The majority of women (61.2%) were admitted in the third trimester with smaller numbers in the second (28.1%) and first (7.9%) trimesters. Only 2.8% were admitted within the first 2 weeks after delivery. Of the 346 women who were pregnant when admitted, 26.0% delivered during their influenza-like illness hospitalization and 74.0% were discharged undelivered. Thirty-five women (9.8%) required admission to an ICU and three received extracorporeal membrane oxygenation. Of the ICU admissions, 42.9% were transferred from another hospital to a Maternal-Fetal Medicine Units Network study hospital. Only 7.8% of the remaining 321 women were transferred from other hospitals. Excluding maternal deaths, the mean duration of hospital stay was 3.2±3.9 days, 9.6±7.9 days in those admitted to the ICU and 2.6±2.5 days in those not admitted in the ICU. Forty-six women (12.9%) received antiviral medication before the current hospital admission and 10.1% received antiviral medication before any hospitalization for the current influenza-like illness (before transfer hospitalization if transferred). All but one of these women received oseltamivir; one received zanamivir. Eighty-eight percent of the women received antiviral medications during their hospitalization; 312 received oseltamivir, two received oseltamivir and peramivir, and one received zanamivir.
Characteristics of the study population by type of hospitalization are presented in Table 1. Nine women (2.5%) were pregnant with a multiple gestation with no significant difference between groups. Fifty-three women (14.9%) smoked cigarettes during the current pregnancy with a significantly higher proportion in the women who required admission to an ICU (29.4% compared with 13.4%). Pregnant women with influenza-like illness requiring ICU admission were more likely to have chronic hypertension but were not significantly more likely to have other concurrent medical conditions, including obesity, asthma, anemia, diabetes, or medication allergy.
Influenza vaccination status was not documented in a large proportion of the patients (26.4% for the 2009–2010 seasonal influenza vaccine and 34.3% for the H1N1 swine flu vaccine). Although women requiring ICU admission appeared less likely to have received the H1N1 vaccine (5.7% compared with 13.4%), the high proportion of missing data (57.1% compared with 31.8%) precludes any definite conclusion.
Women requiring ICU admission were less likely to have received antiviral treatment within 2 days of symptom onset than women not admitted to the ICU (31.4% compared with 56.6%). Women requiring ICU admission were more likely to report difficulty breathing (79.4% compared with 34.6%; P<.001) and to require oxygen support (48.6% compared with 2.5%; P<.001) but were less likely to self-report a headache (14.7% compared with 35.8%; P=.01) or fever (64.7% compared with 81.0%; P=.03) at the time of admission. There were no differences at admission between groups in the frequency of cough, sore throat, nasal stuffiness, body aches or myalgia, nausea, vomiting, or diarrhea. All of the women who were intubated at the time of admission were admitted directly to an ICU.
Table 2 describes the factors independently associated with ICU admission. After multivariable adjustment, cigarette smoking and chronic hypertension remained significantly associated with an increased frequency of ICU admission, and early antiviral treatment remained significantly associated with a decreased likelihood of ICU admission.
Four women in this registry died during their index influenza-like illness hospitalization for a maternal mortality rate of 1.1% (95% confidence interval, 0.3–2.9). All of these deaths were the result of respiratory failure. No maternal deaths were identified after the index influenza-like illness hospitalization discharge through 2 weeks postpartum.
Table 3 describes the frequency of maternal morbidity and its components by use and timing of antiviral treatment. Overall, antiviral therapy was not associated with maternal morbidity. However, maternal morbidity was significantly less frequent in those receiving antiviral therapy within 2 days of symptom onset. Renal or liver dysfunction could not be assessed because the majority of patients (58.1%) did not have relevant laboratory testing. Superimposed bacterial infections from urine or throat cultures were uncommon; four women had culture-proven pyelonephritis or urosepsis and three had Group A streptococcal pharyngitis; all were in women who had a positive influenza test and therefore included in this registry.
Delivery outcomes were obtained in 315 (88.5%) of the patients. Among the patients discharged undelivered, the patients lost to follow-up were more likely to have been transferred from another hospital and were uninsured or self-pay (data not shown).
Table 4 describes the frequency of delivery outcomes by use and timing of antiviral treatment. Mode of delivery and the perinatal composite outcome did not vary by antiviral status. The overall preterm birth rate (less than 37 weeks) was 18.7%, including 15.9% in those treated with antivirals within 2 days of symptom onset, 19.6% in those treated after 2 days, and 29.7% in those not treated with antivirals; these differences were not statistically significant. No neonate had grade III or IV intraventricular hemorrhage and neonatal influenza infection could not be assessed because only 2.5% had an influenza test.
Ninety (25.3%) patients delivered during their index influenza-like illness hospitalization with a mean duration of hospital stay of 5.3±5.4 days. Among these women, the percent experiencing preterm labor, preterm rupture of the membranes, and a preterm delivery was 5.6%, 7.8%, and 26.7%, respectively. Forty (44.4%) delivered by cesarean, 40% of which were the result of nonreassuring fetal status. Fourteen women (15.6%) had an emergency cesarean delivery, eight of which were in intubated women.
In this large prospective observational cohort of hospitalized pregnant and recently postpartum women with influenza-like illness, 9.8% were admitted to the ICU and 1.1% died. Admission to the ICU was more common if women smoked or had chronic hypertension and was less common if women received antivirals within 2 days of the onset of symptoms.
Our data are derived from an active surveillance protocol using detailed real-time review of medical records. This allows for more detailed and precise information than can be acquired from passive reporting and surveillance.8,9 However, this study was conducted under a waiver of consent to minimize selection bias, which precluded interview of hospitalized women or their healthcare providers to obtain additional medical history or pregnancy follow-up. As a result, pregnancy outcomes for 41 of 256 (16.0%) women discharged undelivered were not available.
The majority was admitted in the third trimester (61.2%), a trend noted by other investigators.9 – 11 This presumably reflects the increased vulnerability imposed by the physiological changes of late pregnancy3–4 and likely also reflects increased concerns for fetal well-being. Although the increase in cardiac output and extracellular fluid seen in the latter half of pregnancy is more pronounced in women with multifetal pregnancies, we did not see an increased rate of influenza-like illness hospitalizations in women with multifetal pregnancies.
This registry is limited to pregnant and recently postpartum women with influenza-like illness whose illness was sufficiently severe to warrant hospitalization and our findings should not be extrapolated to the general obstetric population. Nonetheless, women with severe disease requiring admission to an ICU were more likely to smoke cigarettes or to have chronic hypertension.
Twenty percent of our cohort had a diagnosis of asthma. This finding is similar to an early report from Australia in which 21.4% of pregnant women hospitalized with influenza also had underlying asthma.12 Three women required extracorporeal membrane oxygenation, similar to other studies that have described the use of this intervention in pregnant women who were critically ill with influenza pneumonia.12 – 14
Likewise, the association of increased influenza severity in individuals with vascular disease has been described.15 The association of chronic hypertension with increased severity of influenza illness during pregnancy, however, has not been commonly reported.
Hospitalized pregnant women with influenza-like illness and either asthma or diabetes were not significantly more likely to require ICU admission, although the frequency of influenza in women with asthma or diabetes who did not require hospital admission is not available.
The chronologic distribution of hospital admissions parallels other concurrent real-time reporting systems. More than half occurred in October 2009 and an additional one-fourth in November 2009 with rapidly decreasing numbers thereafter (Fig. 2). It should be noted that the 2009–2010 U.S. influenza-like illness pandemic began in the summer of 2009 and we are unable to comment on the frequency or severity of illness or the response of healthcare providers before October 2009. The absence of an additional large outbreak during the usual U.S. peak influenza season is at least in part a testament to effective public education and immunization campaigns nationwide during the 2009–2010 influenza pandemic.
Increased rates of preterm labor, delivery, or both have been reported during previous H1N1 influenza A pandemics.16,17 Considering the association between infection and preterm birth, this association is not surprising. Early reports from the current pandemic have also suggested an increased rate of preterm birth.12 Similarly, we observed a preterm birth rate of 18.7% overall and 26.7% in those who delivered during their index hospitalization.
The majority of our cohort (88.5%) received antiviral medication during their hospitalization. Women in our study admitted to ICUs were less likely to have received antiviral treatment within 2 days of symptom onset, a finding reported by others.18 Consistent with other reports,19 we did not observe any obvious fetal or immediate neonatal adverse effects from in utero exposure to antiviral medications (almost entirely oseltamivir). However, our sample size and relatively high lost-to-follow-up rates for delivery outcomes preclude any definitive statement. In addition, the majority of our participating hospitals serve as referral centers for their surrounding communities. As such, it is likely that our reported rates of admissions and complications are higher than those found in a nonreferral population.
These data also re-emphasize the importance of smoking cessation efforts for all pregnant women. In addition, 17.7% (Fig. 1) of patients had a positive influenza test and symptoms but did not fulfill the CDC influenza-like illness diagnostic criteria at the time of admission, emphasizing the importance of a high index of suspicion of influenza in symptomatic pregnant women.
Our data cannot comprehensively assess the effect of vaccination on the morbidity associated with 2009–2010 H1N1 pandemic. Although we were relieved that our original sample size estimates were not reached, it remains disappointing to have seen such serious outcomes associated with influenza-like illness during a time period when vaccination of the pregnant population was a public health priority.
In summary, chronic hypertension and smoking in pregnancy, but not asthma or diabetes, were associated with an increased likelihood of ICU admission in influenza-like illness hospitalizations in this large prospective cohort. In addition, early treatment with appropriate antivirals was associated with a decreased frequency of ICU admissions.
2. Centers for Disease Control and Prevention Definition of influenza-like illness. Available at: www.cdc.gov/h1n1flu/casedef.htm
. Retrieved January 27, 2011.
3. Mabie WC, DiSessa TG, Crocker LG, Sibai BM, Arheart KL. A longitudinal study of cardiac output in normal human pregnancy. Am J Obstet Gynecol 1994;170:849–56.
4. Robson SC, Hunter S, Moore M, Dunlop W. Haemodynamic changes during the puerperium: a Doppler and M-mode echocardiographic study. Br J Obstet Gynaecol 1987;94:1028–39.
6. Fraser C, Donnelly CA, Cauchemez S, Hanage WP, Van Kerkhove MD, Hollingsworth TD, et al.. Pandemic potential of a strain of influenza A (H1N1): early findings. Science 2009;324:1557–61.
7. Li FCK, Choi BCK, Sly T, Pak AWP. Finding the real case-fatality rate of H5N1 avian influenza. J Epidemiol Community Health 2008;62:555–9.
8. Creanga AA, Johnson TF, Graitcer SB, Hartman LK, Al-Samarrai T, Schwartz AG, et al.. Severity of 2009 pandemic influenza A (H1N1) virus infection in pregnant women. Obstet Gynecol 2010;115:717–26.
9. Louie JK, Acosta M, Jamieson DJ, Honein MA; California Pandemic (H1N1) Working Group. Severe 2009 H1N1 influenza in pregnant and postpartum women in California. N Engl J Med 2010;362:27–35.
10. Jamieson DJ, Honein MA, Rasmussen SA, Williams JL, Swerdlow DL, Biggerstaff MS, et al.. H1N1 2009 influenza virus infection during pregnancy in the USA. Lancet 2009;374:451–8.
11. Creanga AA, Kamimoto L, Newsome K, D'Mello T, Jamieson DJ, Zotti ME, et al.. Seasonal and 2009 pandemic influenza A (H1N1) virus infection during pregnancy: a population-based study of hospitalized cases. Am J Obstet Gynecol 2011;204(suppl 1):S38–45.
12. Hewagama S, Walker SP, Stuart RL, Gordon C, Johnson PD, Friedman ND, et al.. 2009 H1N1 influenza A and pregnancy outcomes in Victoria, Australia. Clin Infect Dis 2010;50:686–90.
13. Welch SA, Snowden LN, Buscher H. Pandemic (H1N1) 2009 influenza, pregnancy and extracorporeal membrane oxygenation. Med J Aust 2010;192:668.
14. Oluyomi-Obi T, Avery L, Schneider C, Kumar A, Lapinsky S, Menticoglou S, et al.. Perinatal and maternal outcomes in critically ill obstetrics patients with pandemic H1N1 Influenza A. J Obstet Gynaecol Can 2010;32:443–7–52, 448–52.
15. Ugarte S, Arancibia F, Soto R. Influenza A pandemics: clinical and organizational aspects: the experience in Chile. Crit Care Med 2010;38(suppl):e133–7.
16. Harris JW. Influenza occurring in pregnant women. JAMA 1919;72:978–80.
17. Freeman DW, Barno A. Deaths from Asian influenza associated with pregnancy. Am J Obstet Gynecol 1959;78:1172–5.
18. Siston AM, Rasmussen SA, Honein MA, Fry AM, Seib K, Callaghan WM, et al.. Pandemic 2009 influenza A (H1N1) virus illness among pregnant women in the United States. JAMA 2010;303:1517–25.
19. Greer LG, Sheffield JS, Rogers VL, Roberts SW, McIntire DD, Wendel GD Jr. Maternal and neonatal outcomes after antepartum treatment of influenza with antiviral medications. Obstet Gynecol 2010;115:711–6.
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