M o n o g r a p h ic s e c t io n 258 Primary prevention as an essential factor ensuring sustainability of health systems: the example of congenital anomalies Domenica Taruscio1, Eva Bermejo-Sánchez2, Paolo Salerno1 and Alberto Mantovani3 1Centro Nazionale Malattie Rare, Istituto Superiore di Sanità, Rome, Italy 2Instituto de Investigación de Enfermedades Raras (IIER), ECEMC (Estudio Colaborativo Español de Malformaciones Congénitas), Centro de Investigación sobre Anomalías Congénitas (CIAC). CIBERER (U724). Instituto de Salud Carlos III, Madrid, Spain 3Dipartimento di Sicurezza Alimentare, Nutrizione e Sanità Pubblica Veterinaria, Istituto Superiore di Sanità, Rome, Italy Ann Ist Super Sanità 2019 | Vol. 55, No. 3: 258-264 DOI: 10.4415/ANN_19_03_11 INTRODUCTION Primary prevention in public health and in the field of rare diseases Since Hyppocrates, public health care means that, be- sides treating disease when it occurs, science and actions should reduce the occurrence of diseases. This is specifi- cally called “prevention”. Primary prevention includes the actions aimed at avoiding the onset of the disease. This means intervening before health effects occur, through measures modifying risk factors, their distribution or the way they reach the individual, for instance by banning substances or conditions known to be associated with one or more disease or adverse health status. Primary prevention, thus, results on eradicating, eliminating or minimizing the impact of disease and disability on the population, through interventions that are applied before there is any evidence of disease or injury, by controlling causative risk factors; the main focus are disease risk fac- tors, in order to reduce the disease incidence. Reducing disease incidence means a healthier soci- ety, while reduced disease burden means improved life quality and working capacity, reduction of avoidable disabilities and mortality, and lower costs for diagnosis and treatments, among other advantages, for the indi- vidual as well as for the society. Thus, strengthening and implementing primary prevention with the support of scientific evidence makes the healthcare system more efficient and sustainable, while providing significant benefits to society as a whole, apart from the individual tangible and intagible advantages. The different and relevant disciplines and actors in- volved in primary prevention often tend to think and operate in silos [1], concentrating on specific determi- nants such as lifestyles or living environment. Indeed, the actual problems call for an integration and cross-fer- tilization among different expertise fields. For instance, communities with low socio-economic status are more prone to live in more polluted settings, with insufficient availability of green areas or healthy food purchases. Therefore, it is also important to gather accurate data that can be analysed wisely to avoid confounding and to properly assess possible interactions of different vari- Address for correspondence: Domenica Taruscio, Centro Nazionale Malattie Rare, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. Email: domenica.taruscio@iss.it. Key words • primary prevention • sustainability • resilience • health promotion • birth defects Abstract Protection of early development contributes to health of next generations. Congenital anomalies (and other adverse reproductive outcomes) are an important public health is- sue and early indicator of public health risks, as early development is influenced by many risk factors (e.g., nutrition, lifestyles, pollution, infections, medications, etc). Effective primary prevention requires an integrated “One Health” approach, linking knowledge and action. This requires surveillance of health events and potential health-damaging fac- tors, science-based risk analysis, citizens’ empowerment and education of health profes- sionals. From the policy standpoint, joint budgeting mechanisms are needed to sustain with equity intersectoral actions (involving policy domains of health, social affairs, edu- cation, agriculture and environment). States should devote resources to strengthen reg- istries and systematic data collection for surveillance of congenital anomalies, to better inform national prevention strategies. Investing in primary prevention based on scientific evidence is essential to support sustainable and resilient health systems and sustainable development of the society. Primary Prevention for sustainable health M o n o g r a p h ic s e c t io n 259 ables and linked factors. These accurate analyses will have an impact on the identification of risk factors and the delineation of primary prevention measures. It is important to note that, although primary preven- tion makes the health systems more sustainable, and despite its recognized major role among public health actions, paradoxically it does not attract a correspond- ing fraction of resources devoted to health by policy makers. For instance, countries from the European Union (EU) overall allocate less than 3% of healthcare expenditure, and as low as 1% in some countries, to pri- mary prevention actions [2]. The reduction of risk factors for poor health out- comes may involve actions beyond the specific domain of healthcare systems. The capacity to fulfill the primary requirements (food security, housings), the quality and safety of living environment (air, water, food), the social environment (education, income, lifestyles), the deci- sions of policy makers (in what refers to resources de- voted to health services), are all determinants involved in increasing or reducing threats for health. In prin- ciple, policies should consider their potential impact on health and undergo “health-proofing”, as recently implemented in Ireland and a few other EU Countries. The 2013 Annual Growth Survey [3] recognised that “in the context of the demographic challenges and the pressure on age-related expenditure, reforms of health- care systems should be undertaken to ensure cost-effec- tiveness and sustainability, assessing the performance of these systems against the twin aim of a more efficient use of public resources and access to high quality health- care”. The assessment of healthcare policies should be more prevention-oriented. Effective prevention is evalu- ated on the basis of “diseases avoided”. This means that fit-to-purpose sets of performance indicators and out- come measurements should be developed accordingly to better plan future programs and strategies. When extending the considerations on primary pre- vention to rare diseases, congenital anomalies (CA) rep- resent a proper field of reflection and action. Many rare diseases are congenital because they result from altera- tion of prenatal development. This means that their man- ifestations are present at birth or can be even evident before the delivery. In fact, prenatal diagnosis is possible for many of them. CA, also known as birth defects, are defined by the World Health Organization (www.who. int/topics/congenital_anomalies/en/) as structural or functional anomalies that occur during intrauterine life and can be identified prenatally, at birth or later in life. Indeed, CA represent an important fraction of rare dis- eases and, at the same time, most CA can be considered rare diseases, based on their frequency [4]. They repre- sent a significant health burden, leading to an overall in- creased morbidity and to a considerable risk for prema- ture death among affected people, as well as for lifelong disabilities and dependence in many surviving cases [4]. CA’s presence since birth or earlier implies that they, and their consequences, must be faced from that early point in life, Due to the critical role of non-genetic factors in their etiology, CA are the main group of rare diseases in which primary prevention measures have a known benefi- cial impact. Indeed, since 2013 the European Union has endorsed a body of evidence-based Recommendations for primary prevention of CA [5]. These recommendations may be relevant to other adverse pregnancy outcomes as well (prematurity, stillbirths, developmental delays and related disabilities), and even they can have an impact on parents’ health (since for instance modifying lifestyles or adopting better protection in the workplace will also benefit them), as non-genetic risk factors are frequently shared. The Recommendations [5] discussed the differ- ent institutional and societal levels relevant for develop- ing and implementing primary prevention strategies. MATERIALS AND METHODS The paper reviews the main literature available on the primary prevention of rare diseases, with a special fo- cus on CA. Several medical databases and additional information resources were utilised and included gov- ernment documents, reports from international bodies such as the World Health Organisation, and academic studies. The key search terms were primary preven- tion, congenital anomalies and rare diseases, from 2000 through January 2018. Articles of interest were reviewed to determine which were relevant and sub- jected to analysis. Selected papers were later used to extrapolate the most relevant messages about primary prevention of on CA. RESULTS The reviwe showed that the importance of CA on public health is clear: Christianson et al. [6] estimated that overall 7.9 million children are born each year with serious CA of genetic or partially genetic (multifacto- rial, gene-environment) origin, and additional hundred thousand more are born with serious CA of post-con- ception origin. In general, and depending on the popu- lation considered, it is estimated that approximately 3-6% of newborn infants worldwide are affected by seri- ous CA [7-9]. Moreover, according to the 2015 Global Burden of Disease study, CA led to 8.5% (7.7-9.5%) of deaths under the age of 5 years in 2015 [10], and at least 3.3 million children under 5 years of age die from CA each year [9]. CA represented the most important cause of death below 5 years of age in countries with low and very low under-5 mortality [11]; in addition, Oza et al [12] observed that the proportion of deaths from CAs was relatively stable across their study period (data for 2000-2013 in 194 countries), showing the smallest relative decrease in risk compared to other causes (e.g., infections); some authors have estimated that mortality due to CA for the under-5 age group is likely to be a four-fold underestimate [13]. Beyond mortality, an esti- mated 3.2 million of those who survive may be disabled for life [9]; disability-adjusted life-years (DALY) rates due to CA have increased lately [14]; the years lived with disability (YLD) have increased for CA [15]. Ter- minations of pregnancy for CA were almost three times more frequent than infant deaths and stillbirths with CA combined [16], and this affects the Global Burden of Disease figures and their interpretation. These eloquent figures, matched with their intrauter- ine origin and the major role of non-genetic factors, en- hance the interest of their study within the field of rare Domenica Taruscio, Eva Bermejo-Sánchez, Paolo Salerno and Alberto Mantovani M o n o g r a p h ic s e c t io n 260 diseases, and make them priority targets for research [17] and prevention. Primary prevention of CA is fea- sible because scientific evidence points to several risk factors (e.g., obesity, infectious and toxic agents) and protective factors (e.g., folic acid supplementation and glycemic control in diabetic women) [18]. The bullet points below summarize the main fields pertinent to primary prevention of CA, encompassing both health systems and policies in relevant fields: • Actions to mitigate low socio-economic status and poor education might have an impressive impact on a num- ber of critical determinants, such as lifestyles (tobac- co smoking and alcohol drinking during pregnancy, among others), and unbalanced diet associated with the increased risk of overweight/obesity, which, in its turn, is a significant risk factor for CA. • Lifestyles can partly be tackled by specific policies, whose effectiveness should be evaluated in the con- text of specific countries. It is critical to reduce the consumption of energy-dense foods and drinks, to- bacco and alcohol: a combination of policy actions and individual empowerment, starting from school, seems a suitable general approach. For instance, in Italy, smoking in public places, including the work- place, has been forbidden by law in 2003: the law, matched with publicly-supported anti-smoking adver- tising, has been received by society with a favourable attitude and has contributed to reduce the number of smokers and especially the environmental exposure to passive smoking. Indeed, as already pointed out, exposure to tobacco smoking is a risk factor for CA and other adverse pregnancy outcomes. • Low socio-economic status and poor education are associated with a reduced access to correct informa- tion about health-protecting and health-promoting behaviours, such as the periconceptional supplemen- tation with folic acid, and other preconception care measures. • The schooling system can play a major role in reducing health inequalities due to different socio-economic status and promoting health awareness and empow- erment. The promotion of health literacy programmes since primary school can support the adoption of a healthy lifestyle from childhood; a timely empower- ment during school age toward correct lifestyles and behaviors may significantly reduce the risk factors for CA in the next generation. • Actions to control and reduce the exposure to pollut- ants in living environment, workplace and foods: the cur- rent EU regulations on hazardous chemicals (e.g., the REACH regulation [19]) put emphasis on the identi- fication and management of developmental toxicants. The EU food safety is possibly the domain where pre- vention and control of pollutants is most developed: however, emphasis needs to be put on the identifica- tion of emerging risks [20]. In particular, food safety systems should exploit the available knowledge to im- prove prevention of long-term risks along the whole food chain, such as those related to endocrine dis- rupting substances [21]. Full implementation of the EU regulations, currently the world’s most advanced ones, calls for a balance between scientific evidence, a reasonable use of the precautionary principle and the necessary involvement of the industrial and agro- food sectors. • Pollution is not evenly distributed throughout the EU population: a number of areas are highly exposed to releases from toxic industrial activities and/or chemi- cal waste from different sources (e.g., petrochemicals or persistent and bioaccumulative –“legacy” – con- taminants). In communities with higher exposure to these hazardous chemicals in living environment, CA (together with other adverse reproductive outcomes) represent an important public health issue [22]. As shown, for instance, in Italy by Sentieri, a Istituto Superiore di Sanità-led project. CA are also a sensi- tive sentinel for environmental quality [23], due to the relatively short latency time and the high suscep- tibility of the intrauterine life to major toxicological modes of action, such as endocrine disruption. • The majority of the EU population aged between 18 and 65 years spends over half of their lives at the work- place. Workplace represents a diversified environment where exposures through multiple physical, chemical and biological agents can occur: to date women at fertile age are involved in every job role in the EU. But importantly, also men can be exposed to these hazards in the workplace, therefore their gametes will form and mature in an environment that can have an impact on the risk for gene mutations as well as on fertility. Effective prevention and health monitoring interventions in the workplace should be achieved through the co-operative involvement of employers, workers, occupational health professionals and legis- lators. Health and societal policies should recognize the basic right for a workplace environment that min- imizes the health risks for workers as well as for their offspring. • Chronic diseases such as diabetes, infectious diseases such as rubella and the emerging Zika viruses, as well as the inappropriate use of certain drugs, such as the antiepileptic drugs with known teratogenic efects, among others, are recognized risk facts for CA. Such risk factors can be significantly mitigated by function- ing and accessible healthcare services. Hence, actions of top relevance for the protection of the generation(s) to come include the care for maternal chronic diseases (e.g., diabetes, epilepsy), the deliverance of vaccina- tion programmes (e.g., toward rubella) and the en- forcement of pharmacovigilance programmes. These measures are supported by teratology information ser- vices where the different actors involved in primary prevention (health care professionals and lay people) can solve their questions on the different risks and possible measures. Such policies could also receive a significant support by fostering the consistent in- volvement of pharmacists and nurses. • Pre-conception care is surely the most effective way to put in practice all the known measures for primary prevention of CA, adapting them to the specific char- acteristics of each couple. Therefore, policies should put special focus on the establishment of services spe- cifically devoted to this approach by which risk fac- tors can be identified, the most appropriate measures Primary Prevention for sustainable health M o n o g r a p h ic s e c t io n 261 can be adopted accordingly, the most convenient in- formation can be provided (adapted to the specific characteristics of each couple of parents to be) by health care workers or specialists, and some preven- tive measures can be put in practice. • Pregnancy planning is another pivotal issue, that should be promoted by all means. • The inadequate access to health services may be a spe- cial concern for low-status population groups and/or groups considered as “marginal” (immigrants, gypsies and other social-cultural groups, isolated communi- ties). The primary prevention of CA in such popula- tion groups may require, therefore, specific attention and ad hoc actions. • Health systems include data collection and surveil- lance: CA and rare disease registries of adequate quality can provide a valuable support to prevention strategies, e.g., by allowing ad hoc studies in order to assess potential risk factors (maternal diseases, drug treatment, occupation, etc.) or preventive actions, e.g., the diffusion of periconceptional folic acid sup- plementation at the right timing and dosing. • Also, considering that the frequency of every single CA is rather low, data sharing and networking are very important for the research of any aspect related to CA, but specifically on preventive measures [24]. DISCUSSION In 2015, countries under the umbrella of United Na- tions adopted the 2030 Agenda for Sustainable De- velopment and its 17 Sustainable Development Goals [25]. Governments, businesses and civil society togeth- er with the United Nations are mobilizing efforts to achieve the Sustainable Development Agenda by 2030. Universal, inclusive and indivisible, the Agenda calls for action by all countries to improve the lives of people everywhere. In particular Goal 3 “Ensure healthy lives and promote well-being for all at all ages” specifically states “Ensuring healthy lives and promoting the well- being for all at all ages is essential to sustainable de- velopment. Major progress has been made. However, many more efforts are needed to fully eradicate a wide range of diseases and address many different persistent and emerging health issues.” Primary prevention, therefore, clearly pertains to the domain of sustainability. Health system sustainabil- ity means that today’s efforts to protect and promote health will not reduce resources so to jeopardize the future efforts to provide an equitable and functioning health system to the next generation(s). Hence, owing to primary prevention, the health system will be more sustainable for the society. A science-based primary pre- vention will reduce both burdens of premature deaths and of chronic disabilities (measureble as DALY) re- lated to CA. This is important also in an ageing society: following the paradygm of “Developmental Origins of Health and Diseases”, an effective primary prevention in the early lifestages (starting from intrauterine life, and even preconceptionally) can improve the quality of life of the increasing aged population, and reduce the societal costs for long-term treatment and care of chronic, often invalidating conditions [26]. Data suggest that local and national public health in- terventions are highly cost-saving. Cuts to public health budgets in high income countries therefore represent a false economy, and are likely to generate billions of eu- ros of additional costs to health services and the wider economy [27]. Sustainable development in the field of health is the goal of meeting the needs of the present without compromising the ability of future generations to cover their own needs. In the fields of food safety and envi- ronmental health, for instance, the phasing-out and re- placement of hazardous chemicals (such as mutagens, teratogens, endocrine disruptors) are actions that can reduce the burden of disease for generations to come, by enforcing a safer living environment today. Disease prevention must start with improved nutrition and re- duced exposure to environmental chemicals during de- velopment [26]. Also, sustainable food safety implies the efforts towards the comprehensive knowledge and management of key factors related to to food and diet for protecting and promoting next generation’s health; such efforts will contribute to the effectiveness of the overall sustainability policies [28]. Besides sustainability, prevention may also involve the concept of resilience at different levels. Resilience means to adapt the system to changes in order to keep it functioning. The system must be able to adapt itself effectively to changing environments and identify and apply innovative solutions to tackle signifi- cant challenges – shortages of expertise/resources in spe- cific areas, unexpected surges in demand with limited resources. In other words, the system needs to build and maintain resilience. Emerging risks, presenting either as new hazards or as new aspects of recognized hazards, call for resilient responses: one example in CA field is the recently recognized teratogen Zika virus [29]. Emerging risks make evident the need for the health system to be able to understand changes and to adapt/modify its re- sponses accordingly. The World Health Organization has considered Zika virus as a case study for emerging risk challenge. European countries can learn from the expe- rience of other regions on how to communicate about Zika and apply these lessons to the European context, as the possible scenarios of Zika outbreaks can show sig- nificant differences in terms of size, and composition of the population at risk, cultural and socioeconomic real- ity and preparedness and response capacity. To this respect, health promotion is important. It is the process of empowering people to increase control over their health and its determinants through health literacy efforts and multi-sectorial action to increase healthy be- haviors. This can be addressed to the community-at-large or to populations at increased risk of negative health outcomes. Disease prevention and health promotion share many goals, and there is considerable overlap between functions. In fact, it is useful to characterize disease pre- vention services as those primarily concentrated within the health system domain, while health promotion ser- vices depend on intersectorial actions and/or are con- cerned with the social determinants of health. Primary prevention actions should be targeted based on scientific evidence. This statement should not hide Domenica Taruscio, Eva Bermejo-Sánchez, Paolo Salerno and Alberto Mantovani M o n o g r a p h ic s e c t io n 262 the many uncertainties still existing. A few examples of gaps of knowledge that increase the burden of un- certainties on primary prevention actions regarding CA can be mentioned: in the field of health interventions, the benefit-to-risk assessment of flour fortification with fo- lic acid; in the field of chemical safety, the possible role of developmental exposures to pollutants in the obesity/ diabetes epidemics; in the field of response to emerging risks, the role of climate changes on emerging infectious agents (such as Zika virus) and the associated terato- genic risks; in the field of safe use of medications, the as- sessment of possible risks derived from the use of herbal drugs and other widespread “alternative” medicines, in relation to pregnancy; in the field of safe food, undertak- ing actions to identify and characterise emerging risks . On one hand, the recognized presence of significant gaps of knowledge cannot, by any means, hamper the enforcement of evidence-based actions here and now. On the other hand, and importantly, prevention needs research and innovation. An uncertainty is a gap of knowledge that can impair the assessment of the ben- efits introduced by a certain action. Therefore, uncer- tainties have to be identified and characterized, in order to plan and launch relevant research activities. Recently, it has been stated that for better sustainability and use- fulness, it is crucial to refocus and streamline surveil- lance activities, avoiding a “recreational” data collection, in order to turn the statistically significant results into clinically relevant data. Also, it has been recommended to perform a “triple surveillance” [30]: surveillance of causes, of disease occurrence, and of health outcomes. Such integral surveillance can be a really effective tool for primary prevention of CA. RECOMMENDATIONS AND CONCLUSIONS CA, which include an important fraction of rare diseases, are liable to risk reduction by means of sci- ence-based primary prevention. In order to achieve an effective primary prevention, the following general rec- ommendations have to be taken into account: • the professional education and training of all health professionals (not limited to physicians) should pro- vide an adequate room to primary prevention from both the qualitative and quantitative standpoint; this should include epidemiology, social medicine, envi- ronmental health, food safety and nutrition, as these themes can be relevant to the work of the majority of health professionals. • EU Member States should consider the “health- proofing” of all their policies. As pointed out in the above paragraphs, side to the health system, primary prevention involves several other legislative, interven- tion and scientific domains. • Health is a fundamental human right; at the same time, it can be considered that the “investment” on primary prevention generates both tangible and in- tangible benefits. It has been said that “early child- hood development is a smart investment” and “the earlier the investment the greater the return” [31]: investing in primary prevention is obviously the earli- est possible investment. Nobel Laureate Economist James Heckman’s research makes the economic case for early childhood investments starting before birth. In conclusion, the considerations on CA as an ex- ample for primary prevention in the rare diseases field identify the following highlights: 1. investing in primary prevention based on scientific evidence is one essential factor supporting sustainabil- ity of health systems; 2. primary prevention is a pillar of sustainable develop- ment of the society; protection of the early develop- ment will enable healthier next generation(s) reaching full adulthood and ageing; 3. in regard of many risk factors (e.g. nutrition, life- styles, pollution, infections, medications), CA (together with other adverse reproductive outcomes) represent both an important public health issue per se as well as an early indicator of public health risks; 4. effective primary prevention requires an integrated “One Health” approach, linking knowledge and action pertaining to human health as well as to physical and social living environments. From the policy standpoint, joint budgeting mechanisms can be envisaged to sus- tain intersectorial actions, involving the policy domains of health as well as others, e.g., social affairs, education, agriculture, and/or environment; 5. EU Member States (and any country, in fact): should devote resources to strengthen registries, and other tools for systematic data collection and surveillance on CA, so as to better inform national prevention strategies. 6. pillars of primary prevention include science-based risk analysis and surveillance of potential health-dam- aging factors, citizen’s empowerment and education of health professionals; 7. characterization of uncertainties that weaken scien- tific evidence should target research programmes aimed at supporting the scientific basis of primary prevention; 8. EU Member States should consider the health and equity aspects [32, 33] in all their policies (short, mid and long term). Moreover, The DG SANTE Scientific Committees recommend more dialogue between risk assessors and socio-economists [34]. In summary, primary prevention for CA as well as for other rare diseases, must be considered (better earlier than later) as a pillar of sustainability of health systems and a duty of policy makers with respect to society, which expects that the system provides a better quality of life to all, leaving no one behind. Funding This research was supported by the Health Pro- gramme of European Union, in the framework of the Joint Action for Rare Diseases, Project n. 677024 “Promoting Implementation of Recommendations on Policy, Information and Data for Rare Diseases – RD- ACTION”. Conflict of interest statement The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publi- cation of this article. Submitted on invitation. Accepted on 24 April 2019. 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