Varner, Michael W. MD; Rice, Madeline Murguia PhD; Anderson, Brenna MD; Tolosa, Jorge E. MD, MSCE; Sheffield, Jeanne MD; Spong, Catherine Y. MD; Saade, George MD; Peaceman, Alan M. MD; Louis, Judette M. MD; Wapner, Ronald J. MD; Tita, Alan T. N. MD, PhD; Sorokin, Yoram MD; Blackwell, Sean C. MD; Prasad, Mona MPH, DO; Thorp, John M. Jr MD; Naresh, Amber MD; Van Dorsten, J. Peter MD; for the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units Network (MFMU)
From the Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, Salt Lake City, Utah; Brown University, Providence, Rhode Island; Oregon Health & Science University, Portland, Oregon; the University of Texas Southwestern Medical Center, Dallas, Texas; the University of Texas Medical Branch, Galveston, Texas; Northwestern University, Chicago, Illinois; Case Western Reserve University–MetroHealth Medical Center, Cleveland, Ohio; Columbia University, New York, New York; the University of Alabama at Birmingham, Birmingham, Alabama; Wayne State University, Detroit, Michigan; the University of Texas Health Science Center at Houston, Houston, Texas; The Ohio State University, Columbus, Ohio; the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; the University of Pittsburgh, Pittsburgh, Pennsylvania; the Medical University of South Carolina, Charleston, South Carolina; the George Washington University Biostatistics Center, Washington, DC; and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland.
* For a list of other members of the NICHD MFMU, see the Appendix online at http://links.lww.com/AOG/A251.
Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HD40544, HD40500, HD53118, HD53097, HD40512, HD40560, HD34208, HD27917, HD40545, HD27915, HD34116, HD40485, HD21410, HD36801, HD27869 and 5UL1RR025777). Its contents do not necessarily represent the official view of NICHD or the National Institutes of Health.
The authors thank Peggy Reed, RN, and Jo-Ann Tillinghast, RN, MSN, for protocol development and coordination between clinical research centers; and Elizabeth Thom, PhD, for protocol and data management, and statistical analysis.
Presented in part at the 2011 Society for Maternal-Fetal Medicine, February 10–12, 2011, San Francisco, CA.
Dr. Spong, Associate Editor of Obstetrics & Gynecology, was not involved in the review or decision to publish this article.
Corresponding author: Michael W. Varner, MD, Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, 30 North 1900 East, Room 2A226, Salt Lake City, UT 84132; e-mail: email@example.com.
Financial Disclosure The authors did not report any potential conflicts of interest.
In April 2009, an outbreak of a novel H1N1 influenza A began in Mexico1; it was a triple recombinant virus, including gene segments of human, swine, and avian origin. The initial reports described a mortality rate of 7% with this infection.1 The virus quickly spread, and on June 11, 2009, the World Health Organization raised the pandemic alert to level 6, indicating efficient human-to-human spread in multiple countries.2 As part of the World Health Organization preparedness statement, individual countries were expected to implement individual, societal, pharmaceutical, and national action plans. Given that the severity of this pandemic was still unknown, and that pregnant women were considered to be at risk of increased morbidity and mortality, it was of clinical and public health importance to capture accurate information on pregnant and immediately postpartum women during the pandemic. The objective of this study was to estimate characteristics and outcomes of pregnant and immediately postpartum women hospitalized with influenza-like illness during the 2009–2010 influenza pandemic and the factors associated with more severe illness.
MATERIALS AND METHODS
This was an observational study of the Maternal-Fetal Medicine Units Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development designed to estimate characteristics and outcomes of pregnant and immediately postpartum women hospitalized with influenza-like illness during the 2009–2010 influenza pandemic in the United States. The study was conducted at 28 hospitals in 14 states of the United States and the Maternal-Fetal Medicine Units Network's independent data coordinating center. Potential eligible women were identified by daily surveillance from October 1, 2009, through May 31, 2010. Hospital inpatient units, observation units, intensive care units, emergency room departments, and mortality logs or mortality committee reviews were screened daily by trained research personnel for women who were pregnant or within 14 days after delivery of a pregnancy of at least 20 0/7 weeks of gestation by best obstetric estimate. The 2-week postpartum interval was included because women who acquired an influenza-like illness would still have pregnancy-associated physiology.3,4 This interval would also have allowed direct comparison with then-current Centers for Disease Control and Prevention (CDC) recommendations.5 Hospitalization was defined as any hospital stay lasting 12 or more hours or in-hospital death before admission. Influenza-like illness was defined as a clinical suspicion of influenza and either meeting the CDC definition of influenza-like illness2 (fever 100.0°F or higher and cough, sore throat, or both) or having a positive influenza test during a current influenza-like illness (including preadmission, in-hospital, or postmortem).
Women were excluded if they had infectious conditions in the absence of a positive influenza test: acute pyelonephritis or urosepsis; positive rapid test or culture for group A streptococcal pharyngitis; aspiration pneumonia or pneumonitis from smoke inhalation; Pneumocystis pneumonia; Epstein-Barr virus or mononucleosis; cytomegalovirus; and active tuberculosis.
Because of public health concerns and potential selection bias, this study was conducted under a waiver of informed consent and a Health Insurance Portability and Accountability Act waiver from each of the participating hospitals. The study was approved by the institutional review boards of all participating centers.
Clinical data were collected from available hospital medical records by trained and certified research personnel who abstracted the information onto prespecified research data forms. Data forms were entered at each clinical center using a web-based data entry system that was managed by the data coordinating center, which was responsible for data analysis.
All registry patients were followed for pregnancy outcomes. The primary outcome was maternal mortality attributed to influenza-like illness during the index influenza-like illness hospitalization. Secondary maternal outcomes included mortality resulting from influenza-like illness after discharge, cesarean delivery, and severe maternal morbidity, defined as intensive care unit (ICU) admission, superinfection with bacterial pneumonia (positive radiograph and positive sputum culture), intubation, renal or liver dysfunction, or bacteremia or sepsis (positive blood culture). The secondary perinatal composite outcome included fetal death, preterm birth (less than 37 weeks), neonatal influenza infection (positive influenza test), neonatal ICU admission, respiratory distress syndrome, grade III or IV intraventricular hemorrhage, necrotizing enterocolitis, neonatal sepsis, neonatal death, or major congenital malformations. These primary and secondary outcomes were determined a priori.
At the time of study initiation, the estimated general population case fatality rate for 2009 H1N1 influenza A was 0.4%6 and 0.1% for seasonal influenza.7 Assuming a 50% higher rate for hospitalized patients with influenza-like illness (ie, 0.6%), a sample size of 3,490 would be required to detect with 90% power a doubling of the mortality rate for influenza-like illness among hospitalized pregnant and immediate postpartum women compared with that expected among the general hospitalized population.
Continuous variables were compared by type of maternal hospital admission (ICU admission compared with non-ICU admission) with the use of the Wilcoxon rank-sum test and categorical variables with the use of the chi-squared test or the Fisher's exact test when appropriate. Logistic regression was used to examine which baseline factors were independently associated with ICU admission. Logistic regression was used to examine the association between antiviral treatment and cesarean delivery and between each of the composite secondary outcomes adjusting for maternal age, smoking, asthma, anemia in current pregnancy, chronic hypertension, diabetes (pregestational or gestational), and medication allergy. The cesarean delivery and perinatal composite outcomes were also adjusted for maternal ICU admission during the index influenza-like illness hospitalization. For all secondary outcomes, P values of <.05 were considered to indicate statistical significance and no adjustments were made for multiple comparisons.
Because the characteristics of the impending epidemic were not known, provisions were made for interim analyses and possible early dissemination of results.
From October 1, 2009, through May 31, 2010, 356 women met eligibility criteria. Figure 1 summarizes eligibility characteristics of the patients. Most of the women (293 of 356 [82.3%]) had CDC symptom-defined influenza-like illness (158 with a positive influenza test plus an additional 135 with no positive influenza test). Sixty-three (17.7%) had a positive influenza test but not CDC symptom-defined influenza-like illness, including 56 without a documented fever measured by a healthcare provider. Of the 221 patients with a positive influenza test, 54.3% were subtyped novel H1N1, 7.2% were influenza A not novel H1N1, and 38.5% were not subtyped. No in-hospital death before admission was observed. As noted in Figure 2, more than half (197 of 356 [55.3%]) of all women were enrolled in October 2009 and an additional 25.0% (89 of 356) were in November 2009 with rapidly decreasing numbers thereafter.
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
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© 2011 by The American College of Obstetricians and Gynecologists.