\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.
",isbn:"978-1-83968-248-3",printIsbn:"978-1-83968-247-6",pdfIsbn:"978-1-83968-321-3",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"1f8fd29e4b72dbfe632f47840b369b11",bookSignature:"Dr. Suvanjan Bhattacharyya",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10695.jpg",keywords:"Free Turbulent Flow, Discretisation Methods, Aerodynamics, Phase Flow, Bluff-Body, Complex Geometries, Drag Force, Flow Separation, Laminar Diffusion Flame, Non-Premixed Combustion, Fluid Dynamics, Biomechanics",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"January 28th 2021",dateEndSecondStepPublish:"February 25th 2021",dateEndThirdStepPublish:"April 26th 2021",dateEndFourthStepPublish:"July 15th 2021",dateEndFifthStepPublish:"September 13th 2021",remainingDaysToSecondStep:"6 days",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr. Suvanjan Bhattacharyya is currently working as an Assistant Professor in the Department of Mechanical Engineering of BITS Pilani, Pilani Campus. 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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Comprising less than 2% of all intracranial aneurysms, they are typically found on the dorsal or dorsomedial wall of the internal carotid artery (ICA). With a characteristic thornlike appearance on angiography, blister aneurysms’ most prominent feature is the fragility of their wall. This explains for their aggressive clinical course and grave prognosis.
Although most authors agree that blister aneurysms are either dissecting or false lesions, their exact nature as well as their optimal management remains unknown. Traditionally, surgery has been advocated as the first-line treatment. Primary clipping, wrapping, wrap-clipping or even carotid artery sacrifice (with or without a bypass) have all been tried. However, results have always been far from satisfying, often making neurosurgeons reluctant to operate on such cases.
During the past few years, clinicians’ interest in blister aneurysm has been renewed with the introduction of endovascular modalities in everyday practice. Among all the different available approaches, flow diversion seems lately to be gaining ground, showing promising results. Of course, until consensus has been reached, blister aneurysms are still to be treated on a case-by-case basis.
Blister aneurysms are a distinct form of cerebral vascular lesions with often mixed characteristics and uncertain pathogenesis. They comprise less than 2% of all intracranial aneurysms [1]. Originally described by Sundt and Murphey more than 40 years ago [2], the typical configuration of blister aneurysms consists of a shallow and broad-based or even semifusiform focal protrusion located on the internal carotid artery [3]. Arising from the anteromedial carotid wall in up to 65% of cases [4], these lesions seem to be unrelated to major arterial junctions, although very fine branches such as those supplying the optic nerve may sometimes be involved [5]. Rarely, blister aneurysms can be found on the anterior communicating artery or even the basilar trunk [6, 7], while in a recent case report, the posterior inferior cerebellar artery has also been implicated as another potential site of origin for such a lesion [8].
A prominent characteristic of blister aneurysms is the marked weakness of their wall, a feature that not only reflects the unique pathology of these lesions but also predetermines their high rupture risk, aggressive clinical course, and tendency for rapid growth and progression. In the most common scenario, a blister aneurysm will be diagnosed after an episode of subarachnoid hemorrhage (WFNS grade > 3 in 68% of cases) [9]. Being initially small and sessile, it will substantially enlarge within days of presentation, reaching finally a shape much similar to that of its saccular counterparts [4]. Commonly, the end result is a rerupture with potentially catastrophic consequences for the patient.
On a side note, and regarding terminology, blister aneurysms were originally known as dorsal, anterior or superior carotid wall lesions, a nomenclature though that soon became obsolete failing to recognize the presence of such anomalies on the medial, posteromedial or lateral surface of the internal carotid artery [10]. Additionally, intracranial vessels have never—by tradition—been designated as dorsal or ventral, adding another reason to abandon at least the first of these denominations [11]. An alternative, broader term used mainly by Japanese authors was carotid trunk aneurysms [4]. Still, confusion remained since bleb-like but essentially stable carotid lesions have been encountered during surgery, an observation that clearly indicates that not all such morphological entities fulfill the requirements to be considered as true blister aneurysms, and as a matter of fact, some of them may even be the precursors of typical berry lesions [12, 13]. Whatever the case, the term blister (or blister-like) aneurysms seems to be by now the dominant one within the relevant literature and as such will be used throughout the present manuscript.
Blister aneurysms are rare lesions comprising less than 2% of all intracranial aneurysms [1] and 0.9–6.6% of internal carotid artery lesions [14]. In the three largest series published to date, Yaşargil et al. reported 3 blister aneurysms in a total of 319 carotid lesions [15], Nakagawa et al. reported 8 cases in a series of 460 surgical patients [3] and Meling et al. reported 14 lesions in a total of 912 aneurysms [16].
Having a slight female preponderance and occurring more frequently on the right side, blister aneurysms tend to affect patients at a rather younger age than their saccular counterparts [17, 18]. In a series of six patients, Abe et al. found a mean presentation age of 56 years [11], while Park et al. calculated this in their own cases at 35.4 years [19]. Risk factors include arterial hypertension [6] and atherosclerosis [16].
Due to the rarity of blister aneurysms, our understanding of the relevant pathology is only limited. For most authors these lesions are of a dissecting nature [20], and, as such, they are considered to be the consequence of a tear in the affected artery’s inner wall followed by intramural hemorrhage [21, 22]. The resultant protrusion is covered by only the adventitial layer. At this point, it should be noted that the adventitia of intracranial arteries is well known to be thicker over bifurcation sites, partially compensating for the underlying medial defect. Arising exclusively at nonbranching arterial segments, blister aneurysms lack this relatively rigid coverage and are thus much more fragile than their saccular counterparts [23]. This difference between the two accounts for the prominently aggressive clinical course of blister lesions (i.e. increased risk of bleeding and tendency for rapid subsequent growth and rerupture). In their series of 40 blister aneurysms, Ogawa et al. found signs of dissection (double lumen, arterial narrowing or dilation, etc.) in 10 cases [4], while Satoh et al. reported a similar association in as many as 16 out of their 18 in total patients [13].
An alternative hypothesis on the pathology of blister aneurysms is that they are in fact false lesions, essentially representing a focal arterial wall defect [8]. In this direction, Abe et al. suggested a few years back that the characteristic bleb-like protrusion seen by surgeons in such cases is nothing more than an organized blood clot covering the diseased arterial site [11]. Removal of this clot during surgical preparation of the aneurysmal dome is highly likely to cause a rerupture [4]. The pseudoaneurysm theory was initially based on macroscopic intraoperative findings but was later confirmed in at least two cases reported by Charbel et al. [24]. According to these authors, pathological examination of the aneurysmal sacs, which were resected in both cases, in their entirety revealed only blood clot and no fibrous, elastic or smooth muscle tissue (Verhoeff-vanGieson staining plus immunostaining) [24].
The first-ever complete microscopic description of a blister aneurysm has been delivered by Ishikawa et al. in their, classic by now, publication in neurosurgery in 1997. To do this, the authors of the article applied an Elastica Masson stain on cross section specimens of the internal carotid artery of a patient who sustained a fatal rupture of such a lesion [25]. According to their report, the examined blood vessel was heavily atherosclerotic with prominent underlying thickening of the intima. Near the edge of the atheromatous plaque, both the internal elastic lamina and the tunica media were abruptly terminated, and the resultant gap (i.e. the aneurysm sac) was covered only with fibrinous tissue and adventitia. The latter was neither thickened nor rich in collagen as is usually seen in a saccular aneurysm. At the rupture point, the adventitia was lacerated and fragmented. Notably, and contrary to what it would be expected in a dissecting lesion, no inflammatory infiltration or dissection of the artery outside the actual aneurysm was observed.
In a more recent publication, Kim et al. reported a blister aneurysm with a typical clinical course whose dome was resected during surgery for histologic examination. Their conclusions, although interesting, seem to have only added to the confusion: immunohistochemical staining for smooth muscle actin proved to be positive, a finding compatible with an intact tunica media and thus a true lesion. Medial fibroblast proliferation and laminar thrombosis were also noted [26].
It is obvious that the literature on pathology of blister aneurysms has been, up until now, far from conclusive. Speculations stray widely with data supporting each theory being only limited. A possible explanation is that we are dealing with different stages of a rapidly evolving disease or, alternatively, that there is no single entity but a whole range of these. Our only certainty seems to be that morphological changes taking place in blister aneurysms are much more destructive than those seen in berry lesions.
Similar to their pathology, etiogenesis of blister aneurysms remains, despite our best efforts, unclear. Both Stehbens and Ohara have traditionally associated such lesions with atherosclerosis, a concept that has by now gained wide acceptance [12, 27]. Atheromatous changes affecting the carotid artery lead to degeneration of the internal elastic lamina [28]. The latter is reported to be the major anatomic structure resisting the pressure of blood flow within a given vessel [29]. The end result is an overall weakening and subsequent laceration of the arterial wall (penetrating ulceration) [30]. Focal subadventitial dissection leads to the formulation of a blister aneurysm [14]. For reasons not yet fully understood, this whole process usually takes place at the periphery of an atherosclerotic plaque where its stiff degenerated wall borders that of a normal elastic vessel segment [25]. Further research is needed to explain carotid vulnerability at these locations.
Apart from atherosclerosis, another factor that seems to play an important role in the formation of blister aneurysms is hemodynamics. The anteromedial surface of the supraclinoid carotid segment, where most of blister lesions arise, is curved in such a way that blood flow directly impinges on the arterial wall [4, 11]. In the most probable scenario, increased hemodynamic stress acts on an already diseased, sclerotic arterial segment, and it is the combination of these two that finally results in an aneurysm formation.
Given that the vast majority of blister aneurysms presents with subarachnoid hemorrhage, the diagnostic evaluation of such a lesion usually starts with a brain CT scan. Hemorrhage is typically lateralized and mainly involves the carotid and suprasellar cisterns as well as the Sylvian fissure. Of note is that, when performed within 24 hours after ictus, CT scans detect subarachnoid blood with a sensitivity of up to 95%, a figure though that quickly drops to less than 50% a week later [31]. This is attributed to the rapid decrease of the hemorrhage density due to dilution by cerebrospinal fluid [32].
The second step in the diagnostic triage of subarachnoid hemorrhage is, for most centers nowadays, a CT angiogram. Blister aneurysms appear, initially at least, as shallow, broad-based lesions, usually less than 2 mm and with a characteristic triangular or thornlike shape (Figure 1) [33, 34]. Unfortunately, their small size in combination with their unusual location (i.e. nonbranching arterial sites) and close proximity to the skull base often makes detection of these lesions obscure [35]. Adding to the difficulty, the aneurysmal dome presumably collapses right after rupture, while its parent artery contracts as a reaction to the presence of subarachnoid blood. The end result can be a significant delay in diagnosis and initiation of treatment. Sensitivity of single slice CT angiography in the investigation of intracranial aneurysms smaller than 3 mm has been reported to be 25–64% [36]. Better results with improved image quality and spatial resolution have been achieved with the introduction of multidetector row technology [37]. Blister lesion diagnosis can be also greatly facilitated through the application of a meticulous technique (decreased section thickness, increased pitch, proper bolus timing and elimination of venous contamination) along with appropriate postprocessing of CTA scans (maximum intensity projections, multiplanar reconstructions and volume-rendered 3D images) [33]. Notably, most false-negative CT angiograms, when evaluated in retrospect, do reveal suspicious anomalies that could be well associated with a blister aneurysm. This observation underlines the significance in such cases of a high index of suspicion.
Reconstructed CTA showing a blister-like aneurysm on the dorsal wall of the internal carotid artery (ICA).
Despite advances in the field of CT angiography, conventional DSA with its excellent spatial resolution remains the gold standard for the detection of cerebral aneurysms, and, as such, it should be performed whenever initial investigations prove to be negative. The appearance of blister lesions on a DSA closely resembles that of their CTA counterparts, but luminar irregularities related to atherosclerosis of adjacent arterial segments may obscure the diagnosis (Figure 2) [35]. Multiple oblique views or even rotational 3D scans significantly increase the sensitivity of the method [38]. Signs of dissection have been reported in up to 89% of blister aneurysm cases and include a false lumen, an intimal flap, a filling defect or contrast pooling [39]. Should the presence of a blister aneurysm be suspected on the basis of DSA findings, the evaluation of collateral flow through the circle of Willis is always advisable in case an occlusion procedure is to be carried out [18, 33]. Cross-compression carotid injections may help demonstrate the anterior communicating artery, while patency, size and collateral potential of its posterior counterpart can be assessed through an Alcock test (vertebral injections with carotid artery compression). For a more detailed study, temporary balloon occlusion will be required [31].
Internal carotid injection, AP view. A characteristic thornlike blister aneurysm is noted opposite to the anterior choroidal artery origin. Large posterior communicating artery supplying the posterior circulation noted.
Another important aspect of imaging in cases of blister aneurysms is that, on short-term follow-up angiography after initial presentation, these lesions usually show rapid growth to a saccular configuration [19]. Being at least partially related to lysis of an intra-aneurysmal clot [26], this progression is considered to be a good indicator of a blister lesion even though the only real way to authenticate such a diagnosis is through direct intraoperative inspection [1, 40].
Management of blister aneurysms is associated with a high overall rate of mortality and morbidity [35]. The main causes for this include the small size and broad neck morphology along with the prominent fragility of such lesions, features that often lead to intraprocedural rupture when traditional surgical or endovascular techniques such as clipping or primary coiling are to be applied [6, 19]. Additionally, and even if an initial intervention proves successful, subsequent regrowth requiring further treatment has been commonly reported [9]. Other factors contributing to the grim prognosis of blister aneurysms include a commonly grave clinical presentation as well as delays in an appropriate diagnosis.
Given the lack of universal consensus in blister aneurysm treatment, a wide variety of approaches and methods has been employed up to date and will be discussed below. These have included both reconstructive and deconstructive surgical and endovascular techniques, with different authors competing for best results in an ever-changing field. In any case, attention should be given to specific measures to prevent rerupture while awaiting final treatment (tight arterial blood pressure control, cautious cerebrospinal fluid drainage in patients with a ventricular drainage in place and selective use of aminocaproic acid) [41]. The latter must be instituted as soon as possible to secure the aneurysm and to allow aggressive management of subarachnoid hemorrhage-related complications such as vasospasm and hydrocephalus.
The alternative treatment modalities for blister aneurysms are:
Reconstructive techniques
Surgery: primary clipping (including encircling clips), wrapping, clip-wrapping, wrap-clipping and direct suturing
Endovascular therapy: primary coiling, stent-assisted coiling, telescopic stenting (stent-in-stent technique) and flow diverters
Deconstructive techniques
Parent artery occlusion with surgical or endovascular means with or without bypass surgery
Traditionally, surgical clipping has been the preferred mode of treatment for all forms of cerebral aneurysms, including blister lesions. In a typical case, the procedure starts with exposure of the cervical internal carotid artery to ensure proximal control in case of an intraprocedural rupture. This is usually achieved with an incision along the medial border of the ipsilateral sternocleidomastoid muscle [42]. Subsequently, a standard pterional craniotomy with generous sphenoid ridge drilling is carried out, and through this, the Sylvian fissure is opened widely. Gentle retraction of the frontal lobe provides access to the supraclinoid internal carotid artery which, in most cases, is found to be prominently sclerotic [43]. The aneurysm itself is usually seen protruding from the dorsomedial carotid wall. Careful preparation of the aneurysmal dome is crucial. As a matter of fact, should the frontal lobe be attached to it, most authors propose a subpial dissection in order to minimize direct manipulation of the lesion [44]. Special care is needed to avoid removing the platelet plug that typically covers the aneurysm as this may result in a large wall defect and uncontrollable bleeding [4].
Direct clipping of a blister aneurysm is performed under temporary trapping and in such a way that the blades of a usually angled or curved Sugita clip are parallel to the longitudinal axis of the carotid artery [19, 45]. This has been shown to lower the risk of intraprocedural rupture [17]. Given that the underlying pathological process seems to extend well beyond the limits of the aneurysm itself, the surgeon should try, when closing the clip, to include part of the “normal” arterial wall outside the lesion in order to avoid breakage of the transitional zone found in between them [4]. A valid alternative is to envelope the entire diseased arterial segment with a wrapping material such as gauze, cotton or Gore-Tex on top of which the clip can be applied to obliterate the lesion [46]. Wrap-clipping not only reinforces the carotid wall as a whole but also helps avoid slippage of the clip, a complication not uncommonly seen in blister aneurysms surgery [47]. One yet alternative is to wrap the lesion after the clip has been applied (clip-wrapping). Whatever the exact technique, induced hypotension [11], burst suppression with desflurane or thiopental, cooling of the patient or even transient flow arrest with adenosine can all prove useful adjuncts [11, 24, 41, 48].
Primary clipping of blister lesions is known to carry an up to 30% risk of complications, both intraoperative and postoperative [9, 49]. In the former group, aneurysm avulsion and internal carotid artery laceration seem to be our major concerns, while progression of the lesion often accompanied by rerupture seems to be the main danger during the postoperative period [50].
When confronted with a laceration of the carotid artery during surgery, the most commonly used rescue technique has traditionally been sacrifice of the vessel to control bleeding. As proven by numerous studies, this is associated with a high risk of cerebral ischemia, not only because collaterals may be inadequate in the first place but also due to hemorrhage-related vasospasm that often further aggravates the whole situation [16]. Other alternatives include direct suturing, placement of an encircling clip graft and reapplication of the originally placed clip to intentionally narrow the carotid artery and thus achieve hemostasis [4, 43]. In every case, surgeons must be always prepared for such an event, and large aspirators need to be available throughout the procedure. Initial hemorrhage control is usually achieved by applying direct pressure on the artery with oxidized cellulose and a small cottonoid. Brief periods of cardiac arrest with the aid of adenosine are also useful to improve visibility and help gain control of the situation [41].
Direct suturing of an arterial tear during surgery for a blister aneurysm is made possible because the edge of the lesion is relatively well outlined [51]. It entails removal of the original clip, trimming of the aneurysmal sac with microscissors (to prevent tissue buckling into the lumen) and repair of the arterial wall defect with 8/0 nylon stitches [43]. Suturing in the acute stage is usually extremely difficult due to the deep and narrow surgical field. As a result, initial attempts at this required prolonged trapping of the diseased segment invariably led to cerebral ischemia [52, 53]. To avoid this, recent studies propose reformation of the arterial wall with only a few stitches rather than its complete restoration [43]. Subsequent circumferential wrapping of the artery or, alternatively, placement of an encircling clip graft should be enough to stop oozing and stabilize the end result [54].
Encircling clip grafts have been developed by Sundt almost 40 years ago and specifically to address the problem of repairing the wall defect associated with a blister aneurysm [2, 55]. They can be used either as a primary modality (instead of the classic clip) or in cases of intraoperative rupture. Applied typically with the aid of a straight or right angle clip holder, Sundt clips provide a rigid sleeve and a soft woven fabric lining, allowing surgeons to essentially reconstruct the lacerated arterial wall [56]. Produced in various sizes, the appropriate clip for each case can be estimated on the basis of preoperative angiographic studies with a 3–4 mms diameter and a 3–5 mms length being the most widely used options [42]. Major disadvantages associated with these devices are that they cannot be used in cases of lesions close or opposite to carotid branches (i.e. posterior communicating and anterior choroidal arteries) and also that they come in certain fixed diameters that may or may not fit the vessel involved [48]. The latter limitation occasionally leads to postprocedural stenosis, a risk that surgeons must always be aware of and act accordingly [6]. Of note is a recent publication by Cho et al. who used a Sundt clip in combination with an endovascularly placed carotid stent to treat a ruptured blister aneurysm with good results [42]. Being a valuable adjunct in blister lesion surgery, encircling clip grafts should be readily available in all such procedures. Sadly, these adjuncts are rarely part of the modern day aneurysm clip tray, and young neurosurgeons are often not even aware of their existence.
Despite all efforts, intraoperative rupture of a blister aneurysm carries a mortality rate of up to 25% [57]. On this basis, and with surgeons trying for improved results, novel techniques continue to emerge. An interesting addition to our armatorium has been recently proposed by Kazumata et al. in the form of a protective bypass concept. According to these authors, when dealing with a blister aneurysm, and knowing the fragility of such a lesion, surgeons should at least contemplate an STA-MCA bypass prior to any attempted clipping. Ensuring adequate cerebral perfusion, this technique allows, in case of an intraoperative laceration, time for corrective measures to be applied accordingly. The duration of temporary occlusion for direct suturing or clip reapplication seizes to be a limiting factor, while, should the need for a carotid occlusion arise, this can be done safely, combined with a proper high-flow, radial artery graft bypass [58].
In an effort to limit intraoperative manipulation of the lesion, neurosurgeons, especially in the past, have widely used wrapping of blister aneurysms as an alternative to clipping mode of treatment. In this context, wrapping is undertaken when a traditional clip cannot be properly applied due to either the morphology of the aneurysm itself or the underlying sclerotic changes of the parent vessel (i.e. the carotid artery) [46]. The technique entails encasing of the entire diseased segment of the carotid artery with an appropriately sized thin sheet of—usually—cotton. On occasions, cuts along its longitudinal axis are made to accommodate for branch vessels and perforators. Creation of ample room to allow free movement of surgical instruments and circumferential dissection of the aneurysm dome can prove dangerous but are, at the same time, essential. The wrapping material is applied with the aid of microforceps, and an angled clip is used to fit it snugly around the artery. Once the wrapping is secured, any excess length is cut and removed [39, 41].
The concept behind wrapping is that mechanical reinforcement of the diseased carotid artery provides protection from a potential rerupture during the immediate postoperative period while, in the long term, induced inflammatory changes eventually lead to connective tissue formation and remodeling of the weak arterial wall into a histologically competent structure [47, 59, 60]. Wrapping materials that have been tried out include muscle, muslin gauze, Teflon, silicon, collagen-impregnated Dacron fabric and cotton [46]. The latter seems to dominate today the relevant literature with most authors proposing it as the most effective option. Notably, Biobond, a cyanoacrylate glue widely used in the past, is by now obsolete due to its toxicity [60, 61, 62].
Complications associated with wrapping are rare. Perforator injury or parent vessel narrowing following placement of whichever material has been chosen make postoperative angiography an absolute necessity [63]. Delayed development of a granuloma or arachnoiditis has also been reported resulting in cranial neuropathies [64, 65], an observation that has led many authors to suggest that cotton must be used with the utmost care and never be placed in contact with adjacent cranial nerves, especially the chiasm [46, 63].
In the premicrosurgery era, numerous studies have been published on the efficacy and safety of wrapping. Among these, the largest series has been the one presented by Todd et al. in 1989. According to it, the risk of early (within 6 months) rehemorrhage after wrapping of an aneurysm has been calculated to be 8.6%, while late incidents were at 1.5% per year [66]. Results seem to have been significantly better after the introduction of the surgical microscope although only few relevant articles exist. Characteristically, Cudlip et al. reported in 1998 a series of 15 wrapped aneurysms with no rehemorrhages within 1 year after surgery [67].
Wrapping is unquestionably inferior to clip ligation for the treatment of ruptured aneurysms. However, it does offer a degree of protection during the immediate postoperative period, and, by doing so, it remains today a valid—even though last resort—therapeutic option when confronted with a blister aneurysm [47].
Initial attempts at endovascular treatment with primary coiling of blister aneurysms (Figure 3) have returned, in most cases, disappointing results [68]. A high risk of intraprocedural rupture and coil protrusion or migration were problems commonly encountered due to the small size and shallow morphology of such lesions, their fragile nature and their proximity to vascular curves on the carotid wall (the latter, in combination with the typical orientation of blister aneurysms, has been known to necessitate a difficult and extremely gentle catheterization maneuver in order to gain access to the sac while avoiding a potential perforation) [19, 35]. Additionally, the lack, in many cases, of a true wall often allowed for posttreatment progression and—possibly—rebleeding [40]. As a consequence, most authors advocated that blister aneurysms are unsuitable for endovascular treatment and should therefore be left to surgery [69].
Simple coiling of a right ICA blister aneurysm. Intraprocedural images.
With the introduction of intracranial stents in clinical practice, our conception of blister lesion management has gradually changed. Surgical techniques are increasingly looked down upon as outdated and old-fashioned while stent-assisted coiling (Figure 4) became, initially at least, the new trend in the field. The procedure is carried out either by first placing the stent (e.g. Neuroform or Enterprise stents) and then introducing coils through its struts (trans-stent coiling) or by catheterizing the aneurysm sac and deploying the stent over the microcatheter prior to coiling (jailing technique). Facilitating stable intrasaccular coil deployment while at the same time reinforcing the underlying diseased arterial wall, stent-assisted coiling promised to provide a safe and reliable therapeutic alternative [20, 70]. However, it was soon realized that results, even though better than those of surgery, were far from optimal. Intraoperative complications, mainly bleeding, were encountered in up to 17% of cases, while the risk for recurrence of the lesion, need for further treatment and postoperative repeat hemorrhage were reported at 65, 50 and 13%, respectively [9, 35, 71]. Notably, Meckel et al. found that the latter, a potentially catastrophic and fatal event, is seen only in cases that show incomplete occlusion (i.e. neck remnant or residual sac) by the end of the initial already procedure and especially if the patient receives full double antiplatelet treatment postoperatively or if the aneurysm in question is atypically large or partially thrombosed [35]. In this context, early and tight angiographic follow-up of partially obliterated lesions is essential, while any signs of regrowth should prompt complementary treatment. In the face of all these, most authors are by now moving away from stent-assisted coiling being the preferred primary and sole mode of treatment. Instead, they are using it, if possible, as a preliminary means to achieve a certain degree of protection until definite treatments, in the form of some other techniques, can be instituted.
Intraprocedural images showing stent-assisted coiling of a left ICA blister lesion.
Prior to moving on, and in order to close the discussion of stent-assisted coiling, it should be noted that one more major argument against it is the need for subsequent antiplatelet therapy [72]. This, combined with a potentially still unsecure aneurysm, requires careful consideration. Additional risks include the frequent need for a surgical intervention at a later time (e.g. extraventricular drainage or shunting procedures) [73, 74] and delayed spontaneous intraparenchymal bleeding with the rate of the later though not being affected by the initial subarachnoid hemorrhage [75, 76]. The exact therapeutic antiplatelet regimen that should be used in such a setting is still debatable. Some authors suggest that a similar to elective case scheme should be followed: loading with full doses of aspirin and clopidogrel just prior to the procedure, double antiplatelets for 3–6 months (usually 75 mg aspirin and 75 mg clopidogrel daily) and then continuation of only aspirin for another 6 months to life [77]. Going even further, Lee et al. augmented this regimen by a full-dose heparinization for 24–48 hours postoperatively [1]. On the contrary, other authors favor a reduced or even single-drug scheme. The rationale for this is that in the presence of a high-flow state within the stented lumen of large-size vessels (e.g. internal carotid artery), fibrin formation or clotting is relatively unlikely. Moreover, the risk of and the consequences of a potential intraprocedural rerupture are minimized, while at the same time occlusion of the aneurysm through thrombus formation is significantly facilitated. Using such an approach, Meckel et al. reported in 2011 only 1 fatal rehemorrhage in between 11 patients who were primarily treated with stent-assisted coiling of blister aneurysms. In other reports, stent-assisted coiling under systemic heparinization and loading with dual antiplatelets only after the procedure was found to be associated with a cumulative risk of thrombotic and hemorrhagic complications as low as 2% [78], while the intraprocedural use of aspirin and later introduction of clopidogrel carried a 21% overall risk of perioperative complications [79]. In any case, and because of significant heterogeneity of response to antiplatelet drugs, platelet function should be performed prior to any intervention as well as during the postoperative period (a patient’s response may be found to change over time) [80, 81].
A recent development in blister aneurysm treatment and a welcome addition to our armatorium has been flow diversion. According to advocates of such a concept, and given that blister lesions are regarded by many as pseudoaneurysms, flow diversion is the only endovascular technique capable of actually reconstructing the vessel wall and sealing off any underlying defect [8, 82]. This can be achieved either through a stent-in-stent technique or with the aid of devices such as the pipeline or the Silk flow diversion systems. The former typically entails telescopic deployment of multiple overlapping stents within the diseased vessel in an effort to increase the total mesh density and thus restore proper parent artery laminar flow [8]. This results in thrombosis of the lesion, an effect augmented by endothelial proliferation along the length of the implanted stents. In the same direction, and specifically designed with this in mind, proper flow diverters like the Silk or the pipeline systems provide significantly better hemodynamic results at the expense however of increased perioperative complications due to their stiffness and thrombogenicity [83, 84, 85]. Notably, and regardless of the technique selected, flow diversion allows for preservation of branching vessels, an important feature when it comes to blister aneurysms since such lesions are usually located close to the posterior communicating or the anterior choroidal arteries [86].
Major concerns with the use of flow diversion for the treatment of blister lesions include an even more prominent need for antiplatelets as well as the fact that such an approach does not guarantee protection from postoperative progression and rerupture. Regarding the latter, and despite reports of a marked decrease in intra-aneurysmal flow on the intraoperative already angiogram, hemodynamic stress upon the lesion theoretically remains at least for a few days [40]. Rasskazoff et al. recently reported that even with the use of double SILK flow diverters, complete occlusion of a blister aneurysm they treated did not occur till 18 days after the intervention, while Consoli et al. verified obliteration of a similar lesion no less than 6 months postprocedurally [8, 75]. A valid alternative possibly addressing the whole issue is the combination of flow diversion with coiling. On this basis, Kim et al. have reported favorable results with stent-assisted coiling as a primary treatment augmented by deployment of a second flow diverting stent if needed (i.e. postoperative progression of the lesion) [39]. In cases with extremely small lesions where coil deployment is perceived as carrying a significant risk, the reverse route can also be followed: telescopic stenting and subsequent trans-stent coiling should the lesion further grow to allow that [40]. Another attractive option involves covered stents; their use however is still limited due—mainly—to their stiffness, a feature that makes their intracranial delivery not only difficult but also dangerous since they may impinge on the fragile aneurysm neck portion resulting in intraoperative rupture. In addition, they often prove impossible to fully conform to the curved supraclinoid carotid wall, and, in this way, they can potentially leave an underlying aneurysm essentially open [39]. Whatever the case, further experience is needed should such devices gain a significant role in blister aneurysm treatment.
Although often considered as inherently inferior, deconstructive techniques allow for definitive occlusion of a blister aneurysm with minimal direct manipulation of its walls. In this context, carotid artery sacrifice and trapping of blister lesions significantly reduce the overall risk of rerupture during the perioperative period [19, 87].
Should carotid artery occlusion be contemplated as a final treatment, endovascular rather than surgical trapping is recommended due to its convenience, rapidity and safety. In an often cited article, Park et al. have described an elegant technique entailing the use of two microcatheters and a proximal balloon to control blood flow intraoperatively [19]. The first microcatheter is placed distal to the aneurysm, while the second is positioned just at the level of its neck. With the aid of the latter, and after inflation of the balloon, a framing coil is deployed inside the carotid artery. Prior to detachment, the distal microcatheter is retrieved and repositioned within the coil mess. Additional coils are deployed till a stable result is achieved. The use of trapping coils instead of detachable balloons is perceived as having a lesser risk of intraprocedural rupture.
When occlusion of the carotid artery is suggested, postoperative patency of its cardinal branches requires careful consideration. A detailed study of the ophthalmic, the posterior communicating and the anterior choroidal arteries as well as their collaterals is essential:
i. Ophthalmic artery
Blister aneurysms arise on the communicating segment of the internal carotid artery, and therefore the ophthalmic artery does not usually present a problem when dealing with such a lesion. If a choroidal blush via the external carotid circulation is visualized on preoperative angiograms, the trapped segment of the carotid artery is typically extended to include the origin of the ophthalmic artery as well, achieving thus a more robust result. As an additional precaution, proximal occlusion of the cervical internal carotid artery may also be performed. If, on the other hand, no ophthalmic collateral vessels are visualized, preservation of the ophthalmic artery is absolutely essential, and carotid trapping should be kept short. Accordingly, the proximal carotid artery cannot be occluded, and, as a consequence, close follow-up is mandatory to exclude recanalization of the trapped segment.
ii. Posterior communicating artery
Due to its proximity to blister lesions, the posterior communicating artery often needs to be included in the trapped carotid segment. In most cases this is safe with the only exception being a fetal-type vessel. In the latter case, an alternative therapeutic strategy should be considered.
iii. Anterior choroidal artery
Preservation of the anterior choroidal artery is essential in order to avoid postoperative hemiplegia. On this basis, precision of segmental occlusion offers obvious advantages. Should the origin of the anterior choroidal artery prove impossible to save, the procedure should be abandoned.
Apart from carotid side branches, another important concern with all deconstructive procedures is postoperative early or late ischemia. Unselective, abrupt occlusion of the internal carotid artery is known to carry a 26% risk of cerebral infarction and 12% risk of death [88]. A balloon occlusion test should always be performed when such an approach is contemplated. This entails inflation of a nondetachable balloon at the site of the intended occlusion and subsequent clinical and angiographic evaluation of hemispheric collateral circulation [89, 90]. However, one should always keep in mind that—in the setting of a subarachnoid hemorrhage—results of a balloon occlusion test can be misleading. This is due to the fact that a balloon occlusion test does not take into account the hemodynamic effects of a posthemorrhagic vasospasm which may complicate such cases [16].
For patients who fail a balloon test occlusion, surgical bypass should be contemplated. Traditionally, this is in the form of an artificial communication between the superficial temporal and the middle cerebral artery with or without an interposed vascular graft (radial artery or saphenous vein) (STA-MCA bypass) [16, 58]. In the case a graft is to be used, this is termed as a high-flow bypass and ensures significantly better results [91]. As a matter of fact, there are authors recommending high-flow bypasses as a primary mode of treatment for blister aneurysms. However, experts in the field seem skeptical advocating that a high-flow bypass should never be thought of as complete substitute for normal carotid artery supply, quoting an 80% rate of postoperative complications, including graft occlusion and vasospasm-related cerebral infarction [41]. Additionally, surgical bypass in patients with severely atherosclerotic vessels typically requires antiplatelets, a feature that only adds to the overall risk.
Our understanding of blister aneurysms is still today incomplete. Having a relatively wide spectrum of pathological differentiations, they can be classified as either true or false lesions. Whether this represents consecutive stages of the same entity or a different, in each case, disease remains to be clarified. Further research on the field is an absolute necessity, and young physicians should thus be encouraged toward this direction by their senior colleagues.
A direct consequence of our limited knowledge on the nature of blister aneurysms is the lack of an established and universally accepted treatment modality. This lack of consensus has led to numerous attempts at novel and often promising therapies. However, and with the sole exception of the recently introduced flow diverters, all previous options have invariably failed to rise to initial expectations. Flow diversion, despite its limitations, arises today as probably the most attractive future prospect. However, until our technology reaches that point, blister aneurysms are still to be treated on a case-by-case basis. In this context, when confronted with such a lesion, physicians should consider all available alternatives, both surgical and endovascular, in order to maximize the chances of a good outcome.
Whichever end treatment modality is to be used, an important point when dealing with a patient that has suffered rupture of a blister aneurysm is amelioration of perihemorrhage management in its entity. Careful consideration of all measures to prevent and, if needed, manage rebleeding or any other related complications (i.e. vasospasm, hydrocephalus, seizures) is essential. All these issues would preferably be addressed within a multidisciplinary team consisting of neurosurgeons, interventionists and ICU specialists should the best possible result be achieved.
As with every other such case, and despite initial enthusiasm, each new therapeutic approach proposed for blister lesions needs careful consideration and long periods of follow-up to evaluate its efficacy, safety and durability of results. It is obvious that further research in the field is an absolute necessity and young physicians should be encouraged toward this direction.
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.
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\\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).
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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
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