Objective
The objective of the study was to identify characteristics of influenza illness contrasted with noninfluenza acute respiratory illness (ARI) in pregnant women.
Study Design
ARI among pregnant women was identified through daily surveillance during 2 influenza seasons (2010-2012). Within 8 days of illness onset, nasopharyngeal swabs were collected, and an interview was conducted for symptoms and other characteristics. A follow-up telephone interview was conducted 1-2 weeks later, and medical records were extracted. Severity of illness was evaluated by self-assessment of 12 illness symptoms, subjective ratings of overall impairment, highest reported temperature, illness duration, and medical utilization.
Results
Of 292 pregnant women with ARI, 100 tested positive for influenza viruses. Women with influenza illnesses reported higher symptom severity than those with noninfluenza ARI (median score, 18 vs 16 of 36; P < .05) and were more likely to report severe subjective feverishness (18% vs 5%; P < .001), myalgia (28% vs 14%; P < .005), cough (46% vs 30%; P < .01), and chills (25% vs 13%; P < .01). More influenza illnesses were associated with fever greater than 38.9°C (20% vs 5%; P < .001) and higher subjective impairment (mean score, 5.9 vs 4.8; P < .001). Differences in overall symptom severity, fever, cough, chills, early health care–seeking behavior, and impairment remained significant in multivariate models after adjusting for study site, season, age, vaccination status, and number of days since illness onset.
Conclusion
Influenza had a greater negative impact on pregnant women than noninfluenza ARIs, as indicated by symptom severity and greater likelihood of elevated temperature. These results highlight the importance of preventing and treating influenza illnesses in pregnant women.
Pregnant women are at greater risk of hospitalization and serious complications from influenza virus illness than nonpregnant women. Women in their third trimester and those with comorbid conditions are especially vulnerable to hospitalization. Little is known about the clinical characteristics and severity of laboratory-confirmed influenza illness among nonhospitalized pregnant women or how influenza illness differs from noninfluenza acute respiratory illness (ARI) in pregnant women.
In a previous study, we examined the relationship between vaccination status and influenza positivity. This study examined symptom severity and duration of laboratory-confirmed influenza illness among pregnant women compared with noninfluenza ARI during 2 influenza seasons. Although the number of confirmed influenza cases was limited, we conducted exploratory analyses to assess whether influenza illness severity was higher among the women with comorbid conditions or in their third trimester and whether vaccination with a seasonal influenza vaccine was associated with less severe illness among those women with vaccine failure.
Materials and Methods
Recruitment and eligibility
The study methodology and recruitment of the study participants have been described in detail previously. Eligible participants were Kaiser Permanente members who made at least 1 prenatal visit in the Portland, OR (Kaiser Permanente Northwest), or San Francisco, CA, metropolitan areas (Kaiser Permanente Northern California) during the study period, had an expected delivery date after Nov. 15, 2010, and were at least 16 years of age for Kaiser Permanente Northwest or at least 18 years of age for Kaiser Permanente Northern California. The study instruments, procedures, and written consent documents were approved by the institutional review boards at both sites.
Surveillance
The influenza season was defined by the regional/state health department and the Centers for Disease Control and Prevention influenza surveillance data. Thresholds for the beginning and end of the season were defined a priori at each site. During both study seasons, we identified potential ARIs using daily surveillance of electronic medical records (EMRs) for medically attended acute respiratory illness using International Classification of Diseases , ninth revision (ICD-9) codes 460-466, 480-488, and 490-491.
The women were contacted by telephone, screened for eligibility, and asked to provide written consent for study participation. Inclusion criteria included enrollment in the health plan for the study season and completion of the enrollment interview.
During the first season, weekly Internet- or telephone-based surveillance monitored the occurrence of non-medically attended ARI among a prospective cohort of participants at both sites. First-season participants were encouraged to contact staff directly if they became ill; those who did not complete a weekly surveillance report received a reminder e-mail or telephone call to assess current ARI status. For both seasons, nasopharyngeal swab specimens were collected at the homes of women with self-reported cough and fever, feverishness, or chills within 8 days of illness onset.
Participant characteristics
Sociodemographic characteristics were assessed during an enrollment interview. Health status prior to illness was assessed with 3 measures. First, overall self-rated health was assessed using a standard question on current health (poor, fair, good, very good, or excellent) on the enrollment interview. Second, we identified high-risk comorbidities associated with an increased risk of influenza complications by the presence, during 2 or more visits over 1 year prior to conception, of the following conditions: cancer, diabetes mellitus, neurological disorders, chronic pulmonary disease, chronic cardiac disease, immunosuppressive disorders, and chronic renal disease. Third, pregnancy complications, from conception to start of surveillance, were identified from EMRs, using ICD-9 codes related to adverse pregnancy outcomes. All ICD-9 codes are available upon request. Obesity was defined by body mass index, calculated using self-reported prepregnancy weight and height.
Illness characteristics
Illness characteristics were assessed during an illness episode interview at specimen collection and again at a follow-up telephone contact approximately 8 days later. In the first season, participants who were still ill were called again approximately 14 days after the original illness interview.
We assessed 5 indicators of illness severity. First, participants rated the presence and severity of 12 symptoms, using a 4 point scale (0, absent; 1, mild; 2, moderate; and 3, severe). Ten participants who initially reported a cough at the screening interview described a cough as absent during their illness interview; in these instances, responses were recoded as 1 (mild). All symptom ratings were summed to form a 12 symptom severity score, ranging from 1 (a single mild symptom) to 36 (all symptoms severe), as described previously.
Second, participants assessed the overall subjective severity of illness from 0 (normal health) to 9 (worst possible health) and the extent of illness impairment from 0 (able to perform usual activities) to 9 (unable to do so), as described previously.
Third, we examined febrile severity using the subjective severity of feverishness (mild, moderate, or severe) and the highest temperature recorded using any of the following: EMR vital signs (if the illness was medically attended), self-reported highest temperature at either the illness interview or 8–14 day follow-up interview(s), or measured temperature by visiting study staff. Severe fever was defined as 38.9°C, which represents the threshold for assessing teratogenic exposure in the fetus.
Fourth, we calculated illness duration by subtracting the illness onset date (determined from screening or illness episode interview) from the date of symptom resolution as indicated in follow-up interviews. Seventy-eight women (53 noninfluenza and 25 influenza) who either were unable to recall a recovery date or had not yet recovered when the follow-up interview occurred were excluded from our analysis of illness duration.
Fifth, we examined medical utilization and self-care as indicated by the following: (1) any or more than 1 medical visit, (2) any illness-associated hospitalization, (3) seeking health care within 2 days of onset, and (4) use of antibiotic, over-the-counter (OTC), or antiviral medications associated with the ARI as reflected in an EMR-confirmed prescription or self-reported use of a medication during the illness.
Vaccination status
Influenza vaccination status was documented by EMRs if available or by self-report if the participant was vaccinated outside the health plan; 14 (5%) were based on self-report. Participants who received seasonal influenza vaccine 14 days or more before illness onset were considered vaccinated.
Laboratory methods
Respiratory specimens were collected using nasopharyngeal swabs and stored with transport medium in cryovials at –70°C before overnight shipping on dry ice to the Marshfield Clinic Research Foundation laboratory (Marshfield, WI). Real-time reverse transcription polymerase chain reaction (RT-PCR) was performed using primer, probes, reagents, and proficiency panel provided by the Centers for Disease Control and Prevention Influenza Division (more information at http://www.cdc.gov/flu/clsis ). We excluded participants whose specimens were collected more than 8 days after illness onset from our analysis.
Statistical methods
Six participants (2%) reported having had more than 1 ARI episode during the study period. For women testing positive for an influenza virus, we used the illness episode associated with the positive result. For influenza-negative participants, we used their first illness episode.
We compared participant characteristics using the 2-tailed χ 2 or Fisher exact test for categorical outcomes and the Student t test for continuous variables. Statistically significant ( P < .05) bivariate associations between influenza and severity indicators were followed by multivariate analyses (logistic regression) to determine whether the observed association persisted after adjusting for site, season, age, days since illness onset, and vaccination status; results were expressed as adjusted odds ratios with accompanying 95% confidence intervals. Analyses were conducted using IBM SPSS (IBM, Armonk, NY) and SAS 9.3 (SAS Institute, Cary, NC) software.
Results
Participant and illness characteristics
Of 1873 participants enrolled in the study, 353 pregnant women with 1 or more ARIs (107 influenza and 246 noninfluenza) were identified over 2 consecutive seasons. Seven influenza illnesses and 54 noninfluenza ARIs were excluded because illness onsets were outside the surveillance season or after delivery or because specimens were collected more than 8 days after illness onset.
After limiting the analyses to a single illness episode per participant, we included 292 illnesses: 100 influenza-positive and 192 noninfluenza ARIs ( Figure 1 ). All of these illnesses were medically attended, with the exception of 27 ARIs (8 influenza and 19 noninfluenza illnesses) identified as part of cohort surveillance during the first season. All 3 influenza viruses circulated in both seasons, although the median onset date of influenza illnesses was 3 weeks later in the second season (Feb. 22, 2011, vs March 14, 2012; Appendix ; Supplemental Figure ).
Influenza positivity differed by days since illness onset when the specimen was collected ( P < .05); this difference was due to the relatively high influenza positivity on day 1 since illness onset (65%) compared with a varying range of positivity noted on days 2-8 (26-44%). Combining both seasons, 45 women had RT-PCR–confirmed A(H1N1)pdm09 virus infections, 33 had A(H3N2), 1 had an unsubtyped A virus, and 21 had influenza B virus infections.
Participant characteristics are presented in Table 1 . About half of participants (54%) were white non-Hispanics, and 24% were Hispanics. At the time of illness onset, the mean age was 30.7 years, and most women were in their second (44%) or third (41%) trimester.
| Characteristics | Noninfluenza ARI (n = 192) | Influenza (n = 100) | P value | Total (n = 292) | |||
|---|---|---|---|---|---|---|---|
| Study site | |||||||
| Kaiser Permanente Northern California | 111 | (58) | 69 | (69) | NS | 180 | (62) |
| Kaiser Permanente Northwest | 81 | (42) | 31 | (31) | 112 | (38) | |
| Study season | |||||||
| 2010-2011 | 115 | (60) | 53 | (53) | NS | 168 | (58) |
| 2011-2012 | 77 | (40) | 47 | (47) | 124 | (42) | |
| Age, y, at illness onset | |||||||
| Mean ± SD | 30.9 | ±5.8 | 30.5 | ±5.8 | NS | 30.7 | ±5.8 |
| Race/ethnicity | |||||||
| Hispanic | 45 | (23) | 25 | (25) | NS | 70 | (24) |
| White, non-Hispanic | 110 | (57) | 48 | (48) | 158 | (54) | |
| Asian, non-Hispanic | 14 | (7) | 13 | (13) | 27 | (9) | |
| Other, non-Hispanic | 23 | (12) | 14 | (14) | 37 | (13) | |
| Trimester at illness onset date | |||||||
| First (7-13 wks) | 31 | (16) | 13 | (13) | NS | 44 | (15) |
| Second (14-26 wks) | 85 | (44) | 44 | (44) | 129 | (44) | |
| Third (27-42 wks) | 76 | (40) | 43 | (43) | 119 | (41) | |
| Recent health history, mean days ± SD | |||||||
| For how many days during past 30 days was… | |||||||
| Your physical health not good? | 7.1 | ±9.7 | 2.0 | ±4.9 | < .001 | 5.2 | ±8.6 |
| Your mental health not good? | 4.8 | ±8.8 | 3.0 | ±5.4 | NS | 4.1 | ±7.7 |
| Self-rated health status, at time of enrollment | |||||||
| Very good or excellent | 116 | (61) | 68 | (68) | NS | 184 | (63) |
| Good | 60 | (31) | 27 | (27) | 87 | (30) | |
| Fair or poor | 16 | (8) | 5 | (5) | 21 | (7) | |
| High-risk comorbidities a | |||||||
| At least 1 | 57 | (30) | 17 | (17) | < .05 | 74 | (25) |
| >1 | 23 | (12) | 2 | (2) | < .005 | 25 | (9) |
| History of asthma b | 27 | (14) | 2 | (2) | < .005 | 29 | (10) |
| Obese (BMI >30 kg/m 2 ) c | 59 | (31) | 15 | (15) | < .05 | 74 | (25) |
| High-risk pregnancy d | 41 | (21) | 24 | (24) | NS | 65 | (22) |
| Influenza vaccination status | |||||||
| Current season e | 112 | (58) | 42 | (42) | < .01 | 154 | (53) |
| Current season and at least 1 comorbidity | 40 | (21) | 9 | (9) | < .01 | 49 | (17) |
a High-risk comorbidities, identified during 1 year prior to conception, for which influenza vaccination is recommended by the ACIP, including cancer, diabetes mellitus, neurological disorders, chronic pulmonary disease, chronic cardiac disease, immunosuppressive disorders, chronic renal disease (codes available upon request)
b Any asthma ICD-9 code (493) in the electronic medical record within the prior year to conception
c BMI was calculated using self-reported prepregnancy weight and height
d Pregnancy complication was indicated by a medical visit associated with a subset of ICD-9 codes related to adverse pregnancy outcomes from conception through the end of the vaccine campaign for the study year (codes available upon request)
e Current season vaccinated defined as receipt of vaccine at least 14 days prior to illness onset.
Women with influenza illnesses were similar to those with noninfluenza ARIs on most sociodemographic and health indicators, with 2 exceptions: women with influenza were less likely to have a preexisting comorbidity (17% vs 30%; P < .05), including asthma (2% vs 14%; P < .005) or obesity before pregnancy (15% vs 31%; P < .05), and women with influenza reported fewer days of poor physical health in the prior 30 days (2.0 vs 7.1 days; P < .001). The lower influenza positivity associated with high-risk conditions and poor health remained statistically significant after adjusting for the higher influenza vaccination rate for those in poor health (values of P < .05).
Comparisons of influenza and noninfluenza ARI severity
Small but significant differences in symptom severity and illness impairment were observed between influenza and noninfluenza ARI. Specifically, the median summed subjective severity of 12 symptoms was 18 for influenza ARI vs 16 (of 36) for noninfluenza ARI ( P < .05; Table 2 ). Women with influenza rated their illnesses as causing greater impairment to their activities than women with noninfluenza ARI (5.9 vs 4.8 on a 9 point scale; P < .001).
| Characteristics | Noninfluenza ARI (n = 192) | Influenza (n = 100) | P value | ||
|---|---|---|---|---|---|
| Illness and specimen collection timing | |||||
| Days from onset to swab, mean days ± SD | 4.7 | ±1.8 | 4.2 | ±2.0 | < .05 |
| Subjective symptom severity and impact | |||||
| 12-symptom severity score, median/IQR a | 16 | 12-20 | 18 | 14-20 | < .05 |
| Overall subjective severity, mean score ± SD b | 4.7 | ±1.8 | 4.3 | ±2.0 | NS |
| Subjective impairment, mean score ± SD c | 4.8 | ±2.3 | 5.9 | ±1.9 | < .001 |
| Illness duration, mean days ± SD d | 10.3 | ±4.8 | 9.3 | ±4.2 | NS |
| Fever severity | |||||
| Any fever, ≥37.8°C | 47 | (24) | 63 | (63) | < .001 |
| Highly elevated fever of ≥38.9°C | 9 | (5) | 20 | (20) | < .001 |
| Highest recorded temperature, mean °C ± SD | 37.2 | ±0.8 | 38.0 | ±1.0 | < .001 |
| Medical utilization during illness | |||||
| Any medical visit for ARI e | 156 | (81) | 88 | (88) | NS |
| Two or more medical visits for ARI | 76 | (40) | 42 | (42) | NS |
| Early care-seeking behavior f | 68 | (35) | 53 | (53) | < .001 |
| First medical encounter, mean days ± SD g | 3.0 | ±2.1 | 2.4 | ±2.2 | < .05 |
| Emergency department visits | 15 | (8) | 12 | (12) | NS |
| Illness-associated hospitalization | 7 | (4) | 5 | (4) | NS |
| Use of medications | |||||
| Antibiotic prescription | |||||
| Prescribed | 30 | (16) | 11 | (11) | NS |
| Self-reported use | 21 | (11) | 9 | (9) | NS |
| Antiviral prescription | |||||
| Prescribed | 2 | (1) | 8 | (8) | NS |
| Self-reported use | 6 | (3) | 10 | (10) | NS |
| OTC medications, self-reported use | 155 | (81) | 92 | (92) | < .05 |
a Summed subjective severity of 12 symptoms: cough, fatigue, feverishness, congestion, headache, myalgia, sore throat, chills, wheezing, ear pain, nausea, and vomiting. Each symptom was rated as absent (0), mild (1), moderate (2), or severe (3), except for cough, which did not have a response option (0)
b Participants were asked to rate their health during their illness (0, normal health; 9, worse possible health)
c Participants were asked to rate their ability to perform activities during their illness (0, able to perform usual activities; 9, unable to perform usual activities; severe was defined as an impairment rate of ≥6)
d Mean illness duration was calculated using only the response from those participants who could recall the date their illness ended (noninfluenza ARI [n = 139] and influenza [n = 75])
e Medically attended acute respiratory illness visits that occurred between onset and recovery date with at least 1 of these ICD-9 codes: 460-466, 480-488 or 490-491
f Medically attended 2 days or less following onset
g Days between illness onset and first medical visit (includes only those people who had medical encounters).
In terms of specific symptoms, women with influenza were more likely to report severe subjective feverishness (18% vs 5%; P < .001), myalgia (28% vs 14%, P < .005), cough (46% vs 30%, P < .01), and chills (25% vs 13%; P < .01; Table 3 ). On average, women with influenza described their cough, nasal congestion, and fatigue as severe; however, only cough was statistically more severe for those with influenza ( Figure 2 ); myalgia, fever, and chills were more severe among those with influenza, but the mean severity rating for each of these symptoms was moderate.
| Characteristics | Percentage self-reported as severe | ||||
|---|---|---|---|---|---|
| Noninfluenza ARI (n = 192) | Influenza (n = 100) | P value | |||
| Upper respiratory symptoms | |||||
| Nasal congestion | 90 | (47) | 42 | (42) | NS |
| Sore throat | 65 | (34) | 23 | (23) | NS |
| Ear pain | 17 | (9) | 11 | (11) | NS |
| Lower respiratory symptoms | |||||
| Cough a | 57 | (30) | 46 | (46) | < .01 |
| Wheezing | 11 | (6) | 4 | (4) | NS |
| Systemic symptoms | |||||
| Fatigue | 66 | (34) | 41 | (41) | NS |
| Myalgia | 26 | (14) | 28 | (28) | < .005 |
| Feverishness | 9 | (5) | 18 | (18) | < .001 |
| Chills | 25 | (13) | 25 | (25) | < .01 |
| Headache | 48 | (25) | 18 | (18) | NS |
| Gastrointestinal symptoms | |||||
| Vomiting | 15 | (8) | 5 | (5) | NS |
| Nausea | 18 | (9) | 5 | (5) | NS |
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