Recommendations for preoperative glycemic control
\r\n\tComputational fluid dynamics is composed of turbulence and modeling, turbulent heat transfer, fluid-solid interaction, chemical reactions and combustion, the finite volume method for unsteady flows, sports engineering problem and simulations - Aerodynamics, fluid dynamics, biomechanics, blood flow.
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His research interest lies in computational fluid dynamics, experimental heat transfer enhancement, solar energy, renewable energy, etc.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"233630",title:"Dr.",name:"Suvanjan",middleName:null,surname:"Bhattacharyya",slug:"suvanjan-bhattacharyya",fullName:"Suvanjan Bhattacharyya",profilePictureURL:"https://mts.intechopen.com/storage/users/233630/images/system/233630.png",biography:"Dr. Suvanjan Bhattacharyya is currently working as an Assistant Professor in the Department of Mechanical Engineering of BITS Pilani, Pilani Campus, India. Dr. Bhattacharyya completed his post-doctoral research at the Department of Mechanical and Aeronautical Engineering, University of Pretoria, South Africa. Dr. Bhattacharyya completed his Ph.D. in Mechanical Engineering from Jadavpur University, Kolkata, India and with the collaboration of Duesseldorf University of Applied Sciences, Germany. He received his Master’s degree from the Indian Institute of Engineering, Science and Technology, India (Formerly known as Bengal Engineering and Science University), on Heat-Power Engineering.\nHis research interest lies in computational fluid dynamics in fluid flow and heat transfer, specializing on laminar, turbulent, transition, steady, unsteady separated flows and convective heat transfer, experimental heat transfer enhancement, solar energy and renewable energy. He is the author and co-author of 107 papers in high ranked journals and prestigious conference proceedings. He has bagged the best paper award in a number of international conferences as well. 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Great strides have been made in technique, safety and outcomes within the past decade and in the face of the advent of newer procedures. This speaks to a better organization of bariatric surgery as a specialty, improved training and the unwavering demand and pursuit of excellence. Despite substantial improvement within the specialty there are a number of comorbid conditions and preoperative findings revealed that necessitate optimization to obtain the best surgical outcomes.
The ultimate goal of bariatric surgery should be to achieve, in as safe a manner as possible, weight loss for the reduction in comorbid conditions and overall long-term effect on mortality and quality of life. A significant contribution to this task has been a more thorough understanding of obesity-related comorbidities and their effects on patient outcomes with respect to perioperative morbidity and mortality. The evaluation of different comorbid conditions through large patient databases has elucidated which comorbid factors contribute towards perioperative morbidity and mortality.
The goal of this chapter will be to review the preoperative evaluation of patients preparing for weight loss surgery. An overview of the general concepts will be described, and then a detailed discussion of the more common comorbid conditions will be presented, along with relevant points and recent literature to support the recommendations. We will utilize an organ system approach. The strategy and rationale for the evaluations that are recommended (or not) will be discussed. Their impact on outcomes will be elucidated for the reader to understand and use to appropriately assess the patient preparing for surgery. An evidence-based approach will show us how to maximize our evaluations of these patients. Awareness of these details empowers healthcare providers to choose and counsel patients appropriately in the preoperative setting.
Weight loss surgery has been shown to have a significant impact on the lives of our patients. Yet, we still face the issue of effectively evaluating and optimizing these patients in the preoperative setting to allow them to partake of the benefits that await them on the other side. The following preoperative evaluations will be addressed in the chapter: indications, cardiovascular, vascular (venous system), pulmonary, endocrine, gastrointestinal, nutritional, psychological, education, functional status. The significance of the final evaluation by the anesthesiologist will also be discussed. Irrespective of the procedure chosen (gastric bypass, gastric bypass, sleeve gastrectomy, duodenal switch), approach used (laparoscopic or open) the preoperative evaluation is essential to prepare the patient for this major lifestyle change.
In 1991 the National Institutes of Health published a consensus statement regarding weight loss surgery. Surgery was indicated in patients with a BMI ≥ 40 kg/m2 and in patients with a BMI between 35 and 40 if they also had comorbidities. Severe sleep apnea, Pickwickian syndrome, obesity related cardiomyopathy, severe diabetes mellitus and lifestyle limitations were all considered comorbidities that would allow the patient to pursue surgery [1]. Since 1991 significant strides have been made in the field of weight loss surgery. It has since been proven to be a method for sustained weight loss and resolution of comorbid conditions. As the benefits to surgery continually develop, movements to change the indications to allow for more patients to achieve the benefits of weight loss have been published. In 2009, recommendations were made to expand the indications to both adolescent (12 – 18 years old) and elderly (>65 years old) patients [2].
For patients with a BMI ≥ 40 kg/m2, surgery is indicated for ages 19 – 64, even without comorbid conditions. Adolescents with a BMI ≥ 40 kg/m2 must have prediabetes, diabetes with Hgb A1c > 9, regardless of therapy or 7-9 on maximal medical therapy, severe hypertension (SBP > 140 and DBP > 90), hyperlipidemia, any degree of sleep apnea or joint pain interfering with daily life in order to qualify for surgery. Elderly patients with BMI ≥ 40, like adolescents, require comorbid conditions to qualify for surgery. The presence of diabetes with Hgb A1c > 9, regardless of therapy or 7-9 on maximal medical therapy, hypertension, hyperlipidemia, moderate to severe sleep apnea, venous stasis, or severe chronic joint pain would indicate the need for weight loss surgery.
Patients with a BMI 35 – 39 kg/m2 and aged 19 – 64 should be recommended for surgery as outlined in the 1991 NIH consensus statement. For adolescents in this BMI range diabetes with Hgb A1c > 7, refractory severe hypertension or moderate to severe sleep apnea are required to proceed with surgery. In the elderly population with BMI 35 – 39 kg/m2, diabetes with Hgb A1c > 9, regardless of therapy or 7-9 on maximal medical therapy, refractory hypertension, and moderate to severe sleep apnea are all criterion which support proceeding to surgery.
Around the world, the indications for surgery differ based on the populations and prevalence of obesity related comorbidities. In Europe, the guidelines allow for surgery in patients with a BMI ≥40 kg/m2, BMI ≥ 35 kg/m2 with severe comorbidities, BMI 30-35 kg/m2 with diabetes, in adolescents if BMI ≥ 40 kg/m2 and in the elderly with a favorable risk to benefit profile [3]. In the Asian population, the visceral fat percentage is higher than in Caucasian persons [4]. Asian persons also have a higher risk of developing diabetes mellitus, hypertension and hyperlipidemia at a lower BMI relative to persons of other ethnicities. These factors support the guidelines in Asia where surgery is recommended for all patients with a BMI ≥ 35 kg/m2. Surgery is also considered for patients with a BMI > 30 kg/m2 with diabetes mellitus or metabolic syndrome and inability to control with lifestyle alterations or medications [5].
Obesity has a negative effect on cardiovascular health. The presence of obesity increases the risk for coronary artery disease, heart failure, cardiomyopathy, atrial fibrillation and hypertension [6]. All of these conditions, if not optimized, can lead to poor surgical outcomes in bariatric surgery patients.
The approach to perioperative cardiovascular evaluation for non-cardiac surgery has been extensively studied. The general principle to follow is that intervention is rarely needed in order to lower risk unless it is indicated irrespective of the perioperative context [7]. There are clinical predictors which place patients into categories based on risk of perioperative cardiac events. Major predictors are unstable coronary syndromes, acute or recent myocardial infarction with ongoing ischemic risk factors, unstable or severe angina, decompensated heart failure, significant arrhythmias, high-grade atrio-ventricular blocks, certain arrhythmias and severe valvular disease. Intermediate predictors include mild angina pectoris, previous myocardial infarctions, compensated or prior heart failure, diabetes mellitus and renal insufficiency. Minor predictors are advanced age, abnormal ECG, rhythm other than sinus, low functional capacity, uncontrolled systemic hypertension and previous stroke. The type of surgery is also associated with cardiac risk. Bariatric surgery is considered an intermediate risk procedure.
Hypertension is found in 13.8 to 25.7 percent of obese patients [8,9]. In patients with stage three hypertension, systolic blood pressure ≥180 mm Hg and a diastolic blood pressure ≥ 110 mm Hg, the risk of proceeding with surgery must be evaluated [7]. Presence of hypertension as a comorbidity is an independent risk factor for mortality after open or laparoscopic gastric bypass with an odds ratio of 2.783 [10]. Treatment with beta blockers has been shown to decrease the risk of myocardial infarction and cardiovascular death in high risk patients [11]. When indicated, beta blockers should be initiated several weeks prior to surgery and titrated to achieve a resting heart rate of 50 to 60 beats per minute [12]. As bariatric surgery is an elective procedure, we recommend delaying surgery until adequate blood pressure control is achieved. Hypertension should be controlled before surgery with continuation of the preoperative antihypertensive treatment through the perioperative period [7]. Caution is advised when preparing a patient taking clonidine or beta blockers for surgery, due to known rebound hypertension upon abrupt discontinuation. These antihypertensive agents may be converted to transdermal or intravenous forms, respectively, during the time a patient is nil per os (NPO)[11]. Continuation of beta blockers through the perioperative period is recommended in those patients being treated for angina, specific arrhythmias, hypertension and other American College of Cardiology (ACC)/American Heart Association (AHA) Class 1 guideline indications [7].
The myriad of available tests to assess cardiac function can be overwhelming and choosing which test to order can be confusing. Generally evaluation begins with a 12-lead electrocardiogram (ECG). In bariatric surgery patients ECG abnormalities can uncover predictors of perioperative and long term cardiovascular risk. ECG is recommended in all patients who have had a recent episode of chest pain, asymptomatic patients with diabetes mellitus, patients with prior coronary revascularization, asymptomatic males over 45 years old or females over 55 years old with two or more atherosclerotic risk factors and those patients who have had prior hospital admissions for cardiac causes [7]. Further evaluation of cardiac function involves stress testing and coronary angiography. Both methods are geared towards identifying patients with cardiac ischemia.
Exercise or pharmacological stress testing is recommended in adult patients with intermediate pretest probability of coronary artery disease based on ECG, those undergoing initial evaluation for suspected or proven coronary artery disease and patients with a significant change in clinical status. Exercise testing is also useful to evaluate exercise capacity when subjective measures are unreliable [7]. Some patients will not tolerate an exercise stress test. In this group of patients a pharmacological stress test should be considered. Noninvasive cardiac imaging without the use of pharmacological stressing agents is able to provide visualization of left ventricular function at rest. Although this test is commonly done during preoperative evaluations it is not a consistent predictor of perioperative ischemic events. Non-invasive stress testing, such as a dobutamine stress echocardiogram, is able to predict perioperative cardiac events by visualizing the amount of myocardium at risk for ischemia [7]. It has been shown, however, that the accuracy of thallium-201 nuclear cardiac imaging can be diminished in patients who have a BMI over 30 kg/m2, which is specific to our patient population [13]. There is mounting evidence that cardiac computed tomography angiogram can be used as a method to evaluate the coronary vasculature in patients unable to tolerate exercise prior to invasive imaging procedures [14].
Coronary angiography is the definitive test for intraluminal causes of cardiac ischemia. The procedure is diagnostic and can also be therapeutic with the usage of balloon angioplasty with or without stent placement. Coronary angioplasty should be done on patients with suspected or known coronary artery disease. These patients have a high risk of adverse outcome based on noninvasive test results, angina unresponsive to adequate medical therapy or unstable angina [7]. Percutaneous coronary intervention (PCI) does not decrease the risk of perioperative cardiac events except in those patients in whom PCI is indicated for acute coronary syndrome. Although the PCI can reduce perioperative cardiac events, one of the major limitations of treatment is the subsequent delay in surgery due to the direct mechanical effects of angioplasty or the required anti platelet therapy. Patients who undergo PCI with balloon therapy alone should undergo surgery between four and eight weeks after catheterization. Before four weeks the dilated blood vessels have not fully healed and after eight weeks the risk of restenosis is high [7].
Cardiac medications after coronary artery stenting present a controversy for the surgeon as the drugs increase the risk of bleeding during the perioperative period. Stent placement requires dual anti platelet therapy with clopidogrel and aspirin in the post PCI period to prevent stent thrombosis. The American College of Cardiology and The American Heart Association recommend that dual anti platelet treatment is required for at least one month in patients receiving bare metal stents and for one year with drug eluting stents [7]. In a literature review currently in press, the authors examined the perioperative management of anti platelet therapy and they found variability among the recommendations. However, they recommend delaying surgery for at least four to twelve weeks in patients with bare metal stents. In patients with drug eluting stents they recommend postponing surgery for at least six to twelve months [15]. Specific to elective surgery, such as the bariatric population, Katkhouda et al recommends that patients with bare metal or drug eluting stents should not undergo surgery within the first year of stent placement. If, as determined by a cardiologist, the patient requires dual therapy longer than one year after stent placement, clopidogrel and other thienopyridines should be stopped five to ten days preoperatively and restarted ten days postoperatively [12]. The continuation of aspirin through the perioperative period is recommended [12,15]. In patients undergoing gastric bypass it is recommended to start proton pump inhibitors one week preoperatively and subsequently continue them through the perioperative period to minimize the risk of gastrointestinal bleeding upon restarting clopidogrel therapy [12].
Management of valvular heart disease is dependent on the pathophysiology of the valve. Patients with symptomatic aortic stenosis should have their surgery delayed and undergo valve replacement prior to non-cardiac surgery. If the patient has severe stenosis but is asymptomatic the aortic valve should be evaluated with imaging. Patients unwilling or unable to undergo cardiac surgery for severe aortic stenosis have a 10% mortality rate from non-cardiac surgery. With mild or moderate mitral valve stenosis, the heart rate must be controlled during the perioperative period to minimize pulmonary congestion created by decreased diastolic filling times. Patients with significant mitral stenosis are at risk for heart failure during the perioperative period. Operative correction of mitral stenosis is not recommended unless the valvular condition should be corrected to prolong survival and prevent complications that are unrelated to the non-cardiac surgery [11].
Congestive heart failure (CHF) has been found to be a significant factor in perioperative cardiac events. The preoperative evaluation must include screening for CHF which can be done with history and physical exam alone – look for prior history of heart failure, symptoms of paroxysmal nocturnal dyspnea, presence of an S3 gallop, jugular venous distention, peripheral edema, bilateral rales on lung auscultation and evidence of pulmonary vascular redistribution on chest x-ray [11]. The Framingham Heart Study identified obesity as an independent risk factor for the development of heart failure; with the risk increasing by 5% in men and 7% in women for every 1 kg/m2 in BMI [16]. The optimal treatment for CHF is determined by identifying the cause and degree of failure.
Close collaboration with the patient’s cardiologist during the preoperative workup can allow for a smooth progression through preoperative cardiac testing, while accurately assessing and optimizing risk factors.
Venous thromboembolic events (VTE) continue to be one of the most significant postoperative complications after weight loss surgery; the other being staple line leaks and the associated septic sequelae. Obesity is considered a hypercoagulable state. The odds ratio of VTE is between 1.97 and 2.39 in those with a BMI greater than 30 kg/m2 [17]. Bariatric surgery has been also been associated with a hypercoagulable state due to increased levels of clotting factors during the perioperative period from surgical trauma [18,19]. VTE events are a leading cause for mortality after bariatric surgery [20]. It is generally recommended that patients undergoing weight loss surgery receive VTE prophylaxis during the perioperative period. Postoperative ambulation and lower extremity sequential compression devices are safe and recommended for all bariatric patients when appropriate. The proper use of chemoprophylaxis and the preoperative insertion of inferior vena cava (IVC) filters have been controversial.
The identification of deep venous thrombosis is fundamental to preventing further complications from clot progression or embolus. The preferred method for evaluation is venous duplex ultrasound. This study has a sensitivity and specificity of 97% and 94%, respectively, of diagnosing a proximal lower extremity DVT [21]. Traditionally, many bariatric centers included this exam as part of the preoperative workup. A five year retrospective review of our own bariatric patient population revealed that only one of 555 patients (0.2%) was found to have a DVT on preoperative workup. This patient had a history of a chronic DVT, known prior to the examination. Our findings coincided with two previous studies which also showed that no preoperative investigation is needed [22,23]. Based on these finding we do not recommend routine preoperative venous duplex ultrasound; however, testing may be warranted in patients with prior history of DVT or significant venous insufficiency.
The preoperative placement of inferior vena cava (IVC) filters has been reported in high risk bariatric surgery patients. In some institutions, it was routine to have an IVC filter placed in patients with BMI greater than 55 kg/m2, immobility, venous stasis, pulmonary hypertension, obesity hypoventilation syndrome, hypercoagulability, and a history of VTE [20]. It was recommended that patients with BMI greater than 55 kg/m2 undergoing open gastric bypass undergo placement of IVC filter while those having laparoscopic surgery could forego the filter placement [24,25]. Recently, however, the routine use of IVC filters has undergone scrutiny. The Michigan Bariatric Surgery Collaborative (MBSC) published the largest series to date regarding the efficacy of preoperative IVC filters in gastric bypass patients. They found that there was no difference in the rates of VTE, serious complications and death or permanent disability [26]. In the same month, the United States Food and Drug Administration (FDA) published an advisory report regarding the use of retrievable IVC filters. They highlighted 921 device related adverse events since 2005. The FDA recommended a judicious approach to placement and vigilant follow up for prompt removal of IVC filters [27]. This prompted another study from the MBSC to investigate outcomes in patients treated with IVC filters. They discovered that patients with IVC filters had worse outcomes than comparable patients without IVC filters. A significant number of patients with IVC filters were also subjected to device related complications, such as thrombosis and occlusion, filter migration, contrast induced nephropathy and incision site infection. They found the rate of DVT and VTE were significantly higher in patients with IVC filters, odds ratios 2.7 and 3.3, respectively. Furthermore, there was no difference in the rates of pulmonary embolus between the groups. They concluded that IVC filters do not reduce the risk of pulmonary embolism in high risk bariatric surgery patients and that their use should be discouraged in bariatric surgery patients [28].
Chemoprophylaxis is generally achieved with subcutaneous injections of unfractionated heparin (UFH) or low molecular weight heparin (LMWH). Since patients are most susceptible to venous stasis during the induction of anesthesia, the first dose of chemoprophylaxis should be given preoperatively [29]. Our patients receive 5,000 units of unfractionated heparin administered subcutaneously immediately prior to entering the operating room. All patients are also treated with bilateral lower extremity sequential compression devices, which are placed prior to induction of anesthesia. This combination of chemical and mechanical prophylaxis has been shown to limit the development of deep venous thrombosis and bleeding complications [22]. Dosages and frequency vary among the different formulations of low molecular weight heparinoids, as does their method of action. A recent literature review concluded that there are three “standard regimens” for chemoprophylaxis of VTE – UFH 5000 units 2 – 3 daily, LMWH 30 mg twice daily, 40 mg once daily or weight adjusted LMWH [30]. The authors concluded that there was no difference in the rate of VTE among the different regimens, but the use of weight adjusted dosing increased the risk of major bleeding.
Patients with a history of heparin induced thrombocytopenia (HIT) type 2 present a unique challenge in VTE prophylaxis. This population has not been studied in bariatric surgery; however, VTE prophylaxis in the orthopedic population with HIT type 2 is accomplished by the use of desirudin administered subcutaneously [31]. More investigation is needed to recommend this medication usage beyond the specialty of orthopedics.
Obesity related impairment of respiratory function is caused by mechanical restriction of adequate ventilation. The increased adipose tissue reduces diaphragmatic excursion, chest wall expansion and oropharyngeal patency. Obesity is also a risk factor for airway disease and there is a 50% higher incidence of severe asthma in obese patients when compared to normal controls [32,33].
A reduction in the expiratory reserve volume (ERV) is the most commonly identified abnormality on spirometry. Both body mass index and body fat distribution contribute to the degree of decrease in ERV. Hamoui et al has shown that in patients undergoing open duodenal switch procedures there is a relative risk of 2.29 to develop postoperative complications for every 10% decrease in percent of predicted value of vital capacity (VC). They also found that patients with a VC of less than 80% of predicted have a 54.5% prevalence of postoperative complications [34].
The increased rate of complications was also found in laparoscopic bariatric surgery. In 2013, van Huisstede et al prospectively examined their patients undergoing laparoscopic gastric bypass and laparoscopic sleeve gastrectomy. Among the 485 patients studied, they found patients with airflow obstruction (FEV1/FVC < 70%) or airflow reversibility (change in FEV1 > 12%) after administration of a bronchodilator, had an increased risk of postoperative complications with an adjusted odds ratio of 2.9 [35]. They recommend spirometry be done routinely on all patients being evaluated for bariatric surgery. The authors of this chapter follow these recommendations and routinely evaluate all patients with preoperative pulmonary function tests.
As pulmonary function tests are often abnormal in obese patients, the causes for abnormality must be identified and optimized prior to surgery [34]. Smoking is a common entity which significantly impacts pulmonary function therefore smoking cessation is an essential component of the preoperative assessment. In a study of over 300,000 patients from the Nationwide Inpatient Sample database smoking was identified as an independent factor associated with a greater incidence of acute respiratory failure after bariatric surgery [36]. Smoking has also been shown to be an independent predictor of increased hospital length of stay. Current and past smokers have been shown to require four and one days longer in the hospital, respectively, than patients that never smoked [37]. Nicotine, in all forms, is known to have vasoconstrictor properties. This may add to the microvascular disease caused by smoking which has been reported to increase the incidence of marginal ulceration and gastrointestinal anastomotic dehiscence [38,39]. It is our recommendation to not offer surgery to patients who are current smokers and to those using a nicotine replacement in an attempt to quit smoking. It is our practice to require smoking cessation to minimize the above mentioned morbidities.
Obstructive sleep apnea (OSA) is a condition in which the upper airway periodically becomes narrowed or obstructed during sleep and results in reduction or cessation of breathing during sleep. The reduction in airway caliber is due to the sleep induced loss of muscle tone in the soft tissues of the oropharyngeal airway. Obstructive sleep apnea is found in 38 – 88% of morbidly obese patients [40]. There are many screening tools available to the bariatric surgeon to identify patients at risk for having OSA. The Epworth Sleepiness Score, the Maintenance of Wakefulness Test, the Berlin Questionnaire and the STOP-BANG Questionnaire are designed to quickly asses if a patient should be screened further. The definitive diagnosis of OSA is made with an overnight polysomnography. The test measures the number of hypopnea (30% or greater decrease in airflow for at least 10 seconds followed by an arousal and/or 3% oxygen desaturation) and apnea (complete or near complete cessation of airflow for at least 10 seconds followed by an arousal and/or 3% oxygen desaturation) events and results with an ‘apnea hypopnea index’, which is classified to the severity of the sleep apnea [41]. Nonoperative treatment of OSA is achieved with non invasive positive pressure ventilation in the form of continuous positive airway pressure (CPAP) or bi-level positive airway pressure (Bi-PAP). Many patients receive the diagnosis for the first time during the preoperative work up for bariatric surgery. These patients should be allowed to adapt to the device prior to undergoing surgery. With regards to anastomotic integrity, the use of CPAP has been proven to be safe after roux-en-y gastric bypass [42]. In order to maximize compliance, patients should bring their own machine and mask to the hospital. Although the use of CPAP or BiPAP is recommended in the postoperative setting, its omission has also been proven safe provided the patient is an a monitored setting with aggressive pulmonary physiotherapy [40].
In addition to OSA, patients with super morbid obesity can have pulmonary derangements while awake; this is termed obesity hypoventilation syndrome (OHS). More specifically, obesity hypoventilation syndrome manifests with daytime hypercapnia with PaCO2 > 44 mm Hg or 6 kPa, elevated hematocrit, and sleep disordered breathing. These patients are at high risk for pulmonary complications and VTE [40]. Obesity hypoventilation syndrome occurs in 11% of patients with OSA and in 8% of bariatric surgical patients [43]. Patients with OHS have severe upper airway obstruction, impaired respiratory mechanics, blunted central respiratory drive and increased incidence of pulmonary hypertension. The diagnosis of OHS is also made with polysomnography. The treatment of OHS is similar to OSA in that positive airway pressure and supplemental oxygen are used to facilitate adequate respiration.
We reviewed our patient database and found that approximately 85% of patients had undiagnosed obstructive sleep apnea with 51% of patients having severe sleep apnea. In the lower BMI range (35-39.9 kg/m2) our population showed 92% prevalence of OSA. There was a 100% prevalence of obstructive sleep apnea in those with a BMI greater than or equal to 60 kg/m2. Based on these results, we can see that BMI does not correlate with the presence of OSA. In a larger study of 2,458 patients, 509 patients underwent polysomnography within one year prior to bariatric surgery. In this population 80.7% of patients were found to have obstructive sleep apnea and 35.5% of these patients had severe sleep apnea [44]. Although some authors advise that polysomnography should only be used if the patient exhibits symptoms of OSA or OHS, we recommend that all patients be actively evaluated with polysomnography in the preoperative period. If found to have sleep apnea, the patients are started on positive pressure ventilation by mask, at the settings recommended, for several weeks prior to surgery. On the day of the surgery, the patient is instructed to bring their machine to the hospital and the machine is routinely used, starting in the recovery room.
The anesthesia preoperative assessment is the culmination of all consults pertinent to the optimization of the physiological status of the patient. Provided that major cardiopulmonary issues, cerebral, and metabolic derangements have been addressed, the anesthesiologist should be able to proceed with the surgery in a controlled and safe manner. As the preoperative optimization of these organ systems have been addressed previously in this chapter, the focus of the anesthesiology section will be intravenous access, blood pressure monitoring, aspiration risk, and airway management on induction of anesthesia.
Peripheral intravenous access in the bariatric patient may be difficult. The anesthesiologist should be prepared to use ultrasound guided techniques or central venous access placement in patients where intravenous access is difficult. Arterial line placement may be utilized when an appropriately sized blood pressure cuff may not reflect accurate readings secondary to the conical shaped arms in this population [45]. The possibility of central line placement preoperatively should be discussed with the patient prior to going into the operating room.
Airway management during anesthesia induction may be challenging in the bariatric population. BMI ≥ to 40 kg/m2 has been associated with significant airway management challenges. Some institutions have mandated having an attending and one other experienced anesthesia provider (attending, an anesthesia resident with floor intubation credentialing, or CRNA available for intubation in this population). Due to excess soft tissue related to the anatomy, face mask ventilation of the morbidly obese patient may be difficult. Increased BMI and a history of OSA also increase the possibility of difficult face mask ventilation [46]. When a Mallampati 3 or 4 score is assessed, there has been increased difficulty in intubation, see figure 1 [47].
Mallampati Classification and Laryngoscopic View Grades.
Ramping position.
Positioning of the bariatric patient in the supine position, as seen in figure 2, such that the external auditory meatus is in line with the sternal notch, known as ramping, is recommended [48]. A recent study demonstrated that in the morbidly obese population undergoing bariatric surgery, when using the “ramping” position, there was no correlation between difficult direct laryngoscopy and OSA in Mallampati 1 and 2 classifications. Patients with a BMI of 35kg/m2 have been associated with a greater than 6 fold increase in difficult direct laryngoscopy. Neck circumference over 40 cm has also been implicated in difficult direct laryngoscopy [49].
In addition to ventilation and intubation concerns, aspiration risk must be considered. It has been reported that the gastric fluid of morbidly obese patients is more voluminous and of lower pH than that of the leaner patients [50]. These patients can be considered for rapid sequence induction, a technique for inducing a patient without ventilation. This technique may expose the anesthesiologist to a greater chance of airway failure. Neutralization of gastric acid with clear antacid solutions such as sodium citrate can be prophylactically given preoperatively.
There are many adjunct airway devices available to assist in the intubation of a challenging airway. The advent of video laryngoscopy, a plethora of supraglottic airways and flexible fiber optic intubation has provided multiple modalities and techniques for intubation of the challenging airway.
When assessing the airway of the bariatric patient, a preoperative plan for securing the airway safely is invaluable. The American Society of Anesthesiology (ASA) Difficult Airway Algorithm gives several pathways for the management of the difficult airway, whether the patient is awake or asleep, see figure 3 [51].
If the anesthesiologist’s evaluation raises doubt in the ability to safely manage the airway, awake intubation should be undertaken [52]. It is also important to remember that BMI alone does not predict the probability of a difficult intubation. Preparedness, vigilance and communication with the surgeon will result in a favorable patient outcome.
Difficult Airway Algorithm.
Evidence is accumulating that suggests obesity is closely related to endocrine disorders, some at a subclinical level. Obesity has been found to be associated with type 2 diabetes mellitus (T2DM) and hypothyroidism [53,54].
Management of T2DM is important during the perioperative period. Targets have been established by the American Association of Clinical Endocrinologists, The Obesity Society and the American Society for Metabolic and Bariatric Surgery for preoperative glycemic control which may be associated with improved outcomes, see table 1 [53].
• Hemoglobin A1c of 6.5 – 7.0 % or less • Fasting blood glucose level of less than or equal to 110 mg/dL •2-hour postprandial blood glucose concentration of less than or equal to 140 ml/dL | \n\t\t
Recommendations for preoperative glycemic control
Optimal glycemic control should be achieved preoperatively, as patients with an elevated preoperative hemoglobin A1c are found to have a higher incidence of postoperative complications. A hemoglobin A1c level greater than 8% increases the risk of wound infection and acute renal failure postoperatively. An elevated A1c in the preoperative setting also increases the likelihood of elevated blood glucose in the postoperative setting and decreases the rate of resolution of T2DM after bariatric surgery [55]. Preoperative control can be achieved with a combination of diet modification, weight loss and pharmaceuticals.
Hypothyroidism is a known cause of obesity; however, de novo thyroid dysfunction has been observed in obese patients. It has been suggested that subclinical hypothyroidism is associated with obesity [54]. In some patients, the TSH level has been shown to return to normal levels after significant weight loss, however the outcome is not universal. The ASMBS does not recommend routine screening for primary hypothyroidism in the obese patients, however many bariatric programs require such preoperative screening in keeping with the NIH guidelines to ensure there is no organic cause to the obesity [53,56].
Obesity is a risk factor for gastroesophageal reflux disease, erosive esophagitis, and esophageal adenocarcinoma [57]. The presence of gastrointestinal diseases has an effect on the type of bariatric procedure, which can be recommended for a patient and may require treatment prior to weight loss surgery. In addition, after surgery, the restrictions and rearrangement of the alimentary tract can limit evaluation and surveillance options. There are many modalities for assessing the gastrointestinal tract in the preoperative setting.
The American Society for Gastrointestinal Endoscopy (ASGE) recommends an upper endoscopy be performed in all patients with upper GI tract symptoms and in all patients undergoing weight loss surgery [58]. Preoperative esophagogastroduodenoscopy has been found to reveal abnormalities in 46 to 90% of patients, with 62% having clinically significant findings. In our practice, all patients being evaluated for bariatric surgery undergo upper endoscopy. However, a five year, internal review of 555 patients has shown 98% of our patients had positive findings on routine upper endoscopy yet the findings did not cause a delay or impact on the choice of surgical procedure – questioning the clinical significance of the findings.
During endoscopy tissue biopsies should be obtained to evaluate for H. pylori. If the bacterium is isolated, eradication with one of several standard regimens is recommended. Recently, there has been growing support for non-invasive testing for H. pylori in an effort to reduce costs associated with preoperative testing [59]. One potential algorithm for non-invasive testing involves screening patients with serum H. pylori test and treating the patient if it is positive. In either case, proof of eradication should be obtained, typically via urea breath test. Recently published data indicates that preoperative H. pylori status does not increase the risk for marginal ulcer or stomal stenosis post roux-en-y gastric bypass [60].
The World Health Organization (WHO) reports the incidence of gastric cancer is highest in the western pacific region, which comprises 27 countries including China, Japan, Republic of Korea, Malaysia, Singapore and the Philippines. The incidence in this region was 521,000 cases in 2004, greater than 50% of the worldwide incidence [61]. In countries where gastric and other upper gastrointestinal cancers are more prevalent, the importance of preoperative upper endoscopy cannot be underestimated. Ultimately, practice patterns should reflect the prevalence of significant findings specific to the patient population being prepared for weight loss surgery.
As an adjunct to endoscopic examination of the gastrointestinal tract several radiographic investigations are also considered during the preoperative evaluation for bariatric surgery. Gastroesophageal reflux disease associated with hiatal hernias is commonly found in obese patients. Completing a bariatric procedure without recognizing and repairing a hiatal hernia can potentially lead to worsening of reflux and poor surgical outcomes [62]. In order to identify a hiatal hernia some surgeons obtain contrast enhanced upper GI series. We do not employ upper GI series routinely in our preoperative evaluations. Hiatal hernias that are identified on preoperative upper endoscopy are discussed with the patient for informed consent and subsequently investigated during the operation. In our experience, clinically significant hiatal hernias are readily identifiable upon laparoscopic inspection and repaired as indicated.
In our practice we routinely assess the size of the liver prior to surgery by abdominal ultrasound. Greater than 30% of morbidly obese patient show fatty infiltration of the liver [63]. As an enlarged liver is one of the most common reasons for conversion to an open procedure, it is our practice to place the patient on a liquid diet for two weeks prior to surgery if hepatic steatosis is identified [64]. Two weeks of a low energy diet has been shown to decrease liver size and body fat by greater than 5% [63]. In addition to liver size, the gallbladder is also evaluated for the presence of stones and wall thickening to suggest chronic gallstone disease. The management of concurrent gallstones in the morbidly obese patient undergoing bariatric surgery has been a controversial topic. During the era of open weight loss surgery concomitant cholecystectomy was recommended for all patients undergoing open gastric bypass [65,66]. The view on cholecystectomy has changed since the widespread adoption of laparoscopic bariatric surgery. Addition of cholecystectomy to laparoscopic roux-en-y gastric bypass was found to add approximately 50 minutes to the operative time and significantly increased hospital length of stay, 2.69 days versus 4.35 days [67]. A study of 625 patients by D’Hount et al showed that only 6.9% of patients developed symptomatic gallstone disease post gastric bypass. The mean time between gastric bypass and cholecystectomy was 17.4 ± 13.1 months [68]. We do not advocate performing cholecystectomy at the same time as primary bariatric procedures unless absolutely necessary due to the increased operative time and length of stay. We do employ the use of ursodeoxycholic acid in the postoperative period to reduce the rate of gallstone formation in our gastric bypass patients due to the challenge of addressing choledocholithiasis in this patient population [53].
A preoperative nutritional assessment with a registered dietitian is essential when preparing for surgery. The preoperative nutritional assessment is designed to help the patient recognize the need for positive lifestyle changes and develop a plan to implement them. This will likely result in improvement of nutritional status, better management of nutrition-related comorbidities and development of habits that will positively influence weight loss outcomes and maintenance [69]. It is also a time to thoroughly review the postoperative diet with the patient, which includes gradually advancing the diet in terms of texture and variety, including exercise on a regular basis, staying hydrated with appropriate fluids, and adhering to the recommended vitamin and mineral regimen. In this section, we will discuss preoperative behavior changes that could potentially affect long-term outcomes.
A thorough preoperative nutritional assessment should include review of anthropometrical data, weight history, past diet history, medical history, available laboratory values, psychological history (including history of eating disorders), social history, substance abuse history, nutrition-focused physical findings (such as poor dentition), dietary intake, physical activity, and psychosocial factors that affect weight loss [70]. When discussing dietary intake with a patient, it is important to determine how many meals the patient includes on a daily basis, whether or not the patient snacks all day (i.e. grazing, picking, nibbling), if the patient has a past or current history of eating disorders, macronutrient and micronutrient composition of frequently chosen foods and beverages, and alcohol intake [69]. Preoperative nutrition counseling should be adapted to each individual patient.
Patients\' eating habits and exercise patterns are determined by a variety of environmental, psychological, biological, and social factors. Environmental factors include work schedule, occupation, socioeconomic status, and family traditions. Psychological factors include low self-esteem, feeling a lack of control in life, feeling inadequate, depression, anxiety, stress, and loneliness. Social factors include cultural glorification of the "perfect body", society placing more value on physical appearance and not on inner qualities, and stress related to size/body shape due to past discrimination [71]. Biological and biochemical factors are still being explored, but recent research has shown that gastrointestinal hormone imbalance can affect hunger and appetite [72]. It is important for patients to understand that, regardless of the reasons behind them, current eating patterns will likely result in poor weight loss, weight regain, and malnutrition after surgery. Preoperative nutritional counseling should focus on addressing these behaviors, working with the patient to avoid or manage them, and having the patient demonstrate compliance with the recommended changes.
Two environmental factors that are of particular concern are socioeconomic status and shift work. In low-income areas, access to nutrient-rich foods is oftentimes limited [73]. Planning grocery lists and affordable recipes with a low-income patient would be an appropriate intervention. Having the patient complete food logs that show more meals are prepared in the home with the ingredients purchased from the grocery list will demonstrate that he/she is able to incorporate this healthy behavior on a routine basis, thus lowering the risk of postoperative malnutrition. Obesity is frequently seen in people who work overnight shifts or who have alternating shifts and late shift workers have higher rates of weight gain after starting their jobs [74,75]. In our practice, patients report that they feel it is inappropriate to eat in the middle of the night. This often results in eating large portions before work and after work, as well as grazing on empty-calorie foods during the night. Working with the patient to break the idea that it is "bad" to be eating in the night is key when it comes to changing behaviors to positively affect weight loss and nutrition status postoperatively. Including regularly-timed meals and snacks that include an appropriate balance of protein, carbohydrates, and fat will set the patient up for long-term success.
Sometimes, patients have a past or present history of eating disorders that likely require additional psychological counseling in addition to nutritional counseling. Hence, coordination between the dietitian and the mental health care provider is critical. There is a fair amount of literature regarding Binge Eating Disorder (BED), subdiagnostic BED, and night eating syndrome in the preoperative setting, most of which states that psychological counseling is encouraged for patients that have either been diagnosed with an eating disorder or show tendencies towards one [76-78]. Some studies have suggested that patients with preoperative BED might be more inclined to graze after surgery, thus sabotaging weight loss, while other research suggests that prior history of eating disorders is not a predictor of poor outcomes following bariatric surgery [78,79]. Emotional eating is technically not considered an eating disorder, but its presence oftentimes has psychological roots. Some case studies have shown that cognitive behavioral therapy can help manage emotional eating both pre and postoperatively [80]. The only eating disorder that is a contraindication to bariatric surgery is active bulimia nervosa, but ultimately it is up to the multidisciplinary bariatric surgery team to decide if they feel a patient\'s past history of eating disorders could potentially jeopardize the patient\'s health [78]. Bariatric surgical teams should keep in mind that the psychological evaluation is not the only setting in which a patient might disclose episodes of disordered eating. Questions inquiring about eating disorders should be included in the nutrition evaluation, and if during subsequent visits the patient suggests that he or she has tendencies towards these behaviors, the patient should undergo psychological treatment before proceeding with surgery.
Most commonly, the areas dietitians will find they need to counsel patients on before surgery include portion control, macronutrient and micronutrient composition of frequently chosen foods, skipping meals, and physical activity. Dietitians use various tools to help assess a patient\'s food and beverage intake, including the 24-hour recall and food frequency questionnaires. When counseling patients preoperatively, it is important to put the emphasis on how dietary and lifestyle changes positively affect long-term weight maintenance. Adhering to portion control before surgery will likely lead to preoperative weight loss, resulting in a lower weight 24 months after surgery. It will also help patients maintain their weight loss over the long term. Patients often state they are limited in food choices postoperatively. Developing a menu before surgery that includes a variety of soft proteins (e.g. low-fat dairy, beans, nut butters, fish), whole grains, fruits, vegetables, and healthy fats will empower patients to try new foods and recipes after surgery that are appropriate for the texture that they are able to tolerate. This will help stave off taste fatigue and provide a more nutritious diet as they are able to include more solid, textured foods [81]. Patients should also be working towards eliminating intake of sugar-sweetened beverages in the preoperative period and including mostly water and sugar-free beverages. While skipping any meal is discouraged, observational studies highlight that eating breakfast regularly can be an effective tool for weight management [82]. Regularly eating breakfast is associated with lower BMI in adults, and inclusion of whole grains, fruit, and low-fat dairy may be related to appetite control and blood glucose regulation, both contributing factors to obesity [83]. Patients often have the misconception that skipping breakfast will lead to eating fewer calories in the day, when in fact, skipping breakfast can lead to cravings of high-calorie foods later in the day [84]. Therefore, patients should be encouraged to include breakfast daily in order to better maintain weight loss after surgery.
Lastly, physical activity is consistently cited as a predictor of weight loss maintenance [85]. Despite being aware that physical activity has health benefits, barriers to exercise still remain. They include inability to self-motivate, lack of encouragement from family and friends, time constraints, low self-efficacy, fear of being injured, recent injury, and lack of resources (i.e. no sidewalks or parks in neighborhood) [86]. Overcoming barriers to exercise will likely take a team approach, including the dietitian, psychologist, and possibly a physical therapist. The patient should be encouraged to begin a rather simple exercise program that takes into account reservations about exercise and physical limitations. We often see that as patients begin exercise programs, they are hesitant and resistant; however, as their self-esteem improves and physical activity becomes less taxing on the body, they build upon the program and welcome the exercise. They report having more energy, looking forward to the time by themselves, and overall mood improvement. Walking for as little as 5 minutes per day can often lead to walking for 30 minutes 3-4 times per week over a 3-month span.
With regard to micronutrients, it is estimated that 2 billion people worldwide suffer from vitamin and mineral malnutrition despite adequate calorie intake. In the United States greater than 75% of people are taking in below the daily recommended value of vitamins A, D and E. Additionally, 50 to 75% of Americans are also not taking enough vitamin C [87]. These deficiencies are also seen in patients presenting for weight loss surgery. Obese patients are at increased risk for nutritional abnormalities in the preoperative setting; they have been found to be deficient in thiamine, folate, zinc, iron, ferritin, selenium, beta-carotene, magnesium, and vitamins A, B-12, C and D [88-92]. Vitamin D levels are also affected by latitude and this should also be taken into consideration when screening and supplementing these deficiencies. It is imperative to evaluate and supplement all nutritional deficits prior to surgery to prevent deficiencies which can be significantly more difficult to correct in the postoperative period. These micronutrients should be supplemented in the preoperative setting and monitored to ensure normal values before surgery. All patients undergo postoperative monitoring to guide supplementation after bariatric surgery with frequent regularly scheduled blood tests.
As bariatric surgery becomes a safer, more popular, and more accepted form of weight loss amongst health professionals, it is clear that a thorough preoperative nutritional assessment and consistent preoperative follow-up with the dietitian is essential for the patient to lose an appropriate amount of weight, avoid malnutrition, and to maintain the weight loss hopefully for life [93-95]. Whether the dietitian has 6 weeks or 6 months to work with the patient preoperatively, the main focus should be to build the foundation for a healthier lifestyle and better eating habits.
The fight against obesity has many fronts. Simply reducing the capacity or absorption of the gastrointestinal tract will not have long lasting effects on weight if the psychosocial aspects of the disease are not addressed. An essential part of the preoperative evaluation is a psychological clearance [96]. The psychosocial and behavioral evaluation is geared to confirm the patient’s ability to incorporate nutritional and behavioral changes before and after bariatric surgery. The psychological investigation is also used to identify cognitive, environmental, or psychiatric contraindications prior to surgery and to offer treatment for any disorders identified [97]. The obese adult population in the United States has been found to have higher incidence of major depression, bipolar disorder, generalized anxiety and panic disorder [98]. Intervening in these disease processes can enhance postoperative weight reduction; however, no definitive significant improvement in weight loss has been shown [53].
The interview consists of a standard psychological evaluation, evaluation of the patient’s appropriateness for surgery, an assessment of eating behavior, stress, coping mechanisms, and social support. It is also used to confirm that the patient has the ability to consent and evaluate all the potential risks and possible benefits to surgery [96]. The psychosocial evaluation should be performed by a credentialed expert in psychology and behavior modification for all patients. Screening for eating disorders can involve using standardized assessments, see table 2 [96].
• Eating Disorder Examination Questionnaire • Cleveland Clinic Behavioral Rating System • Millon Behavioral Medicine Diagnostic (MBMD) (Pearson, San Antonio, Texas, USA) • Alcohol Use Disorder Identification Test – Consumption (AUDIT-C) • Beck Depression Inventory – II (BDI-II) • Beck Anxiety Inventory (BAI) • Multidimensional Health Locus of Control Scale • Overeater’s questionnaire | \n\t\t
Mental health assessment tools prior to weight loss surgery
Mental illnesses and eating disorders identified during the screening process are not necessarily contraindications to surgery [99]. Their optimization is key for a durable and satisfying outcome. The bariatric surgeon should be aware that the patient may exhibit impression management during the preoperative psychological evaluation. This is done by purposefully minimizing psychological symptoms to receive a recommendation to proceed with surgery from the mental health professional. It is recommended that mental health professionals use measures to assess for impression management, as this will allow for proper preoperative treatment and minimize postoperative surprises [97].
The process towards obtaining successful results after bariatric surgery begins during the preoperative period. The algorithm of care is a multi step process and requires full participation of both the practitioners and the patient. The ability to follow the plan of care and manage lifestyle changes required for successful weight loss depends on how well the patients are prepared prior to surgery. High patient satisfaction rating has been demonstrated after instituting a preoperative class for their bariatric patients [100]. Their class covered the following content: presurgery appointments, preparing for surgery, postoperative procedures, pain management, activity levels, wound care, nutrition, lifestyle changes and discharge instructions.
The ASMBS recommends having educational objectives and assessments throughout the preoperative period. It is suggested that the materials provided to the patients be at a sixth to eighth grade reading level to maximize comprehension [53]. Multimedia tools are also useful, however patients should be cautioned against using the internet as an information source as there is a high degree of bias, conflicting statements and out of date information [100]. The main goal of preoperative education is to provide information needed for informed consent, prepare the patient for the required lifestyle change and to establish realistic expectations regarding potential weight loss and quality of life improvements.
A crucial component of the preoperative evaluation includes assessing the patient’s ability to complete the activities of daily living. Bariatric patients have a high rate of comorbid conditions, some of which can cause physical limitation. Morbidly obese patients are also limited by their body habitus and weight related pain; this is especially true in the super morbidly obese patients. The limitations in mobility can impede on preoperative weight loss, cause psychological stress and limit access to care [101]. Preoperative functional status should be evaluated as it has been shown to be the strongest predictor for postoperative in hospital morbidity and mortality [102]. Our previously published data revealed that a completely dependent patient was 27 times more likely to experience mortality after bariatric surgery. The information gained from investigations into the patient’s functional status is shared with the patient and risks, benefits and alternatives are discussed with the ability to offer a reasonable prognosis of the postoperative period.
Preoperative exercise has been found to reduce surgical complications, facilitate healing, achieve the mindset needed for positive behavior changes, and augment the rate of increased postoperative physical activity [103]. The ASMBS suggests exercise for 20 minutes, three to four days a week is sufficient to achieve these results [104]. Most bariatric surgery patients have sedentary lifestyles and low physical activity level. King and Bond describe a five step process to providing physical activity counseling to patients undergoing weight loss surgery [103].
The first step is to assess the patient’s knowledge, beliefs and values regarding exercise along with prior and current levels of physical activity. The potential barriers successful implementation of a physical activity program should also be investigated at this point. Prior to beginning a physical activity program, the patients with current or a history of exercise intolerance should be referred to a cardiologist for proper exercise testing. Aside from cardiopulmonary restrictions to exercise, patients should be assessed for physical limitations such as sensory, balance and gait abnormalities – all of which can increase the risk of injury.
The second step is to advise the patient on the benefits of physical activity and develop realistic expectations. Strategies to increase safety and decrease barriers should be established. The patients should be taught how to gauge the level of intensity using the talk test or by measuring their own heart rate.
The thirds step is to come to a mutual agreement with the patient regarding their short, intermediate and long term physical activity goals. The goals should not be end results such as weight loss or maximal activity, but rather, specific goals regarding the frequency, duration and type of physical activity performed. It is recommended that the clinician set one goal that the patient has a high likelihood of achieving to boost confidence and encourage the patient to continue increasing their level of physical activity.
The fourth step is to assist the patient in achieving the goals by providing the patient printed materials and other resources that support self monitored physical activity. Such items include diaries, pedometers and a list of safe walking paths or fitness facilities. Patients who need a high level of encouragement or guidance, and those with significant barriers should be referred to professional personal trainers or other exercise professionals to achieve the best results.
The final step is to arrange for follow up and monitoring to answer questions and provide reinforcement. The patient and clinician should not be discouraged if the level of physical activity is not immediately increased after one meeting. It may take many visits for the patients to overcome their barriers and begin a physical activity plan. The healthcare provider should remain vigilant and provide continual counseling to the patient.
The preoperative evaluation of the bariatric surgery patient requires a multidisciplinary approach, ultimately coordinated by the surgeon. There are many details to which attention must be paid including medical, nutritional and psychological aspects in an effort to fully evaluate the patient as a whole. This multi faceted approach is one of the factors which have allowed bariatric surgery to become a safe and effective method for weight loss and comorbidity amelioration. These evaluations may reveal problems which should be addressed before surgery to ensure safety and success in the postoperative period. These assessments offer the best way to prepare and counsel a patient for these life altering operations and provide a reasonable basis of expectation on the part of the surgeon and the patient. Many of the learning points incorporated into the preoperative evaluation of bariatric patients can potentially be applied to other disciplines.
Infertility is defined as failure to conceive within 12 months of the first pregnancy attempt [1], while subfertility describes any form or grade of reduced fertility [2, 3].
The National Survey of Family Growth interviewed over 12,000 women of childbearing age (15–44 years old) to estimate the prevalence of infertility in the United States (US) [4]. A woman was considered infertile if she reported she and her partner were continuously cohabiting during the previous 12 months or longer, were sexually active each month, had not used contraception, and had not become pregnant [4]. From 1982 to 2006–2010, the percentage of infertile women based on this definition fell from 8.5 to 6.0% [4]. These estimates are lower than the 12–18% incidence of infertility in the US [5]. The frequency of infertility in nulliparous women (i.e., primary infertility) increased with age and was reported to be: 7.3–9.1% in women 15–34 years old, 25% in the 35–39 year olds, and 30% in the 40–44 year olds [4].
Infertility and subfertility may be due to conditions originating from the male and/or female reproductive systems [6]. Between 8 and 20% of couples will experience difficulty conceiving [6, 7, 8, 9]. Between 1982–1985, the World Health Organization (WHO) performed a multicenter study where they attributed 20% of infertility cases to male factors, 38% to female factors, 27% to causal factors identified in both partners, and 15% could not be attributed to either partner [10]. In the following section, we will provide you with an overview of the main causes of infertility.
A cross-sectional survey of men in the United States aged between 15–44 years showed a prevalence of male infertility of 12% [11]. Male infertility accounts for 19–57% of the identified causes of infertility in couples [9]. In about 30–40% of cases of male infertility, the cause remains unknown [11, 12]. Male infertility can be classified into four main categories which we will briefly describe in the following section.
Testicular diseases including primary testicular defects account for 30–40% of male infertility [13]. Primary testicular defects can be further classified into: (1) congenital disorders including Klinefelter syndrome [14] and (2) acquired disorders which can be due to infections (e.g., chlamydia) [15] and smoking [16]. Hypothalamic pituitary diseases account for 1–2% for male infertility [13]. Secondary hypogonadism can cause gonadotropin deficiencies, which in turn leads to infertility [13]. Secondary hypogonadism can be (1) congenital [17], (2) acquired (e.g., tumors of the pituitary gland [18]) or (3) systemic (e.g., obesity [19]).
Genetic disorders affecting spermatogenesis can be identified in 10–20% of male infertility cases [13]. With the increasing use of genome-wide association studies, genetic disorders have been linked to male infertility [12, 20]. Specifically, microdeletions and substitutions on the Y chromosome are increasingly recognized as genetic causes of azoospermia (i.e., semen without sperm) and severe oligozoospermia (i.e., semen with a sperm concentration < 15 million sperm/mL compared to the norm of >48 million sperm/mL [20]. Additionally, mutations linked to the X chromosome in men have also been linked to azoospermia [21, 22, 23].
Posttesticular defects lead to disorders of sperm transport, which account for 10–20% of male infertility cases [13]. The epididymis is an important site for sperm maturation and essential to the sperm transport system. The vas deferens transports sperm from the epididymis to the urethra, where they are diluted by secretions from the seminal vesicles and prostate. Abnormalities at any of these sites, particularly the epididymis and vas deferens, can lead to infertility [13]. The causes of these abnormalities include congenital obstructions of the vas deferens and obstruction following an infection (e.g., chlamydia). Additionally, given that sperm must be ejaculated, any disorder of the ejaculatory ducts can also lead to infertility [13].
In 30–40% of male infertility cases, the cause is classified as idiopathic [13]. In these cases, despite attempting to identify potential mechanisms at play, a cause for abnormal sperm number, morphology, or function cannot be identified [13]. Idiopathic causes should be distinguished from unknown causes which is where men with normal semen analysis and no other identified cause for infertility are unable to impregnate an apparently clinically normal female partner.
In terms of female infertility, the main causes of infertility are ovulatory disorders which account for 21–32%, tubal disorders for 14–26%, while endometriosis is responsible in 5–6% of the cases of infertility [6, 9]. Approximately 30% of couples will have both male and female factors contributing to their infertility [6, 9]. When the cause is identified, a treatment plan can be put in place with the physician. The concern however, is that 8–30% of infertility will remain unexplained, which makes the choice of the course of fertility treatment difficult [24]. In the section below, we have provided you with an overview of the main causes attributed to female infertility.
Infrequent ovulation (oligoovulation) or absent ovulation (anovulation) results in infertility because an oocyte is not available every month for fertilization. WHO classifies ovulatory disorders into three classes [42]:
Class 1—Hypogonadotropic hypogonadal anovulation occurs in 5–10% of cases. This would describe women with hypothalamic amenorrhea from excessive exercise or low body weight.
Class 2—Normogonadotropic normoestrogenic anovulation accounts for 70–85% of cases and includes women with polycystic ovary syndrome (PCOS) and hyper/hypothyroidism.
Class 3—Hypergonadotropic hypoestrogenic anovulation occurs in 10–30% of cases and characterizes women with premature ovarian failure.
Tubal disease and pelvic adhesions prevent normal transport of the oocyte and sperm through the fallopian tube [27]. The primary cause of tubal factor infertility is pelvic inflammatory disease caused by pathogens such as chlamydia or gonorrhea [28]. Tubal and pelvic adhesions could also be a consequence of endometriosis [27].
Conditions that distort the uterine cavity can result in implantation failure, which may lead to infertility or recurrent pregnancy loss [29]. The most common malformation, a septate uterus, was associated with pregnancy losses >60% and fetal survival rates of 6–28% [30, 31].
Adhesions within the uterus, the fallopian tubes, and/or the pelvic floor caused by endometriosis could be a cause of infertility [27]. This could be mediated through ovulatory dysfunction, defective implantation, alternations within the oocyte, or impaired fertilization among other hypotheses [32].
Evidence has demonstrated that obese women are at an increased risk of sub-fecundity and infertility [33]. It has been shown that the pathway through which obesity could be a precursor to subfertility/infertility may involve a dysregulation in the hypothalamic-pituitary-ovarian axis as well as decreased oocyte quality and endometrial receptivity [33]. Studies have demonstrated a correlation between higher body mass index (BMI) and poor fertility [33].
Fertility treatments are procedures and/or medication interventions used to initiate a pregnancy. MARs include assisted reproductive techniques (ART) as well as ovarian stimulators (OS). In Figure 1, we provide you with a visual classification of MAR techniques as a whole, which we have briefly described below.
Overview of the classification of methods of assisted reproduction. Assisted reproductive techniques (ART) are defined as procedures that include handling the oocytes and/or sperm, or embryos to generate a pregnancy (i.e., IVF, ICSI, IUI, in vitro maturation [IVM], assisted hatching [AH], zygote intrafallopian transfer [ZIFT], gamete IFT [GIFT]), while MAR techniques include ART and OS [1]. Depending on the indication of the use of fertility treatments, women will either be given a course of OS, undergo ART procedures alone or will be subjected to a combination of both OS and ART.
ART are defined as procedures that include handling of the oocytes and/or sperm, or embryos to generate a pregnancy [1]. ART methods can be categorized as follows:
Intrauterine insemination (IUI) is a procedure in which processed and concentrated motile sperm are placed directly into the uterine cavity, and will often be used when the cause of infertility is related to the male [1].
In vitro fertilization (IVF) with or without in vitro maturation (IVM) is a cycle of procedures in which oocytes are retrieved from ovarian follicles, fertilized in vitro then subsequently the resulting embryo(s) are transferred into the uterus [1]. The number of embryos transferred into the uterus largely depends on the common practice imposed by the country where the procedure is performed. A more recent practice is to perform single embryo transfers (SET). This practice was put in place to decrease the odds of producing multiple embryos per pregnancy. However, through the Canadian ART register’s (CARTR) last reports in 2012, it was shown that SET has yet to become common practice. Australia/New Zealand and Sweden used SET in >70% of the reported ART cycles involving transfers, compared to 44% in Canada and 14% in Germany [34, 35]. These numbers translated into different rates of multiple pregnancy per country: Australia/New Zealand and Sweden had the lowest rates at 6.9% and 5.9%, respectively, while Canada was at 16.5% and Germany had the highest rates of all reported countries at 32.5% [34, 35]. IVF procedures can be categorized as follows:
Intra cytoplasmic sperm injection (ICSI) is an in vitro procedure in which a single spermatozoon is injected into the oocyte cytoplasm [1].
Assisted hatching (AH) an in vitro procedure in which the zona pellucida of an embryo is either thinned or perforated chemically, mechanically or by laser in order to assist the separation of the blastocyst. The blastocyst is the stage that the embryo reaches 5–6 days following fertilization [1].
Gamete intrafallopian transfer (GIFT) is an in vitro procedure in which both gametes (oocyte and sperm) are transferred into the fallopian tube [1].
Zygote intrafallopian transfer (ZIFT) is an in vitro procedure in which the zygote(s) is/are transferred into the fallopian tube [1].
Ovarian stimulators (OS) are used to promote the development and ovulation of more than one mature follicle among subfertile women mainly to increase the likelihood of conception [36]. This treatment can be used alone or in combination with IUI, wherein we increase the number of oocytes and sperms together. OS can also be used with other ARTs, described above [1, 37]. In many cases, OS will be used as first line therapy when aiming to treat infertility/subfertility in women or couples. OS alone are more likely to be used in the context of unexplained infertility and age-related subfertility in women [36, 38, 39]. Depending on the underlying cause of infertility, different OS may be used. Mainly, OS can be classified as having two roles as they are either used to induce ovulation (i.e., clomiphene, gonadotropins) or to assist with maturation and/or the release of the oocyte (i.e., human chorionic gonadotropin [hCG], gonadotropin-releasing hormone [GnRH]).
Infrequent or irregular ovulation (i.e., oligoovulation) unrelated to ovarian failure can usually be treated successfully with ovulation induction (OI); women treated with OI agents achieve fecundability nearly equivalent to that of couples not suffering with infertility or subfertility (i.e., 15–25% probability of achieving a pregnancy in one menstrual cycle) [40]. Agents used for OI tend to be used as a first-line treatment to stimulate the development and ovulation of >1 mature oocyte in women with unexplained or age-related subfertility/infertility [36, 39, 41]. OI agents include clomiphene and gonadotropins. Clomiphene is a selective estrogen receptor modulator with both estrogen antagonist and agonist effects that increases gonadotropin release [42]. It is known to be effective in women with normal gonadotropin and estrogen levels but who still have ovulatory dysfunction (WHO Class 2) [42]. Gonadotropins are used in women with WHO class 2 who have not been able to ovulate using clomiphene or an insulin sensitizing agent such as metformin (used in women with PCOS). This therapy may also be used in women classified as WHO Class 1 [42].
Agents used for final ovulation maturation and release are known as trigger shots. The gold standard agent to induce follicular maturation has been hCG which mimics the surge of luteinizing hormone that occurs mid-cycle and allows for the release of the oocyte [43]. GnRH may also be used to replace hCG. Current evidence suggests that GnRH may be used as a first-line treatment in egg donors [43].
It has been speculated that fecundability has declined over the years, but results need to be replicated at the scale of large populations in order to be confirmed [44, 45]. Nonetheless, the number of women resorting to fertility treatments remains on the rise. As reported by CARTR, the use of ART has increased steadily over the years, having more than tripled in the last decade [34]. From the participating fertility clinics in the CARTR reports over the years (n = 28–32), 16,315 ART cycles had been performed in 2009 compared to 27,356 cycles in 2012 across Canada [34]. In 2012, Canada had the second lowest number of ART cycles after Sweden (n = 17,628), while the US had the highest number with 176,247 ART cycles performed as reported by the American Society for Reproductive Medicine [34, 35].
Over 5 million children have been born through IVF specifically worldwide [46]. At present, 1–3% of all children in industrialized countries including France, Germany, Italy, Scandinavian countries, and the United States are born through ART [47, 48, 49]. Over 1.5 million IVF cycles are performed every year, yielding over 350,000 children annually in Europe, as reported by the European Society of Human Reproduction and Embryology [46].
Between 2010 and 2014, the province of Quebec was the first Canadian province to put in place an assisted reproduction program which provided universal reimbursement for MARs. This program aimed to: (1) reduce multiple pregnancies with the practice of SET, (2) help subfertile/infertile couples to have children, and (3) increase Quebec’s birth rate [50]. Following the start of the reimbursement program, reports have shown that MAR represented approximately 2% of all pregnancies [50], of which 43% were from OS without any other ART [51]. Another 20% of women were exposed to OS in combination with IUI, and 33% conceived through IVF [50, 51]. Due to the fact that OS tend to be used the first-line fertility treatment and that it is prescribed with most ARTs, it is the most prevalent exposure [52].
Since Louise Brown, the first IVF baby, was born in the United Kingdom in 1978, over 5 million children have been born with IVF worldwide [46]. General concerns about the safety of pregnancies resulting from MARs and the health implications of these methods on the resulting child remain, as there is a growing body of evidence supporting the association between these methods and adverse perinatal outcomes [53, 54].
The association between MARs and multiple pregnancies has been studied extensively and is known [51, 55, 56, 57, 58]. ART alone and OS use alone have both been associated to increase multiple pregnancies, which occur for two different reasons [57, 59, 60]. On the one hand, ART alone may lead to the transfer of multiple embryos as described above, while on the other hand OS use may lead ovarian hyperstimulation [57, 59, 60, 61]. Indeed, ovarian hyperstimulation occurs in more than 40% of stimulated cycles [62]. In the context of ovarian stimulation, it is more difficult to prevent multiple gestations with OS use because it involves the stimulation of ovulation which leads to an unpredictable follicular growth number [61]. As we have described above, the rate of multiple pregnancies associated with ART around the world varies from 5.9 to 32.5% [19, 20]. In a systematic review and meta-analysis performed by Chaabane et al. [63] looking at the association between OS use and multiple pregnancies, they pooled a total of nine studies that had estimates ranging from 1.01 to 50.20 [63]. They calculated a pooled relative risk (RR) of 8.80 with a 95% confidence interval (CI) ranging from 5.09 to 15.20. To put these numbers in context, the rate of multiple pregnancies in the general population is about 3% around the world [64]. These estimates therefore suggest that OS use alone leads to an approximate multiple pregnancy rate of 26% among its’ users [46].
ART has also been associated with increased perinatal morbidity and mortality, which the scientific community mainly attributes to the increased risk of multiple births, the use of these technologies themselves, as well as the underlying condition for which these methods are used, which is the infertility factor [54, 65, 66, 67, 68, 69, 70]. In fact, it is generally well accepted that multiple pregnancies occurring in the context of fertility treatments due to the transfer of multiple embryos are associated with being born premature (<37 weeks of gestation) or at a low birth weight (LBW; <2500 g at birth) [71]. These complications, among others, carry long-term impacts on the child, which we will explore throughout this chapter.
Researchers have been making an effort to evaluate adverse risks associated with MARs in singleton babies specifically. In fact, MAR-conceived singletons have been shown to be at increased risk of very preterm (28 to <32 gestational weeks) and moderately preterm birth (32 to <37 gestational weeks), LBW, small for gestational age (SGA; weight below the 10th percentile for their gestational age), neonatal intensive care unit (ICU) admissions (odds ratio [OR], 1.27; 95%CI, 1.16–1.40), and overall perinatal mortality (OR, 1.68; 95%CI, 1.11–2.55) compared to spontaneously conceived singletons [72, 73]. In line with these findings, IVF-conceived children tend to be hospitalized for longer (n = 9.5 days versus 3.6 days in non-IVF children), and use more in-patient care than their non-IVF counterparts in the neonatal period and later in life due to increased risk of asthma, cerebral palsy, congenital malformations, and infections [74]. It could be speculated that these results are due to prematurity or multiplicity, but this observation persisted when restricted to term infants and singletons, respectively [74].
A growing body of evidence suggests that children conceived through ART are phenotypically and biochemically different from naturally conceived children [75]. Indeed, MAR involves hyperstimulation, manipulation, and culture of gametes/embryos at the most vulnerable stage of development [76, 77]. ART has been implied to affect the epigenetic control in early embryogenesis [78, 79]. In fact, MARs have been associated with an increased risk of imprinting disorders both in experimental and epidemiological studies [80, 81]. Furthermore, we must take into consideration the impact of iatrogenic factors including gamete manipulations and ovulation hyperstimulation, as well as the initial underlying cause of infertility as discussed above.
In the following section of the chapter, we will present the associations between MARs and the risks of the main perinatal outcomes (i.e., prematurity, LBW, SGA) as well as long-term cognitive outcomes.
In the previous section, we discussed the known association between MARs and the risk of multiplicity. Multiplicity has been shown to increase the risk of preterm birth by 6-fold [82]. More recently, efforts have been made by the scientific community to evaluate the contribution of MARs on the risk of prematurity among singletons specifically. As such, we are able to tease out the role of multiplicity in the association between the MARs themselves and the risk of prematurity [83, 84].
Evidence from a systematic review of matched controlled studies showed that MAR-conceived singletons were at an increased risk for very preterm (28 to <32 weeks’ gestation) and moderately preterm birth (32 to <37 weeks’ gestation), compared to spontaneously conceived singletons [72, 73]. The RRs reported for 13 studies ranged from 0.57 (0.21–1.56) performed among 118 women [85] to 8.00 (1.87–34.2) performed among 240 women [86]. The general consensus among these 13 matched studies was that the risk of preterm birth was doubled [72]. Most studies included in this systematic review adjusted for maternal age and parity by design (i.e., matched case-control studies), but most failed to perform adjustments for confounding variables such as smoking, socio-economic status, and pre-existing chronic conditions [72]. Further supporting these results, ART users were 3.27 times more at risk of prematurity than non-ART users (RR, 3.27; 95%CI, 2.03–5.28). ART was also associated with a doubling of the risk of delivering moderately preterm (RR, 2.05; 95%CI, 1.71–2.47) [87, 88, 89]. To put these results in context, the prevalence of prematurity is of 7.8% in Canada and 10% in the USA [90]. These results indicate that among MAR-conceived children, the prevalence of prematurity could be estimated at 15% or higher.
We found that the current literature does not appropriately take into account the different fertility treatments separately and do not create the necessary distinction between OS and ART [72, 87, 88, 89]. MARs are either pooled all together or only IVF or ICSI are considered in analyses. Further studies are required to explore the biological mechanisms through which these methods could cause premature birth/delivery, which will only be possible once we have assessed each MAR distinctively.
ART conceptions have been associated with being born LBW. Results have mainly been attributed to higher rates of multiple pregnancies and prematurity among MAR conceptions [91]. Recent meta-analyses have shown that the higher rates of LBW are observed in both IVF singletons as well as twins, respectively, compared to natural conceptions [92, 93]. When comparing singleton ART-conceived children to those who were spontaneously conceived, we observed a 1.70-fold increase in the risk of LBW among ART singletons (RR, 1.70; 95%CI, 1.50–1.92) [72]. In Canada, the prevalence of LBW was of 6.2% in 2013 [94] which is lower than the prevalence reported in the USA in 2016, which was of approximately 8% [95]. To put these numbers into context, this would mean that among ART-conceived children, the prevalence of LBW would be between 11 and 13%. Additionally, when comparing singletons conceived through ART to those who were naturally conceived, the meta-analysis showed a 3-fold increase in the risk of being born very LBW which is defined as a birth weight of <1500 g (RR, 3.00; 95%CI, 2.07–4.36) [72].
A number of studies have shown that IVF-conceived singletons were at an increased risk of being born LBW, even following adjustment for gestational age which is a known confounder [96, 97, 98, 99, 100, 101, 102], while two large prospective studies and one matched case-control did not observe any differences following adjustments [85, 103, 104]. Through they did not all adjust for the same variables, the two prospective studies took into account maternal age, gestational age, education, marital status, BMI, intrauterine exposure to smoking/alcohol/coffee as well as the sex of the child, parity, and time since last pregnancy [103, 104].
Aside from the body of evidence examining the association between ART and LBW, the exposure to OS has also been associated with LBW when compared with spontaneous conceptions in conceptions with [68, 105, 106] and without IVF [101, 107].
It has been hypothesized in this context that an alteration in oocyte quality, decreased receptivity of the endometrium or the production of a poor implantation environment may play a role in this observation [101, 107]. These could in part be mediated through the increased levels of estradiol which could impair the implantation process and this hypothesis has been confirmed in animal studies [91].
In the context of infertility treatments, we have discussed the negative implications of OS on the uterine environment. As such, oocyte manipulation as well as hormonal triggers during implantation could be key players in the mother’s response to growth factors [107]. In fact, the capacity of the placental system to transfer nutrients to the fetus as well as the condition of the maternal endocrine system will determine, along with genetics, whether or not the fetus will follow an expectedly normal growth curve during the gestational period [108]. Being born SGA describes newborns who are smaller than the norm for their gestational age established by the average growth curve [109]. It is important to note that definitions of SGA are population-dependent as growth curves differ from one country to another [109].
Limited evidence exists on the association between MARs and SGA. However, when comparing singleton IVF-conceived children to those who were spontaneously conceived, studies observed a 1.4–1.6 fold increase in the risk of SGA among IVF singletons [72, 110, 111]. An additional study published by the United Kingdom government looked at this association and found a significant increased risk of SGA when comparing IVF to spontaneous conception (RR, 1.98; 95%CI, 1.21–3.24) and also when comparing OS use alone to spontaneous conception (RR, 1.71; 95%CI, 1.09–2.69) [112]. In low- to middle income countries, the prevalence of SGA births is of approximately 27% while in industrialized countries, the prevalence ranges around 5–10% [113]. Based on these prevalences, this would indicate that prevalences of SGA among IVF-conceived children could range from 8.5–45%.
Current evidence is suggestive of an association between MARs and conceiving babies that are SGA. Mechanisms leading to growth restriction in utero are those discussed above when describing the probable etiology for the increased risk of LBW [91]. Additional large-scale epidemiological studies are required to confirm these results, as well as to generate further hypotheses to be tested in mechanistic animal studies.
Environmental factors that come into play in the early stages of embryonic development can interact with the genotype and alter the capacity of the organism to cope with this environment later in life, therefore modulating a child’s susceptibility to disease [114, 115]. Evidence suggests that MAR-conceived children are phenotypically and biochemically different from the spontaneously conceived [75]. MAR involves hyperstimulation, manipulation, and culture of gametes/embryos at the most vulnerable stage of development [76, 77]. However, increased risk of neurodevelopmental disorders in MAR-conceived children may be unrelated to the procedure/treatment itself; MAR has been associated with increased risk of multiple gestation [63], which in turn increases the risk of PTB, LBW, and SGA newborns as we have described in detail in previous sections of the chapter [104, 111, 116]. These adverse outcomes are strongly associated with a range of long-term child outcomes, including vision impairment, cerebral palsy (CP), and neurodevelopmental deficits [46, 117, 118, 119, 120]. With the current state of the evidence, results support the hypothesis that MARs could be a contributing factor to the recent increase in the prevalence of neurodevelopmental disorders.
CP is the most common motor disability in childhood. Approximately 1 in 323 children (0.3%) has been identified with CP according to estimates from CDC’s Autism and Developmental Disabilities Monitoring Network. Population-based studies worldwide report prevalence estimates of CP ranging from 1.5 to more than 4 per 1000 live births or children of a defined age range [121, 122, 123, 124].
Very few groups have evaluated the association between MARs and CP. Most available results stem from studies performed within large registries available in the Scandinavian countries, namely Denmark, Finland, and Sweden. In 2009, Hvidtjørn et al. performed a systematic review and meta-analysis to provide an overview of the results pertaining to this association [125]. A total of nine studies were included in this review [74, 126, 127, 128, 129, 130, 131, 132, 133]. They were conscious to separate results by parity (e.g., all children combined, singletons, twins, and triplets) and to isolate estimates that had been adjusted for PTD, as it is a known risk factor for CP [125]. The outcome was defined by appropriate diagnostic codes of the International Statistical Classification of Diseases, 10th Revision (ICD-10). Only two studies used records from rehabilitations centers, one from questionnaires which were later confirmed by discharge registers. All other studies obtained their information on CP diagnoses from hospital discharge registers.
Among studies looking at all children combined, adjusted ORs ranged between 0.88 and 3.7 [74, 126, 127, 129, 132]. The strongest reported association was that of Strömberg et al. with a significant 3.7-fold increased CP risk when comparing IVF to non-IVF children [132]. After adjusting for PTD, the point estimate was reduced to 2.9 but remained significant [132]. Other studies found no significant association when they adjusted for PTD. Among singleton studies, the tendency was towards an increased CP risk among IVF singletons when compared to their non-IVF counterparts [126, 127, 128, 132]. The results of the meta-analysis showed an overall significant 1.8-fold increase (OR, 1.82; 95%CI, [1.31–2.52]) in CP when comparing IVF singletons to non-IVF singletons [125].
Among studies including twins and triplets, the ORs were variable and ranged from 0.6 and 1.5, and most results were not significant [126, 127, 130, 131, 132, 133]. Despite their large sample sizes, they had a low number of MAR-conceived children with CP, with numbers ranging from 3 to 15. Additionally, studies did not take into account PTD which could potentially be biasing these results [126, 127, 130, 131, 132, 133].
Overall, this systematic review of the literature and meta-analysis suggests that there is evidence supporting the implication of MARs, specifically IVF, in the increased risk of CP. To put these results in context, CP remains a rare outcome with a prevalence of 0.3% on average. These results would suggest that among MAR-conceived children, the prevalence of CP could range between 0.6% and 1%. The increased risk of CP among IVF-born children could be in part explained by the known association between IVF and PTD [125]. Indeed, a more recent study published in 2012 indicates that among MAR-conceived children, the risk of neurodevelopmental outcomes, including CP, is more pronounced among those that are born extremely preterm (22–26 weeks’ gestation) [134].
As discussed above, ART-conceived children are phenotypically and biochemically different from naturally conceived children, likely due to the manipulation of gametes and embryos at such a vulnerable stage of development [75, 76, 77]. MARs have been associated with an increased risk of imprinting disorders, which in turn can lead to ASD [80, 81]. Studies have shown that ASD risk is 1.5 to 2 times higher among MAR-conceived children compared with their spontaneously conceived counterparts [125, 135, 136, 137, 138]. However, these associations were reduced after adjustments for sociodemographic and perinatal variables including multiplicity, PTD, SGA, maternal diabetes, hypertension and preeclampsia, and cesarean deliver. One small case-control study (n = 942) performed in India looked at the association between exposure to OS and the risk of ASD (measured through questionnaires), and identified a 2-fold increased risk of ASD when compared to their spontaneously-conceived counterparts [139]. To put these results in context, the estimated prevalence of ASD has increased over time from 0.05% in the 1960s [140] to 1.46% today in the USA [141] and is reported to be 1.36% in Quebec, Canada [142]. This would indicate that among IVF-conceived children, the prevalence of ASD could be of approximately 2%.
On the contrary, other groups have yielded reassuring results when considering ASD as an outcome [143, 144]. Overall, findings remain inconsistent as risk estimate ranges are wide and variable across studies [145]. It is important to note that a number of differences among these studies have been identified, and could therefore explain the disparity among results. Specifically, studies were performed in small populations, which makes it especially difficult to study a rare outcome such as ASD [125, 139, 145]. Additionally, ASD definitions were variable across studies, and were often non-specific which could be due to differences in diagnostic criteria. Some studies used questionnaires which are subject to recall bias, while other studies used diagnostic codes through a registry. However, it is also important to note that over the years, diagnostic criteria used to define ASD have changed between versions of the Diagnostic and Statistical Manual of Mental Disorders (4th versus 5th editions) [146, 147]. Lastly, we have identified that there is a lack of evidence and consideration of the immediate and long-term effect of OS alone as most studies focused on IVF or MARs in general without including the pharmacological approach [125, 145].
Throughout this chapter, we have seen that MARs increase the risk of multiple gestation, prematurity, being born with LBW, and SGA. As such, the observed increased risk of ASD in MAR-conceived children may be due to reasons unrelated to the procedure or treatment itself. As we know, MAR has been associated with increased risk for multiple gestations [63], which in turn increase the risk for prematurity, LBW, and SGA babies [104, 111, 116]. We know that these are major risk factors for neurodevelopmental deficits, including ASD [46, 117]. The main question that remains is how MAR techniques contribute to the increased ASD risk. The identified limitations as well as the inconsistency of results underline the importance to produce more evidence on this association by including all exposures to MARs as identified through this chapter.
Most studies presented herein measured behavioral problems through a questionnaire which included a Strengths and Difficulties Questionnaire (SDQ). The SDQ is a validated tool comprised of 25 items which aims to assess the psychological adjustment of children and youths [148]. Based on this questionnaire, behavioral problems were defined as having emotional symptoms, hyperactivity, conduct problems, prosocial behavior, and problems with their peers [148]. Depending on the study group, the mother, the teacher or the child themselves (i.e., later as an adult) had filled out the questionnaire to assess the outcome.
The rationale for the evaluation of this association is that couples who undergo a long waiting time before being able to conceive and/or who have had to undergo lengthy fertility treatments tend to experience significant amounts of stress and anxiety during the process. Studies have shown that this increased period of stress may affect their ability to adapt to their new parenting role, which in consequence may influence their children’s behavioral and emotional development [149, 150, 151]. Animal studies suggest that this response may be largely due to the activity of the stress-responsive hypothalamic-pituitary-adrenal axis and its end-product, which is cortisol [151]. Higher levels of cortisol in the mother during the pregnancy are translated into higher levels in the offspring, which in turn can influence the child’s behavior [151]. Further supporting this theory, studies found that women who suffered with symptoms of anxiety late in their pregnancy (32+ weeks’ gestation) had higher levels of cortisol in their blood following adjustments for sociodemographic status, gestational age, parity, and lifestyle factors (i.e., smoking and alcohol consumption) [152, 153].
At both 5 and 7 years of age, the mean behavioral difficulties score was significantly higher in the ART-children when compared to children born through spontaneous conception, even after adjusting for other confounding variables [154]. Indeed, a study performed in the Millenium Cohort comprised of 18,552 women, ART-conceived children had double the risk of having children with peer problems at 5 years of age (OR, 2.56; 95%CI, 1.14–5.77—model adjusted for maternal age, age of the child, sex of the child, household socioeconomic status, family type, maternal qualifications) [154]. A weaker association was observed at age 7 and was non-significant. It was also shown that at the age of 5, ART-conceived children seem to have increased emotional difficulties when compared to those who were spontaneously conceived (adjusted OR, 1.80; 95%CI, 0.86, 3.79). Additionally at age 7, increased peer problems remained (adjusted OR, 1.90; 95%CI, 0.90, 3.98) [154]. Studies have shown that children conceived spontaneously, whether or not mothers/couples struggled with infertility, had similar behavioral patterns [155, 156, 157, 158, 159]. These results therefore suggest that the underlying cause of infertility in the parents is unlikely related to resulting behavioral patters in children [159].
To put these results in context, it is estimated that 1 in 10 individuals (10%) will suffer with behavioral problems throughout their life [160]. These results suggest that among MAR-conceived children, the prevalence of behavioral problems could be estimated at 20%.
On the contrary, other studies performed among ART-conceived children did not exhibit any more behavioral problems than their naturally conceived counterparts [125, 155, 156, 157, 158]. Some of these studies, unlike the others we have presented, even suggested a more positive relationship between parents and ART-conceived children [159, 161, 162]. Contrary to the previous theory about higher levels of stress among these parents, these results are explained by the fact that ART-conceived children may have a higher desirability factor than their spontaneously conceived counterparts (i.e., planned and unplanned) [159].
Despite the differences in observed results, there seems to be a trend towards an implication of MARs in the development of behavioral problems later in life. The current evidence on behavioral problems suggests that there is a need for the development of long-term surveillance programs (i.e., registries and databases) for MAR-conceived children as of the age of 5 and until early adulthood.
The prevalence of MAR use around the world has been increased over the last years. With a noticeable surge of infertility/subfertility among women of childbearing age, these numbers are expected to remain on the rise. Through this chapter, we evaluated the current state of the literature and showed that MARs have been associated with a number of significant adverse perinatal outcomes, which have repercussions on the child later in life, but also on their parents, and society. MAR-conceived children seem to have poorer health overall with increased healthcare utilization largely due to an increased prevalence of prematurity, being born LBW or SGA, and later in life, being more at risk for behavioral problems, cerebral palsy, and autism among other neurodevelopmental outcomes. Decision makers as well as healthcare professionals should be aware of the repercussions that these methods could have on the mother as well as the child, and appropriately inform mothers and couples seeking these therapies to achieve pregnancy in the context of infertility. Further stufies are needed to present more evidence to strenghten the findings related to perinatal outcomes when conceiving through MARs.
Dr. Bérard is the recipient of a career award from the Fonds de la Recherche en Santé du Québec (FRQS) and is on the endowment Research Chair of the Famille Louis-Boivin, which funds research on Medications, Pregnancy, and Lactation at the Faculty of Pharmacy of the University of Montreal. Jessica Gorgui is the recipient of the Sainte-Justine Hospital Foundation/Foundation of the Stars doctoral scholarship as well as the FRQS doctoral award.
JG and AB have no conflicts of interest to report.
IntechOpen aims to ensure that original material is published while at the same time giving significant freedom to our Authors. To that end we maintain a flexible Copyright Policy guaranteeing that there is no transfer of copyright to the publisher and Authors retain exclusive copyright to their Work.
',metaTitle:"Publication Agreement - Chapters",metaDescription:"IN TECH aims to guarantee that original material is published while at the same time giving significant freedom to our authors. For that matter, we uphold a flexible copyright policy meaning that there is no transfer of copyright to the publisher and authors retain exclusive copyright to their work.\n\nWhen submitting a manuscript the Corresponding Author is required to accept the terms and conditions set forth in our Publication Agreement as follows:",metaKeywords:null,canonicalURL:"/page/publication-agreement-chapters",contentRaw:'[{"type":"htmlEditorComponent","content":"The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\\n\\n1. DEFINITIONS
\\n\\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\\n\\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\\n\\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\\n\\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\\n\\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\\n\\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\\n\\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\\n\\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\\n\\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\\n\\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\\n\\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\\n\\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\\n\\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\\n\\n3. CORRESPONDING AUTHOR'S DUTIES
\\n\\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\\n\\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\\n\\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\\n\\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\\n\\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\\n\\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\\n\\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\\n\\n4. CORRESPONDING AUTHOR'S WARRANTY
\\n\\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\\n\\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\\n\\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\\n\\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\\n\\n5. TERMINATION
\\n\\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\\n\\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\\n\\n6. INTECHOPEN’S DUTIES AND RIGHTS
\\n\\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\\n\\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\n7. MISCELLANEOUS
\\n\\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\\n\\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\\n\\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\\n\\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\\n\\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\\n\\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\\n\\nLast updated: 2020-11-27
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\n\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\n\nLast updated: 2020-11-27
\n\n\n\n
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Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. 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