Rogers, Vanessa Laibl MD; Sheffield, Jeanne S. MD; Roberts, Scott W. MD; McIntire, Donald D. PhD; Luby, James P. MD; Trevino, Sylvia MT; Wendel, George D. Jr MD
Historical reports of seasonal influenza in pregnancy have suggested that there is associated morbidity and mortality. During the influenza epidemic of 1918, it was reported that 27% of pregnant women with influenza died from complications of the infection.1 Fifty percent were diagnosed with pneumonia. Influenza activity in New York in 1957 was associated with a disproportionate number of deaths in pregnant women.2
More recent studies have shown there to be less morbidity and mortality associated with seasonal influenza than had been reported previously. It is unclear whether this is the result of the virulence of the predominant strain or advances in supportive care. Irving et al, in 2000, found that pregnant women with influenza had significantly more overall obstetric complications compared with matched pregnant women who did not experience antepartum influenza; however, no single complication occurred more frequently and no woman died from influenza.3 Tuyishime et al, in 2003, found that pregnant women had frequent doctor visits for influenza-like illness but infrequent complications.4 There have been no contemporary, prospective studies describing the clinical presentation, diagnostic accuracy, or natural history of laboratory-confirmed seasonal influenza in pregnancy.
The 2003–2004 influenza season was unique in that heavy activity was seen early and moderately severe illness was reported. Activity peaked during weeks 47–52 of 2003. There were more office visits for influenza-like illness documented than any other season since 1998. This was attributed to a mismatch between the circulating strain of influenza A (H3N2) and the vaccine strain.5
Despite the recommendations of the Advisory Committee on Immunization Practices, the Centers for Disease Control, and the American College of Obstetricians and Gynecologists that all women pregnant during the influenza season be immunized regardless of gestational age, a survey by the American College of Obstetricians and Gynecologists administered in 2004 showed that 36% of obstetricians and gynecologists did not offer vaccination in their practice during the 2003–2004 season. In a national survey of health care providers in 2005, the Centers for Disease Control and Prevention (CDC) found that only 15% of pregnant women had been vaccinated for influenza in the previous 12 months.6 This combination of increased seasonal activity and limited vaccination resulted in an unexpected opportunity to better study influenza in pregnancy.
The purpose of this study is to describe the clinical presentation and natural course of laboratory-confirmed influenza in pregnant women followed at Parkland Memorial Hospital in Dallas, Texas during the 2003–2004 influenza season. As we enter a new era in influenza, when the sensitivity of rapid testing is limited, these details can perhaps be used to better identify infected pregnant women. The rise in novel influenza strains like H1N1 (swine), indicates that we must become hypervigilant in an attempt to control resulting morbidity and mortality.7
This was a prospective observational study of all pregnant women presenting to Parkland Memorial Hospital in Dallas, Texas diagnosed with influenza A during the 2003–2004 season. This study was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center in Dallas, Texas. Study participants were identified in the Labor and Delivery triage area, the Obstetrics and Gynecology emergency room, the prenatal clinics serving high-risk obstetrical patients, and the postpartum wards. Data were collected between October 22, 2003, and January 18, 2004.
Patients were uniformly evaluated following clinical practice guidelines developed to direct providers' management of pregnant women presenting with an influenza-like illness. Women complaining of symptoms consistent with influenza including cough, myalgias, sore throat, nasal drainage, headache, malaise and subjective fever were evaluated using rapid diagnostic tests, cultures, or both. Diagnostic tests included an optical immunoassay test (Biostar kit; Inverness Medical-Biostar Inc., Louisville, CO) and a direct fluorescent antibody test (Chemicon monoclonal stain; Millipore, Billerica, MA). Results of the optical immunoassay test were available in 1 hour, and direct fluorescent antibody test results were available in 24 hours. The diagnosis of influenza required confirmation by a positive optical immunoassay test, direct fluorescent antibody test, or viral culture. Viral cultures were initially sent on all patients diagnosed by rapid testing to type the viral isolate. Later, cultures were sent only on patients in whom there was a high clinical suspicion of influenza but negative diagnostic testing. Patients diagnosed with influenza underwent a chest X-ray to evaluate for pneumonia.
Patients were admitted to the hospital if they had sustained tachycardia (at least 110 beats per minute [bpm]), fever at least 38.0°C, pneumonia, threatened preterm labor, or an inability to tolerate oral therapy. Also, during these admissions, other causes of maternal fever such as chorioamnionitis or pyelonephritis could be excluded. Study patients were interviewed by a member of the research team, and prenatal charts were reviewed to assess for risk factors and vaccination history. Obstetric and neonatal outcomes were also collected.
Patients who reported symptoms for 2 days or fewer were treated with 5 days of amantadine or rimantadine in accordance with CDC recommendations.8 Patients were evaluated for evidence of superimposed bacterial infections and treated with appropriate antibiotics when necessary. After resolution of their illness, patients were treated in a specialized infectious disease prenatal clinic. Patients, after recovering, were offered vaccination to protect them from the strains of influenza covered by the vaccine.
Descriptive statistics were calculated on the cohort, and the patients' pregnancy outcomes were compared with all other pregnant women who delivered at Parkland Memorial Hospital in 2003 and 2004. Selected obstetric and neonatal outcomes were obtained from a previously described, continuously updated, obstetric computerized database.9 Statistical analyses included the χ2 for categorical data and the Student t test for continuous variables. P<.05 (two-tailed) was judged to be statistically significant. Data were analyzed by SAS 9.1 statistical software (SAS Institute, Cary, NC).
During the 2003–2004 season, 107 pregnant women were diagnosed with seasonal influenza A. The majority of cases were diagnosed in November 2003 (80 of 107). No patient was diagnosed after January 31, 2004.
Demographic characteristics are listed in Table 1. More than half of the patients were Hispanic, which reflects our general obstetric population. Most of the patients had no comorbid conditions. Influenza was diagnosed most commonly in the third trimester (45%, 95% confidence interval [CI] 35–55%). Those diagnosed postpartum were within 1 week of delivery. Half of the patients reported exposure to a sick contact with influenza; and of those, 56% reported that the sick contact was a child in their home. Other reported exposures included spouses (24%), multiple family members (15%), and non–family members (5%). The majority of patients had not been vaccinated (88%) against influenza during this pregnancy. Of the 13 patients vaccinated before the onset of symptoms, only three had been vaccinated more than 2 weeks before becoming ill (3%, 95% CI 1–8%).
Reported signs and symptoms are listed in Table 2. Cough was the most frequently reported symptom. More than half of patients also reported nausea and vomiting. Most patients had a documented fever before or on admission. The mean maximum recorded body temperature was 38.2°C±0.8°C. Two patients had maximum recorded body temperatures of more than 40°C. Tachycardia was defined as a heart rate higher than 100 bpm and was present in 85% of the cases admitted. In 21% of cases, patients had a maximum recorded heart rate of higher than 130 bpm. In many cases, the degree of tachycardia was disproportionately high compared with maternal fever, assuming an increase in heart rate of 10 bpm for every 1°F increase in body temperature. In addition, the tachycardia was frequently refractory to intravenous fluid resuscitation and not attributable to hypovolemia or hypotension.
The diagnosis of influenza was made by rapid diagnostic tests and cultures. In 89% of cases, the patient was diagnosed by a positive optical immunoassay or direct fluorescent antibody test result. Twelve patients were diagnosed by viral culture. Six of those patients had false negative optical immunoassay and direct fluorescent antibody test results. In the other six diagnosed by culture, either the diagnostic tests were inadequate or were not received by the laboratory. All isolates subtyped were influenza A (H3N2). One patient was diagnosed with both influenza A and B. Overall, 18% (95% CI 12–27%) of optical immunoassay test samples were false negatives, confirmed by direct fluorescent antibody test or viral culture or both.
Sixty-two percent of patients required hospital admission for the previously described indications. Thirty-three percent of the first trimester patients, 66% of the second trimester patients, and 62% of the third-trimester patients were admitted. Forty-one patients admitted for influenza were not delivered during that hospital stay. Those patients' admissions were for influenza alone, and the median length of stay was 3.0 days (interquartile range 3, 3 [first quartile, third quartile]). Ninety-three percent of patients received either amantadine or rimantadine for treatment. Neuraminidase inhibitors were not available for use at our institution at the time of the study.
The most common maternal complication was pneumonia, which occurred in 12% of patients. Chest X-rays identified lobar infiltrates in all cases of pneumonia. One patient was diagnosed with pneumonia, myocarditis, and meningitis. This was an otherwise healthy 15-year-old African-American girl at 25 weeks of gestation. She required admission to the intensive care unit. She had an intrauterine fetal death while in the hospital. The fetus had multiple anomalies as well as growth restriction, and the death was unlikely to have been solely the result of her illness. There were no intubations, maternal deaths, or complications of treatment.
Obstetric and neonatal outcomes were available for 81 of the women and are listed in Table 3. Most women delivered at term. No woman went into spontaneous labor at less than 34 weeks of gestation. Indications for cesarean delivery included previous cesarean (55%), fetal distress (23%), arrest of the active phase of labor (14%), genital herpetic recurrences (4%), and cord prolapse (4%). Two women were diagnosed with influenza at the time of midtrimester inductions of labor for lethal fetal anomalies. One woman had an unexplained fetal demise at term and subsequently developed influenza during labor. This patient underwent an induction of labor and complained of symptoms of influenza on hospital day 2, the day of delivery. The fetus had severe growth restriction, and the stillbirth was felt to be unrelated to influenza. The outcomes for these three patients were not included in the table. Chorioamnionitis and severe preeclampsia each occurred in 10% of patients. These outcomes were compared with those of our general obstetric population delivered in 2003 and 2004. There were no significant differences in the rates observed.
The 2003–2004 influenza season was one of the most active in recent years. This provided an unexpected opportunity to observe and record the infection's presentation and natural course in pregnant women. As opposed to some previous studies, all patients had a laboratory-confirmed diagnosis of influenza A.
Unfortunately, very few of the women had been vaccinated, as most of the cases occurred so early in the season. Typically, influenza activity spans October through March with the peak in January.3 Three patients had been vaccinated more than 2 weeks before the onset of symptoms. We made the distinction of 2 weeks, because that is the time frame thought needed for antibody and active immunity development.3 These patients represented vaccine failures. Currently, we offer vaccination as soon as it becomes available, usually in early October.
Patients were diagnosed in all trimesters of pregnancy and postpartum. This supports the recommendation to vaccinate all pregnant women at any gestational age and any women who may become pregnant during the influenza season. The women infected were young, and most were otherwise healthy. All of the patients with a comorbid condition required hospitalization, perhaps indicating they were more severely affected by the illness. Importantly, the sickest patient with the most severe complications was also one of the youngest, and she had no comorbid conditions. Infected patients in the third trimester were not more likely to be admitted than patients in the second trimester; however fewer admissions occurred in women in the first trimester. Whitley et al reported increased rates of admission for influenza as pregnancy progressed and if comorbidities were present.10 It is possible that clinicians may have a lower threshold for admitting any third trimester pregnant patient with a fever to exclude obstetric infections, such as chorioamnionitis, that would mandate delivery.
The occurrence of postpartum influenza is notable and deserves further comment. Despite strict contact isolation of confirmed cases, it is possible that these women were exposed to influenza while hospitalized. Viral shedding can occur at least 1 day before and up to 5 days after the onset of clinical symptoms.11 Three of the five women diagnosed postpartum denied exposure to sick contacts. This stresses the importance of vaccinating women even late in pregnancy and before discharge from the hospital postpartum.
Symptoms of influenza in pregnancy were mostly consistent with what has been reported in nonpregnant, infected adults.12,13 However, nearly two thirds of patients complained of nausea and vomiting. This group contained the same percentage of women in the first trimester as the overall cohort; thus the nausea and vomiting typically seen in early pregnancy cannot explain this finding. Nausea and vomiting has been reported as a symptom of influenza in the pediatric population,14 but not in adults. The most striking observation we noted was the profound tachycardia identified in the majority of patients. It was frequently sustained and refractory to intravenous hydration and antipyresis. Electrocardiograms indicated a sinus tachycardia, which improved with resolution of symptoms, usually within 24–48 hours.
Patients were included in the cohort if they had any positive laboratory test for influenza, a positive viral culture, or both. Providers were educated on the proper collection of nasopharyngeal samples. Nasopharyngeal samples were collected instead of pharyngeal samples because they are felt to be of higher yield in diagnosing influenza.3,15 We were surprised by the number of false negative diagnostic tests. Hindiyeh et al reported a sensitivity of 54% and a specificity of 97% for the Biostar FLU optical immunoassay test.16 We diagnosed influenza in patients with a positive optical immunoassay test result and initiated treatment without confirmation of the result by another test. However, if a patient had a negative optical immunoassay test result, a direct fluorescent antibody test was ordered from the same specimen. This reflex testing coupled with viral cultures for patients with a negative optical immunoassay and direct fluorescent antibody test, but highly suspicious clinical presentations, improved identification of infected individuals in our cohort. Problems with the sensitivity of rapid testing are also being reported for influenza A (H1N1) with the CDC quoting a sensitivity of 10–70%.17
Given the severity of illness seen in some patients and the frequency of pneumonia, we began antiviral therapy in all pregnant women diagnosed with influenza who had symptoms for less than 48 hours. Amantadine and rimantadine were chosen for their availability on our hospital formulary and efficacy in adults at the time of the study. Both drugs are listed as Food and Drug Administration pregnancy category C.18 Despite limited human safety data, the benefits of maternal treatment were felt to outweigh the potential risks. Since the collection of these data, prevalent strains of influenza A have developed resistance to these drugs as well as oseltamivir. Current recommendations do not include amantadine and rimantadine.19 Oseltamivir and zanamivir are the only medications currently recommended for treatment of influenza; however, data on safety and efficacy in pregnancy are very limited.
There was no significant increase in the rate of preterm births identified in those patients diagnosed with influenza. No patient delivered a fetus at less than 34 weeks of gestation. There were several fetuses with anomalies; however, influenza was diagnosed in these women after the anomalies had been identified. Of the 15 women diagnosed with influenza in the first trimester, 13 delivered at our institution. All delivered term fetuses with no anomalies or complications. For all reviewed parameters, there was no difference between those women with laboratory confirmed influenza A and the general obstetric population.
This study does have some limitations. The total number of patients with influenza-like illness who were tested and not diagnosed with influenza was not available for comparison. A report of a single season may reflect the clinical manifestations of a particular strain of virus and not be generalizable to other strains or seasons. Since data collection for this study, protocols for the evaluation of pregnant women with influenza-like illness have remained in place, and illness of this severity and frequency has not been observed again in our institution until this year with the emergence of influenza A (H1N1). Finally, the lack of maternal morbidity and mortality may be a reflection of the early presentation for evaluation and rapid initiation of treatment in our health system. All pregnant women were seen in an Obstetrics and Gynecology emergency room or Labor and Delivery triage area staffed by specialized nurse practitioners or Obstetrics and Gynecology residents. The value of this rapid response for pregnant women with influenza may be essential to preventing maternal complications.
Influenza, in recent years, has been the subject of great public interest. This likely stems from its potential for great morbidity and mortality in the face of very effective prevention measures like vaccination. It is difficult to predict how severe any given season will be, how well-matched the vaccine will be, or when activity will peak. This study confirms the importance of universal vaccination in all pregnant women regardless of gestational age. It also describes a clinical presentation of antepartum influenza, which should prompt a thorough evaluation and rapid initiation of appropriate care.
We found that the presentation of seasonal influenza in pregnancy is similar to that of adults, except it is usually accompanied by nausea and vomiting and tachycardia out of proportion to the maternal fever. Importantly, we observed no increased rates of maternal complications of influenza, especially pneumonia, and we noted no increased rates of obstetric complications. Clinicians and patients should be reassured that the timely diagnosis and initiation of treatment of influenza in healthy pregnant women most likely will result in an uncomplicated resolution of maternal infection and a normal pregnancy outcome.
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