Matern Child Health J DOI 10.1007/s10995-013-1385-8
Pandemic Influenza A (H1N1) in Non-vaccinated, Pregnant Women in Spain (2009–2010) Marı´a Morales-Sua´rez-Varela • Fernando Gonza´lez-Candelas • Jenaro Astray • Jordi Alonso • Ady Castro • Rafael Canto´n • Juan Carlos Gala´n • Olatz Garin • Nu´ria Soldevila • Maretva Baricot • Jesu´s Castilla • Pere Godoy • Miguel Delgado-Rodrı´guez • Vicente Martı´n • Jose´ Marı´a Mayoral • Toma´s Pumarola • Jose´ Maria Quintana • Sonia Tamames • Agustı´n Llopis-Gonza´lez • ´ ngela Domı´nguez • the CIBERESP Cases and Controls in Pandemic Influenza Working Group, Spain A Ó Springer Science+Business Media New York 2013
Abstract The aim of this study was to investigate the main characteristics of non-vaccinated pregnant women who were hospitalised for influenza A (H1N1) pdm09 pandemic versus pregnant women hospitalised for noninfluenza-related reasons in Spain, and to characterise the clinical presentation of the disease in this population to facilitate early diagnosis and future action programmes. Understanding influenza infection during pregnancy is important as pregnant women are a high-risk population for increased morbidity from influenza infection. We investigated the socio-demographic and clinical features of 51 non-vaccinated, pregnant women infected with the pandemic influenza A (H1N1) virus in Spain (cases) and compared them to 114 controls (non-vaccinated and non-
infected pregnant women) aged 15–44 years. Substantial and significant odd ratios (ORs) for pandemic influenza A (H1N1) were found for the pregnant women who were obese compared with controls (body mass index [ 30) (OR 3.03; 95 % confidence intervals 1.13–8.11). The more prevalent symptoms observed in pandemic influenzainfected pregnant women were high temperature, cough (82.4 %), malaise (80.5 %), myalgia (56.1 %), and headaches (54.9 %). Our results suggest that the initial symptoms and risk factors for infection of pregnant women with the influenza A (H1N1) pdm09 virus are similar to the symptoms and risk factors for seasonal influenza, which make early diagnosis difficult, and reinforces the need to identify and protect high-risk groups.
M. Morales-Sua´rez-Varela (&) A. Llopis-Gonza´lez Unit of Public Health and Environmental Care, Department of Preventive Medicine, University of Valencia, Avda. Vicent Andre´s Estelle´s, s/n, 46100 Burjassot, Valencia, Spain e-mail: [email protected]
J. Alonso O. Garin Universitat Pompeu Fabra, Barcelona, Spain
M. Morales-Sua´rez-Varela F. Gonza´lez-Candelas J. Alonso R. Canto´n J. C. Gala´n O. Garin N. Soldevila M. Baricot J. Castilla P. Godoy M. Delgado-Rodrı´guez V. Martı´n ´ . Domı´nguez J. M. Quintana A. Llopis-Gonza´lez A CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain M. Morales-Sua´rez-Varela F. Gonza´lez-Candelas A. Llopis-Gonza´lez Center for Public Health Research (CSISP), Valencia, Spain F. Gonza´lez-Candelas Research Unit in ‘‘Genomics and Health’’, CSISP, University of Valencia, Burjassot, Spain J. Astray Subdireccio´n de Vigilancia, Comunidad de Madrid, Madrid, Spain
J. Alonso J. C. Gala´n IMIM-Institut de Recerca de l’Hospital del Mar, Barcelona, Spain A. Castro CIBER Enfermedades Respiratorias, Madrid, Spain R. Canto´n Hospital Universitario Ramo´n y Cajal, Madrid, Spain J. Castilla Instituto de Salud Pu´blica de Navarra, Pamplona, Spain P. Godoy Departament de Salut, Generalitat de Catalunya, Barcelona, Spain M. Delgado-Rodrı´guez Universidad de Jae´n, Jae´n, Spain
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Keywords Influenza A (H1N1) Pregnancy Pandemic Symptomatology Clinical characteristics
Introduction In March 2009, an outbreak of a novel influenza A (H1N1) pdm09 virus, now commonly referred to as the 2009 H1N1 pandemic influenza, was detected in Mexico and spread rapidly worldwide. The new virus spread so quickly that the World Health Organization (WHO) raised the pandemic level to category 6 in June 2009, which continued until August 2010 [1]. The WHO defined clinical advisory management guidelines to manage this pandemic, while European national authorities developed national programmes to face this situation, which included pregnant women [2–6]. Currently it is known that influenza A (H1N1) pdm09 infection can appear at different levels of severity as most pH1N1 infections have resulted in mild illness, similarly to seasonal influenza [7] in healthy persons, with a small proportion of more serious infection, severe illness, and even death. Most severe illnesses have been reported in persons with underlying medical conditions (diabetes, lung disease, cardiovascular disease and pregnancy) [8–10]. A high risk of influenza during pregnancy has been postulated. This increased risk can be related to the physiological changes of decreased pulmonary tidal volume and increased cardiac output. In addition, suppressed type 1 T-helper cell-mediated immunity impairs the maternal response to infection with several viruses, including influenza and smallpox [11]. To achieve successful term pregnancy, the mother’s immune system has to adapt to the developing embryo. This adaptation implies changes that can alter the mother’s susceptibility to some infections. For
V. Martı´n Universidad de Leo´n, Leo´n, Spain J. M. Mayoral Servicio de Vigilancia de Andalucı´a, Seville, Spain T. Pumarola Red Espan˜ola de Investigacio´n en Patologı´a Infecciosa (REIPI), Barcelona, Spain J. M. Quintana Fundacio´n Vasca de Innovacio´n e Investigacio´n Sanitarias, Sondika Bizkaia, Spain S. Tamames Direccio´n General de Salud Pu´blica, Desarrollo e Innovacio´n, Junta de Castilla y Leo´n, Valladolid, Spain ´ . Domı´nguez A Department of Public Health, University of Barcelona, Barcelona, Spain
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instance, it is known that pregnancy increases susceptibility to toxoplasmosis and lysteriosis, and that it also increases the severity of symptoms deriving from chickenpox and influenza infections [12]. This is supported by data from previous influenza epidemics and pandemics, which have shown that pregnant women present higher morbidity and mortality rates due to influenza infection than non-pregnant women [13–15]. The data collected between April 2009 and July 2009 from Australia and the USA suggest that pregnant women infected by the influenza A (H1N1) pdm09 virus were particularly vulnerable to morbidity and mortality [1, 16]. In the USA, a higher proportion of hospital admissions due to infection by the A (H1N1) pdm09 virus were observed for pregnant women than for the general population, and these women were also at higher risk of serious, or even deadly infection, by this virus [17, 18]. Furthermore, the health risks deriving from infection by a pandemic virus are even more relevant because these infections seemingly affect women of reproductive age more often and more severely than seasonal influenza epidemics [19]. Moreover, one major difference between the epidemiology of seasonal influenza and pH1N1 is the age distribution of influenza-related deaths. An estimated 90 % of deaths due to seasonal influenza complications occur in persons aged C65 years, with only 6 % occurring in persons aged 50–64 years, 3 % 5–49-year-olds, and \1 % in children of \5 years of age [20]. Yet during the pH1N1 pandemic, only 14 % of laboratory-confirmed influenza-related deaths occurred in persons C65 years of age, whereas 69 % were reported in adults aged 25–65 years [21], including pregnant women. As compared with non-pregnant individuals, pregnant women are approximately 4–5 times more likely to develop severe disease [22]. The mortality rate of influenza A (H1N1) pdm09 virus infections varies substantially in different geographical regions [23, 24]. Susceptibility to influenza A (H1N1) pdm09 infection may vary in different races, as Wenger et al. [34] showed because native people of Alaska and Asian/Pacific Islanders were 2–4 times more likely to be infected by the (H1N1) pdm09 virus and hospitalised than white Caucasians. For these reasons, pregnant women should be considered a population for whom special prevention and treatment considerations for A (H1N1) pdm09 are necessary. Very little is known about the characteristics of women with influenza A (H1N1) pdm09 and the factors affecting the recovery of infected patients in Spain. The aim of this study was to investigate the main characteristics of non-vaccinated pregnant women who were hospitalised for influenza A (H1N1) pdm09 pandemic versus the pregnant women hospitalised for non-influenzarelated reasons in Spain, and to also study the clinical features present in infected women for early diagnosis and future action programmes.
Matern Child Health J
Materials and Methods This comparative study forms part of a multi-centre case– control study of influenza A (H1N1) pdm09 carried out in seven Spanish Autonomous Communities (Catalonia, Andalusia, Madrid, the Basque Country, the Valencian Community, Castile-Leo´n, and Navarre) using a common protocol whose objective was to determine the impact of influenza A (H1N1) on the Spanish population [25].
undertaken, along with the corresponding medical records from hospital databases: age, sex, country of birth, relevant medical conditions (pneumonia in the last 2 years, chronic obstructive pulmonary disease, asthma, other respiratory illness, chronic cardiovascular disease, arterial hypertension, cardiac insufficiency, nervous system, renal failure/ nephritic syndrome, AIDS/HIV). The behavioural variables were ethnicity, level of education and smoking habit. The same variables were obtained from the uninfected controls, except the variables directly relating to the disease.
Recruitment of Cases and Controls Statistical Analysis This is a case–control study carried out in 28 hospitals in seven Spanish Autonomous Communities between 1 November 2009 and 30 June 2010 [25]. Of an initial study population of 813 persons hospitalised with laboratoryconfirmed influenza A (H1N1) pdm09 infection and 2,972 persons attending the same hospitals, but without influenza-like illness, non-vaccinated pregnant women were selected. Fifty-one pregnant women with influenza aged between 15 and 44 years and 114 pregnant women without influenza aged 15–44 years were recruited for this study. A case was defined as a patient with a new diagnosis of influenza-like illness with clinical manifestations and a laboratory-confirmed influenza A (H1N1) pdm09 virus as assessed by a reverse transcriptase polymerase chain reaction (RT-PCR) assay [26], who were hospitalised for more than 24 h following the medical criteria for their illness. The patients with likely nosocomial infection (determined by onset of symptoms at 48 h post-hospitalisation) were excluded. Potential control individuals were excluded if the main reason for hospitalisation was respiratory illness. Informed consent was obtained from all the subjects prior to enrollment. The project was approved by the Ethics Committees of the participating hospitals. Further details of the study design have been provided elsewhere [25]. All the pregnant women, who were either cases or controls in the general study, were included in the present substudy. We specifically compared the pregnant women with influenza A (H1N1) pdm09 infection (cases) with the pregnant women without influenza who had been recruited from the same hospitals (controls). Women who had been vaccinated for pandemic influenza A (H1N1) pdm09 were excluded from the present study. Data Collection A face-to-face epidemiological enquiry was conducted, which was designed specifically for the multi-centre case– control study of influenza A (H1N1) pdm09 using a standardised protocol [25]. For the cases, the following variables were obtained from the personal interviews
Firstly, the characteristics between pregnant women with and without influenza A (H1N1) pdm09 were compared using the Chi square, Fisher’s exact and Student’s t test tests according to the nature of the variables. Subsequently, a logistic regression analysis was done to estimate the crude (cOR) and adjusted odds ratios (aOR) with 95 % confidence intervals (95 % CI) by taking into account any possible confounding variables (Wald’s test). Specifically, pre-pregnancy body mass index (BMI) was adjusted. The analyses were done with the SPSS software (version 17.0; Inc, Chicago III).
Results The most relevant demographic characteristics of these pregnant women are summarised in Table 1, which compares the cases with and the controls without influenza A (H1N1) pdm09, and the corresponding ORs. Cases and controls did not differ in terms of age, pregnancy trimester, level of education, smoking habit, alcohol consumption (categorised: usual alcohol consumption or non-usual alcohol consumption) and diabetes status. However, obesity (BMI C 30) was identified as a statistically significant risk factor for influenza infection in pregnant women (OR 3.03; 95 % CI 1.13–8.11). Higher, yet still non-significant, ORs were observed for Latin American pregnant women (aOR 3.71; 95 % CI 1.00–14.04). The clinical characteristics of the cases with and the controls without infection, and the ORs describing the associations between these clinical characteristics and influenza infection in pregnant women, are summarised in Table 2. Cases and controls did not differ in terms of their medical histories of any comorbidities studied (pneumonia in the last 2 years, chronic obstructive pulmonary disease, asthma, other respiratory illness, chronic cardiovascular disease, arterial hypertension, cardiac insufficiency, nervous system, renal failure, nephritic syndrome, AIDS and HIV). Table 3 reveals that the most prevalent symptoms in the influenza-infected pregnant women were temperature
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Matern Child Health J Table 1 Demographic characteristics of cases with and controls without influenza A (H1N1) 2009, and the crude and adjusted ORs describing the associations between these characteristics and influenza infection in pregnant, non-vaccinated women in Spain Demographic characteristics
Cases (N = 51) %
Controls (N = 114) %
Age (Mean ± SD)
32.64 ± 10.92
31.59 ± 7.50
\20 years
27.5
5.3
20–29 years 30–34 years
5.9 37.3
[34 years
p value
Crude OR (95 % CI)
Adjusted ORa (95 % CI)
p value 0.474b
0.600
1 (Ref.)
1 (Ref.)
29.8 21.9
0.82 (0.18–3.76) 1.28 (0.28–5.86)
1.27 (0.13–12.87) 2.29 (0.23–23.36)
29.4
43.0
0.73 (0.16–3.25)
1.35 (0.14–13.21)
Trimester 1
8.5
13.6
1 (Ref.)
1 (Ref.)
Trimester 2
19.1
34.0
1.00 (0.27–3.72)
0.94 (0.22–4.02)
Trimester 3
72.3
52.4
2.14 (0.65–7.05)
1.92 (0.54–6.63)
74.5
86.6
1 (Ref.)
1 (Ref.)
0.648c
Pregnancy 0.123
0.308c
Ethnicity Caucasian Romanian
0.069
0.053c
0
1.8
–
–
15.7
3.6
5.10 (1.45–17.05)
3.71 (1.00–14.04)
Arabian-N African
3.9
2.7
1.70 (0.27–10.58)
0.92 (0.09–9.26)
Others
5.9
5.4
1.27 (0.30–5.36)
0.37 (0.04–3.32)
Secondary/higher
90.2
92.1
1 (Ref.)
1 (Ref.)
No studies/primary Smoking habit
9.8
7.9
1.49 (0.86–2.57)
1.36 (0.70–2.63)
Non-smoker
64.7
69.9
1 (Ref.)
1 (Ref.)
Smoker
21.6
16.6
1.28 (0.47–3.52)
2.08 (0.66–6.53)
Ex-smoker
13.7
11.5
1.03 (0.32–3.32)
1.39 (0.34–5.76)
Alcoholism
2
0.9
0.546
2.31 (0.14–37.62)
2.00 (0.10–39.22)
0.452c
23.3
9.1
0.023
3.03 (1.13–8.11)
3.03 (1.13–8.11)
0.024c
3.9
3.5
0.896
1.12 (0.20–6.33)
0.83 (0.13–5.23)
0.846c
Latin American
Level of education 0.689
0.802
0.364c
0.210c
Obesity BMI C 30 kg/m2 Diabetes a
Adjusted for obesity
b
Student’s test
c
Chi square test
(mean 38.34 °C), cough (82.4 %), malaise (80.5 %), myalgia (56.1 %), and headaches (54.9 %).
Discussion Summary of the Main Findings The results obtained in the present study indicate a higher risk of the influenza A (H1N1) pdm09 disease in nonvaccinated pregnant women who are obese, and they also suggest an increased risk for subjects with obesity and for Latin American women living in Spain. No statistically significant differences for other characteristics features were observed, although a higher proportion of infection was noted for young pregnant women in pregnancy trimester 3, with a lower level of education and a higher
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incidence of toxic habits (alcohol consumption and smoking habit) than non-infected women. The most frequent symptoms of influenza A (H1N1) pdm09 infection in pregnant women included a high temperature, cough, malaise, headache and myalgia, similarly to seasonal influenza, which can be differentiated by complementary microbiological tests. Interpretation of the Results in Relation to Previous Findings Our results support similar findings reported in previous studies, which reinforces the role of obesity as a risk factor for influenza A (H1N1) pdm09 in Spain. For instance, Van Kerkhove et al. [27–29] found that morbid obesity was a risk factor for ICU admission in patients with influenza A (H1N1) pdm09. Although the comparison made of average
Matern Child Health J Table 2 Clinical characteristics of cases with and controls without influenza A (H1N1) pdm09 infection, and the ORs describing their associations with influenza infection in non-vaccinated pregnant women in Spain Controls (N = 114) %
p valuea
Crude OR (95 % CI)
4.9
2.6
0.485
1.89 (0.31–11.78)
COPD
3.9
0
0.034
–
Asthma
11.8
9.7
0.693
1.23 (0.43–3.55)
Clinical characteristics Pneumonia last 2 years
Cases (N = 51) %
Other respiratory illness
6.3
0
0.009
–
Chronic cardiovascular disease
2.0
0.9
0.561
2.24 (0.14–36.53)
Arterial hypertension
2.0
6.1
0.257
0.31 (0.04–2.60)
Cardiac insufficiency Neurological diseases
2.0 2.0
0.9 0.9
0.557 0.557
0.31 (0.04–2.60) 2.26 (0.14–36.86)
Renal failure/nephritic syndrome
2.0
0.9
0.557
2.26 (0.14–37.29)
AIDS/HIV infection
2.0
0.9
0.551
2.28 (0.14–37.29)
a
Wald’s test
Table 3 Prevalence of symptoms in cases of influenza A (H1N1) pdm09 virus infection in pregnant women in Spain Symptoms
Cases (N = 51) %
Temperature (°C) (Mean ± SD)
38.34 ± 0.70
Cough
82.4
Malaise
80.5
Myalgia
56.1
Headaches
54.9
Respiratory distress
40.8
Rhinorrhea Odynophagia
39.0 38.5
Vomiting
17.1
Hypoxaemia
12.5
Diarrhea
7.3
Renal failure/nephritic syndrome
3.9
Consciousness alteration
2.4
Seizures
2.0
ages between pregnant women with and without pandemic influenza infection showed no statistically significant differences (Table 1), 27.5 % of infected pregnant women were younger than 20 years, whereas only 5.3 % of noninfected pregnant women fell in this age group. This result agrees with other analyses in which a higher risk for pandemic influenza virus was found [21, 30]. Basically, we found an increased risk of influenza A (H1N1) pdm09 virus during the third pregnancy trimester as compared to the first pregnancy trimester, although this risk was not statistically significant (probably due to the limited number of cases analysed). This result agrees with previous analyses [31] which reported an OR of 1.2 (95 % CI 1.1–1.4) in pregnancy trimester 3. Our results also reveal that pregnant Latin American women are at an almost fourfold higher risk of being
hospitalised for the influenza A (H1N1) pdm09 virus, suggesting that this influenza virus follows an ethnic pattern. Ethnic-dependent susceptibility to viral infection in the current pandemic has been discussed in previous research works undertaken in Turkey, New Zealand [32, 33], and people who are native from Alaska are more likely to be hospitalised native people [34]. The results presented herein also agree with the higher mortality described in South America [23]. To date, no explanation for these differences has been provided. One possible explanation for the low mortality rate recorded in China during the 2009 pandemic of influenza A (H1N1) pdm09 virus may be different ethnic susceptibility rather than strict strategies adopted to prevent infections [35]. Consequently, increased medical surveillance of this ethnic group, by means of centralised prevention and treatment efforts, might be advisable. An alternative hypothesis is that past contacts with similar viral strains might explain the greater resistance observed in the European population than in others, like more isolated populations in South America [23, 36] or Asia [35]. Previous AIDS or HIV infection, pathologies affecting the nervous and renal systems, chronic cardiovascular disease and pneumonia in the last 2 years are the main clinical characteristics associated factors to develop influenza A (H1N1) pdm09 infection in pregnant women. These results agree with previous findings [31, 37] obtained for increased risk of influenza A (H1N1) pdm09 infection in pregnant women with some of these comorbidities. The most relevant symptoms found in pregnant women infected with the influenza A (H1N1) pdm09 virus include a high temperature, malaise, myalgia, cough and headache. These symptoms coincide with the typical symptoms of seasonal influenza in pregnant women, and it is not possible to clearly differentiate them. Our findings also suggest the importance of preventive measures, including immunity, which is also likely to benefit offspring [30].
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Strengths and Limitations This study compares pregnant women with and without the influenza A (H1N1) pdm09 virus. Most studies published on the influenza A (H1N1) pdm09 virus have compared pregnant and non-pregnant women [1, 16, 38], which means that this study is more specific. In addition, only non-vaccinated women were included in the analysis to prevent a confusion bias resulting from the protective effects of the vaccine. We acknowledge several limitations in the present study, such as limited statistical power. We attempted to limit the information bias by following a stringent, standardised protocol and by training the interviewers. We believe that the case selection criteria have not changed with time, which limits the validity of the study because laboratory confirmations of infection by the pandemic strain of the influenza virus under study are always required. In order to minimise the confusion bias, we reviewed the most relevant literature and all the variables that can reasonably influence the results which, whenever necessary, were controlled in the logistic regression analysis. Furthermore, we believe that the study sample is representative of the target population because no participants differed in terms of urban/rural location or socioeconomic status, and all the cases and controls were recruited according to the same criteria. In conclusion, our study reveals a higher risk for influenza A (H1N1) pdm09 virus infection in pregnant, nonvaccinated women who are obese and Latin American. Specific efforts should be made to ensure that the risks of influenza during pregnancy are communicated to these women and to their healthcare providers in order to ensure that they can benefit from health care and influenza immunity. Acknowledgments This project has been supported by Instituto de Salud Carlos III (Project GR09/0030). We thank all the physicians and interviewers in the participating hospitals for their collaboration. Finally, we are grateful to all the pregnant women who participated in this study.
Appendix The members of the CIBERESP Cases and Controls in the Pandemic Influenza Working Group are: Andalusia: E. Azor, J. Carrillo, R. Moyano, J.A. Navarro, M. Va´zquez, F. Zafra (Red de Me´dicos Centinela, Andalucı´a), M.A. Bueno, M.L. Go´mez, M. Mariscal, B. Martı´nez, J.P. Quesada, M. Sillero (Complejo Hospitalario de Jae´n), M. Carnero, J. Ferna´ndez-Crehuet, J. del Diego Salas (Hospital Virgen de la Victoria), M. Delgado Rodrı´guez (CIBERESP, Universidad de Jae´n), V. Fuentes (Hospital Costa
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del Sol), V. Gallardo, E. Pe´rez (Servicio de Epidemiologı´a, Junta de Andalucı´a), R. Lo´pez (Hospital Infanta Elena, Huelva), J.R. Maldonado (Hospital de Torreca´rdenas), J.M. ´ . Morillo Mayoral (Servicio de Vigilancia de Andalucı´a), A ´ (Hospital Virgen del Rocıo), J.M. Navarro, M. Pe´rez (Laboratorio de Referencia de Gripe), S. On˜a (Hospital Carlos Haya), M.J. Pe´rez (Hospital Virgen de Valme), M.C. Ubago (Hospital Virgen de las Nieves), M. Zarzuela (Hospital Puerta del Mar). Valencian Community: J. Blanquer (Hospital Clı´nico Universitario, Valencia), F. Gonza´lez Candelas (CIBERESP, CSISP-Universitat de Valencia), M. Morales (CIBERESP, CSISP-Universitat de Valencia, Hospital Doctor Peset). Castilla y Leon: D. Carriedo, F. Dı´ez, I. Ferna´ndez, S. Ferna´ndez, M.P. Sanz (Complejo Asistencial Universitario de Leo´n), J.J. Castrodeza, A. Pe´rez, S. Tamames (Direccio´n General de Salud Pu´blica, Desarrollo e Innovacio´n, Junta de Castilla y Leo´n), V. Martı´n (CIBERESP, Universidad de Leo´n), A. Molina (Instituto de Biomedicina, Universidad de Leo´n), J. Ortiz de Saracho (Hospital del Bierzo), R. Ortiz de Lejarazu (Centro Nacional de Gripe, Valladolid), A. Pueyo, J.L. Viejo (Complejo Asistencial, Burgos), P. Redondo (Servicio Territorial de Sanidad y Bienestar Social, Leo´n). Catalonia: A. Agustı´, A. Torres, A. Trilla, A. Vilella (Hospital Clı´nic de Barcelona), J. Alonso (CIBERESP, Universitat Pompeu Fabra, IMIM-Instituto Recerca Hospital del Mar), F. Barbe´ (Hospital Arnau de Vilanova), M. Baricot, N. Soldevila (CIBERESP), L. Blanch, G. Navarro (Hospital de Sabadell), X. Bonfill, J. Lo´pez-Contreras, V. Pomar, M.T. Puig (Hospital de Sant Pau), E. Borra`s, A. Martı´nez, Nu´ria Torner (Direccio´n General de Salud Pu´blica, Generalitat de Catalunya), C. Bravo, F. Moraga (Hospital Vall d’Hebro´n), F. Calafell, O. Garı´n (Universitat Pompeu Fabra), J. Cayla`, C. Tortajada (Agencia de Salud ` . Domı´nguez (CIBERESP, UniPu´blica de Barcelona), A versitat de Barcelona), I. Garcia, J. Ruiz (Hospital Germans Trias i Pujol), J.J. Garcia (Hospital Sant Joan de Deu), (Universitat Pompeu Fabra), J. Gea, J.P. Horcajada (Hospital del Mar), P. Godoy (CIBERESP, Departament de Salut Generalitat de Catalunya), N. Hayes (Hospital Clı´nicCRESIB), T. Pumarola (REIPI, Universitat de Barcelona), A. Rosell (Hospital de Bellvitge), M. Sa´ez (CIBERESP, ´ lvarez, M. Enrı´Universitat de Girona). Madrid: Carlos A quez, F. Pozo (Hospital 12 de Octubre), J. Astray (Subdireccio´n de Vigilancia, Comunidad de Madrid), F. Baquero, R. Canto´n, J. C. Gala´n (CIBERESP, Hospital Ramo´n y Cajal), A. Robustillo, M.A. Valdeo´n (Hospital Universitario Ramo´n y Cajal), E. Co´rdoba, F. Domı´nguez, J. Garcı´a, R. Ge´nova, E. Gil, S. Jime´nez, M.A. Lopaz, J. Lo´pez, F. Martı´n, M.L. Martı´nez, M. Ordoba´s, E. Rodrı´guez, S. ´ rea de Epidemiologı´a de la CoSa´nchez, C. Valde´s (A munidad de Madrid), J.R. Pan˜o, M. Romero (Hospital Universitario La Paz),. Navarre: J. Castilla (CIBERESP,
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Instituto de Salud Pu´blica de Navarra), P. Fanlo, F. Gil, V. Martı´nez Artola, M. Ruiz (Complejo Hospitalario de Navarra), J. Gamboa, F. Pe´rez-Afonso M. Sota, M.E. Ursua, M.T.Virto (Red de Me´dicos Centinela, Navarra), A. Martinez, L. Martı´nez (Instituto de Salud Pu´blica, Navarra). Basque Country: U. Aguirre, A. Caspelastegui, P.P. Espan˜a, S. Garcı´a (Hospital Galdakao), J. Alustizac (Hospital Mendaro), J.M. Anton˜ana, I. Astigarraga, J.I. Pijoan, I. Pocheville, M. Santiago, J.I. Villate (Hospital de Cruces), J. Arı´stegui, A. Escobar, M.I. Garrote (Hospital Basurto), A. Bilbao, C. Garaizar (Fundacio´n Vasca de Innovacio´n e Investigacio´n Sanitarias), G. Cilla, J. Korta, E. Pe´rez Trallero, C. Sarasqueta (Hospital Donostia), F. Esteban, J.L. Lobo, C. Salado, E. Tato (Hospital Txagorritxu), J.M. Quintana (CIBERESP, Fundacio´n Vasca de Innovacio´n e Investigacio´n Sanitarias).
References 1. Jamieson, D. J., Honein, M. A., Rasmussen, S. A., Williams, J. L., Swerdlow, D. L., Biggerstaff, M. S., et al. (2009). H1N1 2009 influenza virus infection during pregnancy in the USA. The Lancet, 374, 451–458. 2. Mak, T. K., Mangtani, P., Leese, J., Watson, J. M., & Pfeifer, D. (2008). Influenza vaccination in pregnancy: Current evidence and selected national policies. The Lancet Infecioust Diseases, 8(1), 44–52. 3. Satpathy, H. K., & Kawwass, J. F. (2009). Novel H1N1 virus infection and pregnancy. Postgraduate Medicine, 121(6), 106–112. 4. Makele, M. J., Puhakka, T., Ruuskanen, O., Leinonen, M., Saikku, P., Kimpima¨ki, M., et al. (1998). Viruses and bacteria in the etiology of common cold. Journal of Clinical Microbiology, 36(2), 539–542. 5. Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team. (2009). Emergence of a novel swine-origin influenza A (H1N1) virus in humans. The New England Journal of Medicine, 360, 2605–2615. 6. Zarocostas, J. (2009). Worl Health Organization declares A (H1N1) influenza pandemic. The British Medical Journal, 338, b2425. 7. Cauchmez, S., Donnelly, C. A., Reed, C., Ghani, A. C., Fraser, C., Kent, C. K., et al. (2009). Household transmission of 2009 pandemic influenza A (H1N1) virus in the United States. The New England Journal of Medicine, 361(27), 2619–2627. 8. Jain, S., Kamimoto, L., Bramley, A. M., Schmitz, A. M., Benoit, S. R., Louie, J., et al. (2009). Hospitalized patients with 2009 H1N1 influenza in the United States, April—June 2009. The New England Journal of Medicine, 361, 1935–1944. 9. Centers for Disease Control and Prevention. (2009). Novel influenza A (N1H1) virus infections in three pregnant women— United States. Morbidity and Mortality Weekly Report, 58, 497–500. 10. Centers for Disease Control and Prevention. (2009). Hospitalized patients with novel influenza A (H1N1) virus infection—California. Morbidity and Mortality Weekly Report, 58, 536–541. 11. Schlaudecker, E. P., & Steinhoff, M. C. (2010). Helping mothers prevent influenza illness in their infants. Pediatrics, 126(5), 1008–1011.
12. Jamieson, D. J., Theiler, R. N., & Rasmussen, S. A. (2006). Emerging infections and pregnancy. Emerging Infectious Diseases, 12, 1638–1643. 13. Freeman, D. W., & Barno, A. (1959). Deaths from Asian influenza associated with pregnancy. American Journal of Obstetrics and Gynecology, 78, 1172–1175. 14. Harris, J. W. (1919). Influenza occurring in pregnant women. Journal of the American Medical Association, 72, 978–980. 15. Nuzum, J. W., Pilot, I., Stangl, F. H., & Bonar, B. E. (1976). 1918 pandemic influenza and pneumonia in a large civil hospital. Illinois Medical Journal, 150, 612–616. 16. Hewagama, S., Walker, S. P., Stuart, R. L., Gordon, C., Johnson, P. D., Friedman, N. D., et al. (2010). 2009 H1N1 influenza A and pregnancy outcomes in Victoria, Australia. Clinical Infectious Diseases, 50, 686–690. 17. Hanslik, T., Boelle, P., & Flahault, A. (2010). Preliminary estimation of risk factors for admission to intensive care units and for death in patients infected with A (H1N1) 2009 influenza virus, France, 2009–2010. PLoS Currents, RRN1150. doi:10.1371/ currents.RRN1150. 18. Vaillant, L., La Ruche, G., Tarantola, A., & Barboza, P. (2009). Epidemiology of fatal cases associated with pandemic H1N1 influenza 2009. Euro Surveilancel, 14(33), 19309. 19. World Health Organization (WHO). Available at: http://www. who.int/mediacentre/news/notes/2010/sage_20100528/es/. 20. Thompson, W. W., Shay, D. K., Weintraub, E., Brammer, L., Cox, N., Anderson, L. J., et al. (2003). Mortality associated with influenza viruses and respiratory syncytial virus in the United States. JAMA, 289(2), 170–186. 21. Fowlkes, A. L., Arguin, P., Biggerstaff, M. S., Gindler, J., Blau, D., Jain, S., et al. (2011). Epidemiology of 2009 pandemic influenza A (H1N1) deaths in the United States, April–July 2009. Clinical Infectious Diseases, 52, S60–S68. 22. World Health Organization. (2009). Transmission dynamics and impact of pandemic influenza A (H1N1) 2009 virus. Weekly Epidemiological Record, 84, 481–484. 23. Chowell, G., Viboud, C., Munayco, C. V., Go´mez, J., Simonsen, L., Miller, M. A., et al. (2011). Spatial and temporal characteristics of the 2009 A/H1N1 influenza pandemic in Peru. PLoS ONE, 6(6), e21287. 24. Khandaker, G., Dierig, A., Rashid, H., King, C., Heron, L., & Booy, R. (2011). Systematic review of clinical and epidemiological features of the pandemic influenza A (H1N1) 2009. Influenza and Other Respiratory Viruses, 5, 148–156. 25. Domı´nguez, A., Alonso, J., Astray, J., Baricot, M., Canto´n, R., Castilla, J., et al. (2011). Factores de riesgo de hospitalizacio´n por gripe A (H1N1)2009 y efectividad de intervenciones farmacolo´gicas y no farmacolo´gicas en su prevencio´n. Estudio de casos y controles. Revista Espan˜ola de Salud Pu´blica, 85, 3–15. 26. Poon, L. M., Chan, K. H., Smith, G. J., Leung, C. S., Guan, Y., Yuen, K. Y., et al. (2009). Molecular detection of a novel human influenza (H1N1) of pandemic potential by conventional and real-time quantitative RT-PCR assays. Clinical Chemistry, 55, 1555–1558. 27. Van Kerkhove, M. D., Vandemaele, K. A., Shinde, V., JaramilloGutierrez, G., Koukounari, A., Donnelly, C. A., et al. (2011). Risk factors for severe outcomes following 2009 influenza A (H1N1) infection: A global pooled analysis. PLoS Medicine, 8(7), e1001053. 28. Maravı´-Poma, E., Martin-Loeches, I., Regidor, E., Laplaza, C., Cambra, K., Aldunate, S., et al. (2011). Severe 2009 H1N1 influenza in pregnant women in Spain. Criticat Care Medicine, 39, 5. 29. Morgan, O. W., Bramley, A., Fowlkes, A., Freedman, D. S., Taylor, T. H., Gargiullo, P., et al. (2010). Morbid obesity as a risk factor for hospitalization and death due to 2009 pandemic influenza A (H1N1) disease. PLoS ONE, 5(3), e9694.
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Matern Child Health J 30. Zaman, K., Roy, E., Arifeen, S. E., Rahman, M., Raqib, R., Wilson, E., et al. (2008). Effectiveness of maternal influenza immunization in mothers and infants. The New England Journal of Medicine, 359, 1555–1564. 31. Dodds, L., McNeil, S. A., Fell, D. B., Allen, V. M., Coombs, A., Scott, J., et al. (2007). Impact of influenza exposure on rates of hospital admissions and physician visits because of respiratory illness among pregnant women. Canadian Medical Association Journal, 176(4), 463–468. 32. Ozyer, S., Unlu¨, S., Celen, S., Uzunlar, O., Saygan, S., Su, F. A., et al. (2011). Pandemic influenza H1N1 2009 virus infection in pregnancy in Turkey. Taiwan Journal of Obstetrics and Gynecology, 170(3), 333–338. 33. Baker, M. G., Wilson, N., Huang, Q. S., Paine, S., Lopez, L., Bandaranayake, D., et al. (2009). Pandemic influenza A (H1N1)v in New Zealand: The experience from April to August 2009. Euro Surveillance, 14, 34. 34. Wenger, J. D., Castrodale, L. J., Bruden, D. L., Keck, J. W., Zulz, T., Bruce, M. G., et al. (2011). Pandemic influenza A H1N1 in Alaska: Temporal and geographic characteristics of spread and increased risk of hospitalization among Alaska Native and Asian/
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Pacific Islander people. The Journal of Infectious Diseases, 203, 828–837. Chen, C. L., Xiao, L., Wang, Q. L., Zhang, J., & Li, K. (2010). Ethnic differences in susceptibilities to A (H1N1) flu: an epidemic parameter indicating a weak viral virulence. African Journal of Biotechnology, 9, 589–592. Archer, B., Cohen, C., Naidoo, D., Thomas, J., Makunga, C., Blumberg, L., et al. (2009). Interim report on pandemic H1N1 influenza virus infections in South Africa, April to October 2009: Epidemiology and factors associated with fatal cases. Euro Surveillance, 14(42), 19369. Liu, Y., Wang, W., Li, X., Luo, Y., Wu, L., et al. (2011). Geographic distribution and risk factors of the initial adult hospitalized cases of 2009 pandemic influenza A (H1N1) virus infection in Mainland China. PLoS ONE, 6(10), e25934. Yates, L., Pierce, M., Stephens, S., Mill, A. C., Spark, P., Kurinczuk, J. J., et al. (2010). Influenza A/H1N1v in pregnancy: an investigation of the characteristics and management of affected women and the relationship to pregnancy outcomes for mother and infant. Health Technology Assessment, 14(34), 109–182.
Pandemic Influenza A (H1N1) in Non-vaccinated, Pregnant Women in Spain (2009–2010) Marı´a Morales-Sua´rez-Varela • Fernando Gonza´lez-Candelas • Jenaro Astray • Jordi Alonso • Ady Castro • Rafael Canto´n • Juan Carlos Gala´n • Olatz Garin • Nu´ria Soldevila • Maretva Baricot • Jesu´s Castilla • Pere Godoy • Miguel Delgado-Rodrı´guez • Vicente Martı´n • Jose´ Marı´a Mayoral • Toma´s Pumarola • Jose´ Maria Quintana • Sonia Tamames • Agustı´n Llopis-Gonza´lez • ´ ngela Domı´nguez • the CIBERESP Cases and Controls in Pandemic Influenza Working Group, Spain A Ó Springer Science+Business Media New York 2013
Abstract The aim of this study was to investigate the main characteristics of non-vaccinated pregnant women who were hospitalised for influenza A (H1N1) pdm09 pandemic versus pregnant women hospitalised for noninfluenza-related reasons in Spain, and to characterise the clinical presentation of the disease in this population to facilitate early diagnosis and future action programmes. Understanding influenza infection during pregnancy is important as pregnant women are a high-risk population for increased morbidity from influenza infection. We investigated the socio-demographic and clinical features of 51 non-vaccinated, pregnant women infected with the pandemic influenza A (H1N1) virus in Spain (cases) and compared them to 114 controls (non-vaccinated and non-
infected pregnant women) aged 15–44 years. Substantial and significant odd ratios (ORs) for pandemic influenza A (H1N1) were found for the pregnant women who were obese compared with controls (body mass index [ 30) (OR 3.03; 95 % confidence intervals 1.13–8.11). The more prevalent symptoms observed in pandemic influenzainfected pregnant women were high temperature, cough (82.4 %), malaise (80.5 %), myalgia (56.1 %), and headaches (54.9 %). Our results suggest that the initial symptoms and risk factors for infection of pregnant women with the influenza A (H1N1) pdm09 virus are similar to the symptoms and risk factors for seasonal influenza, which make early diagnosis difficult, and reinforces the need to identify and protect high-risk groups.
M. Morales-Sua´rez-Varela (&) A. Llopis-Gonza´lez Unit of Public Health and Environmental Care, Department of Preventive Medicine, University of Valencia, Avda. Vicent Andre´s Estelle´s, s/n, 46100 Burjassot, Valencia, Spain e-mail: [email protected]
J. Alonso O. Garin Universitat Pompeu Fabra, Barcelona, Spain
M. Morales-Sua´rez-Varela F. Gonza´lez-Candelas J. Alonso R. Canto´n J. C. Gala´n O. Garin N. Soldevila M. Baricot J. Castilla P. Godoy M. Delgado-Rodrı´guez V. Martı´n ´ . Domı´nguez J. M. Quintana A. Llopis-Gonza´lez A CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain M. Morales-Sua´rez-Varela F. Gonza´lez-Candelas A. Llopis-Gonza´lez Center for Public Health Research (CSISP), Valencia, Spain F. Gonza´lez-Candelas Research Unit in ‘‘Genomics and Health’’, CSISP, University of Valencia, Burjassot, Spain J. Astray Subdireccio´n de Vigilancia, Comunidad de Madrid, Madrid, Spain
J. Alonso J. C. Gala´n IMIM-Institut de Recerca de l’Hospital del Mar, Barcelona, Spain A. Castro CIBER Enfermedades Respiratorias, Madrid, Spain R. Canto´n Hospital Universitario Ramo´n y Cajal, Madrid, Spain J. Castilla Instituto de Salud Pu´blica de Navarra, Pamplona, Spain P. Godoy Departament de Salut, Generalitat de Catalunya, Barcelona, Spain M. Delgado-Rodrı´guez Universidad de Jae´n, Jae´n, Spain
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Matern Child Health J
Keywords Influenza A (H1N1) Pregnancy Pandemic Symptomatology Clinical characteristics
Introduction In March 2009, an outbreak of a novel influenza A (H1N1) pdm09 virus, now commonly referred to as the 2009 H1N1 pandemic influenza, was detected in Mexico and spread rapidly worldwide. The new virus spread so quickly that the World Health Organization (WHO) raised the pandemic level to category 6 in June 2009, which continued until August 2010 [1]. The WHO defined clinical advisory management guidelines to manage this pandemic, while European national authorities developed national programmes to face this situation, which included pregnant women [2–6]. Currently it is known that influenza A (H1N1) pdm09 infection can appear at different levels of severity as most pH1N1 infections have resulted in mild illness, similarly to seasonal influenza [7] in healthy persons, with a small proportion of more serious infection, severe illness, and even death. Most severe illnesses have been reported in persons with underlying medical conditions (diabetes, lung disease, cardiovascular disease and pregnancy) [8–10]. A high risk of influenza during pregnancy has been postulated. This increased risk can be related to the physiological changes of decreased pulmonary tidal volume and increased cardiac output. In addition, suppressed type 1 T-helper cell-mediated immunity impairs the maternal response to infection with several viruses, including influenza and smallpox [11]. To achieve successful term pregnancy, the mother’s immune system has to adapt to the developing embryo. This adaptation implies changes that can alter the mother’s susceptibility to some infections. For
V. Martı´n Universidad de Leo´n, Leo´n, Spain J. M. Mayoral Servicio de Vigilancia de Andalucı´a, Seville, Spain T. Pumarola Red Espan˜ola de Investigacio´n en Patologı´a Infecciosa (REIPI), Barcelona, Spain J. M. Quintana Fundacio´n Vasca de Innovacio´n e Investigacio´n Sanitarias, Sondika Bizkaia, Spain S. Tamames Direccio´n General de Salud Pu´blica, Desarrollo e Innovacio´n, Junta de Castilla y Leo´n, Valladolid, Spain ´ . Domı´nguez A Department of Public Health, University of Barcelona, Barcelona, Spain
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instance, it is known that pregnancy increases susceptibility to toxoplasmosis and lysteriosis, and that it also increases the severity of symptoms deriving from chickenpox and influenza infections [12]. This is supported by data from previous influenza epidemics and pandemics, which have shown that pregnant women present higher morbidity and mortality rates due to influenza infection than non-pregnant women [13–15]. The data collected between April 2009 and July 2009 from Australia and the USA suggest that pregnant women infected by the influenza A (H1N1) pdm09 virus were particularly vulnerable to morbidity and mortality [1, 16]. In the USA, a higher proportion of hospital admissions due to infection by the A (H1N1) pdm09 virus were observed for pregnant women than for the general population, and these women were also at higher risk of serious, or even deadly infection, by this virus [17, 18]. Furthermore, the health risks deriving from infection by a pandemic virus are even more relevant because these infections seemingly affect women of reproductive age more often and more severely than seasonal influenza epidemics [19]. Moreover, one major difference between the epidemiology of seasonal influenza and pH1N1 is the age distribution of influenza-related deaths. An estimated 90 % of deaths due to seasonal influenza complications occur in persons aged C65 years, with only 6 % occurring in persons aged 50–64 years, 3 % 5–49-year-olds, and \1 % in children of \5 years of age [20]. Yet during the pH1N1 pandemic, only 14 % of laboratory-confirmed influenza-related deaths occurred in persons C65 years of age, whereas 69 % were reported in adults aged 25–65 years [21], including pregnant women. As compared with non-pregnant individuals, pregnant women are approximately 4–5 times more likely to develop severe disease [22]. The mortality rate of influenza A (H1N1) pdm09 virus infections varies substantially in different geographical regions [23, 24]. Susceptibility to influenza A (H1N1) pdm09 infection may vary in different races, as Wenger et al. [34] showed because native people of Alaska and Asian/Pacific Islanders were 2–4 times more likely to be infected by the (H1N1) pdm09 virus and hospitalised than white Caucasians. For these reasons, pregnant women should be considered a population for whom special prevention and treatment considerations for A (H1N1) pdm09 are necessary. Very little is known about the characteristics of women with influenza A (H1N1) pdm09 and the factors affecting the recovery of infected patients in Spain. The aim of this study was to investigate the main characteristics of non-vaccinated pregnant women who were hospitalised for influenza A (H1N1) pdm09 pandemic versus the pregnant women hospitalised for non-influenzarelated reasons in Spain, and to also study the clinical features present in infected women for early diagnosis and future action programmes.
Matern Child Health J
Materials and Methods This comparative study forms part of a multi-centre case– control study of influenza A (H1N1) pdm09 carried out in seven Spanish Autonomous Communities (Catalonia, Andalusia, Madrid, the Basque Country, the Valencian Community, Castile-Leo´n, and Navarre) using a common protocol whose objective was to determine the impact of influenza A (H1N1) on the Spanish population [25].
undertaken, along with the corresponding medical records from hospital databases: age, sex, country of birth, relevant medical conditions (pneumonia in the last 2 years, chronic obstructive pulmonary disease, asthma, other respiratory illness, chronic cardiovascular disease, arterial hypertension, cardiac insufficiency, nervous system, renal failure/ nephritic syndrome, AIDS/HIV). The behavioural variables were ethnicity, level of education and smoking habit. The same variables were obtained from the uninfected controls, except the variables directly relating to the disease.
Recruitment of Cases and Controls Statistical Analysis This is a case–control study carried out in 28 hospitals in seven Spanish Autonomous Communities between 1 November 2009 and 30 June 2010 [25]. Of an initial study population of 813 persons hospitalised with laboratoryconfirmed influenza A (H1N1) pdm09 infection and 2,972 persons attending the same hospitals, but without influenza-like illness, non-vaccinated pregnant women were selected. Fifty-one pregnant women with influenza aged between 15 and 44 years and 114 pregnant women without influenza aged 15–44 years were recruited for this study. A case was defined as a patient with a new diagnosis of influenza-like illness with clinical manifestations and a laboratory-confirmed influenza A (H1N1) pdm09 virus as assessed by a reverse transcriptase polymerase chain reaction (RT-PCR) assay [26], who were hospitalised for more than 24 h following the medical criteria for their illness. The patients with likely nosocomial infection (determined by onset of symptoms at 48 h post-hospitalisation) were excluded. Potential control individuals were excluded if the main reason for hospitalisation was respiratory illness. Informed consent was obtained from all the subjects prior to enrollment. The project was approved by the Ethics Committees of the participating hospitals. Further details of the study design have been provided elsewhere [25]. All the pregnant women, who were either cases or controls in the general study, were included in the present substudy. We specifically compared the pregnant women with influenza A (H1N1) pdm09 infection (cases) with the pregnant women without influenza who had been recruited from the same hospitals (controls). Women who had been vaccinated for pandemic influenza A (H1N1) pdm09 were excluded from the present study. Data Collection A face-to-face epidemiological enquiry was conducted, which was designed specifically for the multi-centre case– control study of influenza A (H1N1) pdm09 using a standardised protocol [25]. For the cases, the following variables were obtained from the personal interviews
Firstly, the characteristics between pregnant women with and without influenza A (H1N1) pdm09 were compared using the Chi square, Fisher’s exact and Student’s t test tests according to the nature of the variables. Subsequently, a logistic regression analysis was done to estimate the crude (cOR) and adjusted odds ratios (aOR) with 95 % confidence intervals (95 % CI) by taking into account any possible confounding variables (Wald’s test). Specifically, pre-pregnancy body mass index (BMI) was adjusted. The analyses were done with the SPSS software (version 17.0; Inc, Chicago III).
Results The most relevant demographic characteristics of these pregnant women are summarised in Table 1, which compares the cases with and the controls without influenza A (H1N1) pdm09, and the corresponding ORs. Cases and controls did not differ in terms of age, pregnancy trimester, level of education, smoking habit, alcohol consumption (categorised: usual alcohol consumption or non-usual alcohol consumption) and diabetes status. However, obesity (BMI C 30) was identified as a statistically significant risk factor for influenza infection in pregnant women (OR 3.03; 95 % CI 1.13–8.11). Higher, yet still non-significant, ORs were observed for Latin American pregnant women (aOR 3.71; 95 % CI 1.00–14.04). The clinical characteristics of the cases with and the controls without infection, and the ORs describing the associations between these clinical characteristics and influenza infection in pregnant women, are summarised in Table 2. Cases and controls did not differ in terms of their medical histories of any comorbidities studied (pneumonia in the last 2 years, chronic obstructive pulmonary disease, asthma, other respiratory illness, chronic cardiovascular disease, arterial hypertension, cardiac insufficiency, nervous system, renal failure, nephritic syndrome, AIDS and HIV). Table 3 reveals that the most prevalent symptoms in the influenza-infected pregnant women were temperature
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Matern Child Health J Table 1 Demographic characteristics of cases with and controls without influenza A (H1N1) 2009, and the crude and adjusted ORs describing the associations between these characteristics and influenza infection in pregnant, non-vaccinated women in Spain Demographic characteristics
Cases (N = 51) %
Controls (N = 114) %
Age (Mean ± SD)
32.64 ± 10.92
31.59 ± 7.50
\20 years
27.5
5.3
20–29 years 30–34 years
5.9 37.3
[34 years
p value
Crude OR (95 % CI)
Adjusted ORa (95 % CI)
p value 0.474b
0.600
1 (Ref.)
1 (Ref.)
29.8 21.9
0.82 (0.18–3.76) 1.28 (0.28–5.86)
1.27 (0.13–12.87) 2.29 (0.23–23.36)
29.4
43.0
0.73 (0.16–3.25)
1.35 (0.14–13.21)
Trimester 1
8.5
13.6
1 (Ref.)
1 (Ref.)
Trimester 2
19.1
34.0
1.00 (0.27–3.72)
0.94 (0.22–4.02)
Trimester 3
72.3
52.4
2.14 (0.65–7.05)
1.92 (0.54–6.63)
74.5
86.6
1 (Ref.)
1 (Ref.)
0.648c
Pregnancy 0.123
0.308c
Ethnicity Caucasian Romanian
0.069
0.053c
0
1.8
–
–
15.7
3.6
5.10 (1.45–17.05)
3.71 (1.00–14.04)
Arabian-N African
3.9
2.7
1.70 (0.27–10.58)
0.92 (0.09–9.26)
Others
5.9
5.4
1.27 (0.30–5.36)
0.37 (0.04–3.32)
Secondary/higher
90.2
92.1
1 (Ref.)
1 (Ref.)
No studies/primary Smoking habit
9.8
7.9
1.49 (0.86–2.57)
1.36 (0.70–2.63)
Non-smoker
64.7
69.9
1 (Ref.)
1 (Ref.)
Smoker
21.6
16.6
1.28 (0.47–3.52)
2.08 (0.66–6.53)
Ex-smoker
13.7
11.5
1.03 (0.32–3.32)
1.39 (0.34–5.76)
Alcoholism
2
0.9
0.546
2.31 (0.14–37.62)
2.00 (0.10–39.22)
0.452c
23.3
9.1
0.023
3.03 (1.13–8.11)
3.03 (1.13–8.11)
0.024c
3.9
3.5
0.896
1.12 (0.20–6.33)
0.83 (0.13–5.23)
0.846c
Latin American
Level of education 0.689
0.802
0.364c
0.210c
Obesity BMI C 30 kg/m2 Diabetes a
Adjusted for obesity
b
Student’s test
c
Chi square test
(mean 38.34 °C), cough (82.4 %), malaise (80.5 %), myalgia (56.1 %), and headaches (54.9 %).
Discussion Summary of the Main Findings The results obtained in the present study indicate a higher risk of the influenza A (H1N1) pdm09 disease in nonvaccinated pregnant women who are obese, and they also suggest an increased risk for subjects with obesity and for Latin American women living in Spain. No statistically significant differences for other characteristics features were observed, although a higher proportion of infection was noted for young pregnant women in pregnancy trimester 3, with a lower level of education and a higher
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incidence of toxic habits (alcohol consumption and smoking habit) than non-infected women. The most frequent symptoms of influenza A (H1N1) pdm09 infection in pregnant women included a high temperature, cough, malaise, headache and myalgia, similarly to seasonal influenza, which can be differentiated by complementary microbiological tests. Interpretation of the Results in Relation to Previous Findings Our results support similar findings reported in previous studies, which reinforces the role of obesity as a risk factor for influenza A (H1N1) pdm09 in Spain. For instance, Van Kerkhove et al. [27–29] found that morbid obesity was a risk factor for ICU admission in patients with influenza A (H1N1) pdm09. Although the comparison made of average
Matern Child Health J Table 2 Clinical characteristics of cases with and controls without influenza A (H1N1) pdm09 infection, and the ORs describing their associations with influenza infection in non-vaccinated pregnant women in Spain Controls (N = 114) %
p valuea
Crude OR (95 % CI)
4.9
2.6
0.485
1.89 (0.31–11.78)
COPD
3.9
0
0.034
–
Asthma
11.8
9.7
0.693
1.23 (0.43–3.55)
Clinical characteristics Pneumonia last 2 years
Cases (N = 51) %
Other respiratory illness
6.3
0
0.009
–
Chronic cardiovascular disease
2.0
0.9
0.561
2.24 (0.14–36.53)
Arterial hypertension
2.0
6.1
0.257
0.31 (0.04–2.60)
Cardiac insufficiency Neurological diseases
2.0 2.0
0.9 0.9
0.557 0.557
0.31 (0.04–2.60) 2.26 (0.14–36.86)
Renal failure/nephritic syndrome
2.0
0.9
0.557
2.26 (0.14–37.29)
AIDS/HIV infection
2.0
0.9
0.551
2.28 (0.14–37.29)
a
Wald’s test
Table 3 Prevalence of symptoms in cases of influenza A (H1N1) pdm09 virus infection in pregnant women in Spain Symptoms
Cases (N = 51) %
Temperature (°C) (Mean ± SD)
38.34 ± 0.70
Cough
82.4
Malaise
80.5
Myalgia
56.1
Headaches
54.9
Respiratory distress
40.8
Rhinorrhea Odynophagia
39.0 38.5
Vomiting
17.1
Hypoxaemia
12.5
Diarrhea
7.3
Renal failure/nephritic syndrome
3.9
Consciousness alteration
2.4
Seizures
2.0
ages between pregnant women with and without pandemic influenza infection showed no statistically significant differences (Table 1), 27.5 % of infected pregnant women were younger than 20 years, whereas only 5.3 % of noninfected pregnant women fell in this age group. This result agrees with other analyses in which a higher risk for pandemic influenza virus was found [21, 30]. Basically, we found an increased risk of influenza A (H1N1) pdm09 virus during the third pregnancy trimester as compared to the first pregnancy trimester, although this risk was not statistically significant (probably due to the limited number of cases analysed). This result agrees with previous analyses [31] which reported an OR of 1.2 (95 % CI 1.1–1.4) in pregnancy trimester 3. Our results also reveal that pregnant Latin American women are at an almost fourfold higher risk of being
hospitalised for the influenza A (H1N1) pdm09 virus, suggesting that this influenza virus follows an ethnic pattern. Ethnic-dependent susceptibility to viral infection in the current pandemic has been discussed in previous research works undertaken in Turkey, New Zealand [32, 33], and people who are native from Alaska are more likely to be hospitalised native people [34]. The results presented herein also agree with the higher mortality described in South America [23]. To date, no explanation for these differences has been provided. One possible explanation for the low mortality rate recorded in China during the 2009 pandemic of influenza A (H1N1) pdm09 virus may be different ethnic susceptibility rather than strict strategies adopted to prevent infections [35]. Consequently, increased medical surveillance of this ethnic group, by means of centralised prevention and treatment efforts, might be advisable. An alternative hypothesis is that past contacts with similar viral strains might explain the greater resistance observed in the European population than in others, like more isolated populations in South America [23, 36] or Asia [35]. Previous AIDS or HIV infection, pathologies affecting the nervous and renal systems, chronic cardiovascular disease and pneumonia in the last 2 years are the main clinical characteristics associated factors to develop influenza A (H1N1) pdm09 infection in pregnant women. These results agree with previous findings [31, 37] obtained for increased risk of influenza A (H1N1) pdm09 infection in pregnant women with some of these comorbidities. The most relevant symptoms found in pregnant women infected with the influenza A (H1N1) pdm09 virus include a high temperature, malaise, myalgia, cough and headache. These symptoms coincide with the typical symptoms of seasonal influenza in pregnant women, and it is not possible to clearly differentiate them. Our findings also suggest the importance of preventive measures, including immunity, which is also likely to benefit offspring [30].
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Strengths and Limitations This study compares pregnant women with and without the influenza A (H1N1) pdm09 virus. Most studies published on the influenza A (H1N1) pdm09 virus have compared pregnant and non-pregnant women [1, 16, 38], which means that this study is more specific. In addition, only non-vaccinated women were included in the analysis to prevent a confusion bias resulting from the protective effects of the vaccine. We acknowledge several limitations in the present study, such as limited statistical power. We attempted to limit the information bias by following a stringent, standardised protocol and by training the interviewers. We believe that the case selection criteria have not changed with time, which limits the validity of the study because laboratory confirmations of infection by the pandemic strain of the influenza virus under study are always required. In order to minimise the confusion bias, we reviewed the most relevant literature and all the variables that can reasonably influence the results which, whenever necessary, were controlled in the logistic regression analysis. Furthermore, we believe that the study sample is representative of the target population because no participants differed in terms of urban/rural location or socioeconomic status, and all the cases and controls were recruited according to the same criteria. In conclusion, our study reveals a higher risk for influenza A (H1N1) pdm09 virus infection in pregnant, nonvaccinated women who are obese and Latin American. Specific efforts should be made to ensure that the risks of influenza during pregnancy are communicated to these women and to their healthcare providers in order to ensure that they can benefit from health care and influenza immunity. Acknowledgments This project has been supported by Instituto de Salud Carlos III (Project GR09/0030). We thank all the physicians and interviewers in the participating hospitals for their collaboration. Finally, we are grateful to all the pregnant women who participated in this study.
Appendix The members of the CIBERESP Cases and Controls in the Pandemic Influenza Working Group are: Andalusia: E. Azor, J. Carrillo, R. Moyano, J.A. Navarro, M. Va´zquez, F. Zafra (Red de Me´dicos Centinela, Andalucı´a), M.A. Bueno, M.L. Go´mez, M. Mariscal, B. Martı´nez, J.P. Quesada, M. Sillero (Complejo Hospitalario de Jae´n), M. Carnero, J. Ferna´ndez-Crehuet, J. del Diego Salas (Hospital Virgen de la Victoria), M. Delgado Rodrı´guez (CIBERESP, Universidad de Jae´n), V. Fuentes (Hospital Costa
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del Sol), V. Gallardo, E. Pe´rez (Servicio de Epidemiologı´a, Junta de Andalucı´a), R. Lo´pez (Hospital Infanta Elena, Huelva), J.R. Maldonado (Hospital de Torreca´rdenas), J.M. ´ . Morillo Mayoral (Servicio de Vigilancia de Andalucı´a), A ´ (Hospital Virgen del Rocıo), J.M. Navarro, M. Pe´rez (Laboratorio de Referencia de Gripe), S. On˜a (Hospital Carlos Haya), M.J. Pe´rez (Hospital Virgen de Valme), M.C. Ubago (Hospital Virgen de las Nieves), M. Zarzuela (Hospital Puerta del Mar). Valencian Community: J. Blanquer (Hospital Clı´nico Universitario, Valencia), F. Gonza´lez Candelas (CIBERESP, CSISP-Universitat de Valencia), M. Morales (CIBERESP, CSISP-Universitat de Valencia, Hospital Doctor Peset). Castilla y Leon: D. Carriedo, F. Dı´ez, I. Ferna´ndez, S. Ferna´ndez, M.P. Sanz (Complejo Asistencial Universitario de Leo´n), J.J. Castrodeza, A. Pe´rez, S. Tamames (Direccio´n General de Salud Pu´blica, Desarrollo e Innovacio´n, Junta de Castilla y Leo´n), V. Martı´n (CIBERESP, Universidad de Leo´n), A. Molina (Instituto de Biomedicina, Universidad de Leo´n), J. Ortiz de Saracho (Hospital del Bierzo), R. Ortiz de Lejarazu (Centro Nacional de Gripe, Valladolid), A. Pueyo, J.L. Viejo (Complejo Asistencial, Burgos), P. Redondo (Servicio Territorial de Sanidad y Bienestar Social, Leo´n). Catalonia: A. Agustı´, A. Torres, A. Trilla, A. Vilella (Hospital Clı´nic de Barcelona), J. Alonso (CIBERESP, Universitat Pompeu Fabra, IMIM-Instituto Recerca Hospital del Mar), F. Barbe´ (Hospital Arnau de Vilanova), M. Baricot, N. Soldevila (CIBERESP), L. Blanch, G. Navarro (Hospital de Sabadell), X. Bonfill, J. Lo´pez-Contreras, V. Pomar, M.T. Puig (Hospital de Sant Pau), E. Borra`s, A. Martı´nez, Nu´ria Torner (Direccio´n General de Salud Pu´blica, Generalitat de Catalunya), C. Bravo, F. Moraga (Hospital Vall d’Hebro´n), F. Calafell, O. Garı´n (Universitat Pompeu Fabra), J. Cayla`, C. Tortajada (Agencia de Salud ` . Domı´nguez (CIBERESP, UniPu´blica de Barcelona), A versitat de Barcelona), I. Garcia, J. Ruiz (Hospital Germans Trias i Pujol), J.J. Garcia (Hospital Sant Joan de Deu), (Universitat Pompeu Fabra), J. Gea, J.P. Horcajada (Hospital del Mar), P. Godoy (CIBERESP, Departament de Salut Generalitat de Catalunya), N. Hayes (Hospital Clı´nicCRESIB), T. Pumarola (REIPI, Universitat de Barcelona), A. Rosell (Hospital de Bellvitge), M. Sa´ez (CIBERESP, ´ lvarez, M. Enrı´Universitat de Girona). Madrid: Carlos A quez, F. Pozo (Hospital 12 de Octubre), J. Astray (Subdireccio´n de Vigilancia, Comunidad de Madrid), F. Baquero, R. Canto´n, J. C. Gala´n (CIBERESP, Hospital Ramo´n y Cajal), A. Robustillo, M.A. Valdeo´n (Hospital Universitario Ramo´n y Cajal), E. Co´rdoba, F. Domı´nguez, J. Garcı´a, R. Ge´nova, E. Gil, S. Jime´nez, M.A. Lopaz, J. Lo´pez, F. Martı´n, M.L. Martı´nez, M. Ordoba´s, E. Rodrı´guez, S. ´ rea de Epidemiologı´a de la CoSa´nchez, C. Valde´s (A munidad de Madrid), J.R. Pan˜o, M. Romero (Hospital Universitario La Paz),. Navarre: J. Castilla (CIBERESP,
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Instituto de Salud Pu´blica de Navarra), P. Fanlo, F. Gil, V. Martı´nez Artola, M. Ruiz (Complejo Hospitalario de Navarra), J. Gamboa, F. Pe´rez-Afonso M. Sota, M.E. Ursua, M.T.Virto (Red de Me´dicos Centinela, Navarra), A. Martinez, L. Martı´nez (Instituto de Salud Pu´blica, Navarra). Basque Country: U. Aguirre, A. Caspelastegui, P.P. Espan˜a, S. Garcı´a (Hospital Galdakao), J. Alustizac (Hospital Mendaro), J.M. Anton˜ana, I. Astigarraga, J.I. Pijoan, I. Pocheville, M. Santiago, J.I. Villate (Hospital de Cruces), J. Arı´stegui, A. Escobar, M.I. Garrote (Hospital Basurto), A. Bilbao, C. Garaizar (Fundacio´n Vasca de Innovacio´n e Investigacio´n Sanitarias), G. Cilla, J. Korta, E. Pe´rez Trallero, C. Sarasqueta (Hospital Donostia), F. Esteban, J.L. Lobo, C. Salado, E. Tato (Hospital Txagorritxu), J.M. Quintana (CIBERESP, Fundacio´n Vasca de Innovacio´n e Investigacio´n Sanitarias).
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