Our analysis represents to our knowledge the first comprehensive assessment of the frequency and distribution of risk factors for severe H1N1pdm infection from a global perspective, with data from approximately 70,000 patients requiring hospitalization, 9,700 patients admitted to ICU, and 2,500 fatalities from 19 countries and administrative regions around the world. Consistent with other published data, our results reaffirm that the age distribution of severe H1N1pdm cases significantly differs from that of seasonal influenza 
. The highest rates of hospitalization per capita were in children <15 y, but the highest rates of mortality per capita were in persons over 64 y. The low apparent attack rate in the oldest age group, evidenced by low rates of hospitalization, and the high odds associated with age in the fatal group compared to hospitalized cases seems to indicate that although older adults may have a lower risk of infection, they have a significantly higher risk of death if they are infected 
. It is likely that increasing prevalence of chronic risk conditions in the oldest age group contributes to this effect, but our data do not allow for quantification of this association.
Our results demonstrate that in a significant portion of severe and fatal cases, patients had preexisting chronic illness, and that the presence of chronic illness increased the likelihood of death. It was notable, however, that approximately 2/3 of hospitalized cases and 40% of fatal cases did not have any identified preexisting chronic illness. It is unknown how many of these cases had other risk factors, such as pregnancy, obesity, and substance abuse (including smoking and alcohol), for which we had insufficient information in this study. These figures are also dependent on the completeness of available data for recorded risk factors. As with seasonal influenza, the most common underlying chronic conditions among hospitalized patients were respiratory disease, asthma, cardiac disease, and diabetes. Interestingly, we found that although asthma was frequently associated with both hospitalization and death in most countries, with an increased RR for both, the OR for death given hospitalization suggested that a higher proportion of hospitalized cases survived compared to patients with other conditions. This may represent the occurrence of manageable influenza-induced exacerbations of asthma prompting admission that do not progress to viral pneumonia or other fatal complications, and may also reflect the fact that asthma tends to occur in younger age groups 
Early data suggested that pregnancy might be an important risk factor for severe disease with H1N1pdm 
. Our analysis is consistent with these reports and more recent studies 
, which found an overall trend that pregnant women, mainly in their third trimester, have a higher incidence of hospitalization than the general population. Several published studies have also shown that pregnancy is associated with a higher risk of ICU admission and fatal outcome 
. In our analysis, the risk associated with pregnancy was elevated for both hospitalization and fatality compared to women of childbearing age, though the latter association was not consistently observed in every country. As with asthma, the proportion of pregnant women generally decreased with severity level for most of the countries. Our results suggest that pregnant women with H1N1pdm are approximately seven times more likely to be hospitalized and two times more likely to die than non-pregnant women with H1N1pdm. The greater risk for hospitalization than for death with H1N1pdm influenza infection during pregnancy may have resulted from a lower threshold for admitting infected pregnant women to hospital and/or a more aggressive approach to antiviral or other treatment for pregnant women. In addition, the occurrence of non-respiratory complications of pregnancy, such as hypertension, pre-eclampsia, and premature labor, provoked by H1N1pdm infection may have increased the risk of hospitalization while not resulting in death 
. This would be consistent with published reports of case series of pregnant patients that list complications of pregnancy as a common cause of admission 
. The dataset did not allow us to adjust for underlying conditions in pregnant women, and thus to distinguish between risks for healthy pregnant women, and pregnant women with underlying medical conditions; however, we believe that the results support an approach of early intervention with pregnant women who develop influenza.
Early in the 2009 pandemic, clinicians from the US reported a surprisingly high prevalence of morbid obesity, a risk factor not previously associated with severe outcomes for seasonal influenza infection, in patients with severe complications of H1N1pdm infection 
. Subsequent studies in several countries, including the US, Mexico, Canada, Spain, Greece, France, Australia, and New Zealand, reported high proportions of obesity among ICU admissions and fatal cases 
. Our results provide supportive evidence that obesity may be a risk factor for severe disease, as seen in the increasing proportion of morbidly obese patients with severity level and the associated elevated OR. Our findings also suggest that morbidly obese patients with H1N1pdm are more likely to die if hospitalized; however, the results in our analysis were not consistent across all countries. The association between obesity (or morbid obesity) and severe outcomes may reflect direct causation (e.g., due to greater respiratory strain of infection on obese individuals), causation through other known risk factors (e.g., obesity causes diabetes and heart disease, which pose an increased risk for severe outcome 
), or a noncausal association, if some other factor (e.g., genetic or dietary) caused both morbid obesity and increased risk of severe outcome. Unfortunately, our dataset did not allow us to distinguish among these nonexclusive alternatives.
Indigenous populations and ethnic minorities have been reported to experience a disproportionately high burden of severe H1N1pdm infection, particularly in the Americas 
and the Australasia-Pacific region 
, similar to reports during the 1918 influenza pandemic 
. Our analysis of Australian, New Zealand, and Canadian data concur with these published reports, and while compelling, were not universal. Neither Thailand nor Mexico observed a significantly increased burden of severe H1N1pdm disease among indigenous or minority populations. Our data are not sufficient to explain the observed differences in the reported risk of severe disease among minority groups, but several hypotheses have been proposed, including a higher prevalence of chronic medical conditions known to increase risk of severe influenza, delayed or reduced access to healthcare, cultural differences in healthcare-seeking behavior and approaches to health, potential differences in genetic susceptibility, and social inequalities 
. More research is needed to better understand and quantify the increased risk of severe H1N1pdm disease among these groups. However, an imperfect understanding of the mechanisms of health disparities related to severe H1N1pdm disease should not impede the public health community in undertaking actions to mitigate this risk by disseminating appropriate public information, targeting outreach and prevention programs, and involving at-risk population groups in pandemic planning.
Our analysis has a number of limitations, not least of which is the wide differences in surveillance systems, case management policies, and antiviral use in the countries studied. The criteria and indications for hospital and ICU admission for certain conditions (e.g., pregnancy and asthma) and by age (e.g., pediatric patients) varied significantly by country, and may have been somewhat dependent on capacity for admission, which likely varied over time. Risk factors are also dependent on the completeness and quality of data on risk factors reported and classification of death in the absence of complete testing. These variables could lead to a bias in the estimate of these conditions among severe cases and could make direct comparisons across countries difficult. Second, our data do not consider multiple risk factors for individual H1N1pdm patients. A lack of individual-level data on underlying medical conditions of H1N1pdm patients precludes our ability to sufficiently control for confounding and therefore identify the independent contribution of individual risk factors for severe disease and death. The differences observed in risk factors for hospitalization and death among H1N1pdm patients compared to among seasonal influenza patients, and the wide range of RR values between countries may be explained by differences in age structure in the general population. Several studies have identified important differences in the proportions of underlying conditions by age among hospitalized and fatal cases, including, but not limited to, the UK 
, the US 
, Canada 
, and Singapore 
A third limitation is related to our imperfect calculation of the point prevalence of pregnancy among women of childbearing age in the general population. However, we believe that our findings of the range of RR values for hospitalization and death is valid, but may be very slightly inflated because of undercounting in the denominator. The inflationary effect of undercounting is likely greatest for pregnant women in the first trimester, as we didn't adjust for common first trimester events such as miscarriages or abortions, and in this group there is likely substantial undercounting in the numerator as well because of women not knowing they are pregnant in that period. Fourth, the data used in our analysis relied on hospital records, which were not standardized, and were likely to be incomplete or vary in quality between hospitals or countries. This poses a problem in the direct comparativeness between settings.
Despite these limitations, this analysis is the first to our knowledge to compare risk factors across a variety of countries using data from a very large number of patients, and we found a great deal of consistency for much of the data. Clearly, cardiac disease, chronic respiratory disease, and diabetes are important risk factors for severe disease that will be especially relevant for countries with high rates of these illnesses. We provide evidence to support the concern regarding obesity, particularly morbid obesity, as a risk factor, though this needs more study. We found large between-country variations for some important risk factors, most notably pregnancy, and the reasons for these differences need more study. There is evidence to suggest that the differences observed for pregnancy might represent differences in case management practices, and we believe that the available evidence supports vaccination and early intervention for pregnant women. Our study reinforces the need to identify and target high-risk groups for interventions, such as immunization, information, early medical advice, and use of antiviral medications. Experience with the 2009 H1N1 pandemic and the differences observed between countries have highlighted the need for country-specific surveillance data and global standardization of case definitions and data collection, and the usefulness of data sharing to aid policy makers in critical decision making for global influenza epidemics.