and Shi64} Downregulation of BCL2 genes and miR-181a molecules with a role in obesity, anti-inflammatory, and antioxidant pathways in infants of GDM pregnancies could pose as potential biomarkers for childhood obesity. ^{Reference Marcondes, Andrade, Sávio, Silveira, Rudge and Salvadori65} Further findings suggest an upregulated expression of the cardiac biomarkers cardiotrophin 1 and titin in LGA infants and especially in the GDM subgroup. ^{Reference Briana, Germanou and Boutsikou66} Ultimately oxidant/antioxidant balance is disturbed in favor of oxidants in IDMs presenting with significantly higher total antioxidant capacity, total oxidant status, and oxidative stress index. The extent of oxidative stress is directly associated to the severity of myocardial and hematological involvement in IDMs in the first days of life. ^{Reference Topcuoglu, Karatekin and Yavuz67}