\r\n\tNotably, the book encourages academic scholars and researchers to contribute to the modern concepts of CSR. Fundamentally, it speaks for well-developed literature for entrepreneurs and managers, thus assisting them in the decision-making process.
\r\n\tFurthermore, this book is of great value to policymakers, practitioners, and corporations, thus contributing to various disciplines (e.g., social science and management).
\r\n\tThese proposed themes encourage future researchers and professionals to share their ideas, concepts and work concerning these subject domains. All these suggested topics had recommended under the rubrics of CSR. Perhaps, all the professionals, researchers, and scholars are welcome to submit their piece of work, in particular to the suggested topics.
\r\n\tIndeed, the recommended topics include the following but are not limited to these only.
\r\n\t• Corporate Governance and Sustainability
\r\n\t• Green Innovation and CSR
\r\n\t• Social Entrepreneurship
\r\n\t• Green Economy and Social and Environmental Sustainability
\r\n\t• Sustainable Development and Industrialization
Cardiopulmonary bypass serves the purpose of acting in place of the patient’s heart and lungs during a cardiac operative procedure. The mechanism allows for blood to become reoxygenated in order to ensure sufficient perfusion throughout the patient’s body. The application of this novel concept is attributed to John Gibbon Jr., and its first successful clinical use was reported in 1953 [1]. However, it did not become more practically available until in 1955 when both John Kirklin at the Mayo Clinic and C. Walton Lillehei at the University of Minnesota introduced its routine use in open heart surgery [1].
The utilization of cardiopulmonary bypass increased significantly between the years 1960 and 1969 due to the increased demand brought on by advances in the field of cardiothoracic surgery. Prior to this era, the majority of cardiac surgeries being performed addressed congenital heart disease in an expeditious fashion. Bypass allowed more complex problems to be repaired by allowing more time for the surgeon to operate while the patient maintained perfusion. Additionally, the need for reliable extracorporeal circulation was expanded with the introduction of coronary artery bypass grafting, the development of artificial heart valves, the utilization of deep hypothermia to facilitate circulatory arrest, and heart transplantation [1].
With the use of cardiopulmonary bypass increasing so dramatically, research into further understanding and improvement of the process was initiated, particularly in the 1980s. Special investigative attention was given to the inflammatory reaction induced by cardiopulmonary bypass, the development of drugs to reduce adverse neurologic events, and flow pulsatility [1, 2, 3]. The field of cardiothoracic surgery and the advancement of cardiopulmonary bypass have continued to be refined and improved.
Arterial cannulation is necessary in order to provide oxygenated blood systemically during cardiopulmonary bypass. Currently, there are three different sites that can be utilized to achieve this function:
Distal ascending aorta
Femoral artery
Axillary artery
The most commonly utilized site is the distal ascending aorta. In this instance, cannulation is performed near the origin of the brachiocephalic trunk [4]. In the event this site is not a viable option, the femoral artery is the standard peripheral site. Femoral arterial cannulation can be accessed both by open cutdown technique and percutaneous techniques. If a percutaneous approach is taken, the arteriotomy will need to be closed using a percutaneous vessel closure device or an open repair. If both the distal ascending aorta and femoral artery prove to be high-risk options due to complications, the axillary artery is the next alternative, preferably on the right side. This vessel is accessed via the deltopectoral groove via a standard infraclavicular cutdown.
Determining which arterial cannulation site to use depends on factors such as the procedure being performed, patient body habitus, and the degree of atherosclerotic disease present [5]. Therefore, each case should be evaluated individually to decide upon the best course of action. Based on the surgical procedure, it must be determined if the distal ascending aorta is an appropriate cannulation site. Instances where this may not be the case include repeat sternotomy, emergency surgery, minimally invasive surgery, anatomic anomalies, prohibitive atherosclerotic disease, and robotic cardiac surgery, among others [4]. The benefits of antegrade versus retrograde flow must also be weighed. Both the distal ascending aorta and the axillary artery have the advantage of anterograde flow, whereas the femoral artery exhibits retrograde flow [5]. This is especially important in cases involving aortic dissection. When contemplating using femoral access, excessive arterial calcification, previous groin operations, and body habitus must be considered.
Obtaining the appropriate imaging studies prior to conducting cardiopulmonary bypass is essential, as the information gathered can influence the surgical approach. There are several different imaging options that can be utilized. The most routine preoperative imaging study performed is chest radiography. Chest x-ray (anteroposterior and lateral) can provide information such as the size and shape of the cardiac silhouette, traces of previous thoracic interventions or hardware, severe atherosclerotic disease, and significant pulmonary disorders, in addition to other pertinent information [6]. In the current era, nearly every patient who presents with chest pain has CT imaging ordered by a provider during the work-up. Chest CT can provide an abundance of information regarding the patient’s anatomy and quality of vasculature, as well as many anomalies and abnormalities. Certain findings such as porcelain aorta, dissections, and subclavian stenosis can alter the operative treatment plan. Recent data has suggested that CT should be the standard preoperative imaging for patients with prior sternotomy, as doing so has been associated with a lower risk of perioperative complication [7]. This type of imaging allows for the surgeon to visualize and analyze the sternum more effectively, providing information that will ultimately optimize planning of the surgical procedure [7].
Additional imaging modalities that can be utilized preoperatively include transesophageal echocardiogram (TEE) and transthoracic echocardiogram (TTE). Echocardiography has the ability to provide critical information in order to optimize hemodynamics and identify conditions that had not been appreciated on static imaging [8]. In regard to determining which form of echocardiography (TEE vs. TTE) is most appropriate, several factors should be considered. The imaging quality of TTE is limited by the structures the signal must traverse. TEE has shown to provide superior imaging, particularly for posterior structures that are closer in association to the esophagus including the aorta and both atria [9]. The disadvantages of TEE in comparison to TTE include its invasive nature, requirement for sedation, and increased time to perform. Despite these factors, TEE’s improved ability to visualize critical structures suggests that it should be the echocardiography imaging of choice for procedures requiring cardiopulmonary bypass. In our practice, TEE is regularly performed in the operating room after induction and prior to incision to verify and support the other preoperative cardiac function tests.
Aortic cannulas come in a variety of commercially available options. Cannula size should be selected in conjunction with the perfusionist team so as to utilize the appropriate cannula for adequate flow within the circuit. Too large of a cannula may require an aortotomy that is difficult to close in a standard fashion, while too small of a cannula will not allow sufficient flows. A narrower cannula can cause high pressure gradients, cavitation, or jets of flow which can increase the likelihood of dissection. Diffusion-tip cannulas are available which provide multidirectional flow to reduce jets. The tip of the cannula may be straight, tapered, or angled, as well as made from metal or plastic. Various tip modifications, such as flanges or adjustable rings, are available to prevent the cannula from being inserted too far into the aorta and impeding flow to the head vessels. When using an alternate arterial cannulation site, certain adjustments must be made. Adequate bypass support via femoral cannulation is best achieved with a long, wire-reinforced cannula, whereas the diameter of the axillary artery must be taken into account when selecting an appropriate cannula [10].
Arterial cannulation is almost always completed prior to venous cannulation during the setup for cardiopulmonary bypass. The steps below outline the appropriate manner in which arterial cannulation can be achieved.
Identify the appropriate cannulation site through the use of preoperative imaging, surgical history, and operator preference (Figure 1).
Utilize additional intraoperative imaging, such as TEE and epi-aortic ultrasound (discussed below), and surgical palpation to ensure avoidance of atherosclerotic regions to minimize risk of embolization. Adequate surgical exposure should be obtained through tedious dissection of the desired vessel. When using the axillary or femoral artery, proximal and distal control should be obtained in the form of vessel loops. Ascending aortic exposure should include the origin identification and isolation of the brachiocephalic trunk and the main pulmonary artery, at a minimum.
Two purse string sutures should be placed at the intended access site, typically with monofilament (Prolene™) or braided (Ethibond™) nonabsorbable suture, at a distance that can accommodate an average 20–22F cannula (Figure 2).
These should be snared in the standard fashion, as they will be tightened and tied after the cannula has been removed to close the aortotomy. The adventitia within the sutures is then gently divided to prepare for aortotomy (Figure 3).
Close attention should be paid to the systemic blood pressure, which should be below 100 mmHg prior to aortotomy to decrease the incidence of dissection. A #11 or #15 blade is used to make the aortotomy within the purse string sutures, while the adventitia superior to the incision is pulled gently inferiorly to cover the defect in order to prevent excessive bleeding (Figure 4). The incision should be adequate to accommodate the selected cannula but not excessively wide so as to cause difficulty snaring the cannula in place while on bypass. The selected cannula is then inserted into the aorta, and the sutures snared down (Figure 5). As previously mentioned, the cannula tip should not be inserted any further than necessary so as to provide optimal systemic flow.
Appropriate placement of the cannula is then verified by checking for adequate back-bleeding, which is an opportunity to de-air the cannula as well. Alternatively, the perfusionist may check the arterial waveform for flow verification after the line has been de-aired and connected to the circuit.
The arterial cannula and snares are then tied together with silk ties to provide additional stability [11] (Figure 6).
Ascending aortic exposure prior to cannulation.
Cannulation site opposite brachiocephalic artery with purse string sutures placed. Note the cannula at the lower border of the image with a flange marking the maximum length of desired insertion.
The adventitia is gently removed from the cannulation site within the purse string sutures.
A scalpel is used to make the aortotomy at the cannulation site, while gentle inferior traction is placed with the adventitia to prevent excessive bleeding.
The aortic cannula has been inserted, and the purse string sutures snared down.
The aortic cannula and snared purse string sutures are secured together with a heavy silk suture.
Closing the aortic cannulation site is rather straightforward. The purse string sutures that were placed prior to the cannula insertion are utilized to close the incision once the tubing has been removed. If needed, an additional mattress or figure-of-eight suture can be placed to reinforce the aortotomy [12]. The use of felt pledges is left to the discretion of the surgeon. These are composed of prosthetic material such as polytetrafluorethylene and are used to achieve a greater level of hemostasis, especially in patients with fragile tissue such as the elderly [12]. There is, however, a theoretically increased risk of bacterial infection with their use [12]. When closing femoral or axillary cannulation sites, a bovine pericardial patch is frequently used so as not to narrow the arterial diameter significantly.
If the axillary artery is selected as the cannulation site, the exposure should be completed prior to median sternotomy. The right side is preferred. To isolate the artery, an incision is made 2 fingerbreadths inferiorly at the middle 1/3 of the clavicle. The incision may be extended laterally. The subcutaneous tissue is dissected down to the level of the pectoralis major. The pectoralis major is then split in the direction of its fibers, and the pecoralis minor is retracted laterally. The axillary vein is the first vascular structure encountered. It is dissected out and retracted inferiorly. Care should be taken to ligate small venous branches. The brachial plexus is superior to the artery and should be avoided if possible. Once the axillary artery is dissected from the surrounding tissue and isolated, the decision must be made to cannulate the artery directly or use an extension graft, such as Dacron. If the artery is to be cannulated directly, open transverse arteriotomy may be made or Seldinger technique employed for cannula placement. A graft is most helpful for small arteries where there is concern that the size of the cannula will completely occlude distal flow or if there is concern that the artery will be significantly narrowed when the arteriotomy is closed. If a graft is to be used, proximal and distal clamps should be placed on the artery, followed by a longitudinal arteriotomy. Graft anastomosis is typically completed with a 6-0 polypropylene suture. After the anastomosis is complete, the graft can be cannulated and blood flow to the arm restored. At the completion of cardiopulmonary bypass, the graft may be ligated and oversewn. If a graft is not used, the arteriotomy can be closed in the standard fashion after decannulation. Standard cannulation strategies should be used, as discussed above. After decannulation, the pectoralis major should be reapproximated so as to cover the arteriotomy, and the incision should be closed in layers [13, 14].
The femoral artery has long been used for cardiopulmonary bypass since the advent of cardiac surgery. As mentioned above, the femoral artery is a good alternative to direct aortic cannulation in the setting of porcelain aorta, type A aortic dissection, and re-operative cardiac surgery, as well as minimally invasive cardiac procedures [15, 16, 17]. The femoral artery can be cannulated percutaneously or directly. An extension graft is almost never needed for femoral cannulation, as opposed to axillary artery cannulation.
Several commercial sets are available to assist in percutaneous cannulation. A percutaneous cannulation is unlikely to be successful in patients who do not have a palpable femoral pulse. To start, the femoral artery should be identified by palpation or ultrasound guidance. The common femoral artery should be punctured well above the superficial/profunda femoral artery bifurcation so as to decrease the incidence of limb malperfusion. Seldinger technique is then employed to completed cannulation. When using femoral artery cannulation for aortic dissection, it is vital to identify the guide wire in the true lumen by TEE prior to cannula placement. Closure preferences for the arteriotomy vary. Several commercial closure devices are available, such as Perclose Proglide Vascular Closure Device (Abbott Inc., Santa Clara, CA) [18]. The field of endovascular closure devices is rapidly growing due to the popularity of endovascular procedures such as abdominal aortic aneurysm repair and transcatheter valve replacement. If the arteriotomy is not hemostatic after attempted endovascular closure and prolonged pressure, a femoral cutdown may be necessary for direct surgical closure of the artery.
For open surgical femoral artery cannulation, an incision should be made parallel to the inguinal crease. The subcutaneous tissues should be dissected down until the femoral artery can be identified and isolated. Proximal and distal control is obtained, and the common femoral artery can be directly cannulated. At the termination of cardiopulmonary bypass, the artery is the repaired directly, typically with 4-0 or 5-0 polypropylene suture. Femoral approach, both percutaneous and via cutdown, can be significantly more difficult to successfully perform on obese patients and patients with severe peripheral vascular disease.
Patients undergoing cardiopulmonary bypass are at risk for developing neurological deficits due to the dislodgement of atheroma from the aorta and proximal arch during the procedure [19]. Therefore, it is imperative that these atheromas are identified accurately to avoid the development of such complications. The standard method for detecting atherosclerotic disease of the aorta intraoperatively is manual palpation performed by the surgeon [20]. However, it has been noted that this traditional technique is unable to detect approximately 50% of atheroma lesions due to the presence of soft calcifications that the surgeon cannot appropriately identify [21].
An imaging modality that is routinely utilized in cardiac procedures is intraoperative transesophageal echocardiogram (TEE). TEE has shown to be effective in identifying areas of the aorta that are affected by atherosclerotic disease [10]. However, this method is not comprehensive as the bronchus creates a blind spot due to its position between the aorta and esophagus [19].
The best approach to identifying the presence of atheroma lesions in the aorta and proximal arch is epi-aortic scanning. This method involves directly imaging the aortic root and arch via ultrasound. An investigation conducted by Syliviris and colleagues [21] found that epi-aortic scanning was superior to both palpation and TEE in both identifying areas of atherosclerosis and grading the lesions.
Once the locations of atheroma lesions have been identified, modifications to the surgical approach can be made in order to ensure appropriate cannulation and clamping sites. Avoidance of these diseased locations will help to decrease the likelihood of neurologic complications due to disruption of the atherosclerotic regions.
Intraoperative bleeding can be a painful complication for both the surgeon and the patient. Bleeding from the aortic cannulation site is most commonly from too large of an aortotomy or inadequate snaring of the purse string sutures. To prevent this, careful attention should be paid to the diameter of the purse string “circle” that is created to ensure that it is 3–5 mm wider than the cannula diameter, typically 1.5–2 cm in total diameter. It can be challenging to place an additional circumferential suture after the aortotomy has been made. Additionally, care should be taken when making the aortotomy that the scalpel is not inserted too deeply so as to injure the posterior wall of the ascending aorta.
Monitor circuit and peripheral arterial line mean arterial pressures to ensure adequate systemic circulation. Unequal mean arterial pressures suggests cannula malposition, which can typically be corrected by slightly withdrawing the cannula while taking care not to withdraw the cannula completely. Circuit flow rates should be maintained around 2.4 L/min/m2 to ensure cerebral perfusion. If the flow rates are decreased, cannula position should be verified both visually and with intraoperative TEE.
Visual inspection and palpation of the distal ascending aorta prior to cannulation is of utmost importance in preventing embolic events. A calcified aortic wall is more likely to cause not only difficulty in successfully inserting an aortic cannula but also showering of plaque to the systemic circulation. In addition, intraoperative TEE and epi-aortic ultrasound can be employed to help select an adequate cannulation site for complex aortic walls. If a heavy calcified porcelain aorta is present but not appreciated on preoperative imaging (which would be rare), alternate cannulation sites should be considered. A caveat to this is that atherosclerotic disease that majorly affects the aorta is also likely to affect femoral or axillary vessels.
Aortic dissection is the most feared complication related to aortic cannulation. If not promptly recognized and addressed, the effects can be devastating. Placement of the cannula into the true aortic lumen, as detailed above using adequate pressure gradient monitoring in the bypass circuit, sufficient blood return in the cannula after placement, and verification of placement with TEE significantly decrease the risk of dissection. Atherosclerotic plaques can tear between the medial and intimal layers causing dissection if a cannula is attempted to be forced though a calcified area on the aortic wall. In addition, severe hypertension after decannulation when the aortic purse string sutures are being tied down can lead to tears in the aortic wall layers [3, 22, 23].
Cardiac surgery has undergone significant progress over the last 65 years that would not have been possible without the evolution of cardiopulmonary bypass. Several strategies, tips, and pitfalls have been presented above to provide the greatest opportunity for successful arterial cannulation for bypass.
Vitamin D is a fat-soluble secosteroid. It is a prohormone that can be ingested or derived from body sterols by the photolytic activity of ultraviolet rays on human skin. Vitamin-D is not only an essential element in bone health, but it is also a pro-hormone that plays a well-recognized role in other organs of body. Vitamin D deficiency is a worldwide health issue that affects more than one billion children and adults globally [1]. Vitamin-D deficiency in neonates has been linked to higher risk of respiratory distress syndrome, lower respiratory infections, food sensitivities, asthma, type I diabetes, autism and schizophrenia [2, 3, 4, 5, 6, 7, 8, 9]. Serum 25-hydroxycholecalciferol (25[OH]D) is the main circulating metabolite of vitamin D with a reported half-life of approximately three weeks [10]. It is the best estimator of human body vitamin D stores. During pregnancy it crosses the placenta through passive or facilitated transport according to a concentration gradient [11, 12]. Vitamin-D status in the fetus and newborn infant is largely determined by maternal vitamin-D status [11]. The main risk factor for vitamin-D deficiency in neonates is maternal vitamin-D deficiency [13]. Rickets was a global problem in the early 20th century. It virtually disappeared in developed countries after its causal pathway was identified and fortification of milk with vitamin-D was implemented at population level [14]. Recent reports have suggested that rickets is re-emerging [15, 16] and vitamin-D deficiency is widespread in developed and developing countries [15, 17, 18, 19, 20, 21]. Globally, vitamin-D deficiency at birth is prevalent and in general reflects deficient maternal vitamin-D status [10, 22, 23, 24].
Vitamin D is unique among vitamins because it can be made in the skin from sunlight exposure. Vitamin D has two forms: Ergocalciferol (D2) and Cholecalciferol (D3). D2 is produced from ultraviolet irradiation of the yeast sterol ergosterol and is naturally found in sun-exposed mushrooms. D3 is synthesized in the skin from the cholesterol precursor 7-dehydrocholesterol which is naturally present in the skin or obtained from lanolin [25]. Vitamin D (in the form of D2, or D3, or both) that is ingested is assimilated into chylomicrons, which are absorbed into the lymphatic system and enter the venous blood. Vitamin D that comes from the skin or diet is biologically inert and needs its first hydroxylation in the liver by the vitamin D-25-hydroxylase to 25[OH]D [25, 26]. 25[OH]D undergoes a second hydroxylation in the kidneys by the 25[OH]D-1α-hydroxylase to form the biologically active form of vitamin D 1,25[OH]2D (3, 8). 1,25[OH]2D interacts with its vitamin D nuclear receptor, which is present in the small intestine, kidneys, and other tissues [25, 26].
1,25[OH]2D plays a main physiological role in bone hemostasis. It stimulates intestinal calcium absorption [27]. Without vitamin D, only 10 to 15% of dietary calcium and about 60% of phosphorus are absorbed. Vitamin D sufficiency enhances calcium and phosphorus absorption by 30–40% and 80%, respectively [25, 28]. 1,25[OH]2D interacts with its vitamin D receptor in the osteoblast to stimulate the expression of receptor activator of nuclear factor κB ligand; this, in turn, interacts with receptor activator of nuclear factor κB to induce immature monocytes to become mature osteoclasts, which dissolve the matrix and mobilize calcium and other minerals from the skeleton. In the kidney, 1,25[OH]2D stimulates calcium reabsorption from the glomerular filtrate [25, 29].
The strong correlation between maternal and infant 25[OH]D levels offers further evidence that newborn 25[OH]D levels are dependent on maternal plasma 25[OH]D levels [12, 30, 31]. There is no clear consensus on the cut off levels of serum 25[OH]D levels to define vitamin deficiency. The US Endocrine Society has categorized vitamin D deficiency as 25[OH]D < 20 ng/mL, vitamin D insufficiency as levels 21–30 ng/mL, sufficiency as levels greater than 30 ng/mL, and toxicity as vitamin D levels more than 150 ng/mL [32]. The American Academy of Pediatrics (AAP) and Institute of Medicine define vitamin D deficiency as serum 25[OH]D < 15 ng/mL, mild to moderate deficiency as 5–15 ng/mL, severe deficiency as levels less than 5 ng/mL, and insufficiency as 16–20 ng/mL. They define sufficiency as levels between 21 and 100 ng/mL, excess as 101–149 ng/mL, and intoxication as levels more than 150 ng/mL [33]. The Kidney Disease Outcome Quality Initiative supports the AAP in defining vitamin D deficiency as levels <15 ng/mL. However, it defines insufficiency as levels between 16 and 30 ng/mL and sufficiency as levels of more than 30 ng/mL. An expert committee of the US Food and Nutrition Board (FNB) at the National Academies of Sciences, Engineering, and Medicine (NASEM) concluded that people are at risk of vitamin D deficiency at serum 25[OH]D concentrations less than 12 ng/mL. The same cutoffs were used for both pregnant women and neonates, because experts contend that there is no reason to think the definition of vitamin-D sufficiency varies by age [16].
An US survey from National Health and Nutrition Examination Survey (NHANES) 2011–2014 on serum 25[OH]D levels found that 5.7% women had vitamin D deficiency (<12 ng/ml) and 17.8% women had vitamin D insufficiency (12–20 ng/mL). Rates of deficiency and insufficiency were 7.6% and 23.8% respectively in adults aged 20–39 years. Rates of deficiency varied by race and ethnicity: 17.5% of non-Hispanic Blacks, 7.6% of non-Hispanic Asians, 5.9% of Hispanics, and 2.1% of non-Hispanic White people were at risk of vitamin D deficiency respectively. Vitamin D status in the United States remained stable in the decade between 2003 and 2004 and 2011–2014 [34].
Boston’s cross-sectional study from 2005 to 2007 reported vitamin-D deficiency (25[OH]D < 20 ng/mL) in 35.8% of the mothers and 58% of the neonates, severe deficiency (25[OH]D < 15 ng/mL) in 23.1% of the mothers and 38.0% of the neonates. Risk factors for neonatal vitamin-D deficiency included maternal deficiency (adjusted odds ratio [aOR]: 5.28 [95% CI: 2.90–9.62]), winter birth (aOR: 3.86 [95% CI: 1.74–8.55]), African-American (AA) race (aOR: 3.36 [95% CI: 1.37–8.25]), and maternal body mass index of 35 (aOR: 2.78 [95% CI: 1.18–6.55]) [31].
A Canadian study found a prevalence of 25% vitamin D insufficiency (defined as serum 25-[OH]D < 40 nmol/L) in women aged 18–35 years during the winter season [17]. Vitamin D deficiency is also common in Europe and the Middle East. Vitamin D deficiency defined as serum 25[OH]D < 50 nmol/L or 20 ng/mL, occurs in 6–33% of the population in Northern Europe, in 30–60% in Western, Southern and Eastern Europe and 30–90% in the Middle East countries. Severe deficiency (serum 25(OH)D < 30 nmol/L or 12 ng/mL) is found in >10% of Europeans [35]. Vitamin D deficiency is usually is more prevalent in immigrants from non-Western countries, compared with native European people [36]. This is even worse in pregnant non-Western immigrants, who displayed mean serum 25(OH)D levels around 25 nmol/L [37].
The major proportion of vitamin D is produced endogenously with skin exposure of the skin to sunlight. In tropical areas like India, Africa and middle east, where there is abundant overhead sun for most or all of the year, deficiency of vitamin D is unexpected. However, despite stable and sufficient sun exposure in countries across equator, high prevalence of vitamin D deficiency in pregnancy ranging 26–95% in such areas was reported [38]. In Africa, Asia and the Middle East, women have been always regarded as “high risk” for vitamin D deficiency [39, 40]. In 2009, the International Osteoporosis Foundation reported that vitamin D deficiency was seen in 84% of pregnant women and 96% of infants in Asia [41]. In India, 50–90% of the population suffers from vitamin D deficiency due to inadequate exposure to sunlight and a lower dietary intake [42, 43, 44]. A recent study from northern India reported the prevalence of vitamin D deficiency in 85.5% of mothers and 74% of infants [45]. Vitamin D deficiency, defined as <50 nmol/L of 25[OH]D and severe vitamin D deficiency defined as <30 nmol/L of 25[OH]D was reported in 34% and 18% of the population respectively in African countries [46]. Vitamin D deficiency is even worse in mainland China with deficiency seen in 72% and severe deficiency seen in 37% of pregnant women [47].
Despite the wide intake of prenatal vitamins, Vitamin D deficiency in pregnancy is still common worldwide. The adverse outcomes of pregnancy secondary to vitamin D deficiency include miscarriages, preeclampsia, intrauterine growth restriction (IUGR), increased risk for gestational diabetes, preterm birth and low birth weight infants [48, 49, 50]. Vitamin D deficiency in pregnant women may affect fetal growth, tooth enamel formation and bone ossification [13]. Decreased vitamin D levels in general is associated with increased mortality and vitamin D supplementation reduces mortality [51]. The reasons behind increased mortality include diabetes mellitus, cardiovascular disease and cancer [52]. Vitamin D deficiency has been associated with several autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), Hashimoto Thyroiditis (HT), and multiple sclerosis (MS). Autoimmune diseases are more commonly seen in females than males. Pregnant women with these autoimmune disorders are at increased risk for poor pregnancy outcomes [48, 53].
Animal studies showed that vitamin D deficiency causes placental inflammation which leads to placental insufficiency and potentially fetal IUGR [53]. In both pregnancy and lactation it is important to have adequate vitamin D levels to avoid disturbances in bone and mineral metabolism [54]. The fetal and neonatal status of vitamin D is entirely dependent on the mother’s vitamin D levels. This confirms the correlation of mother and cord blood 25[OH]D concentrations. While 25[OH]D crosses the placenta, 1,25[OH]2D is produced by the fetal kidneys [54]. Research regarding the exact physiological role of vitamin D in pregnancy and lactation is ongoing. There is convincing data that vitamin D is important for the immunomodulation of the maternal-fetal interface [54, 55, 56, 57, 58]. Vitamin D is also crucial for the prevention of pre-eclampsia by stabilizing the endothelium through non-genomic mechanisms [54]. Other functions of vitamin D may include stimulation of sex hormone secretion, implantation/placentation and respiratory epithelium maturation. Vitamin D may also induce epigenetic changes in expressing vitamin D receptors and enzymes involved in vit D metabolism throughout the male and female reproductive tracts [54, 55, 56, 57, 58].
Vitamin D deficiency is prevalent worldwide in pregnant women and infants. In pregnancy, maternal vitamin D physiology is altered to facilitate the transfer of calcium to the fetus. In pregnancy there is a significant increase in 1,25[OH]2 D concentrations with a two-fold increase in the first trimester followed by a 2–3-fold increase during the second and third trimesters of pregnancy. Then there is a rapid decrease after delivery. PTH-related peptide may also regulate serum 1,25[OH]2D concentrations in pregnancy. 1,25[OH]2D synthesis is dependent up the levels of 25[OH]D. There is a positive correlation between serum 1,25[OH]2D and 25[OH]D concentrations and it is stronger in pregnant women compared to non-pregnant women [54].
Eating foods fortified with vitamin D as well as adequate exposure to sunlight are needed for upholding a normal vitamin D status. The most common reasons for vitamin D deficiency are low sun exposure, decreased vitamin D intake, obesity, and low socio-economic conditions. Various factors influence vitamin D synthesis from sunlight, such as latitude, pigmentation, and area of skin exposed. Many prevalent social and cultural practices in Asia and middle east that prevent the adequate exposure of young women and adolescent girls to sunlight contribute to vitamin D deficiency [59]. Increasing urbanization resulting in greater pollution and decreased time spent outdoors coupled with greater skin pigmentation contribute to vitamin D deficiency [60]. When women in these circumstances become pregnant with already low serum 25 [OH]D levels, this contributes to vitamin D deficiency or insufficiency in their offspring. These children at increased risk for developing rickets [49]. Furthermore, vitamin D supplementation is not part of antenatal care programs in developing countries like India [59].
Diets low in vitamin D are more common in people who have milk allergy or lactose intolerance and those who consume an ovo-vegetarian or vegan diet. Women who are homebound, have occupations that limit sun exposure, or who wear long dresses, robes, or head coverings for religious reasons are at risk for vitamin D deficiency due to limited exposure to sunlight [61]. The use of sunscreen also limits vitamin D synthesis from sunlight. Obese women have lower vitamin D levels than nonobese individuals. The skin’s capacity to produce vitamin D is not affected by obesity. In fact, thick subcutaneous fat sequesters more of vitamin D [62, 63]. Serum levels transiently increase following weight loss possibly due to the release of vitamin D in the circulation. This was noted in obese patients after roux-en-y gastric bypass surgery as well as patients with non-surgical weight loss. However, 1 year after a Roux-en-y gastric bypass surgery, vitamin D levels returned to baseline values [64]. Finally, since vitamin D is fat soluble, its absorption is poor in individuals with fat malabsorption disorders like celiac disease, cystic fibrosis, ulcerative colitis and Crohn’s disease [65].
Due to the bone deposition that mostly occurs in the latter half of the pregnancy, vitamin D requirements for the fetus are higher at this time frame [66]. In early pregnancy the plasma levels of 1,25(OH)2D increase and peak in the third trimester. It is estimated that the fetus accumulates 2–3 mg/day of calcium in the skeleton in the first trimester. This calcium accumulation doubles in the third trimester [67]. When infants are born prematurely, the time required for this transfer of Vitamin D and calcium is truncated [68].
Saraf and et al. conducted a global summary and systematic review of maternal and newborn vitamin D status by looking at studies published between 1959 and 2014. They found that 75% of newborns had vitamin D deficiency (defined as 25[OH]D level < 50 nmol/L) and that severe vitamin D deficiency (defined as 25[OH]D level < 25 nmol/L) occurred in 29% of newborns. In this summary, the average newborn 25[OH]D levels in nmol/L by region is as follows: 35–77 (Americans), 20–50 (European), 5–50 (Mediterranean), 20–22 (South-East Asia), 32–67 (Western Pacific) and 27–35 (African). They also found wide variability in 25[OH]D levels within in each defined region [24]. Both this study and another systemic review by Hilger and colleagues found that the average 25[OH]D levels in the general populations in North America were higher compared to Europe and the Middle East [69]. Furthermore, two other reviews found that vitamin D deficiency and severe vitamin D deficiency were more common in South-East Asia and the Eastern Mediterranean regions for newborns [41, 70]. Racial disparity in serum 25[OH]D levels has been well documented in several studies. AA preterm infants and their mothers have lower serum 25[OH]D levels compared to white infants [71, 72, 73]. Seto and colleagues measured cord blood 25 [OH]D levels in 276 AA term infants and 162 term white infants and found that AA infants had a 3.6 greater adjusted odds of vitamin D deficiency [74].
Currently, there continues to be emerging information on the distribution of 25[OH]D levels in preterm neonates. A few studies have documented 25[OH]D levels from neonates at birth with sample sizes ranging from 8 to 278 neonates [2, 75, 76, 77, 78, 79, 80] with mean 25[OH]D levels ranging from ~6.5 ng/mL among preterm neonates in the United Arab Emirates [78] to 26.8 ng/mL preterm neonates in Canada [10]. A recent study on 596 preterm infants from Ohio, USA reported median 25[OH]D level of 18.5 ng/mL for infants born at 34–36 weeks and 18.6 ng/mL for infants born <32 weeks [81].
The levels of 25[OH]D between the mother and the fetus are positively correlated [68, 81, 82]. Kassai et al. found that mothers who gave birth to preterm neonates had significantly lower mean 25[OH]D blood levels compared to those mothers who gave birth at term. Also, preterm neonates had significantly lower 25[OH]D levels compared to term neonates [83]. A study by Burris et al. measured umbilical cord plasma levels of 25[OH]D in 471 infants born at <37 weeks. They found that babies born at <32 weeks are at increased risk for vitamin D deficiency (25[OH]D levels <20 ng/dL) compared to infants born between 32 and 37 weeks [79]. Monagni et al. studied 120 mother infant dyads at three children’s hospitals in Ohio where neonates were delivered at <32 weeks. They not only found that low serum concentrations of 25[OH]D (defined as <50 nmol/L) was common in preterm neonates at admission (64%), but they also found that maternal 25[OH]D levels were lower in infants born at <28 weeks compared to those that were born between 28 and 32 weeks’ gestation. Serum 25[OH]D concentrations in preterm infants directly correlated with maternal vitamin D status at the time of delivery. Low 25[OH]D levels were noted at either 36 weeks post-menstrual age (PMA) or at discharge in 40% of infants <28 weeks and 30% of infants between 28 and 32 weeks PMA. Even though infants received vitamin D supplementation from various sources and intake progressively increased during their hospitalization, only 60% received 400 IU vitamin D daily by 36 weeks PMA or discharge [68].
In contrast to the above studies, a Canadian study and an US study did not show any significant difference in vitamin-D status between term and preterm neonates [10, 81]. A study of 3731 term infants in Jordan revealed that 94% had vitamin D deficiency defined as 25[OH]D level < 50 nmol/L. Shahraki et al. found that 25[OH]D levels in preterm neonates were not significantly lower than term neonates. Over 50% of both the term and preterm infants in this study had vitamin D insufficiency and about 25% had vitamin D deficiency [82]. In a cohort born in Cleveland area in US (latitude 410N), Kanike et al. reported a remarkably high proportion of vitamin-D deficiency and insufficiency among neonates at birth, 31% and 49% respectively. Notably, they noted low stores of vitamin D despite 75% of women reporting regular multivitamin intake during pregnancy. Vitamin D deficiency was found to be more common in AA neonates (63%) than Caucasian (27%) neonates [81]. Bodnar et.al studied 400 mother–infant pairs in Pittsburgh. They showed that nearly 50% of AA neonates and 10% of white neonates, had serum 25[OH]D levels at birth less than 15 ng/mL despite adequate compliance with a 400 IU daily vitamin-D intake by 90% of their mothers [22]. A prolonged winter season with limited sun exposure in Cleveland might be a contributing factor to the vitamin-D deficiency found in this population. There has been no significant improvement in the vitamin-D status among neonates born to AA women in the last 3 decades in Cleveland area [12].
Vitamin-D deficiency is the most common cause of rickets and also increases the risk of respiratory distress syndrome, lower respiratory infections, food sensitivities, asthma, type I diabetes, autism and schizophrenia [2, 3, 6, 8, 15]. Vitamin D deficiency in pregnancy impairs fetal lung development partially through suppressing type II pneumocyte differentiation increasing the risk of respiratory distress syndrome in the newborn period [84]. Furthermore, studies have shown that early onset sepsis and late onset sepsis occurs more frequently in term infants with vitamin D deficiency [85, 86, 87]. To highlight, one study by Singh and Chaudari found that vitamin D deficiency was more common in neonates with early onset sepsis and was associated with increased severity of sepsis and mortality [87].
Vitamin D deficiency prevents effective absorption of dietary calcium and phosphorus. Vitamin D stores in newborn are completely dependent on vitamin D supply from the mother [12]. Not surprisingly, poor maternal vitamin D status during pregnancy is a major risk factor for infant rickets [13, 88, 89]. Severe chronic vitamin D deficiency leads to overt skeletal abnormalities in children like rickets [90, 91]. However, neonates who are vitamin-D insufficient have no apparent skeletal or calcium metabolism abnormalities [16]. In developing countries rickets has been ranked among the five most prevalent diseases in children [92]. Poorer outcomes during pregnancy, at birth and during infancy are associated with lower serum 25[OH]D levels [24, 93]. Reduced bone mass at 9 years of age was seen in children born with low serum 25[OH]D concentrations [94].
There is conflicting data about role of vitamin D and neurodevelopmental outcomes. A meta-analysis by Tous and colleauges found that infants born to mothers with vitamin D insufficiency had lower scores in both mental and language development [95]. In contrast, Wang et al. found that vitamin D deficiency was not associated with neurodevelopment in infancy [84]. A prospective cohort study by McCarthy et al. found no association between antenatal 25[OH]D levels and neurodevelopmental outcomes at 5 years. Tous et al. found that maternal vitamin D deficiency is associated with lower birth weights, smaller head circumference, increased risk for small for gestational age (SGA) status, and preterm birth. Maternal vitamin D insufficiency was associated with increased risk for infants with SGA status and preterm birth [95]. Seto and colleagues found that black infants with vitamin D deficiency had 2.4 greater adjusted odds for SGA status at birth. The association between SGA and vitamin D deficiency was not demonstrated in white infants [74]. Furthermore, a systematic review by Pligt et al. found the maternal vitamin D deficiency was associated with low birth weight, SGA status at birth, stunting of growth immediately after delivery, and preterm birth [96].
As per the US federal government’s 2020–2025 guidelines, fortified foods and dietary supplements are beneficial when it is impossible to meet needs for one or more nutrients during certain life stages such as pregnancy. Milk, many ready-to-eat cereals, and some brands of yogurt, orange juice and margarines are fortified with vitamin D. Trout, tuna, salmon, and mackerel are fatty fish with a high content of vitamin D. One tablespoon of cod liver oil has 1360 IU of vitamin D. Cheese, beef liver and egg yolks naturally contain small amounts of vitamin D. The United States and Canada mandates the fortification of infant formula with 1–2.5 mcg/100 kcal (40–100 IU) vitamin D and 1–2 mcg/100 kcal (40–80 IU) respectively.
Global consensus recommendations on prevention and management of nutritional rickets states that pregnant women should receive 600 IU/d of vitamin-D, preferably as a combined preparation with other recommended micronutrients such as iron and folic acid [97]. The Endocrine Society clinical practice guidelines also recommend at least 600 IU/d of vitamin D in pregnant and lactating women. They also recognize that 1500–2000 IU/day of vitamin D may be needed to maintain 25[OH]D levels>30 ng/mL [32]. However, the average prenatal supplements contain only 400 IU of vitamin D [97]. There is also mounting evidence of the importance of vitamin D supplementation to achieve serum 25[OH]D level of ≥40 ng/ml [55].
Rostami et al. evaluated the effectiveness of a prenatal screening study for optimizing vitamin-D status during pregnancy. The outcome of this program was the prevention of complications of pregnancy. They observed a > 25-fold increase in the number of pregnant women who were able to accomplish a 25[OH]D that was >20 ng/mL when they were screened for their vitamin-D status and provided supplementation compared with pregnant women who were not screened and consequently were not counseled to take vitamin-D supplements. They observed an outstanding decrease in adverse outcomes in pregnant women who were screened and received vitamin-D supplementation. They reported 60%, 50%, and 40% decreases in preeclampsia, gestational diabetes, and preterm delivery, respectively [98].
A recent Cochrane review on Vitamin D supplementation in pregnancy included 30 clinical studies on 3700 pregnant women and reported that taking vitamin D supplements in pregnancy probably reduces the risk of pre-eclampsia, gestational diabetes, post-partum hemorrhage and low-birthweight infant, but there was no difference in the risk of preterm birth before 37 weeks. They also reported that taking vitamin D and calcium together in pregnancy may increase the risk of preterm birth. These results warrant further research [99]. Prenatal supplementation with 4400 IU daily decreased the incidence of asthma and recurrent wheezing in these children at age 3 years by 6.1% [100].
In the 2020 WHO guidelines, routine oral supplementation of vitamin D is not recommended for pregnant women to improve maternal and perinatal outcomes. Pregnant women should be encouraged to receive adequate nutrition, which is best achieved through consumption of a healthy, balanced diet. Pregnant women should be advised that sunlight is the most important source of vitamin D. The amount of time needed in the sun is not known and depends on many variables, such as the amount of skin exposed, the time of day, latitude and season, skin pigmentation and sunscreen use. For pregnant women with suspected vitamin D deficiency, vitamin D supplements may be given at the current recommended nutrient intake of 200 IU per day. This may include women in populations where direct sun exposure is limited.
Vitamin D status is more significant during pregnancy, affecting not only the mother but also her growing fetus, and later, her growing child. There are variations in vitamin D status based on gestation at birth, global region of birth, race, and maternal vitamin D status during pregnancy. The current literature suggests that neonates are at high risk of vitamin-D deficiency, even when mothers are compliant with prenatal vitamins. Current prenatal vitamins may not contain enough vitamin-D to prevent deficiency. There has been substantial debate surrounding the daily requirement of vitamin D and what constitutes sufficiency during pregnancy. Higher-dose supplementation may be needed to improve maternal and neonatal vitamin-D status. Future multicenter studies are needed to determine the minimum dose of vitamin-D requirements during pregnancy to achieve vitamin-D sufficiency. It is time to rethink our approach to ensure vitamin-D sufficiency in pregnant women and their newborn infants.
The authors have indicated no financial relationships relevant to this article to disclose. The authors have indicated they have no potential/perceived conflicts of interest to disclose.
N.K and J.C conceptualized and drafted the initial manuscript and reviewed and revised the manuscript. N.KG reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
IntechOpen - where academia and industry create content with global impact
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Accessions of the cultivated species (Capsicum annuum, C. baccatum, C. chinense, C. frutescens, and C. pubescens) have not all been analyzed for their capsaicinoids content. Identifying Capsicum species and accessions (genotypes) within species with high levels of antioxidants and bioactive compounds (capsaicin, dihydrocapsaicin, vitamin C, vitamin E, phenols, and β-carotene) that contribute to human disease therapy is the focus of this investigation. The main objectives of this chapter are to compile an overview of most recent achievements of the pharmacological properties of hot pepper compounds and provide a rationale for their use as analgesics and to present an evidence that supports the use of capsaicinoids in the treatment of neuropathic pain and other top leading death of worldwide human diseases.",book:{id:"6810",slug:"capsaicin-and-its-human-therapeutic-development",title:"Capsaicin and its Human Therapeutic Development",fullTitle:"Capsaicin and its Human Therapeutic Development"},signatures:"George F. Antonious",authors:[{id:"174916",title:"Dr.",name:"George",middleName:"Fouad",surname:"Antonious",slug:"george-antonious",fullName:"George Antonious"}]},{id:"62311",title:"CAP and Metabolic Diseases: A Mini Review on Preclinical Mechanisms and Clinical Efficacy",slug:"cap-and-metabolic-diseases-a-mini-review-on-preclinical-mechanisms-and-clinical-efficacy",totalDownloads:1313,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Capsaicin (CAP) is the chief active ingredient of natural chili peppers. It has culinary and medicinal benefits. CAP activates its receptor, transient receptor potential vanilloid subfamily 1 (TRPV1), which is expressed in the sensory and motor neurons, adipocytes, liver, vascular smooth muscle cells, neuromuscular junction, skeletal muscle, heart and brain. The specificity of CAP to activate TRPV1 is the fundamental mechanism for its medicinal benefits to treat pain, obesity, hypertension, and other diseases. Preclinical data from rodent model of high fat diet-induced obesity collectively suggest that CAP exerts its effects by activating TRPV1 signaling pathway, which stimulates thermogenic mechanisms in the white and brown adipose tissues to induce browning of white adipose tissues and brown adipose tissue thermogenesis. This leads to enhancement of metabolic activity and thermogenesis to counter obesity. Although CAP and its pungent and non-pungent analogs are used in human clinical studies, their effects on satiety and energy expenditure have been the highlights of such studies. The precise mechanism of action of CAP has not been evaluated in humans. This article summarizes these data and suggests that long-term safety and tolerance studies are important for advancing CAP to treat human obesity.",book:{id:"6810",slug:"capsaicin-and-its-human-therapeutic-development",title:"Capsaicin and its Human Therapeutic Development",fullTitle:"Capsaicin and its Human Therapeutic Development"},signatures:"Baskaran Thyagarajan, Vivek Krishnan and Padmamalini Baskaran",authors:null},{id:"61453",title:"A Matter of Taste: Capsaicinoid Diversity in Chile Peppers and the Importance to Human Food Preference",slug:"a-matter-of-taste-capsaicinoid-diversity-in-chile-peppers-and-the-importance-to-human-food-preferenc",totalDownloads:1254,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Chile peppers are valued worldwide for their distinct capsaicinoid compounds that have been used traditionally in medicine and culinary practices. With 32 known species, five of them domesticated, they provide unique chemical profiles, when consumed by humans. Capsaicinoids, the spicy compounds, are alkaloids used to deter herbivory in the wild, offering protection to the chile pepper fruit seeds. Among the 22 known capsaicinoid structures, capsaicin and dihydrocapsaicin are normally the most abundant. In humans, capsaicin binds to nociceptor TRPV1 that generates a heat sensation. Capsaicin also mitigates inflammation responses in the digestive tract and has the potential to aid in nutrient absorption. Distinct heat profiles were recently described for the five domesticated Capsicum species showing a difference in heat sensations specific to species and pod type. Due to the many capsaicinoid structures, we explore the implications and opportunities of having a diverse array of heat profiles in genetically diverse Capsicum species.",book:{id:"6810",slug:"capsaicin-and-its-human-therapeutic-development",title:"Capsaicin and its Human Therapeutic Development",fullTitle:"Capsaicin and its Human Therapeutic Development"},signatures:"Ivette Guzmán and Paul W. 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His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,annualVolume:11421,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. 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Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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