**2. Vascular Alterations of the Umbilical Cord and Its Impact on the Foetus and Newborn**

### *2.1. Arterial Vascular Alterations of the Umbilical Cord*

Single umbilical artery (SUA) is a variation of cord anatomy in which only a single umbilical artery is present. The absence of the left umbilical artery is more frequent than the absence of the right artery. SUA occurs in approximately 0.5–5% of spontaneous pregnancies, although it depends on the population studied [9]. It is usually the result of an atresia or secondary atrophy of one of the arteries, but it may also be due to a primary agenesis of an umbilical artery or the persistence of the single allantoic artery that originates the umbilical arteries. It can be properly diagnosed with a color Doppler ultrasound of the paravesical umbilical vessels [3].

There is no clear relationship between SUA and certain foetal or neonatal pathologies, although studies suggest increased risks of preterm delivery, caesarean section, low birth weight, small newborn for gestational age and admission to the NICU [10]. The association of SUA with other chromosomal or anatomical abnormalities may also imply changes in foetal and neonatal development [9,11]. The highest incidence of malformation associated has been found in the urinary sytem, cardiovascular system and digestive system [9] If these malformations are present, a genetic testing should be performed [9] such as amniocentesis for karyotype [11].

A similar anomaly is hypoplastic umbilical artery, in which two umbilical arteries are present but one has a significantly smaller diameter than the other, with an artery-to-artery diameter difference of more than 50 per cent [12], which increases blood flow resistance. It can be explained by an atrophy of an artery in late pregnancy. Its association with other abnormalities also affects foetal and neonatal prognosis [12]. Some abnormalities found included trisomy 18, polyhydramnios, congenital heart disease, and fetal growth restriction [12].

Supernumerary vessels are rare in humans, and it is usually a result of the persistence of the right umbilical vein.

Aneurysms in umbilical arteries have also been described. They are a very rare condition and are identifiable by the turbulent pulsatile flow at the ultrasound level. They usually occur together with SUA [10] and are detected in areas near the placental insertion site that are less protected by Wharton's jelly, usually during the second or third trimester of gestation. They are associated with delayed intrauterine growth, SUA, aneuploidy like trisomy 18, cardiac abnormalities and foetal demise [13]. When aneurysm is detected a detailed ultrasaound examination with fetal echocardiography and karyotype should be considered, as well as early delivery [13].

### *2.2. Venous Vascular Disorders of the Umbilical Cord and Their Impact on the Foetus and Newborn*

Vascular thromboses (umbilical cord thrombi) mainly affect the umbilical vein and have been related to other cord abnormalities such as anomalous venous insertion of the cord, an excess of cord coiling, long cords, narrowed cord and little Wharton jelly [14]. They are related to FGR (Fetal Growth Restriction), foetal demise and hypoxic-ischemic encephalopathy [14], so fetus should be closely monitored and a cesarean section surgery should be recommended even without delay [14,15].

These thromboses can be favoured by aneurysms or varicose veins in the umbilical vein, which are identifiable at the ultrasound level as turbulent nonpulsatile flows in areas of dilation. They are more frequent than umbilical artery aneurysms. Vascular thromboses are diagnosed by visualizing dilations greater than 9 mm in diameter or with a diameter greater than 50% of the unaffected vessel and can be intra- or extra-abdominal [16]. Maternal coagulation disorders, vascular endothelial damage and elevated blood glucose have been proposed as possible determining factors to the formation of thrombosis [14] however, the pathogenesis has not been fully elucidated.

Umbilical vain varix is a focal dilatation of the intrabdominalumbilical vein, which has a varix diameter at least 50% wider than the diameter of the intrahepatic umbilical vein [17]. It appears as a fusiform cystic structure.The presence of umbilical venous varices as the only alteration does not usually have foetal repercussions [18]. However, in some studies, the presence of intra-amniotic varicose veins is also related to an increased risk of intra-amniotic haemorrhage, low birth weight and foetal demise [17,19] so fetal monitoring is highly recommended.

### *2.3. Other Vascular Disorders*

The insertion of the umbilical cord is almost always central or paracentral and coincides with the anchorage of the amnion. Velamentous insertion of the umbilical cord consists of the divergence of umbilical vessels, unsupported by the umbilical cord or placental tissue, as they traverse amnion and chorion before reaching the placenta [3]. It is characterized by the presence of membranous umbilical vessels in the region of placental insertion, little Wharton jelly and susceptibility to compression. Vasa praevia consists in an anomaly of the umbilical vessels that cross the membranes of the low uterine segment, unsupported by umbilical cord or placental tissue, with a hight risk of rupture of the vessels [3]. It occurs in 1% of pregnancies [6] and it is more frequent in twin pregnancies [20]. Membrane rupture can cause vessel rupture with a risk of exsanguination and foetal demise. Flow compression can translate into placental infarcts and limb amputations [21–25]. In addition, the risks of low birth weight and perinatal death are increased [20,26].

Although prenatal diagnosis is difficult, the coiling pattern of the umbilical vessels and its relationships with venous percussion and fetoplacental blood flow have also been studied. A hypercoiled or hypocoiled cord has been associated with increased risks of adverse perinatal events and foetal demise [27].

A hypocoiled or hypercoiled cord has also been associated with increased risks of preterm childbirth, loss of foetal well-being, meconium in amniotic fluid, Apgar > 7, small for gestational age, foetal and cardiac abnormalities, foetal demise and NICU admission [28]. The coil pattern of the umbilical cord also seems to have implications for fetoplacental flow, as cords with segmented patterns and linked patterns may result in chronic foetal vascular obstruction and stillbirth [29].

In addition, the absence of proper cushioning by Wharton jelly in thin cords seems to favour vascular compression, with consequent repercussions for foetal flow and uterine growth [30]. A thin umbilical cord with little Wharton jelly has been associated with small placental size and low birth weight; that is, a thin umbilical cord seems to be related to placental insufficiency, intrauterine growth restriction and low birth weight [31–34].

Regarding the length of the umbilical cord, a short umbilical cord has also been related to a higher incidence of adverse events such as urgent caesarean section or low birth weight [32,34]. A longer cord allows wide foetal movements that can increase the risk of crossed and circular entanglement and true cord knots, which can lead to foetal demise [35].

Angiomyxoma, previously also called haemangioma, is an infrequent tumour that arises from the proliferation of mesenchymal angiogenic cells in close relationship with the umbilical vessels [36]. They are usually incidental ultrasound findings, although they can contribute to the involvement of adjacent vessels, favouring hydrops or cord torsion. They are visualized with solid-cystic, echogenic and vascularized mass lesions, usually located in the area of foetal insertion [37]. In some cases, they have been related to foetal

demise due to the risk of compression of vessels, rupture and formation of haematomas that compromise the umbilical flow with the foetus [38].

Haematomas of the cord produced by the extravasation of blood from the umbilical vein to Wharton's jelly have also been described. Although they are infrequent, they can be spontaneous [39] and have a benign course. However, they are usually associated with invasive procedures, infections or morphological abnormalities [40]. They usually have an isoechoic and heterogeneous appearance on ultrasound. This bleeding can be a cause of loss of foetal well-being, intrapartum asphyxia and hypoxic-ischaemic encephalopathy in the newborn [40]. Some studies relate it to oligoamnios in the third trimester, which can increase susceptibility to cord compression [41]. It has also been related to the performance of amniocentesis in the second trimester and an increased risk of prenatal and perinatal death [41].

### *2.4. Foetal Programming: How Vascular Alterations in the Umbilical Cord Can Impact on the Foetus and Newborn*

Vascular alterations of the umbilical cord, among other placental or maternal vascular pathologies such as chorioamnionitis, hypertension or preeclampsia [42–44] can affect foetal oxygenation during pregnancy. Foetal hypoxia results in anaerobic metabolism in which organic acids such as lactate and ketoacids are produced, leading to metabolic or mixed acidosis.

Different environmental or non-environmental stimuli that make up the intrauterine environment can affect gene expression in the umbilical cord and placenta [45]. The epigenetic changes produced by DNA methylation in different tissues can be decisive in the development of the umbilical cord, placenta, and therefore in the fetus and newborn [45]. These changes conform the concept of fetal health programming. During pregnancy, the hypoxia produced by these vascular alterations leads to a state of fetal programming that can affect the health of the newborn and subsequent development during childhood and adulthood [46,47], affecting cardiac, cerebral or renal function [46]. This concept of fetal programming is evolving as the mechanisms that explain it become clearer [46].

Foetal vascular malperfusion is one of the main patterns of placental damage and is the second most frequent cause of cerebral palsy. Involvement of the umbilical cord has been associated with greater foetal vascular malperfusion at the distal villous level [8].

The pH of arterial and venous blood extracted from the cord at the time of birth can be useful to identify newborns at higher risk of an adverse event in the first hours of life [48], although the criteria for performing this measurement are not clearly established. A pH lower than 7 is a criterion of neonatal asphyxia [48], although the extraction of the umbilical vein or artery should be taken into account. Although this is closely related to neonatal morbidity and mortality, the consequences for the foetus and newborn vary [49], and most newborns do not present long-term neurological or behavioural alterations [50–52].

In addition, elevated lactate is a predictor of short-term neonatal morbidity [53] and is associated with increased risks of moderate-severe encephalopathy, cerebral palsy and other cognitive and neurodevelopment alterations [54].

The Apgar Score is used as a quick assessment of the newborn [55] consisting in the assessment of: heart rate, respiratory effort, muscle tone, color and reflex irritability.

Perinatal risk factors can affect the immediate general condition of the newborn [56]. A reduced value in Apgar score could be a predictor of neonatal mortality, especially in very preterm infants [57,58]. However, it is not appropriate to use it alone to identify asphyxia [55]. Also, a high Apgar score could not be sufficient to identify well being newborns as mild metabolic acidosis could be missed [59].

Some studies show a significant and positive correlation between Apgar score and cord pH values [60–62]. This correlation has been proved specially in high-risk pregnancies, where the use of cord pH and Apgar Score could be crucial [56].

### **3. Umbilical Cord Alterations Related to Non-Hypertensive Maternal Diseases**

Many pregnant women suffer endocrine disorders before and during pregnancy. These conditions have been identified as major contributors to stillbirth [63].

Diabetes Mellitus and carbohydrate intolerance are some frequent metabolic diseases during pregnancy that could affect the structure of the umbilical cord. Some studies suggest that even with optimum glycemic control, diabetes mellitus may be a cause of placental alterations and vascular dysfunction [64–66]. Mothers with gestational diabetes mellitus show a down-regulation of vascular endothelial growth factor A (VEGFA), which has a critical role in angiogenesis, producing an abnormal coiling pattern of the umbilical cord [67]. Histopathologic changes have also been described such as a discontinuous endothelial cell of the intima, extravasation of arterial blood to Wharton's jelly, thinner vein wall, and larger lumen [68]. Also, hypo-coiling has been described as one of the main abnormal patterns of coiling in gestational diabetes [69].

Nowadays, obesity has become a frequent condition among pregnant women. Usually is accompanied by other important conditions such as hypertension and diabetes. It is one of the most important preventable causes of stillbirth [70]. A recent study suggests that umbilical cord abnormalities may account for approximately one-fourth of the effect of obesity on the risk of stillbirth at term [71]. Umbilical hyper coiling, velamentous and marginal cord insertion, thrombosis, and long cord have been described in obese women and all these complications are common causes of stillbirth [71]. Moreover, low umbilical cord blood pH has been found in obese pregnant women, proving that obesity can be an independent risk factor for fetal acidosis at birth increasing newborn morbimortality [72].

### **4. Hypertensive Disorders and Chronic Venous Disease during Pregnancy: Placental and Umbilical Cord Alterations**

#### *4.1. Hypertensive Disorders during Pregnancy*

Both the placenta and the umbilical cord are vascular structures that can be altered by systemic or local vascular changes, including those produced by hypertensive disorders of pregnancy such as chronic hypertension, pregnancy-induced hypertension, preeclampsia, HELLP syndrome and eclampsia [73].

Pregnancy-induced hypertension has been linked to histopathological changes in umbilical vessels. Specifically, a decrease in the lumen of the umbilical vein has been described, along with thickening of the tunica media, increased elastic fibres and decreased collagen fibres [44]. The haemodynamic alterations resulting from these changes would impact foetal blood flow and the foetus. These vascular histopathological changes produce an increase in resistance to the flow of the uterine artery. Recently, it has been proposed that analysis of flow velocity waveforms using machine learning analysis, could be useful to improve the diagnosis of umbilical cord abnormalities [74].

Preeclampsia is a pregnancy condition in wich new-onset hypertension occurs after 20 weeks of gestation and it is related to severe obstetric complications. If affects 2–8% of pregnancies ant it is associated with complications such as FGR and preterm delivery [43].

Decreases in the venous area and wall thickness of the umbilical cord have been observed in pregnant women with preeclampsia and may impact cardiovascular development in the foetus and newborn [43]. However, other studies have reported increased wall and tunica media thickness and an increase in the wall-luminal ratio [53]; therefore, more studies analysing these structural changes are needed. The utility of Doppler ultrasonography in predicting pre-eclampsia has not been extensively studied [75]. However, some studies show that abnormal Doppler ultrasonography has good overall sensitivity in predicting pre-eclampsia [75]. Some studies have also found relationships of preeclampsia with hypercoiling, marginal and paramarginal insertion, and SUA [73].

### *4.2. Chronic Venous Disease during Pregnancy: Placental and Umbilical Cord Alterations and Their Impact on the Foetus and the Newborn*

Chronic venous disease (CVD) is a vascular disorder characterized by increased venous hypertension and insufficient venous return from the lower limbs [76]. The haemodynamic changes that occur during pregnancy, such as vasodilation, compression of iliac veins and venous stasis, favour its development [77–80]. CVD has been associated with several alterations in placental structure and function [80–82]. However, the foetal and neonatal repercussions remain unclear and require comprehensive investigation.

At the placental level, CVD has been linked to changes at the level of placental angiogenesis [80], including increases in lymphangiogenesis and angiogenesis. However, the impacts of CVD on placental function, the foetus and the newborn are still unclear.

Elevations of the markers VEGF, TGF beta and PEDF have been observed in the placentas of pregnant women with CVD [81]. These changes suggest that CVD affects the proper development and functioning of the circulatory system, which ensures the correct supply of nutrients and oxygen to the foetus.

CVD has been linked to an increase in the production of reactive oxygen species (ROS) in the venous wall and plasma of affected patients. Elevation of oxidized NADPH (NOXs) has been linked to placental pathology [83] and hypertensive disorders of pregnancy, such as preeclampsia [84]. This oxidative stress has also been detected in the umbilical cord and umbilical foetal blood [85]. At the umbilical level, increases in the gene and protein expression of NOX-1, NOX-2, iNOS, HIF-1alpha and MDA have been observed [86].

Oxidative stress has been linked to ultrasound and cardiotocographic alterations [87,88] such as intrauterine growth retardation, foetal growth restriction, or preterm delivery. According to the foetal programming hypothesis, this oxidative stress is thought to affect the subsequent development of neonatal pathology [87].

In addition, decreases in the expression of cadherin, cadherin 17 and cadherin 6 in the placentas of pregnant women with CVD have been described [89]. Some studies suggest that cadherins are involved in changes in placentation [90–92].

Moreover, pregnancy itself is a proinflammatory state [93,94]. The foetus and neonate are also participants in this proinflammatory state [95]. Some studies have shown that gestational CVD favours this proinflammatory state, as indicated by increases in the levels of proinflammatory cytokines (IL-6, IL-12, TNF-α, IL-10, IL-13, IL-2, IL-7, IFN-γ, IL-4, IL-5, IL-21, IL-23, GM-CSF, chemokines (fractalkine), MIP-3α and MIP-1β) in pregnant women with CVD and in the umbilical cord blood of their newborns [76]. At the foetal and neonatal levels, this proinflammatory profile has been related to multiple pathologies, such as preeclampsia, preterm delivery, and the development of bronchial hyperresponsiveness or overweight during the first years of life and therefore forms part of the so-called "foetal programming" [46,47].

### **5. Conclusions**

The umbilical cord is the link between the foetus and mother and is key in the proper functioning of foetal-placental circulation. As showed in Figure 1, there are plenty possible vascular alterations that may affect the umbilical cord and maternofoetal structures. These vascular alterations of the umbilical cord can compromise or modify foetal blood flow. Hence, changes in the umbilical cord can have a variety of perinatal and neonatal level implications depending on clinical severity as showed in Table 1. Alterations at the level of the umbilical cord are closely related to foetal programming and thus impact the health of the newborn at birth and in later childhood. This array of vascular alterations and CVD emphasizes the need for more studies that allow the establishment of ultrasound, anatomical, histological or plasma markers for the early diagnosis of foetal or prenatal pathologies to prevent foetal and neonatal morbidity and mortality.

**Figure 1.** Histological description and vascular alterations observed in the umbilical cord or affecting the umbilical cord, along with the many maternofoetal consequences derived.

**Table 1.** Main vascular alterations of the umbilical cord and their impact on the foetal well-being and the newborn.



### **Table 1.** *Cont.*


**Table 1.** *Cont.*


**Author Contributions:** Conceptualization, L.S.-T., M.A.S., M.A.O.; methodology, L.S.-T., M.A.O.; software, L.S.-T., C.G.-M., O.F.-M.; validation, M.A.O.; formal analysis, L.S.-T., M.A.O.; investigation, L.S.-T., C.G.-M., O.F.-M., L.G.G., C.B., J.A.D.L.-L., J.V.S., J.B., M.A.-M., N.G.-H., M.A.S., M.A.O.; resources, M.A.-M., M.A.O.; data curation, L.S.-T., M.A.S., M.A.O.; writing—original draft preparation, L.S.-T., C.G.-M., O.F.-M., L.G.G., C.B., J.A.D.L.-L., J.V.S., J.B., M.A.-M., N.G.-H., M.A.S., M.A.O.; writing—review and editing, L.S.-T., C.G.-M., O.F.-M., L.G.G., C.B., J.A.D.L.-L., J.V.S., J.B., M.A.-M., N.G.-H., M.A.S., M.A.O.; supervision, M.A.O.; project administration, M.A.-M., M.A.O.; funding acquisition, M.A.-M. All authors have read and agreed to the published version of the manuscript.

**Funding:** This study (FIS-PI21/01244) has been supported by the Instituto de Salud Carlos III (Plan Estatal de I+D+i 2020–2027) and co-financed by the European Regional Development Fund "A Road to Europe" (ERDF) and P2022/BMD-7321 MITIC-CM, Halekulani S.L. and M.J.R.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

### **References**

