Dr Brigitte Piso
email: brigitte.piso@hta.lbg.ac.athomepage

MPH Ingrid Zechmeister

Sabine Geiger-Gritsch

Dr Mrs Brigitte Piso

Piso Brigitte

Zechmeister Ingrid

Geiger-Gritsch Sabine

Criteria for vaccine introduction: results of a DELPHI discussion among international immunisation experts on a stepwise decision-making

Keywords: immunisation, vaccination, preventive health services Blinded Basierend auf einem Stufenmodell für Entscheidungen zur Implementierung von 40 internationale Impfexperten wurden zu einer DELPHI Diskussion eingeladen, 14 spezifizieren. Die Erstellung eines Konsensusdokuments wurde dabei nicht Durch die internationale Diskussion konnten vier weitere nationale Dokumente identifiziert werden, welche Entscheidungskriterien definieren. Mit Ausnahme eines Schwellenwertes Das vorgeschlagene Stufenmodell für Impfentscheidungenbietet eine standardisierte und evidenz-basierte Möglichkeit, öffentliche Impfpolitikentscheidungen zu

Criteria for vaccine introduction: results of a DELPHI discussion among international immunisation experts on a stepwise decision-making procedure

Introduction

Some of the vaccines that are currently developed or have been introduced within the last years target at the prevention of less widespread, less severe and often chronic diseases at all age groups rather than severe infectious childhood diseases. Concurrently, they are more expensive than some of the even "cost-saving old vaccines". In an era of rising healthcare costs, cost-effectiveness of vaccination programs on the population level is increasingly taken into consideration. Consecutively Health Technology Assessment (HTA) became an important tool to support decision makers whether or not to introduce a new health technology-including vaccines (Hutt 2008). Except for a few countries, like the UK for example, HTA based decisions are still rare and despite of efforts being undertaken by the European Union, vaccination policies are moreover exclusively defined on national levels (Lopalco 2010). Therefore it is not astonishing that national immunisation programs differ from country to country in their vaccination schedules and decisions regarding the implementation and funding of new vaccines. Assuming that decisions on vaccine introduction should be unbiased, comprehensive and systematic and therefore be based on deliberate, rational, comprehensible and evidence based criteria, we asked ourselves if decision aids concerning rational vaccine introduction exist at all and which criteria are crucial for a rational decision-making process. Therefore we prepared a report assessing the availability of decision tools (Piso and Wild 2009). The comparison of the five decision aids or analytical frameworks (Stratton et al. 2000;Kimman et al. 2006;[START_REF] Erickson | An analytical framework for immunization programs in canada[END_REF]World Health Organization 2005;Mansoor et al. 2000) that had been identified revealed an overall similarity with some differences in the approach as well as the criteria: Burden of disease and vaccine characteristics play a key role in all decision-making processes. Because cost-effectiveness analyses are influenced by various factors and have several limitations, views on its significance vary. Other relevant factors include the immunisation program itself as well as its conformity with other programs, its feasibility and how easily it can be evaluated. Additionally acceptability, equity as well as ethical, legal and political considerations have been mentioned, though they have been discussed to highly differing extents. As a result of the literature comparison we suggested a practical, stepwise approach (table 1) for advisers and decision makers on vaccination policy to use as a basis for vaccine introduction decisions, because we assumed that the most comprehensive framework possible would not provide a feasible tool for decision makers.

-please insert table 1 here -

The aims of this DELPHI discussion were to reveal eventually unpublished knowledge (further decision aids or introduction guidelines), to assess cut-off limits or thresholds (e.g. for costs, burden of disease or vaccine safety) that have already been used for vaccine introduction decisions in industrialised countries and to discuss our model of a stepwise decision-making approach. We did not aim at developing a consensus document.

Methods

We invited 40 international immunisation experts in 16 industrialised countries whom we had identified by contacting international HTA agencies to participate in a DELPHI discussion. 16 experts (in 10 countries) agreed to participate and received the first questionnaire by email. The questionnaire had been developed by two members of our institution and tested for feasibility and comprehensibility within our team. It consisted of two questions on expert's affiliation and immunisation expertise, two questions on identification of further decision aids, five questions on cut-off limits used in vaccine introduction decision-making and three questions to discuss our proposed stepwise decision-making model. Despite a reminder that we sent out one week before closure, only 50% of the experts returned their questionnaires by the end of the first deadline. Therefore the deadline was slightly expanded and participants were invited again individually. Nine weeks after the start of the first DELPHI round we extracted data of 13 completed questionnaires into an Excel sheet and SPSS database. We generated the first anonymous summary report and redistributed it to the participants for further comments.

Additionally we added three questions on applicability of DELPHI results and rational decisionmaking processes in general. Keeping in mind that the study was not aiming at a consensus document, experts were not asked to reconsider their previously given answers taking other experts' views into consideration (and answer the same questions again-in line with the commonly used DELPHI method). Experts were rather asked for comments on other experts' opinions and specification of their previously given answers wherever necessary and reasonable. Finally 12 completed questionnaires could be analysed.

Results

Participants

From 14 DELPHI participants five work at a research institute, none work in the vaccine industry or in an international organisation (e.g. WHO). One is a national politician, five are members of national immunisation committees (affiliation and country of participants table 2). Nine have already participated in national vaccine implementation decision-making, six in the preparation phase prior to the final decision-making and three in decision-making process research.

-please insert table 2 here -

Identification of further decision aids

Most of the experts stated that they didn't know of any other publications than the five previously analysed documents (Piso and Wild 2009) that aim at rational vaccine implementation decisionmaking in industrialized countries. Nevertheless three further documents could be identified by DELPHI participants: a Brazilian (Castillo-Solórzano and Andrus 2004) publication that deals with decision-making on the development of new vaccines, an Australian document (Australian Government Department of Health and Ageing Pharmaceutical Benefits Advisory Committee 2008), that aims at rational medicine implementation decision-making and a Spanish document (González [START_REF] Alonso | Criterios para fundamentar la modificación de los programas de vacunas[END_REF]), which points out the main criteria that can be taken into account to introduce any change in the vaccination program. The latter criteria are related to the burden of disease, intrinsic factors of the vaccine, the cost effectiveness of the vaccine, the impact of the new vaccine for the vaccination scheme and other aspects such as acceptability as well as equity and legal considerations.

Additionally, in the pre-Delphi phase one further document had been revealed by a member of the Dutch HTA agency [START_REF] Houweling | Criteria for inclusion of vaccinations in public programmes[END_REF] . In this report seven criteria for the inclusion of vaccinations in public programmes have been defined. These criteria cover the seriousness and extent of the disease burden, the effectiveness and safety of the vaccination as well as the acceptability, the efficiency (favourable cost-benefit ratio in relation to alternative measures) and the priority of the vaccination (urgency of the public health need).

The majority of experts also didn't know of (un)published guidelines or institutional manuals, only one referred to the existence of "unpublished national guidelines" in her own country. The two Australian experts referred to proformas that communicate advice on decision-making between peak bodies: one is based on a structured set of questions agreed between the two bodies (committees) and precedes an application for funding within the national immunisation program; the other responds to specific technical questions about the application following a preliminary review of the application.

Each proforma is completed by the technical advisory committee and is considered by the recommending committee. Each completed proforma is also provided to the relevant applicant, who can comment on the information provided before any recommendation is considered.

Identification of cut-off limits or thresholds that have already been used in the decision-making process Cost-utility threshold ($/QALY, €/QALY)

Vaccines have been considered to be favourable because they showed a cost-utility ratio below a defined threshold just in one country (about 50.000 US$ or 35.000€/ QALY). One expert referred to an implied threshold (from about 30.000 US$/ 22.000€ to 57.000 US$/ 40.000€ per life year saved), that was derived from a retrospective study which analysed the consistency of funding decisions during a given time period [START_REF] George | Cost-effectiveness analysis and the consistency of decisionmaking: Evidence from pharmaceutical reimbursement in Australia (1991 to 1996)[END_REF]. Other experts didn't give any defined thresholds but stated, that cost-utility data were somehow considered and that thresholds may differ according to various and changing economic situations.

Domestic burden of disease

The majority of experts stated that criteria related to the burden of disease have been used (e.g.: epidemiology, clinical manifestations, mortality, costs, social impact, hospitalisation, medical attendance or disease sequelae). Most of them agreed that there were neither defined "cut-off limits" nor a predefined minimal burden of disease.

Effectiveness

Most experts pointed out, that no quantitative cut-off levels of proposed vaccine effectiveness have been used, "although effectiveness is considered separately as a "building block" of the overall assessment". They explained that effectiveness is "incorporated in the cost-effectiveness model", "a relevant factor in its own right" and "is considered more in the context of overall analysis, including a sensitivity analysis". Vaccine effectiveness is also "considered in vaccine development" and a cut-off limits would "depend on the disease for which the vaccination is proposed". One expert mentioned that "an efficacy less than 70% would be questionable", whereas another one stated that an efficacy of 50% may be acceptable. In the second DELPHI round one expert pointed out, that efficacy thresholds should primarily depend on the outcome being measured (e.g. immunogenicity outcome vs. directly patient-relevant outcome).

Safety

None of the experts gave a defined "safety level" but some referred to safety issues that have been considered in vaccine introduction decision-making: thus, safety is for example "taken into account in the cost effectiveness model" and "depends on the risk/benefit balance and the absence of related serious adverse events". One expert defined safety as "registered by the national medical products agency". Another expert stated in the discussion that "safety versus efficacy has a changing value with respect to the severity of the disease and that saftey considerations have a much higher ranking in socioeconomically well situated countries".

Number needed to vaccinate

Except for two experts who gave examples in which the number needed to vaccinate (NNV) has already been used as decision criterion (in HPV and Herpes Zoster vaccination decisions), most experts agreed, that no defined number needed to vaccinate (NNV) has been used. They see the NNV "incorporated into the cost effectiveness model" or as "one measure of vaccine effectiveness". Still, "the interpretation of an effectiveness outcome should depend on the nature of the outcome being presented". For example, "the NNV to get an extra immunological response should be interpreted differently to the NNV to avoid one extra death". Additionally, "the NNV should always include the time frame of observation (e.g. three months vs. twenty years)". In case of "vaccines preventing non communicalbe diseases (e.g. Tetanus) that provide personal protection only, each immunised individual may benefit". By contrast, in communicable diseases herd effects have to be taken into NNV considerations: "The example of rubella vaccination for the prevention of congenital rubella syndrome has shown that a too low immunisation rate may have worse effects than no vaccination." Discussion of the criteria to be taken into consideration and the suggested stepwise procedure None of the DELPHI participants considered the listed criteria (table 1) redundant. Only three experts added criteria for rational decision-making that they assumed to be missing in the synthesis of the decision support document (Piso and Wild 2009): the "impact on current disease management or prevention" and "immunological interference with other vaccines or the effect on risk behaviour that might increase risk of other diseases spread" were mentioned though these considerations had already been covered by the side-effects criterion (see step 4 in table 1). Also, the "need for re-evaluation of decision, especially when long-term effects are unknown at initial decision point" was added, though the last step of the decision-making model already emphasises the need of re-evaluation of decisions.

Furthermore the "importance of uncertainties" was mentioned, though they should be considered in step 1 in the field of research questions (that have not been answered sufficiently at the time of decision-making).

The majority of participants agreed that there are no general more or less important criteria to be fulfilled or considered in the decision-making process. Others pointed out that "disease burden is most important regardless of (reasonable) costs" or in contrast, an "acceptable incremental costeffectiveness, preferably with minimal uncertainty" is the most important decision criterion. Other major considerations mentioned were, "associated risks", "vaccine production capacity" and "any hurdles for marketing a vaccine". The latter should even be discussed, before large trials are initiated.

Next, participants ranked the 14 criteria, that had been identified in our decision support paper (Piso and Wild 2009), dependent on the influence these criteria should have on vaccine introduction decisions on a scale between 1 (very important) and 5 (not important). The median of grades ranged from 1 to 3, therefore experts agreed that the influence of each single criterion should at least be "important" (table 3). "Burden of disease", "Vaccine", "Side effects" and "Ethical considerations" were considered to be most important (median 1.0).

-please insert table 3 here -

The majority of experts argued that this ranking is dependent on the type of vaccine and the disease against it is introduced, respectively. They acknowledged that the "importance of criteria is variable depending on the individual case, especially the severity of the disease, whether there is already a vaccine available for the intended purpose or not" and that it is "dependant on the type of vaccine (e.g. attenuated or live)". Examples of crucial criteria that led to a decision to introduce or to withhold a vaccine from a national immunisation program in the past were given by almost all participants, e.g.:

-"the burden of disease and the increasing number of cases" (meningococcal C vaccine), -"epidemiology and sequalae" (herpes zoster vaccine), -"high hospitalization rate" (rotavirus vaccine), -"political considerations" (human papilloma virus and herpes zoster vaccine), -"health economic aspects" (pneumococcal vaccine), -"price negotiations due to an unfavourable incremental cost-effectiveness ratio" (human papilloma virus vaccine), -"side effects" (vaccines against tuberculosis or polyomyelitis), -"a lower than expected efficacy" (hexavalent vaccine against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and Haemophilus influenzae type b) as well as -"issues that relate to long term effects of vaccination and the number of areas of uncertainty" (herpes zoster and varicella vaccine).

The majority of experts believe that a stepwise approach could enhance the feasibility of decision-aids.

Most of them even stated that the order and the hierarchy of steps and the criteria themselves should not be changed or moved to a different step. While one participant suggested to change the order of steps 3 and 4 vice versa, another participant disagreed in the discussion, because he stated: "the reason to have a logical order was to help ensure consistent decision-making over time" and "all the influential information of steps 1-4 must be taken into consideration for the decision in step 5" anyway. "The presentation of information in a consistent order" would be "crucial to efficient decision-making in a systematic manner across a series of health care interventions". Another participant suggested, that "HTA agencies need to get involved in a step 0, deciding together with efficacy and safety agencies on primary endpoints and criteria to reach before the starting of large phase 3 trials". In the discussion a different expert commented this suggestion as "laudable", but pointed out that also HTA agencies may want to change their position during the following years, especially "if the lead time to a return on investment is many years during which time the understanding of the disease may move on". Another expert mitigated the role of HTA agencies by stating that "HTA agencies are but one part of the decision-making process". Another expert highlighted "the need for re-evaluation and repetition of the stepwise evaluation as soon as data become available, especially if the results are long-term". The conclusion that "many steps are dependant on each other and cannot only be considered alone" was reassured by a different participant in the discussion.

Most experts gave reasons for situations in which one or more steps have been or would likely to be skipped. "If planning is reactive rather than proactive, political interests" might have a greater influence on vaccine introduction "than evidence-based criteria". Health economic considerations might be less important if a "vaccine for a frequent short term life-threatening disease is effective (e.g. pandemic)". The "immediacy of a problem" might be high, therefore one "may not be able to wait until all data is available". The "public health relevance of disease prevention and prevention of its consequences" might be considered "more important than the burden of disease" (for the individual).

Another expert thought, that "step 1 could sometimes come after step 2, as the availability of a new vaccine from a vaccine manufacturer has sometimes been the impetus to assess the public health burden of disease."

Half of the participants thought that no negative consequences could arise from a stepwise procedure "unless the steps were too rigidly implemented" and it was not "necessary to cover one step before going to the next one". The other half mentioned possible negative consequences, most often "a delay of the vaccine introduction process". This aspect was considered "serious with respect to the everywhere growing administrative burocracy". One the other hand one participant totally disagreed that a stepwise procedure would lead to a delay and endorsed that it is even "a way to have a more organised process".

All experts see strengths of the proposed model. It is "complete and logical" and therefore "its comprehensiveness and thoroughness helps, that all relevant factors are appropriately considered and addressed". Its "clarity and structure may help to avoid mistakes" and it enhances "transparency". It provides a "systematic and evidence based standardised way ("a tool") to support public health policy decision." It was seen to be "easy to repeat" and therefore easy to "compare with others".

A potential weakness of the model could be that it "may need to be flexible in a public health emergency". Additionally, a stepwise decision-making tool could be "weaker than political and economic rationalities" and "too exhaustive for busy decision makers". Furthermore, there "may not be adequate data to access all factors" and "even within one healthcare system" people "may weigh the factors differently, leading to disagreements." One expert mentioned that the decision-making tool "may not accurately encompass particular characteristics of a new intervention". Therefore he stated that "a deliberative committee process" would be more relevant for decision makers "than applying a formulaic approach to decision-making."

Discussion

Though most of the DELPHI participants were not aware of other decision aids, the international discussion revealed four additional national documents that define decision-making criteria. Except of one example for a cost-utility ratio, no defined thresholds or cut-off limits have been used in vaccine introduction decisions so far. All experts agreed that the influence of each single criterion of our model should be at least "important". Almost all participants were convinced that a stepwise approach could enhance the feasibility of decision-aids.

In this DELPHI discussion 14 experts from 10 industrialised countries, who have experience in the field of vaccine introduction decision making, gave insight to the basic principles of national decisionmaking and its process. We did not aim at achieving a consensus document, though we would appreciate any efforts in this direction. In our opinion a consensus among decision makers could only be reached by discussions on a high political level, moderated by an international organisation (e.g. the WHO or the European Commission). It won't be easily achieved whilst decision making criteria still show a wide range between countries or are even completely intransparent. Therefore the results of this DELPHI discussion could be a starting point for such efforts.

Limitations

Because of the small number of immunisation experts participating in this Delphi discussion, the quantitative analysis of the DELPHI results is not representative for the whole immunisation community. Results should rather be discussed in a qualitative manner. 14. surveillance of vaccine coverage and utilisation of epidemiologic changes, the frequency and nature of adverse events and immune surveillance and re-evaluation (revision) *The consecutive numbers reflect the 14 criteria to be considered in a vaccine introduction decision making process that have been identified in our previous work (Piso and Wild 2009); key criteria in bold letters Participants graded criteria from 1 (=very important) to 5 (=not important).The number of valid and missing answers as well as the median of results and their first (Q 1) and third (Q 3 ) quartile are given.

Table 1 :

 1 Suggested stepwise procedure for vaccine introduction decision making

	Step	Criteria to be assessed*
	Step 1	Fundamental considerations concerning the disease as a public health problem and alternative
		operational and delivery strategies (alternative measures)
		1. aims of the planned immunisation strategy
		2. comparison with other programs (conformity of programs)
		3. availability of sufficient basic research data (research questions)
	Step 2	4. "disease" considerations, e.g.:	5. "vaccine" considerations, e.g.:
		-burden of disease	-vaccine characteristics
		-clinical manifestations	-supply
		-current treatment	-administration schedule
		-epidemiology	-immune response
		-risk groups and risk factors	-efficacy and utilisation
		-social impact	-population effectiveness
		-other preventive measures	-safety
	Step 3	6. cost-effectiveness analysis
	Step 4	7. considerations on acceptability and
		8. feasibility of the new program
		9. implications on equity
		10. ethical,
		11. legal and
		12. political considerations
		13. potential side effects (e.g.: vaccine side effects, feasibility side effects or utilization side
		effects)
	Step 5	decision making process itself (final decision)
	Step 6	implementation
	Step 7

Table 2 :

 2 Affiliation and country of DELPHI participants

	Institution

Table 3 :

 3 Results of the criteria ranking (the influence each criterion should have in the decision making process)

			1. Immunisation Strategy	2. Conformity of	Programs	3. Research Questions	4. Burden of Disease	5. Vaccine	6. Cost-Effective-ness	7. Acceptability	8. Feasibility	9. Equity	10. Ethical Con-siderations	11. Legal Con-siderations	12. Political Con-siderations	13. Side Effects	14. Surveillance
	Number	valid missing	13	13		13	13	13	13	13	13	13	13	13	13	11	12

Acknowledgements

First of all the authors gratefully acknowledge the time and effort of the DELPHI participants, without whom this project would not have been possible. Furthermore we thank Claudia Wild, the head of our HTA institution, for "idea input" and guidance as well as our colleague Stefan Mathis for the "technical support" in the preparation of the word form documents and the data export.

All experts acknowledged that they gained some useful information by participating in the DELPHI discussion. Participation permitted them "to know other expert opinions and other documents used in other countries" and most of them thought that the information will be applicable in vaccine implementation discussion or decision-making they are involved in and it could even be used "to improve the own national guideline for the decision-making process". Only one participant "detected nothing specific or unexpected which would be sufficient to form the basis of arguing for a change to the way they have already approached this issue in the national context".

The results of this Delphi discussion among international vaccination experts mainly reflects, what we all know, namely that "national immunisation programs are influenced by political and public opinion about money spending priorities and may not reflect health care priorities" and "many decisions have to be made when not all important information is available." But nevertheless experts agreed that "guidelines may be helpful" to "articulate different rationalities" and to make the decision-making process "more evidence based than based on political considerations". "Careful consideration of available evidence ("using defined criteria"), current context and ongoing discussions in a network of national and international experts" would at least "help to make the best decisions regarding immunisation program planning". But even then decisions could only be "rational for a given context at a given point in time". "Identifying some areas of uncertainty" would not "mean a decision is not rational", but the process would have to be "re-evaluated as more information is available".

Having said this, a more or less consistent structure on which vaccine implementation decisions are based on, could help all of us: vaccine industry would be supported in vaccine development and the following application procedure, if implementation criteria were transparent. Decision makers could insist on pre-defined information that has to be provided prior to the decision-making process. Last but not least, a clearly communicated decision would help health care workers as well as consumers to comprehend whether or not a vaccine has been implemented in a national program. Consequently, sharing all available information would make decisions on both levels-the population and the individual level-more evidence based rather than based on fear.

The increasing number of vaccines implemented in programs on the one hand and the decreasing awareness of diseases that became less common due to successful vaccination programs already threatens program acceptability in the population. Therefore, only a structured, comprehensible decision-making process based on transparent decision criteria will strengthen vaccination as an effective public health tool in the future.

Conflict of interest

The authors declare that they have no conflict of interest.

Hutt HJ (2008) How do we tackle the complex field of vaccinology in the twenty-first century? .

Journal of Public Health 16 (4) Kimman TG, Boot HJ, Berbers GAM, Vermeer-de Bondt PE, Ardine de Wit G, de Melker HE (2006) Developing a vaccination evaluation model to support evidence-based decision-making on national immunization programs.


Gianpiero Dalla-Zuanna

Alessandro Rosina

Dalla Gianpiero

Alessandro Zuanna

Rosina

An analysis of extremely high 19 th century winter neonatal mortality in a local context of northeastern Italy An analysis of extremely high 19 th century winter neonatal mortality in a local context of northeastern Italy

Keywords: infant mortality, event-history analysis, Italy

Beginning in the mid-17th century, infant mortality in Veneto (a region in northeastern Italy) began to increase, starting at 250‰ and rising to 350‰ by the mid-19th centuryone of the highest levels ever recorded in modern Europe. This dramatic changein a period of worsening economic conditionswas due to variations in winter neonatal mortality, which was 3-4 times higher in Veneto than in other areas with similar winter temperatures (such as England). We combine micro data on neonatal mortality with daily data on temperatures for a specific context during the period of 1816-68 characterized by very high neonatal mortality. We find that the risk of death was particularly intense during the first week of life and strongly correlated with external minimum temperature. Through a comparison of these results with other findings in the literature, we suggest that the increase in winter neonatal mortality in Veneto could have principally been caused by the deteriorating physical condition of mothers, lessening the "quality" of infants who consequently were quite susceptible to cold temperatures.

Introduction

Over the last few decades, numerous studies have sought to explain historical differences in the risk of dying during the earliest stages of life (see e.g. [START_REF] Vallin | Mortality in Europe from 1720 to 1914: Long-term trends and patterns by age and sex[END_REF][START_REF] Lee | Regional inequalities in infant mortality in Britain, 1861-1971: Patterns and hypotheses[END_REF][START_REF] Preston | Fatal Years[END_REF]. Nevertheless, two important patterns remain less than fully explained. First, although infant mortality (the risk of dying during the first year of life) during the ancien régime was everywhere higher than 100‰, considerable differences existed between populations living in adjacent regions and countries (Livi Bacci, 1997, point 2). For example, in 1850-54, child mortality during the first month of life (neonatal mortality) and during months 1-11 differed greatly among the regions of the Austrian Empire, that included Veneto and Lombardy, which together make up a large portion of Northern Italy (Dalla-Zuanna and [START_REF] Dalla-Zuanna | Comparisons of infant mortality in the Länder of the Austrian Empire using the Tafeln (1851-54)[END_REF]. In addition, secular trends may have significantly varied between neighboring populations (Livi Bacci, 1997, point 6). Although these issues are not easily disentangled, they are crucial to understanding the historical determinants of infant mortality.

In this paper, we focus on the risk of dying during the earliest stages of life during the 18 th and 19 th centuries in Veneto, the region home to Venice situated in northeastern Italy. A complete comparative map of infant mortality for the regions of Europe from 1650-1900 is not available. However, it is possible to make comparisons by combining the results from a number of different studies. On the secular trends of infant mortality in several northern Italian regions, refer to the article of Del [START_REF] Del Panta | Infant and Child Mortality in Italy, Eighteenth to Twentieth Century: Long-Term Trends and Territorial Differences[END_REF] and Del Panta and Livi Bacci (1980). For Friuli-Venezia Giulia see [START_REF] Breschi | Vivere in Friuli. Saggi di demografia storica (secc. XVI-XIX)[END_REF]. For a comparison of secular trends in Lower Austria, the Austrian Alpine region, and other regions in the Alps, see [START_REF] Viazzo | Alpine Patterns of Infant Mortality in Perspective[END_REF]. Some data for Germanywhich partially depict the secular trend of Venetowere collected by Flinn (1981, Appendix). For some comparative data on the regions of the Austrian Empire around 1850, see [START_REF] Dalla-Zuanna | Comparisons of infant mortality in the Länder of the Austrian Empire using the Tafeln (1851-54)[END_REF].

The history of population change in Veneto during the final centuries of the demographic ancien régime provides an informative case for understanding the fundamental role that changing levels of infant mortality played in influencing both population trends and demographic dynamics [START_REF] Rossi | Il Veneto fra Sette e Ottocento[END_REF]Dalla-Zuanna et al., 2004). Population stagnation in Veneto during the 18 th century (the final decades of the Republic of Venice) and the early 19 th century can be directly associated with increased infant mortality [START_REF] Rosina | -La popolazione del Veneto durante la dominazione austriaca. Un tentativo di ricostruzione (1815-1865)‖[END_REF]. Furthermore, the results of our analysis are potentially of interest, and applicable, well beyond the geographical region under study. Veneto shares this particular historical pattern of infant mortality (1650-1850) with other regions in Europe. This is especially true with regard to several bordering Italian regions (Emilia-Romagna, Lombardy, and Friuli-Venezia Giulia), but also to a number of areas in Germany and in the former Austrian Empire. While some mountainous zones experienced distinct demographic trends [START_REF] Breschi | Vivere in Friuli. Saggi di demografia storica (secc. XVI-XIX)[END_REF], infant mortality in several large and crowded regions of Europe (mainly in the plains and low hill terrain) increased during the 18 th century. That a similar secular pattern of infant mortality occurred across a number of regions suggests that there may exist a common explanation for this change, especially as other areas of Europe experienced quite different demographic levels and trends.

After a review of the literature on the economic and social situation in Veneto during this century (section 2), our first aim is to describe the remarkable pattern of infant mortality in Veneto during the century of 1750-1850: section 3 clearly shows that the extra-mortality is mainly due to the exceptional neonatal risk of death of winter months. As a consequence, the second aim of this paper is to analyse the statistical association between the external temperature and the risk of dying in the winter during the first 30 days of life, using a person-period data-set that combines the daily risk of dying in a parish during 1818-67 with the daily data of external temperature (sections 4 and 5). In the final section, we discuss several possible interpretations of our results, indicating possible directions for future research.

The worsening of living conditions in Veneto during 1750-1850

Studies of Italy's economic history suggest that during the 1700s, the general living conditions of the working class significantly deteriorated. Combined observations of population estimates, real wages, and per capita income from 1700-1859 reveal that while the population doubled (from 13 to 26 million inhabitants), real hourly wages were halved, and per capita income decreased by 20% [START_REF] Malanima | An Age of Decline. Product and Income in Eighteenth-Nineteenth Century Italy[END_REF]. One possible interpretation is that the significant increase in population which followed the end of the great epidemics (the last significant plague occurred in 1630 in northern Italy and 1667 in southern Italy) produced excessive population pressure on an area already characterized (at the end of the 17 th century) by high levels of urbanization. Indeed, at the time, Italy, along with the Netherlands, had the highest population density in all of Europe. In addition, Malanima (2003, p.288) points out that: Italy completely missed the First Industrial Revolution, the age of coal, iron and mixed farming. It was impossible to adapt the English model to the available natural resources. The lack of coal, the scarcity of iron and the dry soils of the peninsula, with the only exception of part of the Po Valley, was thus an obstacle too difficult to overcome considering the technological level of the time. The relative backwardness of the peninsula grew during the 19 th century. From the late Middle Ages to the end of the 19 th century, Italy followed the downward curve from a condition of progress to a state of backwardness. Within the larger context of declining living conditions, it is essential to understand the specific social and economic history of Veneto, here examined in light of its current borders, thus excluding the provinces of Pordenone and Udine, which now belong to the region of Friuli-Venezia Giulia. At the beginning of the 19 th century, approximately two million inhabitants lived in Veneto; one hundred years later this number had risen to three million [START_REF] Rosina | Mortalità infantile[END_REF].

In 1630, the last great plague dealt a devastating blow to the Republic of Venice, wiping out 40% of the population. Over the following century, the number of inhabitants grew rapidly, replacing the human void left by the epidemic and growing to 2.2 million by the mid-18 th century, or 40% greater than the size of the population immediately preceding the plague of 1630. As in other places, substantial population growth in Veneto was sustained by an increased productivity guaranteed by corn crops (rather than wheat) and by the spread of -industrial crops‖ such as the mulberry tree. Inhabitants simultaneously struggled, however, with a dramatic decrease in the real value of wages and the consequent need to increase per capita working hours. Along with the increase in population, entire forests were cut down (even in the high hill areas) in order to make room for the now near omnipresent cultivation of maize and mulberry trees. Although (to the best of our knowledge) thorough research has not been done on this topic, we presume that relentless deforestation led to an increasing scarcity of wood, needed to heat homes in the winter in the absence or prohibitively high price of coal (Lazzarini, 2002. pp. 57-62;[START_REF] Zannini | Contadini, emigranti e "colonos[END_REF]. In addition to these problems, during the 17 th and into the first half of the 18 th century, Venice began a slow but steady decline, gradually loosing its secular ability to attract wealth as European commerce began to move out of the Mediterranean and across the Atlantic Ocean.

It is possible to gain a more precise understanding of the relative economic situation in Italy and Veneto compared to the larger European context. The earliest comparison of income across European nations concerns the year 1870 (Maddison, 2003, appendix 2). In this year, per capita income in Italy was 50% that of the UK, 58% that of the Netherlands, 59% that of Belgium, 85% that of France and 86% that of Germany. The relative position of Veneto was even worse. In 1891 (the first year for which data are available), per capita income in the three regions of northeast Italy (Veneto, Trentino Alto Adige and Friuli) was 15% lower than the average level for Italy as a whole [START_REF] Malanima | Il prodotto delle regioni e il divario Nord-Sud in Italia (1861-2004)[END_REF]. From an economic standpoint, this area was by far the most backward in central-northern Italy, and one of worst off in Western Europe.

In order to consider some consequences of this unhappy economic situation, let us consider the relationship between population and resources in Veneto during 1750-1850. During this period, the nutritional health of several populations in Europe greatly deteriorated (for a review see Livi Bacci, 1990, chapter 5). Several studies show that northern Italy similarly experienced an extensive decline in the quality of nutrition. In the region of Lombardy, for example, draftees born in 1750 had an average height of 168.5 cm, compared to 164.5 cm for those born during the first half of the 19 th century [START_REF] A'hearn | Anthropometric Evidence on Living Standards in Northern Italy, 1730-1860[END_REF]. Although (as far as we know) data on height of this quality for the 18 th -19 th centuries are not available for other Italian regions, a number of clues suggest that this dramatic negative trend was also experienced in Veneto. Several studies showmore directlythat northern Italy experienced an extensive decline in the quality of nutrition. Along with the decreasing income, another important factor influencing nutritional health was the progressive (and for the poorest, almost total) substitution of wheat with corn. This modification began during the last decades of the 16 th century, and was completed by the beginning of the 19 th century [START_REF] Fornasin | Diffusione del mais e alimentazione nelle campagne friulane del Seicento[END_REF][START_REF] Livi Bacci | Population and nutrition[END_REF]. A serving of polenta (corn meal mush) of equal weight to a portion of bread has a significantly lower calorie content. In addition, maize does not have any vitamin PP, thus a diet based solely on polenta facilitates the spread of pellagra, a vitamin deficiency disease (PP stands for Pellagra Prevention). Pellagra affects metabolism and was a leading cause of death in many areas of northern Italy, including a number of districts in Veneto. In 1881, the first year the causes of death were recorded on a national scale, pellagra was high on the list for northeast Italy [START_REF] Livi Bacci | Fertility, Nutrition and Pellagra. Italy During the Vital Revolution[END_REF]. As late as 1881, Sormanni wrote: Of weak parents... poorly nourished, are born wispy and sickly offspring. We have witnessed the predominance of this frailness in Lombardy and Veneto, home also to the greatest endemic infections: malaria, scrofula, and pellagra...

Winter neonatal mortality: a description

Infant mortality in Veneto steadily increased from 1650 to 1800, starting at 250‰ in the mid-17 th century (the ending point of a 300-year period of severe and recurring plagues) and eventually reaching a high of 350‰ by the end of the 18 th and during the earliest decades of the 19 th century. The levels of infant mortality in Veneto during the period of 1750-1850 are among the highest ever recorded for a large area over a significant amount of time. Indeed, among the regions of the Austrian Empire in 1854, the greatest risk of dying during the first month of life is observed in Veneto (table 1). Following this period, however, infant mortality in Veneto steadily began to decline. By the early 1900s infant mortality had dropped to 150‰ (figure 1).

First, a brief description of our main data source. At the turn of the 17 th century, spurred by decrees from the council of Trent and Paolo V's 1614 edict, priests in the Catholic areas began to regularly record baptisms and deaths in the ecclesiastic parish registers. Over the years and through the work of many scholars, data for numerous parishes in Veneto have been gathered in a nonnominative manner (for a review see [START_REF] Rosina | Mortalità infantile[END_REF]. The quality of this data is generally good, better that that observed in other areas of Italy where often neither births nor the deaths of children who died immediately after birth were registered [START_REF] D'angelo | Massimo risultato con il minimo sforzo. Ricostruzione nominativa semiautomatica della sopravvivenza infantile, e analisi del regime demografico di Alì nel XVIII secolo[END_REF][START_REF] Rossi | Storia della popolazione di Adria dal XVI al XIX secolo[END_REF][START_REF] Rossi | Crisi di mortalità ad Adria nel contesto ambientale dei secoli XVII-XIX[END_REF]. For each burial, the parish priest usually indicated the age at death (in days, weeks or months for early deaths). It is thus easy to calculate the probabilities of dying during the first week (early neonatal mortality), the first month (neonatal mortality), and the first year of life (infant mortality). In this paperto the best of our knowledgewe report data for the parishes in Veneto where infant mortality was calculated using these criteria of classification.

In a number of places in Veneto, infant mortality increased during the 18 th century [START_REF] Del Panta | Infant and Child Mortality in Italy, Eighteenth to Twentieth Century: Long-Term Trends and Territorial Differences[END_REF][START_REF] Rosina | La popolazione di Venezia, 1633-1797: una ricostruzione delle dinamiche evolutive[END_REF][START_REF] Rosina | Mortalità infantile[END_REF]. Most of this increase was due to negative variation in winter neonatal survival, whereas the level of neonatal mortality during the summer months remained the same as that observed for the other Italian regions (figure 2; see also [START_REF] Breschi | Vivere in Friuli. Saggi di demografia storica (secc. XVI-XIX)[END_REF]Livi Bacci 1986, 1997). We show the secular trends in the probability of dying during the first month of life by season of birth for four villages spread across the region. For each parish presented in figure 3, changes in neonatal mortality for children born during the cold season played a determinant role in the overall secular trend of infant mortality.

Period

Rate

Sources: For Veneto 1675-1775: [START_REF] Rosina | Mortalità infantile[END_REF], page 36 (mean level of: 5 parishes, 1651-1700;9 parishes, 1701-1750;16 parishes, 1751-1800). For Veneto 1800-1900[START_REF] Del Panta | Infant and Child Mortality in Italy, Eighteenth to Twentieth Century: Long-Term Trends and Territorial Differences[END_REF], page 15. For England: Woods, 1997, page 76. For Tuscany and North Italy: Del Panta, 1997, pages 15-18. In order to emphasize the secular trends, data are interpolated with polynomials. Take, for example, the case of Adria, a town of 9,000 inhabitants located on the left bank of the Po River, near the Adriatic Sea. The data available from 1676-1899 for this town are of quite good quality [START_REF] Rossi | Storia della popolazione di Adria dal XVI al XIX secolo[END_REF][START_REF] Rossi | Crisi di mortalità ad Adria nel contesto ambientale dei secoli XVII-XIX[END_REF][START_REF] Rossi | Analisi della stagionalità in un contesto di alta mortalità infantile. Adria, 1675-1900‖[END_REF]. The secular trend of infant mortality in Adria is as follows: 1651-1700: 207‰; 1701-1750: 254‰; 1751-1800: 279‰; 1801-1850: 329‰; 1851-1899: 220‰ (Rossi, 1970, p. 133). During the 18 th century, neonatal mortality doubled for children born during the winter, reaching as high as 400‰ in the early 1800s. This very high level persisted throughout the first half of the 19 th century. In the following period (1850-1900), winter infant mortality dramatically declined. In contrast, throughout the period 1676-1850, neonatal mortality and mortality in the first 2-11 months of life for children born in the summer did not change. In the parish of Battaglia (located 15 km from Padua), the increase in winter neonatal mortality during the period of 1750-1850 was not due to any exceptional events, although this trend is somewhat complicated by large annual oscillations typical of small communities during the ancien régime [START_REF] Furegato | I registri parrocchiali di Battaglia Terme (1607-1871). Analisi aggregata e ricostruzione nominativa[END_REF]. Moreover, data from Battaglia show that the growth in winter mortality was mainly due to events occurring during the first week of life (return to figure 3).

In order to focus on events occurring during the first month of an infant's life, we considered two parishes where neonatal mortality did not start to decline until 1850 (Agna) and 1860 (Casalserugo). In table 2, infant mortality in these two parishes during the first half of the 19 th century is compared with two different contexts in the 18 th century: Alì (a hill parish in northern Sicily, where temperatures were about the same as those in the Veneto plains in July, and about 10°C higher in January) and England (where temperatures were about the same as in the Veneto plains in January, and around 6°C lower in July). There are certainly differences between the Veneto parishes and the other two contexts presented in table 2; see for example the probability of death in months 1-11 and years 1-4. On the other hand, these dissimilarities seem minimal when one looks at the differences in the probability of dying during the first month, and above all, during the first week (with the exception of the first day). The probability of dying in days 1-6 was six/seven times higher in Agna and in Casalserugo than in Alì and in England. The relevance of winter neonatal mortality is also clearly depicted by the results presented in table 3, which show significant seasonal differences in neonatal mortality in Agna and Casalserugo.

Data

By means of the previously described macro (aggregated) data, it was possible to study the secular trend in infant mortality by season and age at death for several Veneto parishes. In order to enhance our analysis of the association between temperature and the risk of dying during first month of life, we used available micro (individual) data, focusing on the first half of the 19 th century (i.e. when infant mortality in Veneto was extremely high (see again figure 1)).

The micro-data used for this study come from a village in Veneto (Casalserugo, situated 10 km from Padua and quite close to the village of Battaglia, which similarly had very high levels of winter neonatal mortality during the first half of the 19 th century, cf. table 3 and figure 3). The results presented here are part of an extensive research project on infant mortality in the Veneto at the dawn of demographic transition. Thus far, data for the period of 1815-70 have been collected for twenty parishesboth urban and ruralin the provinces of Padua, Vicenza, Treviso, Venice and Verona. Although a comprehensive analysis has not yet been published, we can already observe that infant mortality in the southern part of the province of Paduawhere Casalserugo is situated -was higher than the regional average and began to decline later and more slowly. Indeed, the region in which this parish is located had one of the highest neonatal mortality rates in all of Western Europe during this time period. Focusing the analysis within this context thus enables us to highlight the micro-connection between temperature and neonatal risk of dying in an -extreme‖ situation.

We used two kinds of micro-data. The first consists of civil registers of births and deaths which each parish priest (or rabbi, in the Jewish communities) was required to compile during the period of Austrian rule (1815-1866 in Veneto), in addition to their ecclesiastic registers of baptisms and burials. The civil registers were often checked by state authorities, as testified by their frequent stamps and notes on the register pages. They are generally easier to read than the ecclesiastic registers as they were pre-printed and their overall quality is quite good. As reported above, in this study we use the civil registers from the parish of Casalserugo. In order to analytically study infant mortality, we have linked the events of birth and death recorded in the civil registers to the same individual by using data reported at each event as -linkage-keys‖: family name, given name, the name of the father, and the family name and given name of the mother. Since the (often approximate) age at death was reported in the death registers, it was also possible to calculate the linkage performance: 99% of the deaths of children who died within the first five years of life can be linked to their births. In Casalserugo, the number of births reported in the civil register overlaps with the number of baptisms in the ecclesiastic registers.

In another parish where the same nominative linkage procedure was applied and performed about as well (Agna, 40 km far from Padua), the number of births in the civil registers is higher than the number of baptisms, as children who died before being baptized were still reported in the civil register. Since almost all of the non-baptized newborns of Agna died on the day of birth, we consider them to be stillbirths. The tables reported in the Tafeln zur Statistik der Osterreichischen Monarchie from 1827-1965 provide additional data on infant mortality [START_REF] Rossi | Le statistiche della popolazione nella monarchia austriaca[END_REF][START_REF] Dalla-Zuanna | Comparisons of infant mortality in the Länder of the Austrian Empire using the Tafeln (1851-54)[END_REF]; see also table 1). For several years, data on stillbirths were given separately. For example, in 1854 this source reports a proportion of 1.3% stillbirths in Veneto and 1.5% in the Empire as a whole. It is possible that the criterion adopted in Agna (inclusion in the Civil Register of children who died before baptism) was the general rule, whereas the standard employed in Casalserugo (inclusion in the Civil Register only of children who had been baptized) was an exception. As far as we know, however, a complete analysis of this data has yet to be carried out. Casalserugo did not have a hospice for foundlings. However, some children may have been taken to the foundling hospice in Padua shortly after birth and baptism, and then handed over for nursing in other parishes. Evidence of this practice exists in the form of descriptions such as "a nurse" and "the foundling hospital‖ which replace the place of birth on the acts of child death in some Veneto parishes.. Although a few of these cases are also found in Casalserugo, we did not include them in our calculations of death probabilities, as only linked children, for whom both birth and death acts are known, are considered. This approach could result in some underestimation of infant mortality because not only could a certain number of children born and baptized in Casalserugo have died elsewhere, but also the (relatively few) foundlings who did die in Casalserugo were not taken into account. Given the nature of the data at our disposal, it is impossible to say anything more on this topic. It is likely, however, that very few children were abandoned in Casalserugo as the number of illegitimate infants born in Casalserugo throughout the period under observation is negligible (less than 1%). In addition, neonatal and infant mortality was so high as to suggest thatespecially during the winterpoor people did not abandon babies in order to avoid having to care for them.

These data can thus be considered as reliable. In addition to the high proportion of infant deaths linked to births, it is important to highlight the accuracy of the birth acts, where basic data were always provided with great precision. Moreover, a comparative study shows that the general quality of the data on infant mortality for the Italian regions of the Austrian Empire (Lombardy and Veneto) around 1850 was quite good, comparable with that of the German-speaking Länder, and certainly greater than that observed in the eastern and southern areas of the Empire (Dalla-Zuanna and [START_REF] Dalla-Zuanna | Comparisons of infant mortality in the Länder of the Austrian Empire using the Tafeln (1851-54)[END_REF].

The second micro-dataset used concerns daily temperature (minimum, maximum, and mean) and atmospheric pressure, recently published for several European towns during the period of 1700-2000: Milan (Italy): 1763[START_REF] Rossi | Il Veneto fra Sette e Ottocento[END_REF]Cádiz (Spain): 1786[START_REF] Rossi | La popolazione di una comunità rurale del Padovano. Altichiero, 1700-1900[END_REF]Stockholm (Sweden): 1722[START_REF] Rossi | Il Veneto fra Sette e Ottocento[END_REF]Belgium (multi-site): 1767Belgium (multi-site): -1998;;Uppsala (Sweden): 1756[START_REF] Rossi | Il Veneto fra Sette e Ottocento[END_REF]St. Petersburg (Russia): 1743[START_REF] Rossi | La popolazione di una comunità rurale del Padovano. Altichiero, 1700-1900[END_REF]. Data for Padua have been reliably comparable since 1774 (Camuffo and Jones, 2002). The two datasets just presented were merged and organized into a person-period dataset. The period (unit of observation) is every specific day from birth to the end of the first month of life. Casalserugo is located only 10 kilometers from Padua and thus temperatures in the two places should be very similar. Consequently, for each day, the minimum temperature has been added into the dataset as the main explanatory variable. For a child who was still alive at the end of the first month, the observation is right-censored. For a list of the available daily variables, see table 4. The discrete-time approach is particularly suitable in the presence of ties. As shown in table 4, which contains all the variables available in our dataset, the number of events in each time-unit (especially in the first days of life) is very high. Merging the two datasets was possible only for Casalserugo, as Agna is located far from Padua and daily data on temperature were not available1 .

Results

A detailed analysis of the association between temperature and the risk of neonatal death was carried out using our micro-dataset. First, we looked for further confirmation of newborn excess mortality during the winter. Second, we produced detailed estimates of the probability of death within the first thirty days of life for those births which occurred in the months of December, January, and February. Lastly, we examined the analytical relationship between temperature and mortality during the winter.

In our first model, we estimated the effects of the season without considering specific climatic data. We used a logistic regression where the response variable was death (or not) in the first month of life in Casalserugo (table 5). The risk of dying during the first month of life is very high (310‰). This is especially true in the winter (584‰) compared to the summer (107‰) and confirms the descriptive patterns displayed in table 3the starting point of our analysis. Note. The odds ratios are the result of a logistic model, where the response variable is death (or not) in the first month of life. Other covariates in the model include: sex, year of birth, social class of the parents, distance marriage-birth, distance birth-baptism (see table 4). The total number of births is 2,392.

In a second model, we applied a discrete-time hazard regression to the detailed data of Casalserugo, concentrating on December, January and February. These are the months with the highest neonatal mortality of the year2 . In total, 503 children born in the winter (8,328 person-days) and 294 events (deaths before the end of the first month of life) are included in the dataset. We allowed for a correlation among children within the same family by using the GEE (Generalized Estimating Equations) approach [START_REF] Diggle | Analysis of Longitudinal Data[END_REF]. This tool aids in controlling for unobserved characteristics shared by children of the same mother. The main explanatory variable is the minimum temperature of the day, included in the models as a time-dependent covariate. The other explanatory variables were mainly included as control factors. In order to account for the bellshaped baseline risk of death in the first month, we considered either age as a continuous variable by including a quadratic term on the logit scale (Model A), or age as a categorical variable in suitable classes (Model B). In order to better explain the effect of temperature on neonatal mortality, we fitted several lagged models to the same dataset. However, the minimum temperatures during the preceding days were not statistically significant if the temperature of the current day was included in the model as a covariate (table 6).

The pattern of the risk of death by age (in days) is shown in figure 4. The probability of dying in the wintertime dramatically increases, reaching a peak in the second and third day of life and then subsequently decreasing. In other words, the most critical period is during the first week, omitting the first day. The same model, when applied to children born in the less cold months, shows that the probability of dying monotonically decreases. ) 0 ------1 Note. 503 children born in the winter (8,328 person-days) and 294 events (deaths before the end of the first month of life) are included in the dataset. Other covariates in the model include: sex, year of birth, social class of the parents, distance marriage-birth, distance birth-baptism (see table 4). Intra-family correlation: 0.0132

The effect of temperature on the survival of winter newborns is substantial and strongly significant. A decrease of 1°C corresponds to a 5% increase in the daily risk of death during the first month of life (table 6). According to both models A and B, the daily risk of death during the third and fourth days of life varies from 80‰ to 130‰ to 220‰ if the minimum temperature varies respectively from +5°C to 0°C to -5°C. It is interesting to note that with the inclusion of the minimum temperature in the model, the effect of the month of birth (December, January, or February) is no longer statistically significant (the regression models including month and excluding temperatures are available on request). This is a notable result, as some authors have suggested that the survival chances of children are related to the health conditions of their mothers during several susceptible periods of their pregnancies (particularly the second trimester), and that these conditions may vary seasonally (i.e. due to energy stress induced by the harvest cycle; see Scott and Duncan, 2002, chapter 13). This may also hold true in Casalserugo, but for those unlucky children born during the wintertime, the cause of death seems to be overwhelmingly a matter of external temperature. While the interaction between temperature and age is not significant, the effect of temperature is nevertheless stronger during days 2-6. Furthermore, the probability of death is significantly higher during days 2-6 than during the second week of life (analytical results not shown). If this result is considered together with the shape of the daily-risk function (see figure 4), we again have confirmation that the most critical period during the winter was the first week of life, omitting the first day.

In conclusion, our analysis provides empirical evidence that for the unlucky children born during winter, the risk of dying during the first month of life was extremely responsive to external temperature, particularly during the first week, and above all during the days 2-6. These results further confirm the findings of [START_REF] Ekamper | 150 years of temperature-related excess mortality in the Netherlands[END_REF] about the extreme vulnerability of children when temperatures reached low values.

Discussion

This paper has had two aims: to describe the remarkable intensity of winter infant mortality in Veneto during the century of 1750-1850, and, more specifically, to analyse the effect of external temperature on the risk of dying during the first 30 days of life and to examine whether this effect varies by age. We showed that the significant increase in infant mortality in Veneto during the 18 th century, and its subsequent rapid decline in the second half of the 19 th century was caused mainly by considerable variation in neonatal mortality in the wintertime. The worst time period in this regard was from 1750-1850, when the probability of dying in the first month of life during the colder months (December, January and February, the so called -meteorological winter‖) reached levels as high as four hundred per thousand births. These levels are significantly higher than those observed in other areas of Italy and Europe (i.e. Tuscany and England) where winter temperatures were similar to those in Veneto, but winter neonatal mortality was much lower. With specific regard to the first month of life, the risk of dying in the winter months was not homogenous: the period of highest risk was clearly during the first week.

Although we carefully analysed the statistical association between temperature and the risk of dying during the first thirty days of life in Veneto during the first half of the 19 th century, the available data do not allow us to reliably delve further into the causal mechanisms. Nevertheless, our results, combined with other findings in the literature, provide support for several possible explanations, show others to be less plausible, and suggest directions for future research.

Causes of death. Information regarding the cause of death, reported in the burial records of Veneto parishes from the 18 th and 19 th centuries, is vague and does not fit contemporary disease classification schemes. Our results do, however, allow us to reflect on several plausible illnesses that may have been responsible for low survival rates during the 18 th century. In particular, the observed seasonality of neonatal deaths was probably not due to endogenous causes linked to pregnancy, birth, or congenital anomalies, as these tend to appear in relatively the same measure throughout the year. We may also exclude some other illnesses and contagious diseases that do not specifically affect newborns and are not immediately fatal. Diseases such as diarrhea do, however, have a seasonal pattern, but peak in the summertime for weaned children [START_REF] Kale | Time series analysis of deaths due to diarrhoea in children in Rio de Jeneiro, Brazil, 1980-1998[END_REF]). Respiratory illnesses (pneumonia, bronchitis, pleurisy, and bronchopneumonia), on the other hand, are more common in the winter. An empirical means of examining whether disease is a causal factor of very high winter neonatal mortality is to analyze the evolution of the daily risk of death following birth. Indeed, the newborn is at a higher risk of dying of respiratory diseases precisely during the second and third weeks of life, as shown by the earliest available infant mortality data of good quality, detailed by cause and age at death (Istat, 1934, pages. 128-131).

Temperature shock for low-weight newborns. The winter increases in infant deaths in Veneto during the 18 th century were mainly due to events which occurred during the first week of life. This suggests that high winter neonatal mortality in Veneto during 1750-1850 was caused by factors which amplified the effects of cold temperatures: (1) the increasing inability of newborns to survive low temperatures at birth, and/or (2) the growing incapability of parents to protect their children from the cold. In 18 th and 19 th century Veneto, several issues may have augmented these risks (see below). More specifically, it should be underlined that low-weight newborns are less able to react and adapt to the temperature shock which typically characterizes the hours following delivery, especially when external temperatures are low (see [START_REF] Who | Thermal protection of the newborn: a practical guide[END_REF][START_REF] Costello | New methods for monitopring neonatal hypothermia and cold stress[END_REF][START_REF] Kambarami | Neonatal hypothermia levels and risk factors for mortality in a tropical country[END_REF][START_REF] Darmstadt | Introduction of community-based skin-to-skin care in rural Uttar Pradesh, India[END_REF][START_REF] Knobel | Thermoregulation and heat loss prevention after birth and during neonatal intensive-care unit stabilization of extremely low-birthweight infants[END_REF]. Evidence of general malnourishment suggests that underfed mothers may have given birth to low-weight infants. According to contemporary data collected in developing countries, the risk of a mother delivering a underweight newborn (< 2,500 g) increases for each centimetre below average height, for each kilogram underweight, and for each centimentre below satisfactory mid-upper arm circumference ( [START_REF] Lechtig | Effect of maternal nutrition on infant mortality‖[END_REF][START_REF] Who | Maternal anthropometry and pregnancy outcomes: a WHO Collaborative Study[END_REF][START_REF] Ramakrishnan | Nutrition and low birth weight: from research to practice[END_REF][START_REF] Ashdown-Lambert | A review of low birth weight: predictors, precursors and morbidity outcomes[END_REF].

Economic decline and worsening nutrition in Northern Italy and Veneto during the 18 th century. Thus far we have no direct proof of a growing proportion of malnourished mothers in Veneto. However, there are a number of indications which suggest that during this period the living conditions of the working classes deteriorated throughout the Padana lowland, particularly in the eastern area (see section 2). Consequently, the notion that increasingly high winter neonatal mortality in Veneto over the course of the 18 th century and into the 19 th century can be explained by the deteriorating physical condition of mothers and by the inability of parents to protect their children from the cold is consistent with knowledge of the region's economic and social history.

The lack of preventive Malthusian checks. Population growth which followed the end of the plague epidemics was not accompanied by significant changes in productive capacity or by any preventive checks on uncontrolled population growth. The average age at first marriage of women in the mid-18 th century was young from a Western perspective (20-21 years old), practically identical to the marrying age a century earlier [START_REF] Rosina | Mortalità infantile[END_REF]. In other areas of Italy, however (such as in Tuscany), population growth after the epidemics was slower due to a rise in the average age at marriage [START_REF] Breschi | La nuzialità in Toscana, secoli XIV-XIX[END_REF]. In other words, the preventive Malthusian brakes did not work in Veneto during the 17 th and 18 th centuries.

Post-neonatal control? The proposed explanatory chain (general worsening of living conditions  malnourished mothers  low-weight newborns more susceptible to neonatal hypothermia  lower likelihood of survival in the first days of life during the winter) seems to be the most plausible in the light of available data. An alternative explanation might be an increasing prevalence during the 17 th and 18 th century winters of, -infanticide by neglect‖ (Knodel and van de Valle, 1979, p. 230). It is not easy to imagine extensive rational strategies of -post-neonatal control‖ such as abandonment or infanticide [START_REF] Mason | Explaining fertility transition[END_REF] which, for some unknown reason, became much more common during the winter. However, it is possible that child neglectnot unlike that seen during other seasons or previous centurieshad much worse consequences during colder periods, especially in a setting characterized by a lack of material resources. Early baptismeven if no more frequent than in the previous centuriesmay also have been especially dangerous for frail and low-weight children of weak mothers. On the other hand, such parental behavior would probably fall into a category of -too much (spiritual) attention‖ rather than -infanticide by neglect‖.

We conclude with some reflections concerning possible lines of future research. First, more extensive studies using the extremely clear, simple, and complete pre-printed registers of birth, deaths, and marriages for the provinces once part of the Austrian Empire would allow for rich comparative analysis. By means of these historical records, further work might address not only the topic of infant mortality, but also other important population trends of the 19 th century, such as the demographic transition, its timing, geography, and causes.

Second, the association between daily temperature and mortality could be more fully explored in other territorial contexts, thanks to the availability of lengthy series of tested and verified published data on temperatures in other cities (see the bottom of table 4; see also Camuffo and Jones, 2002, with CD attached).

Third, in order to gain a more in-depth understanding of the hypothesized causal factors of high winter neonatal mortality during the period 1750-1850, more data are necessary. Analysis of the links between neonatal mortality and external temperatures could be extended by considering other indicators that also oscillate across months or years. For example, the prices of essential materials such as firewood and grain typically tended to fluctuate in urban contexts, where these goods were not self-produced and had to be bought. Other direct measures of additional data on the private and public care of infants would help clarify and shed new light on why northern Italy, notwithstanding persistent malnutrition, started so early on the road towards the health transition. There are many signs, however, beginning in the mid-19 th century, of a growing awareness of the importance of caring for an infant in its earliest moments of life, both at the familial level and at the socio-political institutional level [START_REF] Derosas | Watch out for the Children! Differential Infant Mortality of Jews and Catholics in Nineteenth-Century Venice[END_REF]. These data are mainly qualitative, however, and research would best be pursued by exploring the rich archives of the 19 th century.

Figure 1 .

 1 Figure 1. Secular trends in infant mortality rates (‰) in selected areas of Italy and in England. 1675-1900

Figure 2 .

 2 Figure 2. Neonatal mortality during the first month of life in Veneto (Index number: Italy=100). 1872-1879

Figure 3 .

 3 Figure 3. Probability of death by season of birth in selected parishes of Veneto (1650-1900). Specific ages during the first year of life

  parts A, B, C, E of the same figure.

Figure 4 .

 4 Figure 4. Daily probability of dying during the first month of life by season in Casalserugo (1818-1857): observed and predicted values from model A (see Table7).

Table 1 . Probability of infant death (x 1,000) circa 1854 in the provinces of the Austrian Empire Regions (in German) N. of Births

 1

	Stillbirths
	and month 0	Months 1-11	Year 0

Source: our calculation on original data from the Tafeln zur Statistik der Osterreichischen Monarchie (1854). See also

[START_REF] Dalla-Zuanna | Comparisons of infant mortality in the Länder of the Austrian Empire using the Tafeln (1851-54)[END_REF]

(A) Adria (province of Rovigo) 1676-1899 (mean number of births a year: 345) FIRST MONTH

	Rate
									Winter
									Spring
									Fall
									Summer
	1676-00	1701-25	1726-50	1751-75	1776-00	1801-25	1826-50	1851-75	1876-99
					Period
	Source: Rossi and Tesolat, 2006.

(B) Salzano (

province of Venice) 1721-1800 (mean number of births a year: 78) FIRST MONTH

								Winter
								Fall
								Summer
								Spring
	1721-30	1731-40	1741-50	1751-60	1761-70	1771-80	1781-90	1791-00
				Period

Rate

Source: Unpublished data personally communicated by Andrea Zannini in 2008.

(C

) Altichiero (province of Padua) 1766-1900 (mean number of births a year: 62) FIRST MONTH

	Rate
							Winter
							Fall
							Spring
							Summer
	1766-85	1786-05	1806-25	1826-45	1846-65	1866-85	1886-00
				Period
	Source: Rossi, 1996.

(D) Battaglia (

province of Padua) 1766-1900 (mean number of births a year: 72) FIRST WEEK

	Rate
								Winter
								Spring
								Fall
								Summer
	1664-90	1691-15	1716-40	1741-65	1766-90	1791-15	1816-40	1841-71
				Period
	Source: Furegato, 2007.

(E

) Battaglia (province of Padua) 1766-1900 (mean number of births a year: 72) FIRST MONTH

		800
		700
		600
		500							Winter
	Rate	400
		300
									Spring
		200							Fall
		100							Summer
		0
		1664-90	1691-15	1716-40	1741-65	1766-90	1791-15	1816-40	1841-71
					Period
	Source: Furegato, 2007.

(F) Battaglia (

province of Padua) 1766-1900 (mean number of births a year: 72) FIRST YEAR

	Rate
					Period
	Source: Furegato, 2007.
	0 100 200 300 400 500 600 700 800	1664-90	1691-15	1716-40	1741-65	1766-90	1791-15	1816-40	Winter Spring Summer Fall 1841-71

Table 2 . Probability of dying (‰) by age in Casalserugo (Padua, Veneto), Agna (Padua, Veneto), Alì (Messina, Sicily) and England. Children aged 0-4 born during the 18 th and 19 th centuries

 2 Estimated (as the number of children who died during the first day was underreported). Sources: The probabilities for Casalserugo, Agna, and Alì are calculated using nominative linkages. For Alì, see D'Angelo,[START_REF] D'angelo | Massimo risultato con il minimo sforzo. Ricostruzione nominativa semiautomatica della sopravvivenza infantile, e analisi del regime demografico di Alì nel XVIII secolo[END_REF]. For England, seeWrigley and Schofield (1981, page 226)

		CASALSERUGO	AGNA	ALÌ (SICILY)	ENGLAND
	Age
		Born in	Born in	Born during the	Born during the
				th		th
		1818-67	1816-47	18	century	18	century
	Day	0

Table 3 . Probability of dying (‰) in the first month of life by season in Casalserugo and Agna during the first half of the 19 th century. Stillbirths are not included

 3

	Winter	Spring	Summer	Fall
	Casalserugo (1818-67)

Table 4 . Person-days and neonatal deaths by variables in the dataset for Casalserugo (1818-1867)

 4

		Exposures	Occurrences
		N	%	N	%
	Year of birth
	1818-19	2,014	3.6	24	3.3
	1820-29	11,430	20.5	142	19.4
	1830-39	11,028	19.8	138	18.9
	1840-49	10,770	19.3	158	21.6
	1850-59	11,030	19.8	158	21.6
	1860-67	9,474	17.0	111	15.2
	Total	55,746	100.0	731	100.0
	Month of birth
	1	2,885	5.2	105	14.4
	2	3,111	5.6	106	14.5
	3	5,434	9.8	133	18.2
	4	6,077	10.9	72	9.8
	5	7,676	13.8	33	4.5
	6	3,996	7.2	19	2.6
	7	4,905	8.8	26	3.6
	8	6,173	11.1	13	1.8
	9	5,437	9.8	18	2.5
	10	4,305	7.7	56	7.7
	11	3,415	6.1	67	9.2
	12	2,332	4.2	83	11.4
	Total	55,746	100.0	731	100.0
	Age at baptism (days)
	0	11,753	21.1	257	35.2
	1	24,648	44.2	330	45.1
	2	9,350	16.8	91	12.4

Table 5 . Neonatal mortality by season in Casalserugo (1818-1867) Season of birth

 5

		Probability	Odds	95% confidence
		of dying	ratio	limits
		(x 1,000)
	Summer (J-J-A)	107	1	Reference
	Autumn (S-O-N)	265	3.2	2.2	4.4
	Winter (D-J-F)	584	11.6	8.3	16.3
	Spring (M-A-M)	294	3.5	2.6	4.8

Table 6 . Discrete-time hazard regression of daily mortality in the first month. Children born in December, January, and February in Casalserugo (1818-1867) Model A Age as a continuous variable Model B Age as a categorical variable

 6

			Param.	s.e.	p-value	Odds	Param.	s.e.	p-value	Odds
						Ratio				Ratio
	Intercept	-3.75	0.278	<0.001	0.02	-3.16	0.071	<0.001	0.04
	Ln age		2.09	0.305	<0.001	8.08
	(ln age) 2	-0.74	0.082	<0.001	0.48
	Age	0-1					-0.15	0.160	0.340	0.86
		2-3					1.01	0.115	<0.001	2.75
		4-6					0.64	0.111	<0.001	1.90
		7-13					0.02	0.152	0.923	1.02
		14 + (ref.)					0	---	---	1
	December (ref.)	0	---	---	1	0	---	---	1
	January	0.03	0.141	0.842	1.03	-0.03	0.086	0.690	0.97
	February	0.05	0.146	0.741	1.05	0.04	0.088	0.636	1.04
	MIN temperature C°	-0.05	0.015	0.001	0.95	-0.05	0.019	0.016	0.95
	MIN * Age 0-1					0.01	0.044	0.964	1.01
		2-3					-0.04	0.031	0.265	0.96

Data (available upon request) were processed using SAS.

In order to test the consistency of our results, we employed another model in which we included the month of March and obtained very similar results (unpublished and available on request).