Seasonal and 2009 pandemic influenza A (H1N1) virus infection during pregnancy: a population-based study of hospitalized cases

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Seasonal and 2009 pandemic influenza A (H1N1) virus infection during pregnancy: a populationbased study of hospitalized cases Andreea A. Creanga, MD, PhD; Laurie Kamimoto, MD; Kimberly Newsome, MPH; Tiffany D’Mello, MPH; Denise J. Jamieson, MD, MPH; Marianne E. Zotti, DrPH; Kathryn E. Arnold, MD; Joan Baumbach, MD; Nancy M. Bennett, MD; Monica M. Farley, MD; Ken Gershman, MD; David Kirschke, MD; Ruth Lynfield, MD; James Meek, MPH; Craig Morin, MPH; Arthur Reingold, MD; Patricia Ryan, MS; William Schaffner, MD; Ann Thomas, MD; Shelley Zansky, PhD; Lyn Finelli, DrPH; Margaret A. Honein, PhD

We sought to describe characteristics of hospitalized reproductive-aged (15-44 years) women with seasonal (2005/2006 through 2008/2009) and 2009 pandemic influenza A (H1N1) virus infection. We used population-based data from the Emerging Infections Program in 10 US states, and compared characteristics of pregnant (n ⫽ 150) and nonpregnant (n ⫽ 489) seasonal, and pregnant (n ⫽ 489) and nonpregnant (n ⫽ 1088) pandemic influenza cases using ␹2 and Fisher’s exact tests. Pregnant women represented 23.5% and 31.0% of all reproductive-aged women hospitalized for seasonal and pandemic influenza, respectively. Significantly more nonpregnant than pregnant women with seasonal (71.2% vs 36.0%) and pandemic (69.7% vs 31.9%) influenza had an underlying medical condition other than pregnancy. Antiviral treatment was significantly more common with pandemic than seasonal influenza for both pregnant (86.5% vs 24.0%) and nonpregnant (82.0% vs 55.2%) women. Pregnant women comprised a significant proportion of influenza-hospitalized reproductive-aged women, underscoring the importance of influenza vaccination during pregnancy. Key words: human, infectious, influenza, pregnancy, pregnancy complications, seasonal influenza, 2009 pandemic influenza

T

he emergence of 2009 pandemic influenza A (H1N1) virus (2009 H1N1) resulted in the first influenza pandemic in over 40 years. The Centers for Disease Control and Prevention (CDC) estimated that about 61 million people were infected, 274,000 were hospitalized, and about 12,740 died due to 2009 H1N1 in the United States.1 About 90% of all hospitalizations and 87% of all deaths during the 2009 H1N1 pandemic were among people ⬍65 years in contrast with experience from seasonal influenza when about 40% of all hospitalizations and 10% of deaths were found in this age group.1 It is well recognized that pregnancy represents a risk factor for influenza complications and death during both pandemic and seasonal influenza.2-6 Thus, with illness being widespread among the younger segments of the population

From the Epidemic Intelligence Service, Centers for Disease Control and Prevention (Dr Creanga), National Center for Chronic Disease Prevention and Health Promotion, Division of Reproductive Health (Drs Creanga, Jamieson, and Zotti), National Center for Immunization and Respiratory Diseases, Influenza Division (Drs Kamimoto and Finelli and Ms D’Mello), National Center on Birth Defects and Developmental Disabilities, Division of Birth Defects and Developmental Disabilities (Ms Newsome and Dr Honein), Georgia Emerging Infections Program, Georgia Department of Human Resources, Division of Public Health (Dr Arnold), and Emory University School of Medicine (Dr Farley), Atlanta, GA; New Mexico Department of Health, Santa Fe, NM (Dr Baumbach); Department of Medicine, University of Rochester School of Medicine and Dentistry and Monroe County Department of Public Health, Rochester (Dr Bennett), and Emerging Infections Program, New York State Department of Health, Albany (Dr Zansky), NY; Colorado Department of Public Health and Environment, Denver, CO (Dr Gershman); Department of Preventive Medicine, Vanderbilt University School of Medicine, Nashville, TN (Drs Kirschke and Schaffner); Minnesota Department of Health, St Paul, MN (Dr Lynfield and Mr Morin); Connecticut Emerging Infections Program, Yale University, New Haven, CT (Mr Meek); California Emerging Infections Program, Oakland, CA (Dr Reingold); Maryland Department of Health and Mental Hygiene, Baltimore, MD (Ms Ryan); and Oregon Public Health Division, Portland, OR (Dr Thomas). Received Dec. 16, 2010; revised Feb. 4, 2011; accepted Feb. 14, 2011. Reprints: Andreea A. Creanga, MD, PhD, Division of Reproductive Health, 4770 Buford Hwy. N. E., Mail Stop K-23, Atlanta, GA 30341-3717. [email protected]. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Conflict of Interest: none. Publication of this article was supported by the Centers for Disease Control and Prevention and the Association of Maternal and Child Health Programs. 0002-9378/$36.00 • © 2011 Published by Mosby, Inc. • doi: 10.1016/j.ajog.2011.02.037

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www.AJOG.org during the 2009 H1N1 pandemic, it was expected that a higher proportion of pregnant women would be affected during the 2009 H1N1 pandemic than in previous influenza seasons. Early evidence during the 2009 H1N1 pandemic showed that pregnant women were disproportionally represented among hospitalized, intensive care unit (ICU)admitted cases and deaths due to influenza.7,8 Using CDC’s national pregnancy mortality surveillance data from 1998 through 2005, Callaghan et al9 found that, on average, about 5 deaths can be attributable to seasonal influenza annually during the 8 influenza seasons studied. Through active surveillance for pregnancy-related mortality conducted during the 2009 H1N1 pandemic, 56 deaths due to influenza were identified among pregnant women with symptom onset from April 15, 2009, through Dec. 31, 2009.10 Although data from 2009 H1N1 suggest much higher mortality in pregnant women than would be expected based on the previous years’ pregnancy mortality surveillance in the United States, these estimates cannot be directly compared given disparate case ascertainment. Also, compared to seasonal influenza, attack rates were very high among persons in the childbearing age group with 2009 H1N1, and therefore, a commensurate increase in mortality consistent with the attack rates in this age group would have been expected. Thus, while the true magnitude of the difference in mortality between seasonal and 2009 H1N1 is not known, it is plausible that there was an excess mortality from influenza among pregnant women during 2009 H1N1. Most importantly, from the perspective of both public health and clinical obstetrics practice, there were considerably more pregnant women affected during 2009 H1N1 than during seasonal influenza. No studies to date have compared characteristics of pregnant women with seasonal and pandemic influenza. Use of a population-based influenza surveillance system presents an opportunity to not only examine if severity of influenza illness was higher during the 2009 H1N1 pandemic than during previous influ-

enza seasons, but also to assess changes in clinical practices with regard to pregnant women during the 2009 H1N1 pandemic. The main objective of this study is to describe and compare sociodemographic factors, medical history, and clinical characteristics of hospitalized pregnant and nonpregnant reproductive-aged women (15-44 years) with seasonal and 2009 pandemic influenza A (H1N1) virus infection. Additionally, this study examines characteristics of pregnant and nonpregnant women with confirmed seasonal influenza and 2009 H1N1 who were admitted to an ICU, assesses the benefit of antiviral treatment among pregnant women with 2009 H1N1, and reviews pregnancy outcomes among women hospitalized with 2009 H1N1 after Sept. 1, 2009.

Materials and methods We used population-based surveillance data collected by CDC’s Emerging Infections Program (EIP) Network for influenza-associated hospitalizations among women of reproductive age (15-44 years at the time of hospital admission) from Oct. 1, 2005, through April 30, 2010. The EIP influenza surveillance catchment area expanded slightly during this time period. In 2009, EIP influenza surveillance was conducted in 62 counties covering 13 metropolitan areas in the following 10 states: California, Colorado, Connecticut, Georgia, Maryland, Minnesota, New Mexico, New York, Oregon, and Tennessee. Detailed information about the composition of the EIP surveillance catchment area by county for each influenza season is provided elsewhere.11,12 For this analysis, a case was defined as a reproductive-aged (15-44 years) woman residing in the surveillance area, who was admitted to a surveillance-area hospital and had laboratory confirmation of influenza A infection within 14 days of admission during any one of the 2005/2006 through 2008/2009 influenza seasons or during the 2009 H1N1 pandemic. For influenza seasons 2005/2006, 2006/2007, and 2007/2008, EIP influenza-surveillance was conducted from Oct. 1 through April 30 of the following year each season. For the 2008/2009 season, data were collected from Oct. 1,

2008 through April 15, 2009 when the 2009 H1N1 virus was first identified by CDC. For the purpose of this analysis, we used all data collected from reproductive-aged women with confirmed 2009 H1N1 infection from April 15, 2009, through April 30, 2010. Testing for influenza was based on decisions made by individual clinicians during each influenza season and the 2009 H1N1 pandemic, and reflects clinical practice recommendations available during the index influenza season. Laboratory confirmation of influenza infection involved a positive result from a viral culture, a direct or indirect fluorescent antibody staining, a rapid antigen test or real-time reversetranscriptase polymerase chain reaction (rRT-PCR), or documentation of a positive test result in the patients’ medical records.11 Cases were identified prospectively through state-mandated illness reporting systems or retrospectively through review of hospital admissions, discharge or infection control logs, and/or laboratory lists. Medical records data on sociodemographic, medical history, influenza vaccination status, and clinical course and management were abstracted on all identified cases using a standardized data collection form. EIP employed consistent data collection and reporting protocols throughout influenza seasons from 2005/2006 through 2009/2010. Data were collected on the following preexisting medical conditions that confer a higher risk for influenza complications as specified by the Advisory Committee on Immunization Practices: asthma, cystic fibrosis, other chronic lung disease, cardiovascular disease, chronic metabolic disease, hemoglobinopathy, neuromuscular disorder, cancer, renal disease, immunosuppressive condition, cognitive or seizure disorder, and pregnancy.13 To determine a patient’s influenza vaccination status, several approaches were utilized. In cases where the influenza vaccination status was not recorded or recorded as unknown on medical records, the state vaccination registry was checked; if the information was not recorded in the registry or no state registry existed for adults, 3 separate attempts were made to contact the patient’s primary care provider and obtain this information. If these efforts

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TABLE 1

Characteristics of pregnant and nonpregnant women (15-44 years) with seasonal (2005/2006 through 2008/2009) and 2009 pandemic influenza A (H1N1) virus infection

Characteristics

Seasonal influenza

2009 H1N1

No. (%)

No. (%)

Pregnant women n ⴝ 150

Nonpregnant women n ⴝ 489

P value

Pregnant women n ⴝ 489

Nonpregnant women n ⴝ 1088

P value

Age, y

.......................................................................................................................................................................................................................................................................................................................................................................

15-19

19 (12.7)

66 (13.5)

20-24

51 (34.0)

25-29 30-34

⬍ .001

72 (14.7)

147 (13.5)

78 (16.0)

160 (32.7)

178 (16.4)

41 (27.3)

75 (15.3)

140 (28.6)

209 (19.2)

23 (15.3)

62 (12.7)

80 (16.4)

156 (14.3)

35-39

15 (10.0)

92 (18.8)

29 (5.9)

186 (17.1)

40-44

1 (0.7)

116 (23.7)

8 (1.6)

212 (19.5)

⬍ .001

....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................ a

Race/ethnicity

.......................................................................................................................................................................................................................................................................................................................................................................

Non-Hispanic White

45 (30.0)

194 (39.7)

Non-Hispanic Black

47 (31.3)

Non-Hispanic Asian

4 (2.7)

⬍ .001

124 (25.4)

415 (38.1)

177 (36.2)

155 (31.7)

302 (27.8)

8 (1.6)

29 (5.9)

39 (3.6)

⬍ .001

....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... .......................................................................................................................................................................................................................................................................................................................................................................

Non-Hispanic other

3 (2.0)

7 (1.4)

7 (1.4)

21 (1.9)

Hispanic

39 (26.0)

45 (9.2)

131 (26.8)

181(16.6)

Unknown

12 (8.0)

58 (11.9)

43 (8.8)

130 (12.0)

....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................

Pregnancy trimester at admission

.......................................................................................................................................................................................................................................................................................................................................................................

First (1-13 wk’ gestation)

9 (6.0)

NA

NA

27 (5.5)

NA

NA

.......................................................................................................................................................................................................................................................................................................................................................................

Second (14-28 wk’ gestation)

40 (26.7)

144 (29.4)

Third (ⱖ29 wk’ gestation)

69 (46.0)

280 (57.3)

Unknown

32 (21.3)

38 (7.8)

....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................ b

Underlying medical conditions

.......................................................................................................................................................................................................................................................................................................................................................................

At least one recorded

54 (36.0)

348 (71.2)

None recorded

96 (64.0)

141 (28.8)

⬍ .001

156 (31.9)

758 (69.7)

333 (68.1)

330 (30.3)

⬍ .001

....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................ c

Preexisting respiratory conditions

.......................................................................................................................................................................................................................................................................................................................................................................

Yes

38 (25.3)

220 (45.0)

No

112 (74.7)

269 (55.0)

⬍ .001

122 (24.9)

500 (46.0)

367 (75.1)

588 (54.0)

⬍ .001

....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................

Influenza Dx

.......................................................................................................................................................................................................................................................................................................................................................................

Rapid test only

109 (72.7)

331 (67.7)

PCR only

5 (3.3)

Rapid test ⫹ PCR

0 (0.0)

PCR ⫹ any other test(s)

.906

56 (11.5)

146 (13.4)

20 (4.1)

250 (51.1)

561 (51.6)

1 (0.2)

109 (22.3)

185 (17.0)

0 (0.0)

2 (0.4)

39 (8.0)

132 (12.1)

35 (23.3)

129 (26.4)

35 (7.2)

63 (5.8)

1 (0.7)

6 (1.2)

0 (0.0)

1 (0.1)

.018

....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... .......................................................................................................................................................................................................................................................................................................................................................................

Other test combination without PCR

.......................................................................................................................................................................................................................................................................................................................................................................

Unknown

................................................................................................................................................................................................................................................................................................................................................................................

Creanga. Influenza in pregnancy. Am J Obstet Gynecol 2011.

were unsuccessful, several attempts to contact the patient or proxy by telephone were undertaken to obtain vaccination information; of note, for 2009 H1N1, attempts S40

(continued )

to obtain vaccination information are still underway. To assess associations between the timing of antiviral treatment initiation and clinical characteristics of influenza ill-

American Journal of Obstetrics & Gynecology Supplement to JUNE 2011

ness, we compared cases where treatment was received within 2 days of symptom onset and within 2 days of hospital admission with those where treatment was started ⱖ3

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TABLE 1

Characteristics of pregnant and nonpregnant women (15-44 years) with seasonal (2005/2006 through 2008/2009) and 2009 pandemic influenza A (H1N1) virus infection (continued)

Characteristics

Seasonal influenza

2009 H1N1

No. (%)

No. (%)

Pregnant women n ⴝ 150

Nonpregnant women n ⴝ 489

P value

Pregnant women n ⴝ 489

Nonpregnant women n ⴝ 1088

P value

Received influenza vaccine

.......................................................................................................................................................................................................................................................................................................................................................................

Yes, seasonal vaccine

23 (15.3)

118 (24.1)

.055

53 (10.8)

123 (11.3)

⬍ .001

.......................................................................................................................................................................................................................................................................................................................................................................

Yes, 2009 H1N1 vaccine

NA

NA

6 (1.2)

9 (0.8)

Yes, both seasonal and 2009 H1N1 vaccine

NA

NA

4 (0.8)

8 (0.7)

Yes, unknown type

NA

.......................................................................................................................................................................................................................................................................................................................................................................

.......................................................................................................................................................................................................................................................................................................................................................................

NA

16 (3.3)

4 (0.4)

.......................................................................................................................................................................................................................................................................................................................................................................

No vaccine

86 (57.3)

269 (55.0)

302 (61.8)

720 (66.2)

Unknown

41 (27.3)

102 (20.9)

108 (22.1)

224 (20.6)

....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................ d

Hospital stay (d), median (range)

2 (0–21)

3 (0–221)

.005

2 (0–46)

3 (0–145)

.005

................................................................................................................................................................................................................................................................................................................................................................................

ICU admission

.......................................................................................................................................................................................................................................................................................................................................................................

Yes

8 (5.3)

68 (13.9)

57 (11.7)

252 (23.2)

No

142 (94.7)

418 (85.5)

.004

432 (88.3)

834 (76.7)

0 (0.0)

3 (0.6)

0 (0.0)

⬍ .001

....................................................................................................................................................................................................................................................................................................................................................................... .......................................................................................................................................................................................................................................................................................................................................................................

Unknown

2 (0.18)

................................................................................................................................................................................................................................................................................................................................................................................

Mechanical ventilation

.......................................................................................................................................................................................................................................................................................................................................................................

Yes

5 (3.3)

39 (8.0)

27 (5.5)

137 (12.6)

No

145 (96.7)

448 (91.6)

.048

462 (94.5)

949 (87.2)

0 (0.0)

2 (0.4)

0 (0.0)

2 (0.2)

⬍ .001

....................................................................................................................................................................................................................................................................................................................................................................... .......................................................................................................................................................................................................................................................................................................................................................................

Unknown

................................................................................................................................................................................................................................................................................................................................................................................

Pneumonia Dx at discharge

.......................................................................................................................................................................................................................................................................................................................................................................

Recorded

27 (18.0)

127 (26.0)

123 (82.0)

362 (74.0)

.046

77 (15.8)

443 (40.7)

412 (84.3)

645 (59.3)

⬍ .001

.......................................................................................................................................................................................................................................................................................................................................................................

Not recorded

................................................................................................................................................................................................................................................................................................................................................................................

Received antiviral treatment

.......................................................................................................................................................................................................................................................................................................................................................................

Yes

36 (24.0)

270 (55.2)

No

113 (75.3) 1 (0.7)

⬍ .001

423 (86.5)

892 (82.0)

217 (44.4)

66 (13.5)

195 (17.9)

2 (0.4)

0 (0.0)

1 (0.1)

.028

....................................................................................................................................................................................................................................................................................................................................................................... .......................................................................................................................................................................................................................................................................................................................................................................

Unknown

................................................................................................................................................................................................................................................................................................................................................................................

Death

.......................................................................................................................................................................................................................................................................................................................................................................

Yes

0 (0.0)

8 (1.6)

No

150 (100.0)

479 (98.0)

0 (0.0)

2 (0.4)

.208

5 (1.0)

31 (2.9)

484 (99.0)

1056 (97.1)

.027

....................................................................................................................................................................................................................................................................................................................................................................... .......................................................................................................................................................................................................................................................................................................................................................................

Unknown

(0.0)

1 (0.1)

................................................................................................................................................................................................................................................................................................................................................................................

Fisher’s exact and ␹2 tests used to test differences in proportions; rank sum tests used to test differences in medians; all tests performed after excluding unknown/not recorded category. Dx, diagnosis; ICU, intensive care unit; NA, not applicable; PCR, real-time reverse-transcriptase polymerase chain reaction. a

Categories are mutually exclusive; b Any condition other than pregnancy recognized by Advisory Committee for Immunization Practices to increase risk of influenza complications; c Includes asthma, reactive airway disease, cystic fibrosis, and/or other chronic lung diseases; dData missing for 2 nonpregnant seasonal and 1 nonpregnant pandemic influenza cases.

Creanga. Influenza in pregnancy. Am J Obstet Gynecol 2011.

days after symptom onset or hospital admission, respectively. For cases admitted to a hospital after Sept. 1, 2009, additional data were collected from pregnant women including pregnancy status at hospital discharge and pregnancy outcome for those

who delivered during the index hospitalization for influenza. We conducted univariate and bivariate analyses to compare characteristics of reproductive-aged pregnant and nonpregnant women hospitalized with laboratory-

confirmed seasonal (2005/2006 through 2008/2009) and 2009 H1N1 infection; ␹2 and Fisher’s exact tests were performed to test differences in proportions, and rank sum tests for differences in medians. All statistical analyses were conducted using

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TABLE 2

Characteristics of intensive care unit–admitted pregnant and nonpregnant women (15-44 years) with 2009 pandemic influenza A (H1N1) virus infection No. (%) Characteristics

Pregnant women n ⴝ 57

Age (y), median (range)

27.0 (16–39)

Nonpregnant women n ⴝ 252

P value

29.5 (15–44)

.072

.............................................................................................................................................................................................................................................. a

Race/ethnicity

.....................................................................................................................................................................................................................................

Non-Hispanic White

23 (40.3)

108 (42.9)

Non-Hispanic Black

23 (40.3)

64 (25.4)

Non-Hispanic Asian

3 (5.3)

13 (5.2)

Non-Hispanic other

0 (0.0)

5 (2.0)

Hispanic

5 (8.8)

43 (17.1)

Unknown

3 (5.3)

19 (7.5)

.121

..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................

Pregnancy trimester at admission

.....................................................................................................................................................................................................................................

First (1-13 wk’ gestation)

5 (8.8)

NA

NA

.....................................................................................................................................................................................................................................

Second (14-28 wk’ gestation)

20 (35.1)

Third (ⱖ29 wk’ gestation)

29 (50.9)

..................................................................................................................................................................................................................................... .....................................................................................................................................................................................................................................

Unknown

3 (5.3)

.............................................................................................................................................................................................................................................. b

Underlying medical conditions

.....................................................................................................................................................................................................................................

At least one recorded

20 (35.1)

177 (70.2)

None recorded

37 (64.9)

75 (29.8)

⬍ .001

..................................................................................................................................................................................................................................... .............................................................................................................................................................................................................................................. c

Preexisting respiratory conditions

.....................................................................................................................................................................................................................................

Yes

15 (26.3)

101 (40.1)

No

42 (73.7)

151 (59.9)

.053

..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................

Influenza Dx

.....................................................................................................................................................................................................................................

Rapid test only

5 (8.8)

21 (8.3)

PCR only

35 (61.4)

153 (60.7)

Rapid test ⫹ PCR

10 (17.5)

32 (12.7)

PCR ⫹ any other test(s)

3 (5.3)

33 (13.0)

Other test combination without PCR

4 (7.0)

13 (5.2)

.418

..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... .....................................................................................................................................................................................................................................

..............................................................................................................................................................................................................................................

Hospital stay (d), median (range)

7 (1–46)

8 (0–145)

.663

..............................................................................................................................................................................................................................................

Mechanical ventilation

.....................................................................................................................................................................................................................................

Yes

26 (45.6)

129 (51.2)

No

31 (54.4)

123 (48.8)

.467

..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................

Pneumonia Dx at discharge

.....................................................................................................................................................................................................................................

Recorded

31 (54.4)

146 (57.9)

Not recorded

26 (45.6)

106 (42.1)

.625

..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................

Received antiviral treatment

.....................................................................................................................................................................................................................................

Yes

55 (96.5)

224 (88.9)

No

2 (3.5)

28 (11.1)

.087

..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................

Creanga. Influenza in pregnancy. Am J Obstet Gynecol 2011.

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(continued )

STATA, version 10 software (StataCorp, College Station, TX). Both data collection and data analysis for this study have been determined by CDC to be for routine public health surveillance and response purposes. Thus, institutional review board approval was deemed not to be required.

Results Data were available on 150 pregnant and 489 nonpregnant seasonal, and 489 pregnant and 1088 nonpregnant pandemic influenza cases hospitalized during all trimesters of pregnancy (Table 1). Of all females aged 15-44 years admitted to a hospital for influenza infection during seasons 2005/2006 through 2008/2009 and 2009 H1N1, pregnant women represented 23.5% (range by influenza season: 20.425.5%; P ⫽ .609) and 31.0%, respectively (P ⬍ .001). Hospitalized pregnant women were significantly younger than nonpregnant reproductive-aged women during both seasonal and pandemic influenza. Almost half of hospitalized pregnant women in both seasonal (46.7%) and pandemic (47.4%) influenza groups were ⬍25 years of age, while 23.7% and 19.5% of nonpregnant women with seasonal and pandemic influenza, respectively, were ⱖ40 years. There were more Hispanic women in the pregnant than the nonpregnant group during both seasonal and pandemic influenza (P ⬍ .001). The distribution of cases by gestational age was not significantly different between seasonal and pandemic cases– about half of hospitalized pregnant women were in the third trimester of pregnancy. However, gestational age information was missing on 21.3% of seasonal and 7.8% of pandemic influenza cases in pregnant women. About a third of pregnant women in both groups had an underlying medical condition other than pregnancy that confers a higher risk for influenza complications; over twothirds of nonpregnant women in each group had such a condition (P ⬍ .001 when comparing pregnant and nonpregnant women in both groups). Similarly, a preexisting respiratory condition was present in about a quarter of pregnant seasonal and pandemic cases, and in nearly half of nonpregnant cases.

Supplement

www.AJOG.org Influenza testing patterns and diagnosis procedures differed significantly between seasonal and pandemic influenza for all reproductive-aged women, and between pregnant and nonpregnant reproductiveaged women during the 2009 H1N1 pandemic. Specifically, most seasonal influenza cases (72.7% of pregnant and 67.7% of nonpregnant women) were diagnosed by a rapid test alone, while only 11.5% of pregnant and 13.4% of nonpregnant pandemic influenza cases were diagnosed solely by rapid testing. An rRT-PCR test was used either alone or in combination with ⱖ1 other tests to diagnose the infection in over four-fifths of pregnant and nonpregnant women with 2009 H1N1; conversely, only 3.3% of pregnant and 4.7% of nonpregnant women were diagnosed using a rRT-PCR test during the 4 previous influenza seasons. Overall, a significantly higher proportion of pregnant and nonpregnant reproductive-aged women with 2009 H1N1 were admitted to an ICU than during seasonal influenza (11.7% vs 5.3%, P ⫽ .025 for pregnant women; and 23.2% vs 13.9%, P ⬍ .001 for nonpregnant women). Similarly, more pregnant and nonpregnant reproductive-aged women were mechanically ventilated during the pandemic than during seasonal influenza. However, for both seasonal and pandemic influenza, nonpregnant reproductive-aged women had longer median lengths of hospital stay than pregnant women (3 vs 2 days; P ⫽ .005), and were more likely to be admitted to an ICU (13.9% vs 5.3%, P ⫽ .004 for seasonal influenza; and 23.2% vs 11.7%, P ⬍ .001 for pandemic influenza). Also, nonpregnant women were significantly more likely to have pneumonia recorded as a discharge diagnosis than pregnant women for both seasonal (26.0% vs 18.0%, P ⫽ .046) and pandemic (40.7% vs 15.8%, P ⬍ .001) influenza. There was no statistical difference between seasonal and pandemic influenza cases in pregnant women in terms of either the proportion requiring mechanical ventilation or that having a recorded pneumonia diagnosis at discharge. Nonetheless, ⬎80% of reproductive-aged women received antiviral treatment during the 2009 H1N1 pandemic with more pregnant than nonpregnant women doing so; only 24.0%

TABLE 2

Characteristics of intensive care unit–admitted pregnant and nonpregnant women (15-44 years) with 2009 pandemic influenza A (H1N1) virus infection (continued) No. (%) Pregnant women n ⴝ 57

Characteristics

Nonpregnant women n ⴝ 252

P value

Death

.....................................................................................................................................................................................................................................

Yes

5 (8.8)

31 (12.3)

52 (91.2)

221 (87.7)

.647

.....................................................................................................................................................................................................................................

No

..............................................................................................................................................................................................................................................

Fisher’s exact and ␹ tests used to test differences in proportions; rank sum tests used to test differences in medians; all tests performed after excluding unknown/not recorded category. Dx, diagnosis; NA, not applicable; PCR, real-time reverse-transcriptase polymerase chain reaction. 2

a

Categories are mutually exclusive; b Any condition other than pregnancy recognized by Advisory Committee for Immunization Practices to increase risk of influenza complications; c Includes asthma, reactive airway disease, cystic fibrosis, and/or other chronic lung diseases.

Creanga. Influenza in pregnancy. Am J Obstet Gynecol 2011.

of pregnant and 55.2% of nonpregnant women received such treatment during seasonal influenza. Among these hospitalized reproductive-aged women, there were no deaths among pregnant and 8 (1.6%) deaths among nonpregnant women with seasonal influenza (P ⫽ .208), but there were 5 (1.0%) deaths among pregnant and 31 (2.9%) deaths among nonpregnant women with 2009 H1N1 (P ⫽ .027). Among ICU-admitted 2009 H1N1 cases, pregnant women were younger and significantly less likely to have preexisting

medical conditions than nonpregnant women (Table 2). The distribution by trimester of pregnancy for ICU-admitted pandemic influenza cases (Table 2) appears to be similar to that of all hospitalized pregnant cases during the pandemic (Table 1); please note, however, that gestational age data were missing for 38 pregnant pandemic cases, 3 of which were admitted to an ICU. Also, similar proportions of ICU-admitted (Table 2) and overall hospitalized pregnant women with 2009 H1N1 (Table 1) had preexist-

TABLE 3

Pregnancy and infant outcomes among delivered pregnant women with 2009 pandemic influenza A (H1N1) virus infection among women hospitalized on or after Sept. 1, 2009 No. (%) Pregnancy and infant outcome

ICU-admitted women, n ⴝ 20

Non-ICU-admitted women, n ⴝ 97

P value

Healthy newborn

⬍ .001

12 (60.0)

87 (89.7)

Newborn required specialized care

2 (10.0)

8 (8.2)

Neonatal death

0 (0.0)

2 (2.1)

Miscarriage or fetal death

5 (25.0)

0 (0.0)

.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. a ..............................................................................................................................................................................................................................................

Delivered, unknown pregnancy outcome

1 (5.0)

0 (0.0)

Preterm delivery

9 (45.0)

13 (13.4)

.............................................................................................................................................................................................................................................. b

⬍ .001

..............................................................................................................................................................................................................................................

Fisher’s exact test performed after excluding unknown pregnancy status category. The 2 reported P values are for comparisons of the first 5 pregnancy and infant outcome categories shown and of preterm delivery between ICU-admitted and non-ICUadmitted women, respectively. ICU, intensive care unit. a

There were 4 miscarriages at 6, 7, 9, and 10 wk’ gestation and 1 fetal death at 24 wk’ gestation; b Data on gestational age missing for 6 non-ICU-admitted cases.

Creanga. Influenza in pregnancy. Am J Obstet Gynecol 2011.

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Supplement ing medical conditions. Most pregnant (96.5%) and nonpregnant (88.9%) women admitted to an ICU received antiviral treatment at some point during their hospitalization for pandemic influenza. Conversely, only 12.5% of pregnant and 55.9% of nonpregnant women admitted to an ICU received antivirals during the past 4 influenza seasons (data not shown). Information on the timing of antiviral treatment was available for 339 of the 388 pregnant women with 2009 H1N1 admitted after Sept. 1, 2009 (data not shown). Pregnant women who received antiviral treatment within 2 days of hospital admission had a shorter hospital stay (P ⫽ .003) and were less likely to be admitted to an ICU (P ⬍ .001) than those who received such treatment at a later time during hospitalization. Among the 267 pregnant women with information on both antiviral treatment initiation and influenza illness onset, those who started treatment within 2 days of illness onset had shorter hospital stays (P ⬍ .001), were significantly less likely to require care in an ICU (13 of 174 [7.5%] vs 23 of 93 [4.7%], P ⬍ .001), and were significantly less likely to die (P ⫽ .041) than those with a ⬎2-day delay in starting this treatment. Some information was available on pregnancy and infant outcomes among women hospitalized with 2009 H1N1 from Sept. 1, 2009 onward (Table 3). For this time period, 46.5% of women admitted to an ICU and 28.1% of those who did not require ICU admission delivered at the time of hospitalization for 2009 H1N1 (P ⫽ .012). Among the 20 ICU-admitted women, 4 miscarried (gestational ages 6, 7, 9, and 10 weeks), 1 had a fetal death at 24 weeks’ gestation, and 2 had newborns requiring specialized care. Among the 97 pregnant women who were not admitted to an ICU, 8 (8.2%) had newborns requiring specialized care and the infants of 2 (2.1%) other women died during the neonatal period. Most (89.7%) non-ICU-admitted women known to have delivered before hospital discharge had healthy infants, compared to 60.0% of those who were admitted to an ICU (P ⬍ .001). Also, significantly more ICU-admitted than S44

www.AJOG.org non-ICU-admitted women delivered preterm (45.0% vs 13.4%, P ⬍ .001).

Comment This study shows that pregnant women comprised a significant proportion of hospitalized and ICU-admitted influenza cases among reproductive-aged women with 2009 H1N1 compared to the previous 4 influenza seasons. However, with early surveillance data showing that pregnant women and younger age groups (ie, women at the peak of their reproductive years) were especially affected by 2009 H1N1,14 clinicians might have used a lower threshold for admitting pregnant women with milder illness than they did for nonpregnant women. Also, this report provides evidence that most pregnant women hospitalized with either seasonal or pandemic influenza had no underlying risk factors for influenza other than pregnancy, highlighting the hazard conferred by pregnancy alone in otherwise healthy individuals. In contrast, most of the hospitalized nonpregnant women had underlying medical conditions, likely contributing to their longer length of hospital stays, higher percent of admission to an ICU, and higher mortality than pregnant women during both seasonal and pandemic influenza. This study is the first to compare seasonal and pandemic influenza infection among hospitalized pregnant and nonpregnant women of reproductive age. It draws on population-based surveillance data collected and reported using the same methodology during 2005/2006 through 2008/2009 influenza seasons and the 2009 H1N1 pandemic. However, comparison of seasonal influenza and 2009 H1N1 is complicated by the important changes in testing patterns that occurred during the pandemic. Testing by rRT-PCR became widely used at EIP surveillance sites during the 2009 H1N1 pandemic, and use of more sensitive diagnostic tests was prioritized for hospitalized persons. While there is no specific evidence that testing patterns were different for pregnant women than the general population, the data suggest the possibility of a lower threshold for hos-

American Journal of Obstetrics & Gynecology Supplement to JUNE 2011

pitalization of pregnant than nonpregnant women. Considerably more pregnant and nonpregnant women received treatment with antivirals during the 2009 H1N1 pandemic than in previous influenza seasons, likely prompted by recommendations and guidance from CDC and other professional organizations.15,16 Antiviral treatment was associated with a reduced length of hospitalization and decreased risk of ICU admission and death in our analysis, consistent with the findings of earlier studies.7,8,10 Thus, it is possible that the increased use of antiviral medications mitigated the severity of illness associated with influenza infection among pregnant women with 2009 H1N1. The most significant limitation of the study is that it only captures the experience of hospitalized women with influenza, and cannot directly inform questions about the attack rates in the population. The higher number of hospitalized pregnant than nonpregnant women across the 10 US states represented in the EIP surveillance network for 2009 H1N1 than for seasonal influenza could be related to greater population susceptibility to the novel pandemic influenza virus, to a lower threshold for admitting pregnant than nonpregnant women to a hospital, and to both enhanced and prolonged influenza surveillance and case identification during the 2009 H1N1 influenza pandemic; the latter involved widespread use of more sensitive influenza diagnostic tests, particularly so among hospitalized patients. These potential sources of bias make comparisons of seasonal and pandemic influenza cases difficult, and therefore, results should be interpreted with caution. In addition, there are not sufficient data available to consistently distinguish between “no” and “not recorded” for some variables in the data, making interpretation of certain variables, such as pneumonia diagnosis, problematic. Missing data for some critical variables (eg, gestational age, timing of antiviral treatment, influenza vaccination) could also have biased our results in either direction and this limits the extent to which we can draw conclusions from the data. Finally, we pooled data from the 4 previous influenza seasons because of the relatively small numbers of hospitalized pregnant

Supplement

www.AJOG.org women reported in any one season. If significant differences existed among the 4 seasons analyzed here, these would have been obscured by our approach. However, the sociodemographic and clinical characteristics examined did not differ significantly by influenza season (2005/2006 through 2008/2009) among those who were pregnant vs nonpregnant. Enhanced influenza surveillance among pregnant women is needed to inform public health decisions related to the needs of this high-risk subgroup of the population. Given the high risk of complications with influenza infection during pregnancy and the data indicating that the influenza vaccine is safe and effective for use at any time during pregnancy,17 pregnant women should be strongly encouraged to receive the inactivated influenza vaccine. Also, for the 2010/2011 influenza season, as no vaccine confers 100% protection and the 2009 H1N1 virus is still circulating, prompt empiric antiviral treatment of influenza illness during pregnancy is also recommended.13 A recent study by Greer et al18 showed no increase in adverse outcomes among fetuses exposed to antiviral treatment during 2003/2004 through 2007/2008 influenza seasons. Early identification and treatment of influenza in pregnant women might also reduce the risk of preterm delivery and adverse pregnancy outcomes. The important changes in public health recommendations and clinical practices implemented during the 2009 H1N1 pandemic might have reduced influenzarelated morbidity and mortality among pregnant women. Continued surveillance for influenza infection among pregnant women will provide clinicians and public health professionals with season-specific information and will enable appropriate updates and modifications to recommendations for this subgroup of the population. f

ACKNOWLEDGMENTS We wish to thank the EIP surveillance officers and health department staff who identified and collected the surveillance case information: Susan Brooks, Mariah Hamilton, Pamala Daily Kirley, Lauren Pasutti, California EIP, Oakland, CA; Colorado Department of Public Health and Environment, Denver, CO; Kimberly Yousey-Hindes, Darcy Fazio, Christopher McClure, Alexis Beattie, Connecticut EIP, Yale University, New Haven, CT; Kyle Openo, Ariane Reeves, Olivia Almendares, Norisse Tellman, Suzanne Segler, Wendy Baughman, Georgia EIP–a collaboration among Georgia Division of Public Health, Emory University, and the Atlanta Veterans Administration Medical Center, Atlanta, GA; Maya Monroe, Maryland Department of Health and Mental Hygiene, Baltimore, MD; Elisabeth Vaeth, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Dave Boxrud, Susan Fuller, Team FLU, Minnesota Department of Health, St Paul, MN; Emily Hancock, Kathy Angeles, Lisa Butler, Sarah Khanlian, Robert Mansmann, New Mexico EIP, New Mexico Department of Health, Santa Fe, NM; New York State Health Department, Albany, NY; Center for Community Health and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY; Oregon Public Health Division, Portland, OR; Tennessee Department of Health, Nashville, TN; Department of Preventive Medicine, Vanderbilt University School of Medicine, Nashville, TN.

REFERENCES 1. Centers for Disease Control and Prevention. Updated CDC estimates of 2009 H1N1 influenza cases, hospitalizations and deaths in the United States, April 2009-April 10, 2010. Available at: http://www.cdc.gov/h1n1flu/estimates_ 2009_h1n1.htm. Accessed Dec. 15, 2010. 2. Dodds L, McNeil SA, Fell DB, et al. Impact of influenza exposure on rates of hospital admissions and physician visits because of respiratory illness among pregnant women. CMAJ 2007;176:463-8. 3. Neuzil KM, Reed GW, Mitchel EF, Simonsen L, Griffin MR. Impact of influenza on acute cardiopulmonary hospitalizations in pregnant women. Am J Epidemiol 1998;148:1094-102. 4. Jamieson DJ, Honein MA, Rasmussen SA, et al; Novel Influenza A (H1N1) Pregnancy Working Group. H1N1 2009 influenza virus infection during pregnancy in the USA. Lancet 2009;374:451-8. 5. Rasmussen SA, Jamieson DJ, Bresee JS. Pandemic influenza and pregnant women. Emerg Infect Dis 2008;14:95-100. 6. Mak TK, Mangtani P, Leese J, Watson JM, Pfeifer D. Influenza vaccination in pregnancy:

current evidence and selected national policies. Lancet Infect Dis 2008;8:44-52. 7. Creanga AA, Johnson TF, Graitcer SB, et al. Severity of 2009 pandemic influenza A (H1N1) virus infection in pregnant women. Obstet Gynecol 2010;115:717-26. 8. 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. 9. Callaghan WM, Chu SY, Jamieson DJ. Deaths from seasonal influenza among pregnant women in the United States, 1998-2005. Obstet Gynecol 2010;115:919-23. 10. Siston AM, Rasmussen SA, Honein MA, 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;303:1517-25. 11. Dawood FS, Fiore A, Kamimoto L, et al; Emerging Infections Program (EIP) Network. Influenza-associated pneumonia in children hospitalized with laboratory-confirmed influenza, 20032008. Pediatr Infect Dis J 2010;29:585-90. 12. Dao CN, Kamimoto L, Nowell M, et al; Emerging Infections Program Network. Adult hospitalizations for laboratory-positive influenza during the 2005-2006 through 2007-2008 seasons in the United States. J Infect Dis 2010;202:881-8. 13. Centers for Disease Control and Prevention. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. MMWR Recomm Rep 2009;58:1-52. 14. Nokleby H, Nicoll A. Risk groups and other target groups–preliminary ECDC guidance for developing influenza vaccination recommendations for the season 2010-11. Euro Surveill 2010;15:1-4. 15. Centers for Disease Control and Prevention. Updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the 2009-2010 season. Available at: http://www.cdc.gov/h1n1flu/ recommendations.htm. Accessed Aug. 25, 2010. 16. American College of Obstetricians and Gynecologists. ACOG committee opinion no. 305. Influenza vaccination and treatment during pregnancy. Obstet Gynecol 2004;104:1125-6. 17. Tamma PD, Ault KA, Del Rio C, Steinhoff MC, Halsey NA, Omer SB. Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol 2009;201:547-52. 18. 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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