International Journal of Gynecology and Obstetrics 132 (2016) 146–150
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International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
A study of an influenza A (H1N1)pdm09 outbreak in pregnant women in Rajasthan, India Abhishek Agrawal ⁎, Sujata Agarwal, Vinay Kumar, Chuttan L. Nawal, Pradeep Mital, Radheyshyam Chejara Department of Medicine, SMS Medical College and Hospital, Jaipur, India
a r t i c l e
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Article history: Received 10 April 2015 Received in revised form 19 July 2015 Accepted 29 October 2015 Keywords: H1N1 Influenza Pandemic Pregnancy
a b s t r a c t Objectives: To describe the clinical and epidemiological factors of influenza A (H1N1)pdm09-infected patients who were pregnant or in the puerperal period during a recent influenza outbreak in Rajasthan, India. Methods: A retrospective, observational study was performed using hospital records of individuals with confirmed influenza A (H1N1)pdm09 infection admitted to a large tertiary care center in Rajasthan, India, between January 1 and March 15, 2015. Results: The study cohort included 44 patients who were pregnant or in the puerperal period. The mean age was significantly lower in the study cohort than in other female patients treated for influenza A (H1N1)pdm09 infection at the hospital during the study period (25.45 ± 3.45 years vs 40.46 ± 13.99 years; P b 0.001). Mortality was significantly higher in the study cohort than in the comparison female patients (36% vs 17%; P = 0.003). Factors found to be associated with mortality were delayed initiation of oseltamivir, poor oxygen saturation at admission, and more than 50% lung involvement under radiographic examination. None of the patients in the study cohort had received a vaccination against seasonal influenza. Conclusion: Influenza A (H1N1)pdm09 infection during pregnancy causes more severe illness. Early recognition and timely administration of antiviral therapy can improve outcomes. The role of influenza vaccination in this high-risk population cannot be overemphasized. © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Pregnancy is associated with multiple physiological changes in the body and in various organ systems. This results in increased susceptibility to infections including influenza and it is well established that pregnant patients are more severely affected during influenza outbreaks and pandemics [1,2]. A recent influenza pandemic in 2009, caused by a novel strain of influenza named influenza A (H1N1)pdm09, affected millions worldwide and resulted in more than 18 000 deaths. Pregnant women were a group of patients who were affected more severely and had poorer outcomes in comparison with the rest of the population [3,4]. The physiological changes that occur during pregnancy can impair patients’ defense mechanisms against viral infections. The most important alteration that occurs is a reduction in cell-mediated immunity, making pregnant women more vulnerable to viral infections. This, coupled with physical changes occurring in the lungs (decreased vital capacity and increased oxygen demand) and circulatory system (increased heart rate, cardiac output, and blood volume), increases the severity of influenza infection among pregnant patients [5]. It is generally agreed that pregnancy outcomes are adversely affected by influenza ⁎ Corresponding author at: A-13, Indrapuri Colony, Lal Kothi, Tonk Road, Jaipur, 302 015, India. Tel./fax: +91 141 274 4555, +91 982 929 8691 (mobile). E-mail address: [email protected] (A. Agrawal).
infection, leading to preterm delivery, low birth weight, still births, and congenital anomalies [6]. In late 2014, there was a sudden increase in cases of influenza H1N1pdm09 in northern India; by end of the January 2015, this outbreak had reached epidemic proportions. Rajasthan and Gujarat states were affected most severely, with more than 30 000 people affected and more than 2000 deaths occurring [7]. The aim of the present study was to examine the epidemiological and clinical profiles of pregnant patients and patients in the puerperal period presenting during this outbreak in Rajasthan, as well as reviewing patient outcomes. 2. Materials and methods A retrospective, observational study was performed at the department of medicine, Sawai Man Singh Medical College and Hospital, Jaipur, the largest tertiary care health center in the state of Rajasthan, India. Data from adult female patients presenting at the study hospital with confirmed influenza A (H1N1)pdm09 between January 1, 2015 and March 15, 2015 were included in the study. Patients with incomplete records were not included in the study and the validity of the data was cross checked with the other records from the hospital and laboratory. Patients who were pregnant or were in the puerperal period were included as the study cohort. Data from the study cohort were compared with data from the remaining female patients, and comparisons were made between patients who survived and those who died
http://dx.doi.org/10.1016/j.ijgo.2015.07.020 0020-7292/© 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
A. Agrawal et al. / International Journal of Gynecology and Obstetrics 132 (2016) 146–150
within the study cohort. During this influenza outbreak, the state task force committee instructed hospitals to collect and analyze influenza data to determine factors associated with mortality; consequently, ethics committee approval was not needed. In this retrospective study, all patient data used were de-identified and, as a result, individual patient consent was not required. Data were obtained on patients admitted to the study hospital with a history of an influenza-like illness and influenza A (H1N1)pdm09 identified using PCR of a respiratory-tract specimen. The WHO definition of influenza-like illness was used; an acute respiratory infection with a fever of at least 38 °C, the presence of a cough, and onset occurring within the last 10 days [8]. Female patients with influenza-like illness presenting to other departments (e.g. gynecology and obstetrics, otolaryngology) were referred to the department of medicine to rule out influenza A (H1N1)pdm09 infection. All patients with suspected cases of influenza A (H1N1)pdm09 were clinically classified according to categories devised by the Indian Ministry of Health and Family Welfare (Box 1) [9]. Patients classified as being within category C were tested for the presence of H1N1 antigen using RT-PCR and were admitted to the hospital. In the other illness categories, RT-PCR testing was performed if indicators of bilateral lung involvement were observed or if it was considered necessary by the treating physician. Box 1 Classification guidelines of the Indian Ministry of Health and Family Welfare for patients with suspected seasonal influenza H1N1 infections. Category A: Patients with mild influenza-like illness with/without body ache, headache, diarrhea, and vomiting. • Testing for H1N1 not required. • Symptomatic treatment, oseltamivir not required. • Reassessment for progression at 24–48 h. • Home confinement advised. Category B: Category B(1): patients in category A with high-grade fever/ severe sore throat. Category B(2): patients in category A meeting one or more of the following high-risk criteria: 1. Children, elderly patients (N 65 years), or pregnant women. 2. Patients with coexisting pulmonary, cardiac, hepatic, or kidney disease, blood disorders, diabetes, neurological disorders, cancer, and HIV/AIDS. 3. Patients prescribed long-term steroid therapy. • Testing for H1N1 is not required. • Home confinement advised. • May require oseltamivir and antibiotics (as per the treatment protocol for community acquired pneumonia). Category C: Category A and B patients meeting one or more of the following criteria: 1. Breathlessness, chest pain, drowsiness, hypotension, hemoptysis, or cyanosis. 2. Children with influenza-like illness and severe disease manifested by somnolence, persistent high fever, inability to feed, seizures, or dyspnea. 3. Worsening of underlying chronic conditions. • All patients in category C require H1N1 testing, immediate hospitalization, and treatment with oseltamivir.
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Samples for H1N1 analysis were taken on swabs from both pharyngeal pillars using a polyester tipped plastic throat swab stick. They were transported to the department of microbiology using a suitable transport medium. Samples were analyzed using Taqman real-time RT-PCR primers (Applied Biosystems Real-Time PCR System, Thermo Fisher Scientific, Waltham, MA USA) using a Center for Disease Control protocol [10]. Patients were treated according to the protocol prescribed by the Rajasthan state-level task force committee, who were responsible for the management of the outbreak. For all patients who fulfilled the eligibility criteria, information was recorded regarding maternal age, symptoms at admission, the length of pregnancy, the presence of other comorbidities, oxygen saturation at admission (measured using pulse oximetry), the results of chest radiography (with appropriate shielding), the time between the appearance of symptoms and patient hospitalization, the time between the onset of symptoms and commencing antiviral treatment (oral oseltamivir 75–150 mg, twice daily), patient outcomes, and pregnancy outcomes (if any) during hospitalization. Values were expressed as mean ± SD and, for statistical analysis, Microsoft Excel 2007 (Microsoft, Redmond, WA, USA) and SPSS version 22.0 (IBM, Armonk, NY, USA) were used for data storage and analysis. A χ2 test and a Student t test were used to determine the significance of differences between variables. P ≤ 0.05 was considered statistically significant. 3. Results In total, 473 patients with confirmed pandemic influenza A (H1N1)pdm09 infection were recorded at the study hospital during the study period. Of these patients, 291 (61.5%) were female. Pediatric patients were admitted to a separate facility and were not included in the study. Among the 291 female patients, 44 (15.1%) were either pregnant (40) or in the puerperal period (4). Most of the patients in the study cohort came from Jaipur and other nearby areas. Patient characteristics and variables for the study cohort are given in Table 1. The most commonly recorded symptoms at admission among the patients in the study cohort are shown in Fig. 1. The most common indications for hospitalization among patients in the study cohort included breathlessness (40 [91%]), bilateral rales detected through auscultation (30 [68%]) or bilateral lung involvement on chest
Table 1 Characteristics of the study cohort (n = 44).a Variable
Value
Age, y 25 (20–36) ≤18 years 1 (2) 19-30 41 (93) N30 2 (5) Duration of pregnancy at hospital admission (n = 40), wk 1–12 4 (10) 13–26 17 (43) 27–40 19 (48) Length of hospital admission, d 5.0 (0–19) ≤2 9 (20) 3–5 18 (41) 6–10 11 (25) ≥11 6 (14) Time between onset of symptoms and 4 (0–20) administration of oseltamivir, d ≤2 11 (25) N2 33 (75) Time between first receiving oseltamivir and 3.5 (1–41) patient death (n = 16), d ≤2 7 (44) 3–5 4 (25) N5 5 (31) a
Values given as median (range) or number (percentage).
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A. Agrawal et al. / International Journal of Gynecology and Obstetrics 132 (2016) 146–150
45
42
44 39
No. of patients
40 33
35
31
29
30 25 20 12
15
11
10 5 0
Symptoms Fig. 1. Symptoms at clinical presentation among patients in the study cohort.
were hemodynamically stable at the time of admission. All patients were initially treated with oral oseltamivir 150 mg/day at the first suspicion of influenza A (H1N1)pdm09 infection. Other interventions were performed as per individual patient’s requirements and according to standard institutional protocols. The classification of patients from the study cohort according to clinical category at admission (Box 1) was as follows: category A, 7 (16%) patients; category B1, 2 (5%) patients; category B2, 17 (39%) patients; and category C, 18 (41%) patients. Pulse oximetry demonstrated that the mean oxygen saturation at admission was 87.45% ± 0.18% (range 30%–99%) for patients in the study cohort. Of the patients in the study cohort, 21 (48%) required admission to the intensive care unit for the management of serious complications. There were 28 (64%) patients in the study cohort that survived their illness and were discharged and 16 (36%) patients died. All the patients who died had bilateral pneumonia and respiratory failure. Additionally, sepsis, various degrees of multi-organ dysfunction syndrome, and septic shock were observed in 8 (18%) patients, 7 (16%) of whom died. Acute renal failure was recorded in 5 (11%) patients, all of whom died. Intrauterine fetal death was experienced by 5 (11%) patients prior to their own deaths. In addition, 1 (2%) patient in the study cohort died 2 days after giving birth to a live neonate at 37 weeks of pregnancy. Various clinical characteristics of patients in the study cohort and a comparison between patients who died and patients that survived are presented in Table 3.
radiography (32 [73%]), persistent fever (6 [14%]), and respiratory failure (18 [41%]) (Fig. 2). The mean age of patients in the study cohort was 25.45 ± 3.45 years (range 20–36 years) while the mean age among female patients who were not pregnant/in the puerperal period admitted to the study hospital during the study was 40.46 ± 13.99 years (range 13–79 years). This difference in age was statistically significant (P b 0.001) (Table 2). Patients in the study cohort were at different stages of pregnancy at admission; the mean duration of pregnancy was 23.08 ± 8.23 weeks and the median was 26 weeks. Of the patients in the study cohort, 19 (43%) patients were in the third trimester of pregnancy, 17 (39%) were in the second trimester of pregnancy, 4 (9%) were in the first trimester of pregnancy, and 4 (9%) were in the puerperal period. No patients in the study cohort had received a vaccination against seasonal influenza. Of the 44 patients in the study cohort, 9 (20%) had at least one other significant clinical complication. Pre-existing cardiac disease was observed in 3 (7%) patients (rheumatic heart disease in 2 [5%] patients and dilated cardiomyopathy in 1 [2%] patient). Other observed comorbidities included hypertension in 2 (5%) patients, and chronic liver disease, acute kidney injury, severe anemia, and hypothyroidism in 1 (2%) patient each. Intrauterine fetal death and sepsis was recorded in 1 (2%) patient. With these specific exceptions, the majority of patients in the study cohort did not have any significant comorbidity apart from varying degrees of hypoxia at admission, and all except two of these patients 91%
No. of patients
82%
Non-pregnant
72%
68%
Pregnant
56% 44%
41%
18%
14% 8%
7% 9%
5% 7%
Diagnostic finding Fig. 2. Indications for hospitalization among female patients with influenza A (H1N1)pdm09. a Significant lung involvement on chest radiography.
A. Agrawal et al. / International Journal of Gynecology and Obstetrics 132 (2016) 146–150 Table 2 Comparison of age and mortality between the study cohort and non-pregnant female patients with influenza A (H1N1)pdm09.a Variable
Study cohort(n = 44)
Non-pregnant female patients (n = 247)
P valueb
Age, y Mortality, %
25.45 ± 3.45 16 (36)
40.46 ± 13.99 42 (17)
b0.001 0.003
a b
Values given as mean ± SD or number (percentage), unless indicated otherwise. Student t test was used to calculate P values.
4. Discussion The present study describes data from 44 influenza A (H1N1)pdm09infected patients who were pregnant or in the puerperal period, out of a total of 291 female patients hospitalized owing to influenza A (H1N1)pdm09 infection during the study period. Among all female patients admitted to the study hospital for influenza infection, the mean age of patients in the study cohort was significantly lower than in the patients included for comparison (25.45 ± 3.45 years vs 40.46 ± 13.99 years; P b 0.001). This indicates that pregnancy, or having recently been pregnant, increases susceptibility to influenza A (H1N1)pdm09 among younger individuals. The major indications for hospital admission in the present study were dyspnea with type 1 respiratory failure, and/or clinical or radiological evidence of significant parenchymal involvement of influenza. According to hospital policy, patients who exhibited uncomplicated influenza-like illness who were unlikely to progress (classified as categories A and B1 according to the Indian Ministry of Health and Family Welfare guidelines) were not hospitalized and were advised to isolate themselves at home. Bilateral lung involvement, consistent with viral pneumonia, was observed in 32 (73%) patients in the study cohort and 18 (41%) patients had some degree of respiratory failure. These findings are in line with those of an Australian study that has described a similar case series comprising 43 patients who were hospitalized while pregnant [11]. In this study, 58% of pregnant patients exhibited uncomplicated influenza-like illness, pneumonia was observed in 28% of patients, and respiratory failure was recorded in 19% of patients [11]. However, in comparison with patients in this Australian study, patients in the present study had a more severe prognosis at the time of hospitalization. Patient mortality was found to be more than double among the study cohort (36.4%) in comparison with the remaining female patients (17.0%) (P = 0.003). This finding reinforces previous observations of increased mortality following influenza infection among pregnant women in comparison with patients who are not pregnant. A recent publication from Jodhpur, Rajasthan recorded 56% mortality among pregnant women, which increased to 80% when considering only patients in the third trimester of pregnancy [12]. Similarly, another study of influenza H1N1-infected patients in India by Pramanick et al., showed that influenza A (H1N1)pdm09-related mortality was higher in patients who were pregnant than in female patients who were not pregnant [13]. Puvanalingam et al. also reported significantly higher mortality
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among pregnant women with influenza (25% in pregnant women vs 2.7% in non-pregnant patients) [14]. Mehta et al. reported a 2.9-fold higher mortality among pregnant women in comparison with patients who were not pregnant; however, this finding was not statistically significant [15]. Similarly, Ramakrishna et al. did not find any statistically significant difference in mortality among between patients that were pregnant and those that were not [16]. In the present study, no significant difference was observed between the patients that survived and those who died in the study cohort in terms of their mean age. A difference in mean age was found in a study by Kadam et al., which investigated patients with H1N1 infection; the mean age of individuals that survived was 31.4 years, while the mean age of patients who died was 36.2 years [17]. However, separate figures were not available for patients who were pregnant in this study. An important finding in the present study was that none of the patients in the study cohort had received influenza vaccination. The previous Australian study reported influenza vaccination in only one patient who was pregnant and no history of vaccination in 31% of patients; the vaccination status was unknown for the remaining patients [11]. The strategic advice group of experts of WHO has recommended that all pregnant women, as a high-risk group, receive vaccination again influenza [18]. The median duration of pregnancy upon admission for patients within the study cohort that were currently pregnant was 26 weeks of pregnancy. Of these 40 patients, 4 (10%) were in the first trimester of pregnancy, 17 (43%) were in the second trimester of pregnancy, and 19 (48%) were in the third trimester of pregnancy. An additional four patients were in the puerperal period. In the study by Mathur et al., 11%, 49%, and 40% of influenza-infected patients who were pregnant were in the first, second, and third trimester of pregnancy, respectively [12]. Similarly, a review by Liu et al. found that among influenzainfected patients who were pregnant, 9.1% of the infections occurred during the first trimester, 29.8% occurred during the second trimester, and 47.0% occurred during the third trimester of pregnancy [19]. Lim demonstrated that, during the second trimester of pregnancy, the odds of a patient being hospitalized following infection with influenza were 1.2-fold higher in comparison with female patients who were not pregnant; the odds of hospitalization were increased 2.3-fold in patients during the third trimester of pregnancy [20]. The present study considered the effect of the duration of a pregnancy at the time of hospitalization on maternal mortality. It was observed that, while 5 of 21 (24%) patients at up to 26 weeks of pregnancy died as a result of influenza infection, 11 of 19 (58%) patients at longer than 26 weeks of pregnancy died; it should be noted that this difference in mortality was not statistically significant (P = 0.118). However, among patients in the study cohort, the mean duration of pregnancy was significantly longer among patients who died as a result of influenza infection than those who survived (Table 3). Similarly, Kadam et al. concluded that the duration of pregnancy was a risk factor that was associated with increased patient mortality [17]. When comparing data between the patients that died and those who survived, it was observed that the mean time taken between the onset of
Table 3 Clinical characteristics of patients in the study cohort, including a comparison between patients who survived influenza infection and those who died.a Variable
Complete study cohort (n = 44)
Patients from the study cohort surviving (n = 28)
Patients from the study cohort who died (n = 16)
P valueb
Maternal age, y Duration of pregnancy at hospital admission, wk Oxygen saturation at admission, % Time between symptom onset and presentation to study hospital, d Time between symptom onset and beginning treatment with oseltamivir, d Time until outcomec following hospital admission, d Patients exhibiting N50% lung involvement of influenza infection
25.45 ± 3.45 23.08 ± 8.23 87.45 5.05 ± 3.52 4.50 ± 3.58 5.91 ± 4.13 20 (45)
25.54 ± 3.58 21.15 ± 8.68 97.01 4.46 ± 2.25 3.57 ± 2.08 6.43 ± 2.92 4 (14)
24.50 ± 3.76 26.64 ± 6.09 70.63 6.06 ± 3.52 6.13 ± 4.95 5.00 ± 5.67 16 (100)
0.378 0.025 b0.001 0.239 0.065 0.35 b0.001
a b c
Values given as mean ± SD or number (percentage), unless indicated otherwise. Student t test was used to calculate P values. Outcomes were death or discharge from hospital.
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symptoms and attending hospital was higher (6.06 ± 3.52 days) in patients who died than in patients who survived influenza infection (4.46 ± 2.25 days), but this difference was not statistically significant. By contrast, Pramanick and colleagues reported that there was a significant association between patient mortality and delays in presenting to hospital among influenza-infected patients who were pregnant [13]. In the present study, among patients who were pregnant, the time between symptom onset and beginning treatment with oseltamivir was higher in patients who died in comparison with those who survived. The mean time before beginning treatment with oseltamivir was 6.13 ± 4.95 days among pregnant patients who died following influenza infection in comparison with 3.57 ± 2.08 days in patients that were pregnant who survived. While this result did fail to reach statistical significance (P = 0.065), it is in accordance with findings from other studies, which found a significant increase in mortality among influenza-infected patients who began therapy with oseltamivir longer than 48 hours after symptom onset in comparison with those who started treatment with oseltamivir within 48 hours of symptom onset [21]. However, the study that produced these data did not compare findings between patients who were pregnant and those who were not [21]. The USA Center for Disease Control has also recommended that, in influenza-infected patients who are pregnant, antiviral treatment should be started as early as possible and is more beneficial if it is started within 48 hours of symptom onset [22]. Of patients included in the study cohort, 21 (48%) patients required admission to the intensive care unit; similar rates of admission to the intensive care unit were reported by Pramanick et al. [13] among patients who were pregnant (40%), while Chudasama et al. [23] reported that 73% of all patients with influenza A(H1N1) required admission to the intensive care unit, and Palani et al. [24] reported that intensive care unit admission was necessary in three out of 27 patients who were pregnant who had influenza A (H1N1)pdm09 infections. Regarding the factors that were observed to be associated with mortality in the present study, it was observed that, of the 20 patients who were found to have greater than 50% involvement of the lung field at admission, 16 (80%) died. With a total of 16 deaths observed among patients who were pregnant or in the puerperal period, all of the individuals who died had greater than 50% involvement of the lung field under radiography assessment at hospital admission. Oxygen saturation at admission (measured by pulse oximetry) was also significantly lower among patients in the study cohort who died (Table 3). The major complications that were found to be associated with mortality were acute renal failure and sepsis leading to multi-organ dysfunction syndrome and septic shock. The results of the present study underscore the increased morbidity and mortality that occurs in patients who are pregnant, or have recently been pregnant, who are affected by influenza A (H1N1)pdm09. The affected patients were relatively younger and healthier in comparison with patients who were not pregnant that presented with influenza infection, with only nine patients presenting with a comorbid condition. The factors found to be related to mortality were oxygen saturation at admission, greater than 50% lung involvement on chest radiography, and delayed administration of oseltamivir following symptom onset. The use of influenza vaccination in this high-risk population should improve outcomes; with the influenza A (H1N1)pdm09 strain now established in the human population (replacing seasonal influenza virus strains), it is likely that this strain will cause further influenza outbreaks in the future. The present study had some design limitations; it was a retrospective design and was only able to study hospitalized patients, meaning that patients with less severe infections who were not hospitalized were not included. Further, owing to incomplete data, it was not possible to investigate potential correlations between other variables including sequential organ failure assessment score, acute physiology and chronic health evaluation II score, and various laboratory and ventilator variables. Owing to the retrospective design, the post-discharge
perinatal outcomes of the patients could not be studied. Even considering these limitations, the present study provides useful information regarding poor outcomes in this cohort of patients. Conflict of Interest The authors have no conflicts of interest. References [1] Harris JW. Influenza occurring in pregnant women: a statistical study of thirteen hundred and fifty cases. JAMA 1919;72(14):978–80. [2] Freeman DW, Barno A. Deaths from Asian influenza associated with pregnancy. Am J Obstet Gynecol 1959;78:1172–5. [3] ANZIC Influenza Investigators, Australasian Maternity Outcomes Surveillance System. Critical illness due to 2009 A/H1N1 influenza in pregnant and postpartum women: population based cohort study. BMJ 2010;340:c1279. [4] Siston AM, Rasmussen SA, Honein MA, Fry AM, Seib K, Callaghan WM, et al. Pandemic H1N1 Influenza in Pregnancy Working Group. Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States. JAMA 2010;303(15): 1517–25. 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International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
A study of an influenza A (H1N1)pdm09 outbreak in pregnant women in Rajasthan, India Abhishek Agrawal ⁎, Sujata Agarwal, Vinay Kumar, Chuttan L. Nawal, Pradeep Mital, Radheyshyam Chejara Department of Medicine, SMS Medical College and Hospital, Jaipur, India
a r t i c l e
i n f o
Article history: Received 10 April 2015 Received in revised form 19 July 2015 Accepted 29 October 2015 Keywords: H1N1 Influenza Pandemic Pregnancy
a b s t r a c t Objectives: To describe the clinical and epidemiological factors of influenza A (H1N1)pdm09-infected patients who were pregnant or in the puerperal period during a recent influenza outbreak in Rajasthan, India. Methods: A retrospective, observational study was performed using hospital records of individuals with confirmed influenza A (H1N1)pdm09 infection admitted to a large tertiary care center in Rajasthan, India, between January 1 and March 15, 2015. Results: The study cohort included 44 patients who were pregnant or in the puerperal period. The mean age was significantly lower in the study cohort than in other female patients treated for influenza A (H1N1)pdm09 infection at the hospital during the study period (25.45 ± 3.45 years vs 40.46 ± 13.99 years; P b 0.001). Mortality was significantly higher in the study cohort than in the comparison female patients (36% vs 17%; P = 0.003). Factors found to be associated with mortality were delayed initiation of oseltamivir, poor oxygen saturation at admission, and more than 50% lung involvement under radiographic examination. None of the patients in the study cohort had received a vaccination against seasonal influenza. Conclusion: Influenza A (H1N1)pdm09 infection during pregnancy causes more severe illness. Early recognition and timely administration of antiviral therapy can improve outcomes. The role of influenza vaccination in this high-risk population cannot be overemphasized. © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Pregnancy is associated with multiple physiological changes in the body and in various organ systems. This results in increased susceptibility to infections including influenza and it is well established that pregnant patients are more severely affected during influenza outbreaks and pandemics [1,2]. A recent influenza pandemic in 2009, caused by a novel strain of influenza named influenza A (H1N1)pdm09, affected millions worldwide and resulted in more than 18 000 deaths. Pregnant women were a group of patients who were affected more severely and had poorer outcomes in comparison with the rest of the population [3,4]. The physiological changes that occur during pregnancy can impair patients’ defense mechanisms against viral infections. The most important alteration that occurs is a reduction in cell-mediated immunity, making pregnant women more vulnerable to viral infections. This, coupled with physical changes occurring in the lungs (decreased vital capacity and increased oxygen demand) and circulatory system (increased heart rate, cardiac output, and blood volume), increases the severity of influenza infection among pregnant patients [5]. It is generally agreed that pregnancy outcomes are adversely affected by influenza ⁎ Corresponding author at: A-13, Indrapuri Colony, Lal Kothi, Tonk Road, Jaipur, 302 015, India. Tel./fax: +91 141 274 4555, +91 982 929 8691 (mobile). E-mail address: [email protected] (A. Agrawal).
infection, leading to preterm delivery, low birth weight, still births, and congenital anomalies [6]. In late 2014, there was a sudden increase in cases of influenza H1N1pdm09 in northern India; by end of the January 2015, this outbreak had reached epidemic proportions. Rajasthan and Gujarat states were affected most severely, with more than 30 000 people affected and more than 2000 deaths occurring [7]. The aim of the present study was to examine the epidemiological and clinical profiles of pregnant patients and patients in the puerperal period presenting during this outbreak in Rajasthan, as well as reviewing patient outcomes. 2. Materials and methods A retrospective, observational study was performed at the department of medicine, Sawai Man Singh Medical College and Hospital, Jaipur, the largest tertiary care health center in the state of Rajasthan, India. Data from adult female patients presenting at the study hospital with confirmed influenza A (H1N1)pdm09 between January 1, 2015 and March 15, 2015 were included in the study. Patients with incomplete records were not included in the study and the validity of the data was cross checked with the other records from the hospital and laboratory. Patients who were pregnant or were in the puerperal period were included as the study cohort. Data from the study cohort were compared with data from the remaining female patients, and comparisons were made between patients who survived and those who died
http://dx.doi.org/10.1016/j.ijgo.2015.07.020 0020-7292/© 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
A. Agrawal et al. / International Journal of Gynecology and Obstetrics 132 (2016) 146–150
within the study cohort. During this influenza outbreak, the state task force committee instructed hospitals to collect and analyze influenza data to determine factors associated with mortality; consequently, ethics committee approval was not needed. In this retrospective study, all patient data used were de-identified and, as a result, individual patient consent was not required. Data were obtained on patients admitted to the study hospital with a history of an influenza-like illness and influenza A (H1N1)pdm09 identified using PCR of a respiratory-tract specimen. The WHO definition of influenza-like illness was used; an acute respiratory infection with a fever of at least 38 °C, the presence of a cough, and onset occurring within the last 10 days [8]. Female patients with influenza-like illness presenting to other departments (e.g. gynecology and obstetrics, otolaryngology) were referred to the department of medicine to rule out influenza A (H1N1)pdm09 infection. All patients with suspected cases of influenza A (H1N1)pdm09 were clinically classified according to categories devised by the Indian Ministry of Health and Family Welfare (Box 1) [9]. Patients classified as being within category C were tested for the presence of H1N1 antigen using RT-PCR and were admitted to the hospital. In the other illness categories, RT-PCR testing was performed if indicators of bilateral lung involvement were observed or if it was considered necessary by the treating physician. Box 1 Classification guidelines of the Indian Ministry of Health and Family Welfare for patients with suspected seasonal influenza H1N1 infections. Category A: Patients with mild influenza-like illness with/without body ache, headache, diarrhea, and vomiting. • Testing for H1N1 not required. • Symptomatic treatment, oseltamivir not required. • Reassessment for progression at 24–48 h. • Home confinement advised. Category B: Category B(1): patients in category A with high-grade fever/ severe sore throat. Category B(2): patients in category A meeting one or more of the following high-risk criteria: 1. Children, elderly patients (N 65 years), or pregnant women. 2. Patients with coexisting pulmonary, cardiac, hepatic, or kidney disease, blood disorders, diabetes, neurological disorders, cancer, and HIV/AIDS. 3. Patients prescribed long-term steroid therapy. • Testing for H1N1 is not required. • Home confinement advised. • May require oseltamivir and antibiotics (as per the treatment protocol for community acquired pneumonia). Category C: Category A and B patients meeting one or more of the following criteria: 1. Breathlessness, chest pain, drowsiness, hypotension, hemoptysis, or cyanosis. 2. Children with influenza-like illness and severe disease manifested by somnolence, persistent high fever, inability to feed, seizures, or dyspnea. 3. Worsening of underlying chronic conditions. • All patients in category C require H1N1 testing, immediate hospitalization, and treatment with oseltamivir.
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Samples for H1N1 analysis were taken on swabs from both pharyngeal pillars using a polyester tipped plastic throat swab stick. They were transported to the department of microbiology using a suitable transport medium. Samples were analyzed using Taqman real-time RT-PCR primers (Applied Biosystems Real-Time PCR System, Thermo Fisher Scientific, Waltham, MA USA) using a Center for Disease Control protocol [10]. Patients were treated according to the protocol prescribed by the Rajasthan state-level task force committee, who were responsible for the management of the outbreak. For all patients who fulfilled the eligibility criteria, information was recorded regarding maternal age, symptoms at admission, the length of pregnancy, the presence of other comorbidities, oxygen saturation at admission (measured using pulse oximetry), the results of chest radiography (with appropriate shielding), the time between the appearance of symptoms and patient hospitalization, the time between the onset of symptoms and commencing antiviral treatment (oral oseltamivir 75–150 mg, twice daily), patient outcomes, and pregnancy outcomes (if any) during hospitalization. Values were expressed as mean ± SD and, for statistical analysis, Microsoft Excel 2007 (Microsoft, Redmond, WA, USA) and SPSS version 22.0 (IBM, Armonk, NY, USA) were used for data storage and analysis. A χ2 test and a Student t test were used to determine the significance of differences between variables. P ≤ 0.05 was considered statistically significant. 3. Results In total, 473 patients with confirmed pandemic influenza A (H1N1)pdm09 infection were recorded at the study hospital during the study period. Of these patients, 291 (61.5%) were female. Pediatric patients were admitted to a separate facility and were not included in the study. Among the 291 female patients, 44 (15.1%) were either pregnant (40) or in the puerperal period (4). Most of the patients in the study cohort came from Jaipur and other nearby areas. Patient characteristics and variables for the study cohort are given in Table 1. The most commonly recorded symptoms at admission among the patients in the study cohort are shown in Fig. 1. The most common indications for hospitalization among patients in the study cohort included breathlessness (40 [91%]), bilateral rales detected through auscultation (30 [68%]) or bilateral lung involvement on chest
Table 1 Characteristics of the study cohort (n = 44).a Variable
Value
Age, y 25 (20–36) ≤18 years 1 (2) 19-30 41 (93) N30 2 (5) Duration of pregnancy at hospital admission (n = 40), wk 1–12 4 (10) 13–26 17 (43) 27–40 19 (48) Length of hospital admission, d 5.0 (0–19) ≤2 9 (20) 3–5 18 (41) 6–10 11 (25) ≥11 6 (14) Time between onset of symptoms and 4 (0–20) administration of oseltamivir, d ≤2 11 (25) N2 33 (75) Time between first receiving oseltamivir and 3.5 (1–41) patient death (n = 16), d ≤2 7 (44) 3–5 4 (25) N5 5 (31) a
Values given as median (range) or number (percentage).
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45
42
44 39
No. of patients
40 33
35
31
29
30 25 20 12
15
11
10 5 0
Symptoms Fig. 1. Symptoms at clinical presentation among patients in the study cohort.
were hemodynamically stable at the time of admission. All patients were initially treated with oral oseltamivir 150 mg/day at the first suspicion of influenza A (H1N1)pdm09 infection. Other interventions were performed as per individual patient’s requirements and according to standard institutional protocols. The classification of patients from the study cohort according to clinical category at admission (Box 1) was as follows: category A, 7 (16%) patients; category B1, 2 (5%) patients; category B2, 17 (39%) patients; and category C, 18 (41%) patients. Pulse oximetry demonstrated that the mean oxygen saturation at admission was 87.45% ± 0.18% (range 30%–99%) for patients in the study cohort. Of the patients in the study cohort, 21 (48%) required admission to the intensive care unit for the management of serious complications. There were 28 (64%) patients in the study cohort that survived their illness and were discharged and 16 (36%) patients died. All the patients who died had bilateral pneumonia and respiratory failure. Additionally, sepsis, various degrees of multi-organ dysfunction syndrome, and septic shock were observed in 8 (18%) patients, 7 (16%) of whom died. Acute renal failure was recorded in 5 (11%) patients, all of whom died. Intrauterine fetal death was experienced by 5 (11%) patients prior to their own deaths. In addition, 1 (2%) patient in the study cohort died 2 days after giving birth to a live neonate at 37 weeks of pregnancy. Various clinical characteristics of patients in the study cohort and a comparison between patients who died and patients that survived are presented in Table 3.
radiography (32 [73%]), persistent fever (6 [14%]), and respiratory failure (18 [41%]) (Fig. 2). The mean age of patients in the study cohort was 25.45 ± 3.45 years (range 20–36 years) while the mean age among female patients who were not pregnant/in the puerperal period admitted to the study hospital during the study was 40.46 ± 13.99 years (range 13–79 years). This difference in age was statistically significant (P b 0.001) (Table 2). Patients in the study cohort were at different stages of pregnancy at admission; the mean duration of pregnancy was 23.08 ± 8.23 weeks and the median was 26 weeks. Of the patients in the study cohort, 19 (43%) patients were in the third trimester of pregnancy, 17 (39%) were in the second trimester of pregnancy, 4 (9%) were in the first trimester of pregnancy, and 4 (9%) were in the puerperal period. No patients in the study cohort had received a vaccination against seasonal influenza. Of the 44 patients in the study cohort, 9 (20%) had at least one other significant clinical complication. Pre-existing cardiac disease was observed in 3 (7%) patients (rheumatic heart disease in 2 [5%] patients and dilated cardiomyopathy in 1 [2%] patient). Other observed comorbidities included hypertension in 2 (5%) patients, and chronic liver disease, acute kidney injury, severe anemia, and hypothyroidism in 1 (2%) patient each. Intrauterine fetal death and sepsis was recorded in 1 (2%) patient. With these specific exceptions, the majority of patients in the study cohort did not have any significant comorbidity apart from varying degrees of hypoxia at admission, and all except two of these patients 91%
No. of patients
82%
Non-pregnant
72%
68%
Pregnant
56% 44%
41%
18%
14% 8%
7% 9%
5% 7%
Diagnostic finding Fig. 2. Indications for hospitalization among female patients with influenza A (H1N1)pdm09. a Significant lung involvement on chest radiography.
A. Agrawal et al. / International Journal of Gynecology and Obstetrics 132 (2016) 146–150 Table 2 Comparison of age and mortality between the study cohort and non-pregnant female patients with influenza A (H1N1)pdm09.a Variable
Study cohort(n = 44)
Non-pregnant female patients (n = 247)
P valueb
Age, y Mortality, %
25.45 ± 3.45 16 (36)
40.46 ± 13.99 42 (17)
b0.001 0.003
a b
Values given as mean ± SD or number (percentage), unless indicated otherwise. Student t test was used to calculate P values.
4. Discussion The present study describes data from 44 influenza A (H1N1)pdm09infected patients who were pregnant or in the puerperal period, out of a total of 291 female patients hospitalized owing to influenza A (H1N1)pdm09 infection during the study period. Among all female patients admitted to the study hospital for influenza infection, the mean age of patients in the study cohort was significantly lower than in the patients included for comparison (25.45 ± 3.45 years vs 40.46 ± 13.99 years; P b 0.001). This indicates that pregnancy, or having recently been pregnant, increases susceptibility to influenza A (H1N1)pdm09 among younger individuals. The major indications for hospital admission in the present study were dyspnea with type 1 respiratory failure, and/or clinical or radiological evidence of significant parenchymal involvement of influenza. According to hospital policy, patients who exhibited uncomplicated influenza-like illness who were unlikely to progress (classified as categories A and B1 according to the Indian Ministry of Health and Family Welfare guidelines) were not hospitalized and were advised to isolate themselves at home. Bilateral lung involvement, consistent with viral pneumonia, was observed in 32 (73%) patients in the study cohort and 18 (41%) patients had some degree of respiratory failure. These findings are in line with those of an Australian study that has described a similar case series comprising 43 patients who were hospitalized while pregnant [11]. In this study, 58% of pregnant patients exhibited uncomplicated influenza-like illness, pneumonia was observed in 28% of patients, and respiratory failure was recorded in 19% of patients [11]. However, in comparison with patients in this Australian study, patients in the present study had a more severe prognosis at the time of hospitalization. Patient mortality was found to be more than double among the study cohort (36.4%) in comparison with the remaining female patients (17.0%) (P = 0.003). This finding reinforces previous observations of increased mortality following influenza infection among pregnant women in comparison with patients who are not pregnant. A recent publication from Jodhpur, Rajasthan recorded 56% mortality among pregnant women, which increased to 80% when considering only patients in the third trimester of pregnancy [12]. Similarly, another study of influenza H1N1-infected patients in India by Pramanick et al., showed that influenza A (H1N1)pdm09-related mortality was higher in patients who were pregnant than in female patients who were not pregnant [13]. Puvanalingam et al. also reported significantly higher mortality
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among pregnant women with influenza (25% in pregnant women vs 2.7% in non-pregnant patients) [14]. Mehta et al. reported a 2.9-fold higher mortality among pregnant women in comparison with patients who were not pregnant; however, this finding was not statistically significant [15]. Similarly, Ramakrishna et al. did not find any statistically significant difference in mortality among between patients that were pregnant and those that were not [16]. In the present study, no significant difference was observed between the patients that survived and those who died in the study cohort in terms of their mean age. A difference in mean age was found in a study by Kadam et al., which investigated patients with H1N1 infection; the mean age of individuals that survived was 31.4 years, while the mean age of patients who died was 36.2 years [17]. However, separate figures were not available for patients who were pregnant in this study. An important finding in the present study was that none of the patients in the study cohort had received influenza vaccination. The previous Australian study reported influenza vaccination in only one patient who was pregnant and no history of vaccination in 31% of patients; the vaccination status was unknown for the remaining patients [11]. The strategic advice group of experts of WHO has recommended that all pregnant women, as a high-risk group, receive vaccination again influenza [18]. The median duration of pregnancy upon admission for patients within the study cohort that were currently pregnant was 26 weeks of pregnancy. Of these 40 patients, 4 (10%) were in the first trimester of pregnancy, 17 (43%) were in the second trimester of pregnancy, and 19 (48%) were in the third trimester of pregnancy. An additional four patients were in the puerperal period. In the study by Mathur et al., 11%, 49%, and 40% of influenza-infected patients who were pregnant were in the first, second, and third trimester of pregnancy, respectively [12]. Similarly, a review by Liu et al. found that among influenzainfected patients who were pregnant, 9.1% of the infections occurred during the first trimester, 29.8% occurred during the second trimester, and 47.0% occurred during the third trimester of pregnancy [19]. Lim demonstrated that, during the second trimester of pregnancy, the odds of a patient being hospitalized following infection with influenza were 1.2-fold higher in comparison with female patients who were not pregnant; the odds of hospitalization were increased 2.3-fold in patients during the third trimester of pregnancy [20]. The present study considered the effect of the duration of a pregnancy at the time of hospitalization on maternal mortality. It was observed that, while 5 of 21 (24%) patients at up to 26 weeks of pregnancy died as a result of influenza infection, 11 of 19 (58%) patients at longer than 26 weeks of pregnancy died; it should be noted that this difference in mortality was not statistically significant (P = 0.118). However, among patients in the study cohort, the mean duration of pregnancy was significantly longer among patients who died as a result of influenza infection than those who survived (Table 3). Similarly, Kadam et al. concluded that the duration of pregnancy was a risk factor that was associated with increased patient mortality [17]. When comparing data between the patients that died and those who survived, it was observed that the mean time taken between the onset of
Table 3 Clinical characteristics of patients in the study cohort, including a comparison between patients who survived influenza infection and those who died.a Variable
Complete study cohort (n = 44)
Patients from the study cohort surviving (n = 28)
Patients from the study cohort who died (n = 16)
P valueb
Maternal age, y Duration of pregnancy at hospital admission, wk Oxygen saturation at admission, % Time between symptom onset and presentation to study hospital, d Time between symptom onset and beginning treatment with oseltamivir, d Time until outcomec following hospital admission, d Patients exhibiting N50% lung involvement of influenza infection
25.45 ± 3.45 23.08 ± 8.23 87.45 5.05 ± 3.52 4.50 ± 3.58 5.91 ± 4.13 20 (45)
25.54 ± 3.58 21.15 ± 8.68 97.01 4.46 ± 2.25 3.57 ± 2.08 6.43 ± 2.92 4 (14)
24.50 ± 3.76 26.64 ± 6.09 70.63 6.06 ± 3.52 6.13 ± 4.95 5.00 ± 5.67 16 (100)
0.378 0.025 b0.001 0.239 0.065 0.35 b0.001
a b c
Values given as mean ± SD or number (percentage), unless indicated otherwise. Student t test was used to calculate P values. Outcomes were death or discharge from hospital.
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symptoms and attending hospital was higher (6.06 ± 3.52 days) in patients who died than in patients who survived influenza infection (4.46 ± 2.25 days), but this difference was not statistically significant. By contrast, Pramanick and colleagues reported that there was a significant association between patient mortality and delays in presenting to hospital among influenza-infected patients who were pregnant [13]. In the present study, among patients who were pregnant, the time between symptom onset and beginning treatment with oseltamivir was higher in patients who died in comparison with those who survived. The mean time before beginning treatment with oseltamivir was 6.13 ± 4.95 days among pregnant patients who died following influenza infection in comparison with 3.57 ± 2.08 days in patients that were pregnant who survived. While this result did fail to reach statistical significance (P = 0.065), it is in accordance with findings from other studies, which found a significant increase in mortality among influenza-infected patients who began therapy with oseltamivir longer than 48 hours after symptom onset in comparison with those who started treatment with oseltamivir within 48 hours of symptom onset [21]. However, the study that produced these data did not compare findings between patients who were pregnant and those who were not [21]. The USA Center for Disease Control has also recommended that, in influenza-infected patients who are pregnant, antiviral treatment should be started as early as possible and is more beneficial if it is started within 48 hours of symptom onset [22]. Of patients included in the study cohort, 21 (48%) patients required admission to the intensive care unit; similar rates of admission to the intensive care unit were reported by Pramanick et al. [13] among patients who were pregnant (40%), while Chudasama et al. [23] reported that 73% of all patients with influenza A(H1N1) required admission to the intensive care unit, and Palani et al. [24] reported that intensive care unit admission was necessary in three out of 27 patients who were pregnant who had influenza A (H1N1)pdm09 infections. Regarding the factors that were observed to be associated with mortality in the present study, it was observed that, of the 20 patients who were found to have greater than 50% involvement of the lung field at admission, 16 (80%) died. With a total of 16 deaths observed among patients who were pregnant or in the puerperal period, all of the individuals who died had greater than 50% involvement of the lung field under radiography assessment at hospital admission. Oxygen saturation at admission (measured by pulse oximetry) was also significantly lower among patients in the study cohort who died (Table 3). The major complications that were found to be associated with mortality were acute renal failure and sepsis leading to multi-organ dysfunction syndrome and septic shock. The results of the present study underscore the increased morbidity and mortality that occurs in patients who are pregnant, or have recently been pregnant, who are affected by influenza A (H1N1)pdm09. The affected patients were relatively younger and healthier in comparison with patients who were not pregnant that presented with influenza infection, with only nine patients presenting with a comorbid condition. The factors found to be related to mortality were oxygen saturation at admission, greater than 50% lung involvement on chest radiography, and delayed administration of oseltamivir following symptom onset. The use of influenza vaccination in this high-risk population should improve outcomes; with the influenza A (H1N1)pdm09 strain now established in the human population (replacing seasonal influenza virus strains), it is likely that this strain will cause further influenza outbreaks in the future. The present study had some design limitations; it was a retrospective design and was only able to study hospitalized patients, meaning that patients with less severe infections who were not hospitalized were not included. Further, owing to incomplete data, it was not possible to investigate potential correlations between other variables including sequential organ failure assessment score, acute physiology and chronic health evaluation II score, and various laboratory and ventilator variables. Owing to the retrospective design, the post-discharge
perinatal outcomes of the patients could not be studied. Even considering these limitations, the present study provides useful information regarding poor outcomes in this cohort of patients. Conflict of Interest The authors have no conflicts of interest. References [1] Harris JW. Influenza occurring in pregnant women: a statistical study of thirteen hundred and fifty cases. JAMA 1919;72(14):978–80. [2] Freeman DW, Barno A. Deaths from Asian influenza associated with pregnancy. Am J Obstet Gynecol 1959;78:1172–5. [3] ANZIC Influenza Investigators, Australasian Maternity Outcomes Surveillance System. Critical illness due to 2009 A/H1N1 influenza in pregnant and postpartum women: population based cohort study. BMJ 2010;340:c1279. [4] Siston AM, Rasmussen SA, Honein MA, Fry AM, Seib K, Callaghan WM, et al. Pandemic H1N1 Influenza in Pregnancy Working Group. Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States. JAMA 2010;303(15): 1517–25. 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