Evidence from seasonal influenza1,2 and previous influenza pandemics3,4 indicates that pregnant women are at higher risk of morbidity and mortality compared with nonpregnant women. During pregnancy, physiologic adaptations in the respiratory, cardiovascular, and immune systems may increase women's susceptibility to respiratory infections or adversely alter their clinical course.5,6 In addition, if infected with influenza during pregnancy, women have an increased risk of adverse pregnancy outcomes (eg, spontaneous abortion, preterm delivery).7
In April 2009, a novel influenza A (H1N1) virus was identified and has since been recognized as the cause of a pandemic outbreak in the United States and worldwide.8,9 Although pregnant women constitute about 1% of the population at any point in time, recently released national-level data indicate that 28 of the 484 (5.8%) deaths attributable to 2009 H1N1 influenza in the United States through August 21, 2009, were among pregnant women.10
We conducted this investigation to 1) estimate 2009 H1N1 influenza hospitalization and severe hospitalization rates among pregnant and nonpregnant women in New York City during May and June 2009, 2) describe and compare sociodemographic and clinical characteristics of pregnant and nonpregnant hospitalized women with 2009 H1N1 influenza infection, 3) describe the differences in clinical course and pregnancy outcomes among pregnant women with severe and moderate 2009 H1N1 influenza infection, 4) assess the association between the timing of antiviral treatment and the severity of 2009 H1N1 influenza illness among pregnant women, and 5) describe the clinical characteristics of severe 2009 H1N1 influenza cases among pregnant women.
MATERIALS AND METHODS
We included a case series of all hospitalized pregnant women with 2009 H1N1 influenza and a comparison group of hospitalized nonpregnant reproductive-aged women with 2009 H1N1 influenza. The New York City Department of Health and Mental Hygiene initiated enhanced surveillance for 2009 H1N1 influenza infection on April 24, 2009. Between April 24 and May 10, the New York City Department of Health and Mental Hygiene tested hospitalized patients with fever and respiratory distress or other respiratory syndrome for influenza and performed subtyping for H3N2 and seasonal H1N1 on all influenza A–positive specimens. All unsubtypable influenza A–positive specimens were forwarded to the Centers for Disease Control and Prevention (CDC) for testing by real-time reverse-transcriptase polymerase chain reaction (rRT-PCR). Between May 11 and July 7, all hospitalized patients with a positive influenza A test result and all patients who were admitted to an intensive care unit (ICU) with fever and respiratory symptoms for whom a specimen was available were tested for 2009 H1N1 influenza infection at the New York City Department of Health and Mental Hygiene using the CDC 2009 H1N1 rRT-PCR assay.
From May 1 through June 30, 2009, 976 hospitalizations (based on date of admission) and 47 deaths related to rRT-PCR–confirmed 2009 H1N1 influenza were identified through enhanced surveillance in New York City. Because this investigation was a public health response, we had limited resources at our disposal, and therefore, we restricted our data abstraction to only these cases. Sixty-three pregnant women were identified among the hospitalized 2009 H1N1 influenza–infected patients. Nonpregnant reproductive-aged women hospitalized with 2009 H1N1 influenza served as a comparison group. This group comprised all confirmed 2009 H1N1 influenza cases among nonpregnant women who were admitted to a hospital with at least one confirmed 2009 H1N1 influenza case in a pregnant woman and were in the same age range as the pregnant women (14–41 years); this age restriction was made to ensure comparability of pregnant and nonpregnant women. We excluded any woman who developed influenza symptoms more than 3 days after hospital admission to exclude potential nosocomial 2009 H1N1 influenza infections. For our analyses examining differences in 2009 H1N1 influenza case severity, we defined a 2009 H1N1 influenza hospitalized case as severe if the woman 1) died while hospitalized or 2) was admitted to an ICU.
Four clinicians and epidemiologists (A.A.C., S.B.G., T.A., and L.K.H.) reviewed and abstracted data from all available hospital records for all hospitalized pregnant women with confirmed 2009 H1N1 influenza using a standardized abstraction form and completed a standardized abbreviated medical record abstraction form for the nonpregnant comparison group. We pilot tested the instrument and compared initial abstractions to ensure that data-collection methods were standardized across all investigators. For both pregnant and nonpregnant women, we abstracted sociodemographic characteristics, clinical signs and symptoms within 7 days of symptom onset, receipt and timing of antiviral treatment, and history of underlying medical conditions. For the pregnant women, we abstracted more detailed clinical information on the 2009 H1N1 influenza illness including vital signs, laboratory results, the course of their pregnancy, as well as labor and delivery when applicable. In addition, we abstracted data from the medical charts of all neonates born to pregnant women in our sample through September 18, 2009. This investigation was a public health response to the 2009 H1N1 influenza pandemic and was reviewed by the New York City Department of Health and Mental Hygiene Committee for Human Subjects; institutional review board approval was deemed not to be required.
We used 2007 vital registration data on the annual number of live births and induced and spontaneous abortions in New York City provided by the Bureau of Vital Statistics at New York City Department of Health and Mental Hygiene to calculate the hospital admission rate due to 2009 H1N1 influenza infection for pregnant women.11 Similar to previously published studies,12,13 we estimated the number of pregnant women in New York City during the 2-month period between May 1 and June 30, 2009, (113,877) by adding 9/12 of the annual number of live births representing pregnancies at any point in time during May and June 2009 that will end in live birth and 2/12 of the annual number of induced and spontaneous pregnancy losses representing pregnancy losses during May and June 2009. We estimated the nonpregnant 14–41-year-old female population in New York City (1,619,349) by subtracting the above calculated number of pregnant women from the New York City Department of Health and Mental Hygiene 2007 population estimates for the number of women aged 14–41 years in New York City based on 2007 U.S. Census Bureau data.14 We used the number of all 2009 H1N1 influenza severe cases captured by the New York City Department of Health and Mental Hygiene surveillance data between May 1 and June 30, 2009 to calculate the 2009 H1N1 influenza severe case hospitalization rates among pregnant and nonpregnant reproductive-aged women in New York City.
We defined chronic medical conditions as those that confer a higher risk of influenza-related complications as specified by the Advisory Committee on Immunization Practices.15 Gestational age was based on the last menstrual period as recorded in women's medical charts and is reported in completed weeks. We grouped all labor and delivery complications and defined a delivery complications composite variable to include dysfunctional labor, placental abruption, and premature or prolonged rupture of membranes. Also, we created a severe neonatal outcome variable that included deliveries in which the neonate was admitted to the neonatal intensive care unit (NICU) or died.
We conducted univariable analyses and used t tests to test differences in means, χ2, and Fisher exact tests for differences in proportions and rank sum tests for differences in medians. Also, for examining the trend in the association between 2009 H1N1 influenza illness severity and timing of antiviral treatment, we performed a Cuzick nonparametric test for trend across ordered groups.16 Analyses were conducted using STATA version 10 (College Station, TX).
In New York City from May through June 2009, there were 63 hospitalizations of pregnant (55.3 per 100,000 population, 95% confidence interval [CI] 42.5–70.8 per 100,000 population) and 124 hospitalizations of nonpregnant reproductive-aged (14–41) women (7.7 per 100,000 population, 95% CI 6.4–9.1 per 100,000 population) with 2009 H1N1 influenza. Similarly, the rate of 2009 H1N1 influenza severe case (ICU admission or death) hospitalization rate during this period was 7.0 (95% CI 3.0–13.8) per 100,000 pregnant women and 1.7 (95% CI 1.1–2.4) per 100,000 nonpregnant reproductive-aged 14–41-year-old women. Pregnant women represented 6.4% of all hospitalized cases (63 of 976) of 2009 H1N1 influenza and 4.3% of all known deaths (2 of 47) related to 2009 H1N1 influenza in New York City during this period.
We abstracted data on 63 pregnant and 76 nonpregnant women hospitalized with confirmed 2009 H1N1 influenza infection admitted to New York City hospitals during May and June 2009. We excluded one pregnant and two nonpregnant women who developed influenza symptoms more than 3 days after hospital admission, resulting in a final sample of 62 pregnant and 74 nonpregnant women. The two groups were similar in terms of race/ethnicity and medical insurance type (Table 1). However, the nonpregnant comparison group included significantly more women younger than 20 years of age (6.5% of pregnant women and 35.1% of nonpregnant women, P=.001).
Medical histories of pregnant and nonpregnant cases were also notably different. While only 29.0% of the pregnant women had a high-risk condition for influenza complications other than pregnancy, 67.6% of nonpregnant women had at least one such condition as defined by the Advisory Committee on Immunization Practices (P=.001). The most common high-risk condition in both groups was a history of asthma, which was twice as prevalent in nonpregnant women (40.5% compared with 19.4%, P=.008). Two pregnant and four nonpregnant women had sickle cell disease; one pregnant and five nonpregnant women had a chronic renal condition; two pregnant and eight nonpregnant women had diabetes; and one pregnant and 10 nonpregnant women had a condition conferring severe immune compromise (eg, human immunodeficiency virus [HIV] infection; specific CD4 count data were, however, not collected). Among women younger than 20 years of age, none of the pregnant and 21 (80.8%) of the nonpregnant women had an Advisory Committee on Immunization Practices high-risk condition for influenza complications other than pregnancy (data not shown).
The majority of both pregnant (86%) and nonpregnant (97%) 2009 H1N1 influenza–infected women had fever (greater than 100.4°F) within 7 days of symptom onset, and more than three-fourths of both pregnant and nonpregnant women met the case definition of influenza-like illness defined as fever with either a cough or sore throat. Pregnant women were, however, less likely to have fever (P=.01) and influenza-like illness (P=.06) than nonpregnant women. Also, fewer women in the pregnant than the nonpregnant group were diagnosed with pneumonia (9.7% compared with 24.3%, P=.03) during their 2009 H1N1 influenza hospitalization.
Timing of antiviral treatment was similar in the two groups, with 48.4% of pregnant and 48.6% of nonpregnant women receiving oseltamivir within 2 days of symptom onset. A small percentage of women (6.5% and 5.4% in the pregnant and nonpregnant group, respectively) did not receive oseltamivir treatment either before hospital admission or during their hospital stay. Among women who were treated on or after hospital admission, the median time between hospital admission and initiation of oseltamivir treatment was slightly longer among pregnant than nonpregnant women (1 compared with 0 days), but the range was greater in nonpregnant women (Table 2).
During the index hospitalization, 12.9% of pregnant women and 20.3% of nonpregnant women (P=.25) were admitted to an ICU for management of severe complications of 2009 H1N1 influenza infection. Two of the pregnant women and three of the nonpregnant women admitted to an ICU died because of complications related to the H1N1 influenza illness; one nonpregnant woman who was not admitted to the ICU also died. Overall, eight (12.9%) pregnant women and 16 (21.6%) nonpregnant women were classified as having severe 2009 H1N1 influenza illness. There was no significant difference between 2009 H1N1 influenza case severity and women's pregnancy status after stratifying by age (younger than 20 years and 20 years or older). Among women without any high-risk condition for influenza complications other than pregnancy, 13.6% of pregnant women compared with 8.3% of nonpregnant women had severe 2009 H1N1 influenza illness (P=.70); among women with one or more high-risk conditions, 11.1% of pregnant and 28.0% of nonpregnant women experienced severe 2009 H1N1 influenza (P=.20) (data not shown).
Next, we compared pregnant women with severe 2009 H1N1 influenza to pregnant women with moderate 2009 H1N1 influenza illness (Table 3). Pregnant women with severe 2009 H1N1 influenza illness had a similar median time from symptom onset to hospital admission as pregnant women with moderate illness, but they had a longer median hospital stay (18 days with a range between 3 and 38 days compared with 3 days with a range between 0 and 7 days), a longer median time from symptom onset to receipt of oseltamivir (4.5 compared with 2 days) and were more likely to require oxygen supplementation (87.5% compared with 13.7%); all differences were statistically significant at a level of P<.05. Among pregnant women, 2009 H1N1 influenza illness severity was significantly associated with the interval between symptom onset and initiation of oseltamivir treatment. Only 1 of the 30 (3.3%) pregnant women who received oseltamivir treatment within 2 days of symptom onset had severe illness; 3 of 14 (21.4%) pregnant women who started oseltamivir treatment 3–4 days after symptom onset and four of nine (44.4%) pregnant women who received oseltamivir treatment 5 or more days after symptom onset had severe disease (P=.002 for trend). For nonpregnant women, 8 of 36 (22.2%) who received oseltamivir treatment within 2 days of symptom onset had severe illness; 0 of 15 (0.0%) nonpregnant women who started oseltamivir treatment 3–4 days after symptom onset and 7 of 15 (46.7%) nonpregnant women who received oseltamivir treatment 5 or more days after symptom onset had severe disease (P=.180 for trend). Zanamivir was not used by women in this case series.
Both severe and moderate hospitalized cases occurred during all trimesters of pregnancy, but 62.5% of severe and 53.7% of the moderate 2009 H1N1 influenza cases in our series occurred in the third trimester of pregnancy. A significantly higher proportion of women with severe than moderate 2009 H1N1 influenza delivered during their hospitalization for 2009 H1N1 influenza (75.0% compared with 29.6%, P=.03), with some deliveries being a direct result of maternal or fetal distress during maternal 2009 H1N1 influenza illness.
Among women who delivered during their hospitalization for 2009 H1N1 influenza, the mean gestational age at delivery was lower for severe 2009 H1N1 influenza cases relative to moderate cases (34.8 compared with 38.6 weeks of gestation, P=.18). The percentage of cesarean deliveries was higher among women with severe than those with moderate 2009 H1N1 influenza illness (83.3% compared with 37.5%, P=.15). There were two neonatal deaths among deliveries to the six women with severe 2009 H1N1 influenza illness, occurring at 23 and 32 completed weeks of gestation. Three of the neonates born to women with severe 2009 H1N1 influenza illness and two of those born to women with moderate 2009 H1N1 influenza illness were admitted and monitored in a NICU. Overall, significantly more neonates born to women with severe than moderate 2009 H1N1 influenza illness had a severe neonatal outcome (83.3% compared with 12.5%, P=.004).
The six pregnant women with severe 2009 H1N1 influenza illness who delivered at the time of the 2009 H1N1 influenza hospitalization were aged 21 to 28 years, and all but one presented to the hospital with respiratory distress as a chief complaint (Table 4). All six women delivered within 10 days of hospital admission for 2009 H1N1 influenza illness; one woman delivered vaginally at 23 weeks of gestation and five delivered by cesarean: one was moderately preterm (32 weeks of completed gestation) and four at term. Among cesarean deliveries, two had maternal indications, two had fetal indications, and one had both maternal and fetal indications for a cesarean delivery. Five of the women required mechanical ventilatory support, and the sixth received supplemental oxygen by nasal cannula. All six women were treated with broad-spectrum antibiotics and oseltamivir during the index hospitalization, but none (including the two fatal cases) had received oseltamivir treatment within 2 days of symptom onset.
Twenty-two pregnant women delivered during the 2009 H1N1 influenza hospitalization; the remaining 40 pregnant women included 17 who delivered after discharge and before September 18, one who had an elective termination of pregnancy at 10 weeks of gestation, and 22 who had not yet delivered. Of the 17 who delivered after their 2009 H1N1 influenza hospitalization, 3 (17.6%) delivered late preterm (34–36 weeks of gestation) and the remaining 14 (82.4%) delivered at term (37–41 weeks of gestation). Five (29.4%) reported at least one delivery complication, and seven (41.2%) were delivered by cesarean. There were no perinatal or maternal deaths in this group; however, four (23.5%) of these infants were admitted to the NICU.
The 2009 H1N1 influenza infection resulted in increased hospitalization rates and disproportionate mortality among pregnant women (4.3%) relative to the percent of pregnant women in the population at any point in time (approximately 1%). Pregnant women in New York City were 7.2 times more likely to be hospitalized with 2009 H1N1 influenza infection than nonpregnant reproductive-aged women. In addition, the severe case hospitalization rate was 4.3 times higher for pregnant than nonpregnant reproductive-aged women in New York City, suggesting that pregnant women are experiencing disproportionately more severe disease with 2009 H1N1 influenza infection and not just a lower threshold for hospitalization. Also, pregnant women in this investigation were more likely than nonpregnant women to be hospitalized for 2009 H1N1 influenza illness in the absence of a high-risk condition for influenza complications (71.0% compared with 32.4%). Our findings of the increased hospitalization rate in pregnant women are consistent with the elevated hospitalization rate reported in the first month of the outbreak in the United States.12 Similarly, a disproportionate number of severe 2009 H1N1 influenza cases among pregnant women has been reported in recent reports from Canada and Australia/New Zealand in which 7.7% and 9.1% of critically ill patients were pregnant, respectively.17,18
Outcomes for women with underlying conditions were similarly severe, regardless of whether the underlying condition was pregnancy or a chronic medical condition. However, once a pregnant woman progressed to severe illness, adverse pregnancy outcomes were common. Five of six pregnant women with severe illness who delivered during their 2009 H1N1 influenza hospitalization had a cesarean delivery and an adverse neonatal outcome.
Less than half of both pregnant and nonpregnant 2009 H1N1 influenza–infected women received oseltamivir treatment within 2 days of symptom onset, many had treatment delays, and some were not treated. Neither of the pregnant women who died had received oseltamivir treatment within 2 days of symptom onset. A report of patients hospitalized with 2009 H1N1 influenza in the United States also showed that early oseltamivir treatment was associated with better survival and patients not requiring ICU admission.19 Another report of 2009 H1N1 influenza-infected ICU patients in Mexico reported that oseltamivir treatment was associated with improved survival compared with no treatment.20 Prompt clinical suspicion of 2009 H1N1 influenza infection in pregnant women by health care providers and early initiation of empiric oseltamivir treatment are therefore crucial as the effectiveness of antiviral treatment appears to be higher the closer to illness onset it is initiated. However, our findings also suggest that oseltamivir treatment is beneficial for pregnant women with 2009 H1N1 influenza infection even if initiated more than 2 days after symptom onset, although the proportion experiencing severe disease increases significantly with longer time to treatment. While we cannot make definitive claims based on our limited sample of pregnant women, this finding supports the CDC recommendation based on seasonal influenza data to initiate treatment with oseltamivir as soon as possible, even if more than 48 hours after onset of symptoms.21 The CDC, the U.S. Food and Drug Administration, and the American College of Obstetricians and Gynecologists advise clinicians to provide prompt antiviral treatment with oseltamivir for pregnant women with suspected 2009 H1N1 influenza infection.22,23,24
This investigation has a number of limitations. The 2009 H1N1 influenza testing in New York City was focused on hospitalized patients, and this provided us with a small sample and limited statistical power for distinguishing differences in demographic factors. Some women might have been admitted to the hospital specifically for testing purposes, which could have been the case with three women in our sample (one pregnant and two nonpregnant) who were admitted and discharged on the same day. The estimated hospitalization rate among pregnant women may be either inflated due to a provider bias toward admitting pregnant women with milder illness who might not have been admitted if not pregnant or underestimated because of limitations in using vital registration data for our population denominator.
Data collection relied on abstractions from hospital records, which might be incomplete or vary in quality between hospitals and individual providers. For example, if data on women's underlying medical conditions are incomplete, this could result in an overestimation of the risk of severe 2009 H1N1 influenza illness among patients without chronic medical conditions documented in medical records. The comparison group abstraction did not include the full level of detail abstracted on the pregnant 2009 H1N1 influenza cases. The comparison group of nonpregnant reproductive-aged women hospitalized with 2009 H1N1 influenza infection included a notably higher percentage of women with chronic, underlying medical conditions than was found among the pregnant women hospitalized with 2009 H1N1 influenza infection. Thus, it is important to carefully consider the comparison of the two groups in light of the difference in medical risk before infection with 2009 H1N1 influenza virus.
In conclusion, pregnant women were disproportionately represented among all confirmed 2009 H1N1 influenza hospitalized cases and related deaths in New York City in May and June 2009. Antiviral treatment with oseltamivir appears to be most beneficial in pregnant women if initiated early, reinforcing the CDC recommendation for early empiric oseltamivir treatment of suspected influenza illness in this high-risk group of the population. When local surveillance data indicate that 2009 H1N1 influenza virus is circulating, health care providers need to educate pregnant women to seek medical care immediately if they have symptoms of acute respiratory illness, so that empiric treatment with oseltamivir is initiated early in the outpatient setting. In light of 2009 H1N1 influenza monovalent vaccine availability, the public health response for this pandemic is increasingly focusing on preventive measures.25 Severe illness occurred in all trimesters of pregnancy, and thus, it is important to encourage all pregnant women to receive the 2009 H1N1 influenza vaccine, consistent with Advisory Committee on Immunization Practices recommendations.15
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