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1. Introduction
The growth potential of entomophagy is currently attracting much interest [1, 2]. Currently, this practice is declining in many traditional markets and does not extend into mainstream western culture where its introduction is often met by a range of barriers, leaving insect consumption often seen as a taboo [3, 4, 5]. Insect protein has great potential to be used as reliable alternative or supplement to vertebrate ‘meat’ consumption and offers relative advantages over traditional animal protein sources if entry barriers can be overcome. One advantage is the lower environmental impact of mass rearing insects in terms of greenhouse gasses and ammonia [6]. Furthermore, insects are highly nutritious and have been found to be healthier than some meat alternatives [7].
This chapter accessibly reviews known barriers to uptake and uses Rogers Diffusion of innovation theory (Figure 1) to outline possible strategies to overcome these [8].
Figure 1.
Perceived characteristics of an innovation considered to determine the level of penetration into a target audience: relative advantage—the level to which the innovation is perceived to be better than existing alternatives; compatibility—the degree to which the innovation is perceived to be in keeping with values and experiences of the target population; complexity—the level to which an innovation is perceived as difficult to utilise and understand; trialability—the level that a new innovation can be experimented with; observability—the level to which the outcomes of an innovation is viewable by the target population [8].
2. Disgust and food neophobia
Insects can trigger a disgust response for a number of reasons. Disgust is different to an innate distaste reaction, which is a response to the bitterness of many biologically toxic compounds [9]. Rather than being a reflex action, a disgust reaction comes from a cognitive process when assessing foods and explains why differences are seen in cultural perception of entomophagy [10]. Disgust can arise with perceived or real associations of insects to objects of core disgust, which include pathogens and pathogen-related stimuli such as faecal matter and vomit [11]. Scaled disgust ratings can predict participants’ willingness to attend an event with insect-based cuisine; this demonstrated clearly that disgust is a barrier to introduction of entomophagy into western diets [12].
Separate from the disgust response is the effect of food neophobia which also contributes to an unwillingness to try entomophagy. Food neophobia is simply the tendency to avoid the consumption of novel foods and the degree of novelty correlates strongly with willingness to try unfamiliar foods [13, 14].
2.1 Disgust and the ‘law of contamination’
The law of contamination states that a disgust reaction will be elicited not only by objects of core disgust but through any objects that have been contacted. Rozin’s elegant demonstration of this with fruit juice and sterile cockroaches indicates that this barrier to entomophagy is often based on irrational thought. Participants knew their reaction was irrational due to the cockroach having been sterilised [15, 16]. If the reaction does occur even with the knowledge that the organism is safe, then providing information on safety is likely to have little effect on uptake.
Overcoming this barrier to introduction may involve new brands initially selling insect-related products to focus primarily on gaining consumer trust or using established and ‘trusted’ brands to reduce the perceived risk of novel products [17]. Discovering and adopting shared values with consumers may permit entomophagy to become more compatible with western consumption while reducing negative attitudes [18]. Although, for this strategy to find success, individual brands must avoid perceived or real negative impacts on any group of consumers as these would likely impact the entomophagy industry as a whole by reducing trust [19]. For such trust to grow, a foundation of legislation is developing to provide advice and standards in appropriate methodology for hygienic insect handling and storage [20, 21].
2.2 Disgust response to ‘identifiable insects’
Disgust also arises when consumers are reminded that they are eating an animal or are made aware of the animals’ origins [11, 12]. When whole insects are found within a food product, this is considered an extended example of the law of contamination, as it occurs due to an association with dead animals and decay [11]. Many studies have pointed to invisibility of insects (such as in cookies) leading to increased willingness compared to their unprocessed counterparts (such as mealworms and crickets) [7, 10, 22]. These support the idea that, for easier implementation, innovators should focus on products without visible insects and thus simplify the product’s trajectory to western acceptability.
2.3 Food neophobia
Insect protein products are seen as novel, which influences consumer perception and thus their expected experience on trying it [23]. Increased familiarity reduces any anticipated negative assumptions of taste and experience before trying them [24] and incorporating novel food into familiar dishes will accelerate consumer acceptance. This plays into Rogers’ concepts of compatibility with western society as well as that of low complexity. The latter in this case is achieved through individuals being familiar with how common dishes in their culture are created and consumed. Mimicking familiarity also plays a part and people are more willing to try an insect when it comes in the format of a familiar food item [25]. Expectation also plays a role, an expectation of good flavour was found to be an important indicator for willingness to eat for crickets and silkworms [10].
There are examples where food neophobia has been overcome effectively. Rationing of U.S food supplies during World War II promoted consumption of unfamiliar organ protein. A strategy of preparing and serving these novel ingredients in expected and visually familiar ways led to accelerated uptake [24]. This may, however, prove more difficult with insects as they are perceptually distinct from mainstream food products. In order to capitalise on observability, using novel foods in a side dish accompanying a highly favoured familiar main dish can reduce variation in specific perception and in overall evaluation of the meal [26]. Thus, introducing insect protein to side dishes with the ‘delicious’ main course could optimise their introduction to mainstream diets before incorporation into main dishes.
Making a dish familiar is not enough, it is still important for the product to actually be a strongly positive culinary experience in terms of taste and texture. An a priori negative perception may become justified if the dish displays textural characteristics that the consumer does not enjoy and then serve to reinforce or increase aversion to insect dishes [13, 27]. Investment in the gastronomic integrity of dishes as well as in enticing advertising messages will increase the success of insect trials and encourage repeat consumption leading to increased observability [16]. There is much positive feedback between brand and item in the context of gaining consumer trust.
3. Social context and current culture
3.1 Absence of social context
Western culture has little recent experience with entomophagy and this is a barrier to its introduction as diet aligns strongly with the social norms of immediately surrounding culture [28]. This lack of social context for entomophagy allows for a greater level of food neophobia as all insect-based cuisine is seen as a novel food. Harnessing social norms may prove to be a method of increasing insect consumption as almost one-third of participants in one study tried insects ‘in company’ having first stated they would not [29]. This study concluded that having positive social models could result in mitigation of the disgust response. Expanding entomophagy as a social norm through positive models for people to observe and trial for themselves would thus increase compatibility.
3.2 Receptivity and age
Introducing children to entomophagy may bring these social norms into the general populace. People who tried foods in early childhood, even on rare occasions, were more likely to enjoy those foods when they were older. Parental influence is a less reliable indicator of liking foods when older, though this can encourage initial consumption of insect protein [30]. Social influence can be incorporated into the strategy by having parents and teachers as a positive model; observing adult influencers consuming insect products may draw greater willingness to try from the children. The challenge is how to develop the adult model to suit the most receptive ‘primary school’ age range [7]. Introduction to children should incorporate both visual and taste exposure to insect products; however, the focus should be on providing taste exposure to children as this has been shown to increase preference for the food item to a greater extent [31].
3.3 Complexity through absence of social context
Lack of social norms and context also increases the complexity of accepting entomophagy as innovation. With little opportunity for observability, people are less aware of the options available for entomophagy, where to begin, or even if it is possible to adopt it into their lifestyle. Creating social context is vital in allowing individuals to observe entomophagy before trying, it shows them that such dietary options are possible and can be desirable. The approach sometimes taken is that of ‘bug banquets’, events that offer the chance for consumers to try insect products. This approach can be biased as those people who seek out these experiences are more likely to have more positive views on entomophagy or lower neophobia scores. Furthermore, while these often result in reduced aversion to entomophagy, there is little to no follow-up on whether there is long-term uptake [32].
An alternative strategy for creating social context is to use social media. Applications such as Instagram, which has a high presence of food-related content, can offer recipes as well as images of available dishes. These global platforms also allow more insect-experienced countries to encourage the adoption of entomophagy in western countries. The efficacy of this strategy is limited by the notion that sharing of entomophagy may be limited by the fear that it will generate a prejudice towards them [33]. Social media methods create enhanced observability by endorsements from established food pages or celebrities. Some do distrust information from these sources and these endorsements may only need to be reflective of the possible lifestyle with limited focus on information distribution. Social media also allows for peer-group pressure to influence spending of certain age groups (such as teenagers) on insect proteins. This will be important as people are more likely to try an insect-containing product when it is offered by a friend than an unknown individual [7, 34, 35].
3.4 Relative advantage
A lack of necessity is a barrier to entomophagy uptake in westernised countries and countries with high meat production and consumption may perceive a lack of need for meat-based alternatives [36]. This highlights a barrier to the introduction strategy of insects as a meat-based alternative as consumers have a food gradient which they follow when selecting meat-based alternatives with initial choice being fish and eventual choices including tofu and similar products at the bottom. Although not a linear path, this gradient shows that consumers have a hierarchy of foods that they follow with novel foods often situated at the bottom [25]. One proposed strategy to overcome this lack of relative advantage would be to avoid promotion as meat alternative. Instead, comparison to nuts could prove more productive as they share similarities in texture, macronutrient content, flavour and size and will circumnavigate the problem that insects encounter when replacing dishes with larger portions of meat such as steaks [32]. In order to fully capitalise on a relative advantage over other products, the environmental benefits can be emphasised. Most current comparisons, however, are with meat and there is still debate surrounding this area with vegetarian diets becoming ever more popular in western countries [37, 38]. If the environmental benefit argument is to be made, using circular production gives some insect products relative advantage over other ‘green’ alternatives. A total of 1.3 billion tonnes of food produced for human consumption is wasted per year and valorisation can occur through the use of certain insect species to convert this wasted food into a high-protein product to be used for human or livestock consumption [39, 40].
Differences among western populations affect uptake of entomophagy as individual cultures place different values on factors when choosing their food. For example, the French place a higher value on the pleasures and the social aspects of food consumption whereas the English favour convenience, organic and ethical issues when choosing their food options [41]. With entomophagy, French respondents place less value on the relative advantages of insect products and the British have been found to be more repulsed by visible insects. Understanding this variation creates an opportunity to have adaptive introduction models in different countries. This approach will work to increase the compatibility of entomophagy and could also be used to adapt legislation within different legal jurisdictions [42].
4. Availability of product and information
4.1 Absence of available products
The lack of general availability of insect products creates greater complexity through reducing the ease of both trialability and enduring adoption. In some cases, demand may already exceed supply and the currently rising visibility will influence social norms causing an increase in demand [32]. As seen with sushi and lobster, greater observability and supply can change societal views and there is no reason this could not be the same for entomophagy [32, 43]. A great range of well-presented products are now available and this very variety can increase acceptance and adoption by consumers [24]. In addition to this, having a wider variety available can reduce the stigma insects have with their strong associations to pests or to notably high-revulsion species such as cockroaches [16].
4.2 Absence of available information
The limited supply of appropriate resources for the sourcing and preparation of insect-containing dishes adds to complexity; people do not know where to find recipes, choice advice and cooking information [36]. Though this is now changing rapidly, there remains a substantial information deficit. In 2015, recipes using pine needles and whale meat were more common than insect recipes on the food website ‘food.com’ and there are currently almost 40 times more mentions of biscuit recipes than insect recipes in a goggle search (Table 1) [32].
Recipe type
Insect
Nut
Chicken
Vegetable
Biscuit
Number of ‘hits’ (millions)
68
176
991
1960
2550
Relative abundance (to insect)
1
2.6
15
29
38
Table 1.
The number and relative abundance to ‘insect recipe’ as reference, of ‘hits’ (search results) in response to the search terms ‘insect recipe’, ‘nut recipe’, ‘chicken recipe’, ‘vegetable recipe’ and ‘biscuit recipe’. Searches conducted using Google Chrome, 21 June 2019.
Along with a knowledge deficit, there is also a confidence deficit contributing to complexity as many people would rather try insects for the first time in a restaurant setting than at home [25]. It is clear that to move towards lower complexity, there is a need for an increase in the availability of accessible and free resources. To reduce the need for extensive research, social media, online repositories and increased product information and recipes on packaging all have a part to play. These routes can encourage expansion of the range of dishes individuals will be willing to trial, and, through increasing trialability in this way, it can reduce the overall complexity associated with entomophagy.
5. Absence of relative advantage through high prices
Increasing the availability of insect products alone will not be sufficient to drive consumer acceptance for enduring entomophagy. Of those participating in a Dutch study, one-third found insect products to be ‘prohibitively expensive’ and although most people said price alone would not stop them from purchasing, the remaining two-thirds did recognise price as a factor in repeat purchase decisions [44]. In the 2019 online market place, insect protein powders are 3–10 times the price of vegetable and dairy comparators. Many things currently affect sale price and the increased production now happening across Europe and the North American continent will act to reduce this. Quality, reliability and cost effectiveness arising from increased automation and appropriate species selection will help to reduce price and mitigate the current absence of relative advantage [3].
6. Conclusion
Though interest and product availability are rising, western society has yet to adopt entomophagy as common practice. Entomophagy remains largely incompatible with western ideals, and most westerners exhibit a disgust response when faced with the prospect of eating an insect. A lack of social context and awareness increases the complexity of the innovation and is clearly indicated by consumers experiencing high levels of food neophobia or low awareness of purchase and preparation options.
This chapter has outlined a multitude of promising strategies to overcome such barriers and these strategies need to be developed concurrently (Figure 2). When combined, they may help ensure that entomophagy has each of the five characteristics outlined by Rogers as influential to product penetration (Figure 1) [8].
Figure 2.
The relationships between potential strategies to overcome barriers to entomophagy. Boxes of the same colour indicate strategies that share an overarching theme or whose implementation can improve the ability of other strategies to meet their goal.
Though many recent studies reviewed here have found an increase in participant interest and willingness to adopt through the provision of experience with entomophagy, more research on long-term adoption is required. We need to understand what will embed long-term adoption after food neophobia and the disgust response have been attenuated.
Acknowledgments
The authors wish to thank the many people who contribute to advancing entomophagy and the many benefits it may convey.
Conflict of interest
The authors declare no conflict of interest.
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Matilda Collins",authors:[{id:"301019",title:"Dr.",name:"C M",middleName:"(Tilly)",surname:"Collins",fullName:"C M Collins",slug:"c-m-collins",email:"t.collins@imperial.ac.uk",position:null,institution:null},{id:"308239",title:"Dr.",name:"Harry",middleName:null,surname:"McDade",fullName:"Harry McDade",slug:"harry-mcdade",email:"harry.mcdade17@imperial.ac.uk",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Disgust and food neophobia",level:"1"},{id:"sec_2_2",title:"2.1 Disgust and the ‘law of contamination’",level:"2"},{id:"sec_3_2",title:"2.2 Disgust response to ‘identifiable insects’",level:"2"},{id:"sec_4_2",title:"2.3 Food neophobia",level:"2"},{id:"sec_6",title:"3. Social context and current culture",level:"1"},{id:"sec_6_2",title:"3.1 Absence of social context",level:"2"},{id:"sec_7_2",title:"3.2 Receptivity and age",level:"2"},{id:"sec_8_2",title:"3.3 Complexity through absence of social context",level:"2"},{id:"sec_9_2",title:"3.4 Relative advantage",level:"2"},{id:"sec_11",title:"4. Availability of product and information",level:"1"},{id:"sec_11_2",title:"4.1 Absence of available products",level:"2"},{id:"sec_12_2",title:"4.2 Absence of available information",level:"2"},{id:"sec_14",title:"5. Absence of relative advantage through high prices",level:"1"},{id:"sec_15",title:"6. Conclusion",level:"1"},{id:"sec_16",title:"Acknowledgments",level:"1"},{id:"sec_19",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Trends Tracker (Blueshift Research). Interest in Insect-Based Products Grows Slightly but Hovers Around One-Third of Respondents. The Other Two-Thirds are Awaiting Recommendations, Confirmation of Nutritious Value and Taste [Internet]. 2015. Available from: http://blueshiftideas.com/content/june-2015-trends-tracker/'},{id:"B2",body:'Ahuja K, Deb S. Edible Insects Market Size By Product, By Application, Industry Analysis Report, Regional Outlook, Application Potential, Price Trends, Competitive Market Share & Forecast,. 2018. pp. 2018-2024'},{id:"B3",body:'van Huis A. Potential of insects as food and feed in assuring food security. Annual Review of Entomology. 2013;58(1):563-583'},{id:"B4",body:'Caparros Megido R, Sablon L, Geuens M, Brostaux Y, Alabi T, Blecker C, et al. Edible insects acceptance by Belgian consumers: Promising attitude for entomophagy development. Journal of Sensory Studies. 2014;29(1):14-20'},{id:"B5",body:'Berenbaum MR. A consuming passion for entomophagy. American Entomologist. 2016;62:140-142'},{id:"B6",body:'van Huis A, Oonincx DGAB. The environmental sustainability of insects as food and feed. A review. Agronomy for Sustainable Development. 2017;(1):37-43'},{id:"B7",body:'Collins CM, Vaskou P, Kountouris Y. Insect food products in the Western world: Assessing the potential of a new ‘green’ market. Annals of the Entomological Society of America. 2019. Special Issue: Edible Insects 1-11'},{id:"B8",body:'Rogers EM. Diffusion of Innovations. 5th ed. New York: Simon & Schuster; 2003'},{id:"B9",body:'Chapman HA, Anderson AK. Understanding disgust. Annals of the New York Academy of Sciences. 2012;1251(1):62-76'},{id:"B10",body:'Hartmann C, Shi J, Giusto A, Siegrist M. The psychology of eating insects: A cross-cultural comparison between Germany and China. Food Quality and Preference. 2015;44:148-156'},{id:"B11",body:'Rozin P, Fallon AE. A perspective on disgust. Psychological Review. 1987;94(1):23-41'},{id:"B12",body:'Hamerman EJ. Cooking and disgust sensitivity influence preference for attending insect-based food events. Appetite. 2016;96:319-326'},{id:"B13",body:'La Barbera F, Verneau F, Amato M, Grunert K. Understanding Westerners’ disgust for the eating of insects: The role of food neophobia and implicit associations. Food Quality and Preference. 2018;64:120-125'},{id:"B14",body:'Tuorila H, Lähteenmäki L, Pohjalainen L, Lotti L. Food neophobia among the Finns and related responses to familiar and unfamiliar foods. Food Quality and Preference. 2001;12(1):29-37'},{id:"B15",body:'Rozin P, Millman L, Nemeroff C. Operation of the laws of sympathetic magic in disgust and other domains. Journal of Personality and Social Psychology. 1986;50(4):703-712'},{id:"B16",body:'Deroy O, Reade B, Spence C. The insectivore’s dilemma, and how to take the west out of it. Food Quality and Preference. 2015;44:44-55'},{id:"B17",body:'Siegrist M. Factors influencing public acceptance of innovative food technologies and products. Trends in Food Science & Technology. 2008;19(11):603-608'},{id:"B18",body:'Earle T, Siegrist M. Trust, confidence and cooperation model: A framework for understanding the relation between trust and risk perception. International Journal of Global Environmental Issues. 2008;8(1):17'},{id:"B19",body:'Siegrist M, Cousin ME, Kastenholz H, Wiek A. Public acceptance of nanotechnology foods and food packaging: The influence of affect and trust. Appetite. 2007;49(4):459-466'},{id:"B20",body:'Belluco S, Losasso C, Maggioletti M, Alonzi CC, Paoletti MG, Ricci A. Edible insects in a food safety and nutritional perspective: A critical review. Comprehensive Reviews in Food Science and Food Safety. 2013;12(3):296-313'},{id:"B21",body:'Finke MD, Rojo S, Roos N, van Huis A, Yen AL. The European food safety authority scientific opinion on a risk profile related to production and consumption of insects as food and feed. Journal of Insects as Food and Feed. 2015;(1):245-247'},{id:"B22",body:'Gmuer A, Nuessli Guth J, Hartmann C, Siegrist M. Effects of the degree of processing of insect ingredients in snacks on expected emotional experiences and willingness to eat. Food Quality and Preference. 2016;54:117-127'},{id:"B23",body:'Pliner P, Pelchat M, Grabski M. Reduction of neophobia in humans by exposure to novel foods. Appetite. 1993;20(2):111-123'},{id:"B24",body:'Wansink B. Changing eating habits on the home front: Lost lessons from World War II research. Journal of Public Policy & Marketing. 2003;21(1):90-99'},{id:"B25",body:'Schösler H, de Boer J, Boersema JJ. Can we cut out the meat of the dish? Constructing consumer-oriented pathways towards meat substitution. Appetite. 2012;72:1592-1607'},{id:"B26",body:'Peryam DR, Polemis BW, Kamen JM, Eindhoven J, Pilgrim FJ. Food Preferences of Men in the U. S. Armed Forces. Surveys of Progress on Military Subsistance Problems. Chicago: Quartermaster Food and Container Institute; 1960'},{id:"B27",body:'Martins Y, Pliner P. Human food choices: An examination of the factors underlying acceptance/rejection of novel and familiar animal and nonanimal foods. Appetite. 2005;45(3):214-224'},{id:"B28",body:'Higgs S, Thomas J. Social influences on eating. Current Opinion in Behavioral Sciences. 2016;9:1-6'},{id:"B29",body:'Jensen NH, Lieberoth A. We will eat disgusting foods together—Evidence of the normative basis of Western entomophagy-disgust from an insect tasting. Food Quality and Preference. 2019;72:109-115'},{id:"B30",body:'Wadhera D, Capaldi Phillips ED, Wilkie LM, Boggess MM. Perceived recollection of frequent exposure to foods in childhood is associated with adulthood liking. Appetite. 2015;89:22-32'},{id:"B31",body:'Birch LL, Marlin DW. I don’t like it; I never tried it: Effects of exposure on two-year-old children’s food preferences. Appetite. 1982;3(4):353-360'},{id:"B32",body:'Shelomi M. Why we still don’t eat insects: Assessing entomophagy promotion through a diffusion of innovations framework. Trends in Food Science & Technology. 2015;45:311-318'},{id:"B33",body:'Looy H, Dunkel FV, Wood JR. How then shall we eat? Insect-eating attitudes and sustainable foodways. Agriculture and Human Values. 2014;31(1):131-141'},{id:"B34",body:'Lensvelt EJS, Steenbekkers LPA. Exploring consumer acceptance of entomophagy: A survey and experiment in Australia and the Netherlands. Ecology of Food and Nutrition. 2014;53(5):543-561'},{id:"B35",body:'Spero I, Stone M. Agents of change: How young consumers are changing the world of marketing. Qualitative Market Research: An International Journal. 2004;7(2):153-159'},{id:"B36",body:'Clarkson C, Mirosa M, Birch J. Consumer acceptance of insects and ideal product attributes. British Food Journal. 2018;120(12):2898-2911'},{id:"B37",body:'Oonincx DGAB, de Boer IJM. Environmental impact of the production of mealworms as a protein source for humans—A life cycle assessment. PLoS One. 2012;7:12'},{id:"B38",body:'Shelomi M. The meat of affliction: Insects and the future of food as seen in expo 2015. Trends in Food Science and Technology. 2016;56:175-179'},{id:"B39",body:'Gustavsson J, Cederberg C, Sonesson U. Global Food Losses and Food Waste—Extent. Causes and Prevention. Rome, Italy: FAO; 2011'},{id:"B40",body:'van Huis A, Klunder JVIH, Merten E, Halloran A, Vantomme P. Edible Insects. Future Prospects for Food and Feed Security. Rome: Food and Agriculture Organization of the United Nations; 2013'},{id:"B41",body:'Pettinger C, Holdsworth M, Gerber M. Psycho-social influences on food choice in southern France and Central England. Appetite. 2004;42(3):307-316'},{id:"B42",body:'Halloran A, Muenke C, Vantomme P, van Huis A. Insects in the human food chain: Global status and opportunities. Food Chain. 2014;4(2):103-118'},{id:"B43",body:'Luzer D. How Lobster Got Fancy. Pacific Standard [Internet]. 2013. Available from: https://psmag.com/'},{id:"B44",body:'House J. Consumer acceptance of insect-based foods in the Netherlands: Academic and commercial implications. Appetite. 2016;107:47-58'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Harry McDade",address:null,affiliation:'
Department of Life Sciences, Imperial College London, United Kingdom
Centre for Environmental Policy, Imperial College London, United Kingdom
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1. Introduction
1.1 Infertility and subfertility
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.
1.1.1 Male 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.
1.1.1.1 Testicular disease: endocrine and systemic disorders
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]).
1.1.1.2 Genetic disorders of spermatogenesis
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].
1.1.1.3 Posttesticular defects
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].
1.1.1.4 Idiopathic
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.
1.1.2 Female infertility
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.
1.1.2.1 Ovaries
1.1.2.1.1 Ovulatory disorders
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.
1.1.2.1.2 Oocyte aging
Maternal aging is a known factor of female infertility [25]. The decrease in fecundability with aging could be due to a decline in both the quantity and quality of the oocytes [25, 26].
1.1.2.2 Fallopian tubes
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].
1.1.2.3 Uterus
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].
1.1.2.4 Endometriosis
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].
1.1.2.5 Obesity
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].
1.2. Medically assisted reproduction
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.
Figure 1.
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.
1.2.1 Assisted reproductive techniques
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:
1.2.1.1 Intrauterine insemination (IUI)
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].
1.2.1.2 In vitro fertilization (IVF)
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].
1.2.2 Ovarian stimulators
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]).
1.2.2.1 Ovulation induction
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].
1.2.2.2 Ovulation maturation and release
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].
2. Trends in medically assisted reproduction use
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].
3. Medically assisted reproduction and perinatal outcomes
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.
3.1 Prematurity
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.
3.2 Low birth weight
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].
3.3 Small for gestational age
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.
3.4 Long-term cognitive outcomes
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.
3.4.1 Cerebral palsy
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].
3.4.2 Autism
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.
3.4.3 Behavioral problems
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.
4. Conclusions
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.
Acknowledgments
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.
Conflict of interest
JG and AB have no conflicts of interest to report.
\n',keywords:"medically assisted reproduction, prematurity, low birth weight, small for gestational age, delay in cognitive function",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/63784.pdf",chapterXML:"https://mts.intechopen.com/source/xml/63784.xml",downloadPdfUrl:"/chapter/pdf-download/63784",previewPdfUrl:"/chapter/pdf-preview/63784",totalDownloads:393,totalViews:42,totalCrossrefCites:1,dateSubmitted:"May 17th 2018",dateReviewed:"September 5th 2018",datePrePublished:"November 5th 2018",datePublished:"July 17th 2019",dateFinished:null,readingETA:"0",abstract:"Over 5 million children have been born through in vitro fertilization (IVF) across the world. IVF is only one of the many methods of assisted reproduction, which can be used to achieve pregnancy in the context of infertility or subfertility. Since the birth of the first IVF child, Louise Brown, in 1978, a number of researchers have started to study the various impacts of the conception through these methods, on both mothers and children. A growing body of evidence suggests that conception through medically assisted reproduction (MAR) is not without risk. Given that MAR is relatively new and that our look back period is short, there is limited evidence on the risks associated to these procedures, both for the mother and the child. In this chapter, we aim to explore the association between MARs and adverse perinatal outcomes specifically. We will first provide you with an overview of the prevalence and trends of use of these methods around the world, and then delve into the associations between MARs and the risk of perinatal outcomes, namely prematurity, being born with low birth weight and/or small for gestational age, and lastly the impact of MARs on cognitive functions including cerebral palsy, behavioral problems, and autism, which are identified later in the child’s life.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/63784",risUrl:"/chapter/ris/63784",signatures:"Jessica Gorgui and Anick Bérard",book:{id:"7163",title:"Infertility, Assisted Reproductive Technologies and Hormone Assays",subtitle:null,fullTitle:"Infertility, Assisted Reproductive Technologies and Hormone Assays",slug:"infertility-assisted-reproductive-technologies-and-hormone-assays",publishedDate:"July 17th 2019",bookSignature:"Dhastagir Sultan Sheriff",coverURL:"https://cdn.intechopen.com/books/images_new/7163.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"167875",title:"Dr.",name:"Dhastagir Sultan",middleName:null,surname:"Sheriff",slug:"dhastagir-sultan-sheriff",fullName:"Dhastagir Sultan Sheriff"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"55191",title:"Dr.",name:"Anick",middleName:null,surname:"Bérard",fullName:"Anick Bérard",slug:"anick-berard",email:"anick.berard@umontreal.ca",position:null,institution:null},{id:"259161",title:"Ph.D. Student",name:"Jessica",middleName:null,surname:"Gorgui",fullName:"Jessica Gorgui",slug:"jessica-gorgui",email:"jessica.gorgui@gmail.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1 Infertility and subfertility",level:"2"},{id:"sec_1_3",title:"1.1.1 Male infertility",level:"3"},{id:"sec_1_4",title:"1.1.1.1 Testicular disease: endocrine and systemic disorders",level:"4"},{id:"sec_2_4",title:"1.1.1.2 Genetic disorders of spermatogenesis",level:"4"},{id:"sec_3_4",title:"1.1.1.3 Posttesticular defects",level:"4"},{id:"sec_4_4",title:"1.1.1.4 Idiopathic",level:"4"},{id:"sec_6_3",title:"1.1.2 Female infertility",level:"3"},{id:"sec_6_4",title:"1.1.2.1 Ovaries",level:"4"},{id:"sec_6_5",title:"1.1.2.1.1 Ovulatory disorders",level:"5"},{id:"sec_7_5",title:"1.1.2.1.2 Oocyte aging",level:"5"},{id:"sec_9_4",title:"1.1.2.2 Fallopian tubes",level:"4"},{id:"sec_10_4",title:"1.1.2.3 Uterus",level:"4"},{id:"sec_11_4",title:"1.1.2.4 Endometriosis",level:"4"},{id:"sec_12_4",title:"1.1.2.5 Obesity",level:"4"},{id:"sec_15_2",title:"1.2. Medically assisted reproduction",level:"2"},{id:"sec_15_3",title:"1.2.1 Assisted reproductive techniques",level:"3"},{id:"sec_15_4",title:"1.2.1.1 Intrauterine insemination (IUI)",level:"4"},{id:"sec_16_4",title:"1.2.1.2 In vitro fertilization (IVF)",level:"4"},{id:"sec_18_3",title:"1.2.2 Ovarian stimulators",level:"3"},{id:"sec_18_4",title:"1.2.2.1 Ovulation induction",level:"4"},{id:"sec_19_4",title:"1.2.2.2 Ovulation maturation and release",level:"4"},{id:"sec_23",title:"2. Trends in medically assisted reproduction use",level:"1"},{id:"sec_24",title:"3. Medically assisted reproduction and perinatal outcomes",level:"1"},{id:"sec_24_2",title:"3.1 Prematurity",level:"2"},{id:"sec_25_2",title:"3.2 Low birth weight",level:"2"},{id:"sec_26_2",title:"3.3 Small for gestational age",level:"2"},{id:"sec_27_2",title:"3.4 Long-term cognitive outcomes",level:"2"},{id:"sec_27_3",title:"3.4.1 Cerebral palsy",level:"3"},{id:"sec_28_3",title:"3.4.2 Autism",level:"3"},{id:"sec_29_3",title:"3.4.3 Behavioral problems",level:"3"},{id:"sec_32",title:"4. Conclusions",level:"1"},{id:"sec_33",title:"Acknowledgments",level:"1"},{id:"sec_36",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Zegers-Hochschild F et al. International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology, 2009. Fertility and Sterility. 2009;92(5):1520-1524'},{id:"B2",body:'Gnoth C et al. Definition and prevalence of subfertility and infertility. 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Morbidity in a Danish national cohort of 472 IVF/ICSI twins, 1132 non-IVF/ICSI twins and 634 IVF/ICSI singletons: Health-related and social implications for the children and their families. Human Reproduction. 2003;18(6):1234-1243'},{id:"B132",body:'Stromberg B et al. Neurological sequelae in children born after in-vitro fertilisation: A population-based study. Lancet. 2002;359(9305):461-465'},{id:"B133",body:'Pinborg A et al. Neurological sequelae in twins born after assisted conception: Controlled national cohort study. BMJ. 2004;329(7461):311'},{id:"B134",body:'Abdel-Latif ME et al. Neurodevelopmental outcomes of extremely premature infants conceived after assisted conception: A population based cohort study. Archives of Disease in Childhood. Fetal and Neonatal Edition. 2013;98(3):F205-F211'},{id:"B135",body:'Fountain C et al. Association between assisted reproductive technology conception and autism in California, 1997–2007. American Journal of Public Health. 2015;105(5):963-971'},{id:"B136",body:'Sandin S et al. Autism and mental retardation among offspring born after in vitro fertilization. Journal of the American Medical Association. 2013;310(1):75-84'},{id:"B137",body:'Lehti V et al. Autism spectrum disorders in IVF children: A national case-control study in Finland. Human Reproduction. 2013;28(3):812-818'},{id:"B138",body:'Kamowski-Shakibai MT, Magaldi N, Kollia B. Parent-reported use of assisted reproduction technology, infertility, and incidence of autism spectrum disorders. Research in Autism Spectrum Disorders. 2015;9:77-95'},{id:"B139",body:'Mamidala MP et al. Maternal hormonal interventions as a risk factor for autism Spectrum disorder: An epidemiological assessment from India. Journal of Biosciences. 2013;38(5):887-892'},{id:"B140",body:'Gillberg C, Wing L. Autism: Not an extremely rare disorder. Acta Psychiatrica Scandinavica. 1999;99(6):399-406'},{id:"B141",body:'Christensen DL et al. Prevalence and characteristics of autism Spectrum disorder among children aged 8 years—Autism and developmental disabilities monitoring network, 11 sites, United States, 2012. MMWR Surveillance Summaries. 2016;65(3):1-23'},{id:"B142",body:'Boukhris T et al. Antidepressant use during pregnancy and the risk of autism spectrum disorder in children. JAMA Pediatrics. 2016;170(2):117-124'},{id:"B143",body:'Ackerman S et al. No increase in autism-associated genetic events in children conceived by assisted reproduction. Fertility & Sterility. 2014;102(2):388-393'},{id:"B144",body:'Lyall K et al. Fertility therapies, infertility and autism spectrum disorders in the Nurses\' Health Study II. Paediatric and Perinatal Epidemiology. 2012;26(4):361-372'},{id:"B145",body:'Hediger ML et al. Assisted reproductive technologies and children\'s neurodevelopmental outcomes. Fertility and Sterility. 2013;99(2):311-317'},{id:"B146",body:'Association, A.P. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition: DSM-IV-TR®. American Psychiatric Association; 2000'},{id:"B147",body:'Association, A.P. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition: DSM-V. American Psychiatric Association; 2013'},{id:"B148",body:'Shojaei T et al. The strengths and difficulties questionnaire: Validation study in French school-aged children and cross-cultural comparisons. Social Psychiatry and Psychiatric Epidemiology. 2009;44(9):740-747'},{id:"B149",body:'McGrath JM et al. Parenting after infertility: Issues for families and infants. MCN: American Journal of Maternal Child Nursing. 2010;35(3):156-164'},{id:"B150",body:'O\'Connor TG et al. Maternal antenatal anxiety and behavioural/emotional problems in children: A test of a programming hypothesis. Journal of Child Psychology and Psychiatry. 2003;44(7):1025-1036'},{id:"B151",body:'Talge NM, Neal C, Glover V. Antenatal maternal stress and long-term effects on child neurodevelopment: How and why? Journal of Child Psychology and Psychiatry. 2007;48(3–4):245-261'},{id:"B152",body:'O\'Connor TG et al. Prenatal anxiety predicts individual differences in cortisol in pre-adolescent children. Biological Psychiatry. 2005;58(3):211-217'},{id:"B153",body:'O\'Connor TG, Heron J, Glover V. Antenatal anxiety predicts child behavioral/emotional problems independently of postnatal depression. Journal of the American Academy of Child and Adolescent Psychiatry. 2002;41(12):1470-1477'},{id:"B154",body:'Carson C et al. Effects of pregnancy planning, fertility, and assisted reproductive treatment on child behavioral problems at 5 and 7 years: Evidence from the millennium cohort study. Fertility and Sterility. 2013;99(2):456-463'},{id:"B155",body:'Golombok S et al. Families with children conceived by donor insemination: A follow-up at age twelve. Child Development. 2002;73(3):952-968'},{id:"B156",body:'Golombok S et al. Parent-child relationships and the psychological well-being of 18-year-old adolescents conceived by in vitro fertilisation. Human Fertility (Cambridge, England). 2009;12(2):63-72'},{id:"B157",body:'Wagenaar K et al. Behavior and socioemotional functioning in 9–18-year-old children born after in vitro fertilization. Fertility and Sterility. 2009;92(6):1907-1914'},{id:"B158",body:'Wagenaar K et al. Self-reported behavioral and socioemotional functioning of 11- to 18-year-old adolescents conceived by in vitro fertilization. Fertility and Sterility. 2011;95(2):611-616'},{id:"B159",body:'Zhu JL et al. Infertility, infertility treatment and behavioural problems in the offspring. Paediatric and Perinatal Epidemiology. 2011;25(5):466-477'},{id:"B160",body:'Brauner CB, Stephens CB. Estimating the prevalence of early childhood serious emotional/behavioral disorders: Challenges and recommendations. Public Health Reports. 2006;121(3):303-310'},{id:"B161",body:'Golombok S et al. Families created by the new reproductive technologies: Quality of parenting and social and emotional development of the children. Child Development. 1995;66(2):285-298'},{id:"B162",body:'Montgomery TR et al. The psychological status at school age of children conceived by in-vitro fertilization. Human Reproduction. 1999;14(8):2162-2165'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Jessica Gorgui",address:null,affiliation:'
Research Center, CHU Sainte-Justine, Canada
Faculty of Pharmacy, University of Montreal, Canada
Faculty of Pharmacy, University of Montreal, Canada
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This is not a shameful disease on the contrary; it is linked to a mutation that arose for us to defend against severe forms of malaria. It is due to the so-called selective pressure that has enabled AS carriers to resist severe forms of malaria. This advantage explains among other things why, although cosmopolitan, sickle cell disease predominates in Africa and its geographical distribution is superimposed on the malaria one. In the Democratic Republic of the Congo (DRC), it is estimated that there are 25–30% heterozygous healthy carriers (AS) and about 50,000 homozygous newborns (SS) each year, equating to 2% of newborns. Therefore, an effective medical care is very indispensable. The management of any pathology implies the appropriate choice of techniques and technologies. Unfortunately, very often in sub-Saharan countries, there is a lack of global strategy to providing effective solution. 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He holds a Ph.D. in Immunohematology from the Rivers State University of Science and Technology, Nigeria. He completed the University of Greenwich, UK Specialist Training in Blood Transfusion and Laboratory Quality Management System. He holds a Specialist Certificate in Transfusion Science Practice from the British Blood Transfusion Society (BBTS). He is also an alumnus of Francis Tuttle College of Technology in Oklahoma, USA. His teaching experience spans both the African continent and Europe. Dr. Osaro is the chair of the equality and diversity working group of the BBTS and recipient of the Margaret Kenwright Scientist award from the same organization. He is a registered portfolio verifier/examiner for the Institute of Biomedical Science of London. He has authored five scientific books and five book chapters. 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He\nhad held several Adjunct academic appointments with various\nNigerian universities and had taught at both post graduate and\nundergraduate levels for over nine years. His current research interest is focus on\nTransfusion immunology, safety and alternatives, and haematology of infectious\ndiseases. Recent publications have included articles in Journals such as the Journal\nof Blood Medicine; Transfusion Clinque et Biologique, Pathology and Laboratory\nMedicine International amongst others.",institutionString:null,institution:null},{id:"98639",title:"Dr.",name:"Maria",surname:"Rios",slug:"maria-rios",fullName:"Maria Rios",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"United States Food and Drug Administration",institutionURL:null,country:{name:"United States of America"}}},{id:"156995",title:"Dr.",name:"Cristiane",surname:"Wenceslau",slug:"cristiane-wenceslau",fullName:"Cristiane Wenceslau",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"301415",title:"Prof.",name:"Irina",surname:"Kerkis",slug:"irina-kerkis",fullName:"Irina Kerkis",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"304360",title:"MSc.",name:"Vivian",surname:"Gonzaga",slug:"vivian-gonzaga",fullName:"Vivian Gonzaga",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"304363",title:"Ms.",name:"Bruna",surname:"Policiquio",slug:"bruna-policiquio",fullName:"Bruna Policiquio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Instituto Butantan",institutionURL:null,country:{name:"Brazil"}}},{id:"307172",title:"Dr.",name:"Fatima A.",surname:"Aldarweesh",slug:"fatima-a.-aldarweesh",fullName:"Fatima A. Aldarweesh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/307172/images/8809_n.jpg",biography:null,institutionString:null,institution:{name:"University of Chicago",institutionURL:null,country:{name:"United States of America"}}},{id:"308284",title:"Dr.",name:"Emilia",surname:"Sippert",slug:"emilia-sippert",fullName:"Emilia Sippert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"308625",title:"Dr.",name:"Evgeniya",surname:"Volkova",slug:"evgeniya-volkova",fullName:"Evgeniya Volkova",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"publication-agreement-chapters",title:"Publication Agreement - Book Chapter",intro:'
IntechOpen aims to ensure that original material is published while at the same time giving significant freedom to our Authors. To that end we maintain a flexible Copyright Policy guaranteeing that there is no transfer of copyright to the publisher and Authors retain exclusive copyright to their Work.
',metaTitle:"Publication Agreement - Chapters",metaDescription:"IN TECH aims to guarantee that original material is published while at the same time giving significant freedom to our authors. For that matter, we uphold a flexible copyright policy meaning that there is no transfer of copyright to the publisher and authors retain exclusive copyright to their work.\n\nWhen submitting a manuscript the Corresponding Author is required to accept the terms and conditions set forth in our Publication Agreement as follows:",metaKeywords:null,canonicalURL:"/page/publication-agreement-chapters",contentRaw:'[{"type":"htmlEditorComponent","content":"
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7. MISCELLANEOUS
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7.1 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.
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7.2 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.
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7.3 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.
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7.4 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.
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7.5 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).
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7.6 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.
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Any 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.
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7.7 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.
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7.8 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).
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\n
1. DEFINITIONS
\n\n
Corresponding 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\n
Co-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\n
IntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\n
Book: 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.
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2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n
2.1 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:
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An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to publish, communicate to the public, reproduce, republish, transmit, sell, distribute and otherwise use and make available the Chapter in whole, partial or adapted from and/or incorporated in or in conjunction with other works, in electronic and print editions of the Publication and in derivative works and on any platform owned and/or operated by IntechOpen, throughout the world, in all languages, and in all media and formats now known or later developed.
\n\t
An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to create and store electronic archival copies of the Chapter, including the right to deposit the Chapter in open access digital repositories.
\n\t
An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to license others to reproduce, translate, republish, transmit and distribute the Chapter in whole, partial or adapted from and/or incorporated in or in conjunction with other works under the condition that the Corresponding Author and each Co-Author is attributed (currently this is carried out by publishing the Chapter under a Creative Commons Attribution 3.0 Unported License).
\n
\n\n
The aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
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2.2 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.
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The 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.
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Subject 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.
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Subject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
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2.3 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.
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2.4 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\n
3. CORRESPONDING AUTHOR'S DUTIES
\n\n
3.1 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.
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3.2 When submitting the Chapter, the Corresponding Author agrees to:
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Comply with all instructions and guidelines provided by IntechOpen;
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Produce the Chapter with all due skill, care and diligence, and in accordance with good scientific practice;
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Submit all the corrections in due time as defined during the publishing process schedule.
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The Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
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All 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.
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3.3 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\n
The 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\n
3.4 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.
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4. CORRESPONDING AUTHOR'S WARRANTY
\n\n
4.1 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\n
The 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.
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The 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\n
4.2 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.
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5. TERMINATION
\n\n
5.1 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\n
In case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n
6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n
6.1 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\n
6.2 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\n
6.3 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\n
7. MISCELLANEOUS
\n\n
7.1 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\n
7.2 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\n
7.3 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\n
7.4 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.
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7.5 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).
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7.6 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\n
Any 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\n
7.7 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\n
7.8 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\n
Last updated: 2020-11-27
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