Populations at risk for severe or complicated influenza illness: systematic review and meta-analysisBMJ 2013; 347 doi: https://doi.org/10.1136/bmj.f5061 (Published 23 August 2013) Cite this as: BMJ 2013;347:f5061
All rapid responses
Re: Populations at risk for severe or complicated influenza illness: systematic review and meta-analysis
Freitas and Alonso question the finding that pregnancy in our systematic review and meta-analysis1 did not increase the risk of death. They cite 8 studies2-9 to support an increase in mortality with pregnancy during the 2009 H1N1 pandemic. All but one study5 was ecological in design, and did not meet our eligibility criteria. Such studies, in particular those based on passive laboratory surveillance4 6 10, are subject to biases in ascertainment. Ecologic studies provide no baseline for the number of pregnant women tested nor for the effect of comorbid conditions among pregnant women and community based controls. Policy for detection of influenza can vary by jurisdiction and the timing of such testing can also vary. In addition to differential testing based on pregnancy status and illness severity, factors such as uncertain population estimates of pregnancy rates, differences in health seeking behavior, and differences in admission rates based on pregnancy status, can influence results. It is for this reason that comparative research studies should be conducted, to generate primary data that offers rigorous evidence of risk. It is why we excluded ecologic data from our analysis and it is why our results differ from studies that Freitas and Alonso cite in their rapid response.
We arrived at our conclusion based on data from studies that met inclusion criteria assessing outcomes for pregnancy. Studies conducted during pandemics included two community-based studies11 12, 14 studies reporting data on hospitalized patients5 12-24, and 13 in patients admitted to an intensive care unit 16 17 24-34. All but two studies11 13 were conducted during the 2009 H1N1 pandemic.20 22The fact that there was no significant difference in death when these groups were compared argues against pregnancy being an independent risk factor for death. Hospital admission, as Freitas and Alonso suggest, is not necessarily an indicator that severe disease has been established. In pregnancy, the threshold for admission to hospital may be much lower than for non-pregnant women. The statement by Freitas and Alonso that during 2009 “doctors understood that pregnancy translated into a higher risk for complications and acted accordingly” supports this possibility.
Freitas and Alonso argue that inclusion of studies of hospitalized patients may have missed crucial risk factors for the development of complications. Obviously studies that did not begin in the community would not address outcomes occurring prior to hospitalization. Importantly, there was no evidence for a subgroup effect when comparing studies conducted in the community versus studies in the hospital or ICU setting (I2=0%, p=0.41). When we analyzed community studies as separate from those that were initiated from the hospital, we did not find a significant effect of pregnancy (odds ratio (OR) 2.37, 95% confidence interval (CI) 0.66-8.44). In comparison, the odds ratio was 0.93 (95% CI 0.55-1.58) in hospitalized and 1.11 in ICU patients.. That is, there is no change in the interpretation when stratifying by these subgroups.
Freitas and Alonso are concerned that our conclusion about pregnant women may have a negative impact on acceptance of influenza vaccine and suggest that we reassess our findings in the face of the ecologic data that they cite. We believe that policy should be based on the best available data, which is why we conducted this systematic review where > 60,000 studies were screened. We clearly stated that our findings were in keeping with recommendations to prioritise vaccination of pregnant women because of the increased risk for mortality post-partum. Moreover, the limitations of studies addressing risk factors for outcomes following influenza infection are clearly acknowledged as a main finding in our review. We would suggest a call for more rigorous studies of risk factors for influenza complications in pregnancy rather than revising interpretations by incorporating lower quality data.
Mark Loeb, Departments of Pathology and Molecular Medicine, Medicine, and
Clinical Epidemiology and Biostatistics, McMaster University
Dominik Mertz, Departments of Medicine and Clinical Epidemiology and
Biostastics, McMaster University
1. Mertz D, Kim TH, Johnstone J, Lam PP, Science M, Kuster SP, et al. Populations at risk for severe or complicated influenza illness: systematic review and meta-analysis. BMJ 2013;347:f5061.
2. Jamieson DJ, Honein MA, Rasmussen SA, Williams JL, Swerdlow DL, Biggerstaff MS, et al. H1N1 2009 influenza virus infection during pregnancy in the USA. Lancet 2009;374(9688):451-8.
3. Webb SA, Pettila V, Seppelt I, Bellomo R, Bailey M, Cooper DJ, et al. Critical care services and 2009 H1N1 influenza in Australia and New Zealand. The New England journal of medicine 2009;361(20):1925-34.
4. Siston AM, Rasmussen SA, Honein MA, Fry AM, Seib K, Callaghan WM, et al. Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States. JAMA 2010;303(15):1517-25.
5. Louie JK, Acosta M, Jamieson DJ, Honein MA, California Pandemic Working G. Severe 2009 H1N1 influenza in pregnant and postpartum women in California. N Engl J Med 2010;362(1):27-35.
6. Hansen C, Desai S, Bredfeldt C, Cheetham C, Gallagher M, Li DK, et al. A large, population-based study of 2009 pandemic Influenza A virus subtype H1N1 infection diagnosis during pregnancy and outcomes for mothers and neonates. The Journal of infectious diseases 2012;206(8):1260-8.
7. Godoy P, Rodes A, Alvarez J, Camps N, Barrabeig I, Sala MR, et al. [Characteristics of cases hospitalized for severe pandemic (H1N1) 2009 in Catalonia]. Revista Espanola de Salud Publica 2011;85(1):81-7.
8. Critical illness due to 2009 A/H1N1 influenza in pregnant and postpartum women: population based cohort study. BMJ 2010;340:c1279.
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10. Jamieson DJ, Honein MA, Rasmussen SA, Williams JL, Swerdlow DL, Biggerstaff MS, et al. H1N1 2009 influenza virus infection during pregnancy in the USA. Lancet 2009;374(9688):451-8.
11. Identification of epidemic wave of A H1N1 influenza summer in the city of Valencia. [Spanish] Identificacion de la onda epidemica estival por Gripe An H1N1 en la ciudad de Valencia. Boletin Epidemiologico Semanal 2009;17(12):133-36.
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31. Marav-Poma E, Escuchuri J, Macaya L, Aldunate S, Jimenez I, Bentez-Peyrat J, et al. Severity of 2009 pandemic influenza a (H1N1)v infection in pregnant and non pregnant women in spain. Intensive Care Medicine 2010;36:S368.
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Competing interests: No competing interests
Re: Populations at risk for severe or complicated influenza illness: systematic review and meta-analysis
A recent meta-analysis conducted by Mertz and collaborators  assessed the strength of evidence for factors representing a higher risk for influenza-related complications by considering data from 234 studies. Among the findings, perhaps the most unanticipated was that "pregnancy did not increase the risk of death". This affirmation is even more surprising in the context of the 2009 pandemic, when reports of pregnant women dying in exceptional numbers were widespread [2–9]. For example, there were 2,051 laboratory-confirmed pandemic deaths reported to the Brazilian Ministry of Health, of which 713 of women in childbearing age (15 to 49 years old). In this latter group, a striking proportion (26.5%, or 189 individuals) were pregnant women. Pregnant women represent 4.1 % of women in childbearing age in Brazil . These values represent a relative risk of death roughly 6.5 times higher for a woman who is pregnant. This is in agreement with findings such as that “pregnant women represent approximately 1% of the US population, yet they accounted for 5% of US deaths from 2009 influenza A(H1N1) reported to the CDC" 
So why did Mertz et al’s meta-analysis arrive at the opposite conclusion? We believe the answer lies in their study design. Although this meta-analysis was based on 234 studies, assessment of pregnancy as a risk factor derived from only 26 studies that, in total, included little more than 2400 pregnant women. Of these, only about 500 women (~20%) were recruited in the community [11,12]. The analysis therefore compared primarily pregnant and non-pregnant women who were hospitalized. This represents an important limitation, since hospital admission is already an indicator that severe disease has already been established. As a consequence, the analysis may have missed those crucial risk factors associated with the development of complications in the first place. Studies aimed at evaluating risk status should integrate all steps leading to the outcome of interest – in this case, differences in the likelihood of developing severe disease between pregnant and non-pregnant women. Indeed, the authors did find that pregnancy was associated with higher rates of hospital admission, but then concluded that pregnancy did not increase mortality based on the odds of dying among women who were already hospitalized. One should also keep in mind that expected clinical attack rates range from 25% to 45% in a pandemic , but only a small minority of individuals is admitted. Under a hypothetical scenario where mortality is similar between pregnant and non-pregnant women who are hospitalized, as found in this study, the observation of a higher proportion of pregnant-women requiring hospitalization would be enough to raise the risk status of this group. During the 2009 pandemic doctors understood that pregnancy translated into a higher risk for complications, and acted accordingly. We believe those measures have proved to be correct, as shown in several studies [2,3,5,6].
Several health authorities, including the World Health Organization, recognized that the 2009 influenza pandemic increased maternal mortality rates in several countries [4,14–18]. Mertz and collaborators suggest that it would be interesting to continue vaccinating pregnant women to protect the postpartum period and newborn. However, their conclusion that pregnant women were not at higher risk for severe disease and death during the 2009 pandemic may discourage vaccination. It can also have a negative impact on acceptance of any influenza vaccine (both seasonal and pandemic) by this demographic group, which has already been shown to wear some resistance to it [18–23]. A reassessment of those findings in light of the limitations discussed here is thus pressing.
1 Mertz D, Kim TH, Johnstone J, et al. Populations at risk for severe or complicated influenza illness: systematic review and meta-analysis. BMJ 2013;347:f5061–f5061. doi:10.1136/bmj.f5061
2 Jamieson DJ, Honein MA, Rasmussen SA, et al. H1N1 2009 influenza virus infection during pregnancy in the USA. The Lancet . 2009;374:451–8.http://linkinghub.elsevier.com/retrieve/pii/S0140673609613040
3 The ANZIC Influenza Investigators (2009). Critical Care Services and 2009 H1N1 Influenza in Australia and New Zealand. N Engl J Med 2009;361:1925–34. doi:10.1056/NEJMoa0908481
4 Secretaria de Vigilância em Saúde – Ministério da Saúde do Brasil. Boletim Epidemilógico: Especial Influenza. 2010;:1–21.
5 Siston AM, Rasmussen S a, Honein M a, et al. Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States. JAMA 2010;303:1517–25. doi:10.1001/jama.2010.479
6 Louie JK, Acosta M, Jamieson DJ, et al. Severe 2009 H1N1 influenza in pregnant and postpartum women in California. N Engl J Med 2010;362:27–35. doi:10.1056/NEJMoa0910444
7 Hansen C, Desai S, Bredfeldt C, et al. A Large , Population-Based Study of 2009 Pandemic In fl uenza A Virus Subtype H1N1 Infection Diagnosis During Pregnancy and Outcomes for Mothers and Neonates. J Infect Dis 2012;206:1260–8. doi:10.1093/infdis/jis488
8 Godoy P, Rodés A, Àlvarez J, et al. Characteristics of Cases Hospitalized for Severe Pandemic (H1N1) 2009 in Catalonia. Rev Esp Salud Pub 2011;85:81–7.http://scielo.isciii.es/scielo.php?script=sci_arttext&pid=S1135-57272011... (accessed 11 Dec2013).
9 The ANZIC Influenza Investigators and Australasian Maternity Outcomes Surveillance. Critical illness due to 2009 A/H1N1 influenza in pregnant and postpartum women: population based cohort study. BMJ 2010;340:1–6. doi:10.1136/bmj.c1279
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14 World Health Organization. Pregnancy and pandemic influenza A (H1N1) 2009: Information for programme managers and clinicians. jul 2010. Geneva: : World Health Organization 2010.
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18 Center of Disease Control. Influenza vaccination among pregnant women - massachusetts, 2009-2010. MMWR Morb Mortal Wkly Rep 2013;62:854–7.http://www.ncbi.nlm.nih.gov/pubmed/24172879 (accessed 29 Nov2013).
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20 Kfouri R de Á, Richtmann R. Influenza vaccine in pregnant women: immunization coverage and associated factors. Einstein (Sao Paulo) 2013;11:53–7.http://www.ncbi.nlm.nih.gov/pubmed/23579744 (accessed 29 Nov2013).
21 Coonrod D V, Jimenez B-F, Sturgeon AN, et al. Influenza Vaccine Coverage among Pregnant Women in a Public Hospital System during the 2009-2010 Pandemic Influenza Season. Influenza Res Treat 2012;2012:329506. doi:10.1155/2012/329506
22 Influenza Vaccination Coverage Among Pregnant Women — 29 States and New York City, 2009–10 Season. MMWR 2012;61:113–8.http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6107a1.htm (accessed 29 Nov2013).
23 Schindler M, Blanchard-Rohner G, Meier S, et al. Vaccination against seasonal flu in Switzerland: The indecision of pregnant women encouraged by healthcare professionals. Rev Epidemiol Sante Publique 2012;60:447–53. doi:10.1016/j.respe.2012.03.008
Competing interests: No competing interests