The authors have declared that no competing interests exist.
Conceived and designed the experiments: TD. Performed the experiments: TD. Analyzed the data: TD KG JH. Contributed reagents/materials/analysis tools: TD KG JH. Wrote the manuscript: TD.
Pregnant women have been identified as a high risk group for severe illness with 2009 pandemic influenza A(H1N1) virus infection (pH1N1). Obesity has also been identified as a risk factor for severe illness, though this has not been thoroughly assessed among pregnant women. The objectives of this study were to provide risk estimates for adverse maternal and neonatal outcomes associated with pH1N1 illness during pregnancy and to assess the role of obesity in these outcomes.
We established a retrospective population-based cohort of all live births occurring in Florida during the first 15 months of the pandemic. Illness with pH1N1 during pregnancy was ascertained through record linkage with the Florida state notifiable disease surveillance database. Data from the birth record, including pre-pregnancy body mass index, were analyzed to assess risk of adverse outcomes associated with pH1N1 illness.
A total of 194 women were identified through surveillance with pH1N1 illness during pregnancy. Children born to women with pH1N1 illness during pregnancy were at increased risk for low birth weight [OR (95%CI): 1.78 (1.11-2.860)], premature birth [2.21 (1.47-3.330)], and infant death [4.46 (1.80-11.00)], after adjusting for other factors. Women with pH1N1 illness during pregnancy were at increased risk for severe outcomes including admission to an intensive care unit. Obesity was an observed risk factor, both for the more severe pH1N1 illness detected through surveillance, and for severe maternal outcomes.
Case-patients in this analysis likely represent the most severely ill subset of all women infected with pH1N1 during pregnancy, limiting the generalizability of these findings to more severely ill patients rather than influenza infection in general. Nevertheless, these results suggest that more severe pH1N1 illness during pregnancy is associated with adverse neonatal outcomes and that pregnant women should continue to be targeted for appropriate prophylaxis and early treatment.
Infection with influenza virus can result in a spectrum of illness ranging from asymptomatic infection to severe illness and death. Soon after recognition of the novel 2009 pandemic influenza A(H1N1) virus (pH1N1), pregnant women were identified as a high risk group for severe illness [
Florida is the fourth most populous state in the U.S. with an estimated population in 2010 of more than 18.8 million residents [
The 2009 influenza pandemic began early in Florida, with cases identified in April 2009 and more than 1430 cases reported by June 30, 2009 [unpublished surveillance data]. The summer of 2009 was characterized by persistent transmission across the state, amplified by localized outbreaks in group settings. Following resumption of school, peak transmission was observed in October 2009 [
In several of the initial case series of pregnant women with pH1N1 illness, data on birth outcomes was incomplete, and study designs and available data often did not permit control for other factors associated with adverse neonatal outcomes. Longer term follow-up was needed to ascertain pregnancy outcomes, as well as to fully characterize the impact on infant mortality beyond the perinatal period. Population cohort designs, derived from birth certificate data, may permit more precise risk estimates through a population-based comparison group and better control for confounding. In particular, obesity has been previously identified not only as a risk factor for severe pH1N1 illness[
Prior to the recognition of 2009 pH1N1, infection with a novel influenza virus was already a reportable condition in Florida [
On August 3, 2009, the state issued new guidance to health care providers and laboratories to test for influenza and, if positive for pH1N1, report people with influenza that was life-threatening or resulted in death, or resulted in hospitalization of a pregnant woman. Providers and facilities were also asked to report people who were part of clusters or outbreaks of influenza-like illness. Despite the change in disease reporting guidelines, some providers continued for several weeks to report non-hospitalized cases of pandemic influenza that were laboratory confirmed. All individual case reports received by the FLDOH meeting the case definition of an acute respiratory illness, with laboratory confirmation of pH1N1 by a certified laboratory, were maintained in the state’s notifiable disease surveillance database. Illness on the more severe end of the spectrum is more likely to be apparent, lead to specific laboratory testing, and be captured through passive notifiable disease surveillance [
The Florida birth registry is maintained by the FLDOH Office of Vital Statistics and includes records on all live births occurring in Florida. Records are submitted by hospitals and other medical providers and contain information on the newborn, as well as the mother and father. There are >330 variables contained in the comprehensive electronic birth record, including information on maternal and infant demographic variables; pre-pregnancy BMI, pre-natal exposures such as alcohol and tobacco use by the mother; obstetric history, medical care received during labor and delivery; and health status of the infant. For this analysis, we also used a variable indicating if the mother resided within the city limits, or in a more rural location outside the city limits. In addition, the electronic birth record is updated to indicate mortality for any child dying within five years following live birth.
Electronic records of live births from the Florida birth registry were cross-referenced to the state notifiable disease database to identify children born to women with pH1N1 illness during their pregnancy. All pH1N1 confirmed case-patients with onset of illness between April 24, 2009 and May 31, 2010, who were pregnant at the time of their illness, were included. The record matching included a combination of automated methods and manual review, in an iterative process. Firstly, records in the birth registry were matched to the disease surveillance database by the mother’s social security number and date of birth. Other combinations of matching variables subsequently used included mothers first and last name, alone or in combination with social security number, or date of birth. All matched records were manually reviewed to ensure the accuracy of the match.
Data were further compiled from de-identified records of a birth cohort of all live births occurring in Florida between June 1, 2009 and September 1, 2010. This period corresponds with the time interval of live births among women with reported pH1N1 illness. Records for women with multiple gestational (plural) pregnancies were identified and later de-duplicated to also permit analysis of the cohort of pregnant women giving birth during the same interval. Records were excluded for births among non-Florida residents, and in instances in which adoption or foundling was indicated on the birth record. The database was updated in January 2012 to reflect any infant deaths following birth, occurring up to that time. For secondary analysis, an alternative pregnancy and birth comparison cohort was also constructed from the pre-pandemic period to include all live births occurring between January 1 and February 28, 2009.
Illness due to pH1N1 infection during pregnancy was treated as the outcome variable when assessing disease risk and treated as the primary exposure variable for assessing risk of adverse maternal and neonatal outcomes. Women and children in the pregnancy and birth cohorts were categorized as pH1N1 illness in pregnancy (i.e. ‘ill’ for the first analysis or ‘exposed’ for the second) if the birth records matched to the pH1N1 notifiable disease surveillance database by the methods previously described. All women and their newborns who did not match to the disease surveillance database were defined as ‘unexposed’ or non-cases of pH1N1 illness during pregnancy. Measures of association between exposure and outcome were computed using univariate and multivariable logistic regression and expressed as odds ratios (OR) with 95 percent Wald confidence intervals (95% CI). Univariate relative risks (RR) were also computed for comparison with ORs, but were not presented in the results tables. Because minimal differences were generally noted between the univariate RRs and ORs and because outcome frequencies were generally uncommon and less than 10%, odds ratios were used throughout as approximate estimates of relative risk. To adjust for possible confounding, standard and stepwise multivariable logistic regression was used. Multivariable models were constructed using variables identified during univariate analyses as being associated with influenza, or known risk factors for adverse maternal and neonatal outcomes, while also attempting to minimize the exclusion of cohort members due to missing data for a particular variable. For all stepwise analysis, α=0.1 was the threshold used for variable entry into the model, and α=0.05 was used for retaining variables in the final model. Data analysis was conducted using SAS software, version 9.1 [SAS Institute; Cary, NC]. Statistical power computations presented in the results were obtained using the computer program Power v3.0 [National Institute of Health, National Cancer Institute].
Data on pre-pregnancy BMI was available for approximately 94% of records and was expressed as [weight in kilograms/(height in meters)2]. BMI data in the Florida birth registry has previously been found to be generally reliable and valid [
For simplicity, adult BMI categories were used throughout the analysis, despite the fact that some gravida in the analysis were <20 years old, and standard classifications for BMI are different for children and adolescents [
Data regarding influenza vaccination history and antiviral treatment for influenza was missing from the surveillance case reports for a large proportion of case-patients. Furthermore, the majority of case-patients had illness onset before a vaccine specific for pH1N1 became available. Therefore, we did not attempt in this analysis to assess the role of vaccination or antiviral treatment for influenza on maternal and neonatal outcomes.
This activity was reviewed by the Ethics and Human Research Protection Program of the FLDOH, and determined to involve analysis of existing and de-identified data, not human subjects research, and was therefore exempt from further review by an institutional review board.
A total of 194 women with confirmed pH1N1 illness during pregnancy were reported to FLDOH. Of these, matching birth certificates were identified for 187 women (96%); 4 women gave birth to twins, resulting in a total of 191 live births (
Among pH1N1 case-patients, the temporal pattern of cumulative onset of influenza illness and subsequent birth is shown in
Non-pH1N1 associated individuals in the birth and pregnancy cohort included, after exclusions, 300,398 children born to 295,747 women between June 1, 2009 and September 1, 2010. A total of 4,198 birth records were excluded from the cohort due to non-Florida residence of the mother (n=1,547), child adopted (n=2,648), or foundling (n=3). The alternative comparison birth and pregnancy cohort from the pre-pandemic period included, after exclusions, 24,008 children born to 23,679 women.
Among the cohort of pregnant women giving birth between June 1, 2009 and September 1, 2010, univariate analysis indicated increased risk of pH1N1 illness detected through surveillance among non-white women, and those of Hispanic or Haitian ethnicity. Increased risk of detected and reported pH1N1 illness was also associated with being 25 or younger, unmarried, high school graduate or less education, being on Medicaid, receiving Women Infants and Children (WIC) Program food supplements, living within the city limits, having one or more previous live births, and being obese (
187 | 295,747 | ||
Non-white | 95 (51) | 112,968 (38) | 1.67 (1.25-2.23) |
white | 92 (49) | 182,779 (62) | 1.0 (ref) |
Hispanic or Haitian | 86 (47) | 94,253 (32) | 1.88 (1.41-2.52) |
Not Hispanic or Haitian | 96 (53) | 198,249 (68) | 1.0 (ref) |
yes | 69 (37) | 92,053 (31) | 1.29 (0.96-1.74) |
no | 118 (63) | 203,694 (69) | 1.0 (ref) |
≤ 25 | 104 (56) | 117,923 (40) | 1.89 (1.42-2.52) |
>25 | 83 (44) | 177,800 (60) | 1.0 (ref) |
Mean | 25.9 | 27.6 | p<0.01 |
single | 115 (62) | 139,315 (47) | 1.79 (1.34-2.41) |
married | 72 (38) | 156,337 (53) | 1.0 (ref) |
High school graduate or less | 123 (68) | 144,650 (49) | 2.16 (1.58-2.94) |
High school education | 59 (32) | 149,734 (51) | 1.0 (ref) |
<18.5 | 5 (3) | 12,065 (4) | 0.77 (0.31-1.90) |
18.5-24.9 | 74 (44) | 136,848 (50) | 1.0 (ref) |
25.0-29.9 | 41 (25) | 69,260 (25) | 1.10 (0.75-1.60) |
≥ 30.0 | 46 (28) | 56,194 (21) | 1.51 (1.05-2.19) |
Mean | 26.9 | 25.7 | p<0.01 |
Medicaid | 112 (60) | 140,680 (48) | 1.63 (1.22-2.18) |
Private insurance, self, or other | 75 (40) | 153,592 (52) | 1.0 (ref) |
Yes | 126 (68) | 154,191 (53) | 1.95 (1.43-2.66) |
No | 58 (32) | 138,090 (47) | 1.0 (ref) |
Yes | 155 (83) | 210,535 (72) | 1.95 (1.33-2.87) |
No | 31 (17) | 82,161 (28) | 1.0 (ref) |
Yes | 127 (68) | 168,940 (57) | 1.59 (1.17-2.16) |
No | 60 (32) | 126,807 (43) | 1.0 (ref) |
Yes | 28 (15) | 29,028 (10) | 1.62 (1.08-2.42) |
No | 159 (85) | 266,719 (90) | 1.0 (ref) |
Multiple | 4 (2) | 5064 (2) | 1.26 (0.47-3.38) |
Single | 183 (98) | 290,666 (98) | 1.0 (ref) |
* t-test, pooled variance
Age (years) | 0.95 | (0.93-0.98) | 0.95 | (0.92-0.98) |
Residence in city limits | 2.14 | (1.42-3.23) | 1.94 | (1.28-2.93) |
Hispanic or Haitian ethnicity | 1.77 | (1.32-2.39) | 1.88 | (1.37-2.57) |
Other children (live births) | 1.75 | (1.26-2.45) | 1.67 | (1.18-2.38) |
High school graduate or less | 1.55 | (1.10-2.17) | 1.47 | (1.03-2.10) |
Pre-pregnancy BMI | n/a | n/a | 1.03 | (1.01-1.06) |
1 Final model included 178 cases and 287,449 non-cases with available data for all variables (8307 observations deleted for missing data on one or more variables). Multivariable stepwise logistic regression model adjusting for maternal age, maternal education, mother residence in city, maternal ethnicity, presence of past live births, maternal marital status, maternal race, maternal foreign born, and Medicaid payment. All variables not listed in the table were not significant at alpha=0.05 level, after adjusting for other variables, and thus did not appear in the final model.
2 Final model included 160 cases and 267,880 non-cases with available data for all variables (27,894 observations deleted for missing data on one or more variables). Multivariable stepwise logistic regression model adjusting for same variables in model 1, with addition of maternal pre-pregnancy BMI (continuous variable). All variables not listed in the table were not significant at alpha=0.05 level, after adjusting for other variables, and thus did not appear in the final model.
When comparing the distribution of women with pH1N1 illness by variables listed in
Neonatal outcomes among the cohort of live births occurring between June 2009 and September 2010, are shown in
<2500g | 30 (16) | 25,998 (9) | 1.97 (1.33-2.91) | 1.67 (1.06-2.62) | 1.78 (1.11-2.86) |
2500g or more | 161 (84) | 274,400 (91) | 1.0 (ref) | 1.0 (ref) | 1.0 (ref) |
<1500g | 15 (8) | 4893 (2) | 5.16 (3.05-8.74) | 3.66 (1.94-6.91) | 3.93 (2.00-7.69) |
1500g or more | 176 (92) | 295,505 (98) | 1.0 (ref) | 1.0 (ref) | 1.0 (ref) |
<1000g | 6 (3) | 2518 (1) | 3.84 (1.70-8.66) | 2.47 (0.90-6.77) | 2.85 (1.03-7.90) |
1000g or more | 185 (97) | 297,880 (99) | 1.0 (ref) | 1.0 (ref) | 1.0 (ref) |
<37 weeks gestation | 45 (24) | 31,259 (10) | 2.65 (1.90-3.70) | 2.39 (1.64-3.49) | 2.21 (1.47-3.33) |
37 weeks or more | 146 (76) | 268,626 (90) | 1.0 (ref) | 1.0 (ref) | 1.0 (ref) |
<32 weeks gestation | 13 (7) | 5152 (2) | 4.18 (2.38-7.34) | 3.04 (1.57-5.90) | 3.21 (1.59-6.48) |
32 weeks or more | 178 (93) | 294,733 (98) | 1.0 (ref) | 1.0 (ref) | 1.0 (ref) |
<28 weeks gestation | 8 (4) | 2258 (1) | 5.77 (2.84-11.71) | 4.19 (1.82-9.63) | 3.95 (1.58-9.90) |
28 weeks or more | 183 (96) | 297,627 (99) | 1.0 (ref) | 1.0 (ref) | 1.0 (ref) |
<9 | 34 (18) | 31,848 (11) | 1.82 (1.26-2.64) | 1.56 (1.04-2.35) | 1.65 (1.08-2.52) |
9 or greater | 157 (82) | 267,851 (89) | 1.0 (ref) | 1.0 (ref) | 1.0 (ref) |
yes | 36 (19) | 37,480 (12) | 1.63 (1.14-2.35) | 1.34 (0.90-2.00) | 1.43 (0.94-2.17) |
no | 155 (81) | 262,918 (88) | 1.0 (ref) | 1.0 (ref) | 1.0 (ref) |
yes | 2 (1) | 3000 (1) | 1.05 (0.26-4.23) | 1.13 (0.28-4.55) | 1.25 (0.31-5.03) |
no | 189 (99) | 297,398 (99) | 1.0 (ref) | 1.0 (ref) | 1.0 (ref) |
yes | 32 (17) | 22,975 (8) | 2.43 (1.66-3.55) | 1.96 (1.27-3.02) | 2.14 (1.36-3.36) |
no | 159 (83) | 277,129 (92) | 1.0 (ref) | 1.0 (ref) | 1.0 (ref) |
yes | 3 (2) | 1347 (1) | 3.54 (1.13-11.09) | 1.28 (0.18-9.16) | 1.45 (0.20-10.39) |
no | 188 (98) | 298,757 (99) | 1.0 (ref) | 1.0 (ref) | 1.0 (ref) |
yes | 2 (1) | 804 (1) | 3.96 (0.98-15.97 | 4.23 (1.04-17.29 | 2.43 (0.33-17.65) |
no | 188 (99) | 299,156 (99) | 1.0 (ref) | 1.0 (ref) | 1.0 (ref) |
yes | 8 (4) | 2130 (1) | 6.12 (3.01-12.44) | 5.38 (2.50-11.58) | 4.46 (1.80-11.00) |
no | 183 (96) | 297,886 (99) | 1.0 (ref) | 1.0 (ref) | 1.0 (ref) |
yes | 92 (48) | 115,060 (38) | 1.51 (1.14-2.01) | 1.44 (1.07-1.94) | 1.31 (0.96-1.81) |
no | 98 (52) | 185,148 (62) | 1.0 (ref) | 1.0 (ref) | 1.0 (ref) |
1 Adjusted for maternal age (<18, 18-39, ≥ 40), maternal race, maternal ethnicity, maternal education, maternal marital status, plurality (y/n), infant sex, tobacco use during pregnancy (y/n), alcohol use during pregnancy (y/n), previous preterm delivery (y/n), previous poor pregnancy outcome (y/n), pre-gestational diabetes (y/n). Depending on outcome variable, between 6582-7318 records were excluded due to missing data for 1 or more variables.
2 Adjusted for same variables in model 1, with additional adjustment for pre-pregnancy BMI (4 categories: underweight, normal, overweight, obese). Depending on outcome variable, between 26,675-27,176 records were excluded due to missing data for 1 or more variables.
* Infant non-living at time birth certificate was submitted.
** Infant/child died within 5 years of live birth
Illness with pH1N1 was not significantly associated with low birth weight, after adjusting for gestational age and other variables in the multivariable model. This suggests that the association between pH1N1 illness and low birth weight is primarily due to pre-term birth. No interaction was observed between pH1N1 illness and maternal obesity, with respect to the most severe neonatal outcomes of early preterm birth (<28 weeks, p=0.36), and infant death (p=0.32).
Of the 191 children born to women with pH1N1 illness, 8 (4%) died (
6/21/09 | 06/23/09 | M | 27 | 1150 | Yes | 25 | B | Cesarean | 08 | 17 months | 30.2 | Alive |
6/23/09 | 07/02/09 | M | 27 | 1124 | No | 22 | W | Cesarean | 02 | <1day | . | D-7/2/09 |
7/3/09 | 07/18/09 | F | 26 | 936 | No | 27 | W | Cesarean | 01 | 6 minutes | 25.8 | Alive |
8/22/09 | 10/23/09 | M | 22 | 482 | No | 22 | B | Vaginal | 08 | 3 days | 19.2 | Alive |
8/24/09 | 09/22/09 | F | 26 | 595 | No | 25 | W | Cesarean | 08 | 4 month | 25.6 | Alive |
9/6/09 | 09/17/09 | F | 24 | 624 | No | 31 | W-H | Cesarean | 06 | 24 days | 25 | Alive |
11/08/09 | 11/18/09 | M | 34 | 2353 | No | 22 | W-H | Cesarean | 03 | 4 days | . | D-12/8/09 |
2/4/10 | 03/29/10 | F | 38 | 2637 | No | 28 | W-H | Vaginal | 07 | 7 months | 22.3 | Alive |
M=Male, F=Female, B=Black, W=White, H=Hispanic, D=Deceased, DOB=date of birth, GA=gestational age
Based on data available from the birth record, of the 187 women with pH1N1 illness and a live birth, 9 were admitted to ICU. This contrasts with results available from the notifiable disease database, which indicate that 41 (22%) women reported with pH1N1 illness were admitted to ICU. The cause for this discrepancy is unknown, but may be due to the timing of ICU admission following live birth, or incomplete knowledge of the mother’s clinical course by those completing the birth record. Despite this discrepancy, data from the birth record was used to analyze risk of ICU admission for the entire pregnancy cohort. Pregnant women with pH1N1 illness detected through surveillance, were 28 times more likely to be admitted to ICU than other women with a live birth who were not known to be pH1N1 infected (
pH1N1 illness (Y vs N) | 28.28 | (14.40-55.55) | 22.22 | (10.30-47.94) | 22.26 | (9.69-51.12) |
Plurality (Y vs N) | 5.27 | (3.86-7.20) | 5.72 | (4.13-7.90) | ||
Pre-gestational diabetes (Y vs N) | 3.37 | (2.01-5.66) | 2.57 | (1.40-4.71) | ||
Previous poor outcome (Y vs N) | 2.86 | (1.64-4.98) | 3.17 | (1.82-5.53) | ||
Maternal age (≥ 40 vs 18-39) | 2.68 | (1.94-3.71) | 2.51 | (1.75-3.59) | ||
Maternal race (non-white vs white) | 1.97 | (1.66-2.35) | 1.83 | (1.52-2.21) | ||
Pre-pregnancy BMI (≥ 30 vs normal) | 1.52 | (1.21-1.92) |
1 Univariate analysis includes 294,839 pregnant women, 541 of whom were admitted to ICU. Of the 541 admitted to ICU, 9 were pH1N1 infected.
2 Multivariable stepwise logistic regression model adjusting for pH1N1 illness, maternal age (<18, 18-39, ≥ 40), maternal race, maternal ethnicity, maternal education, maternal marital status, plurality (y/n), infant sex, tobacco use during pregnancy (y/n), alcohol use during pregnancy (y/n), previous preterm delivery (y/n), previous poor pregnancy outcome (y/n), pre-gestational diabetes (y/n). 6892 observations were deleted for missing data on one or more variables. All variables not listed in the table where not significant at alpha=0.05 level, after adjusting for other variables, and thus did not appear in the final model.
3 Adjusted for same variables in model 2, with additional adjustment for pre-pregnancy BMI (4 categories: underweight, normal, overweight, obese). 26,473 observations were deleted for missing data on one or more variables. All variables not listed in the table where not significant at alpha=0.05 level, after adjusting for other variables, and thus did not appear in the final model.
This analysis was repeated after recoding ICU admission to “Yes” for 32 women with pH1N1 illness previously coded “No” in the birth record, but for whom data from the notifiable disease database indicated ICU admission. The univariate odds ratio of maternal ICU admission associated with pH1N1 illness increased to 155.28 (95% CI: 108.69-221.83). The same variables were retained in the multivariable stepwise model. Following adjustment for covariates, the multivariable OR was 131.25 (95% CI: 88.21-195.28). This risk estimate, however, is likely to be unreliable, as case-patients were more likely to have complete information regarding ICU admission than non-case patients.
Of the 8 women with pH1N1 illness who died, 6 gave birth to a live infant, and 4 of these 6 infants survived (
Age | Race | Onset of symptoms | Hospital admission date | Gestational age at time of illness | Interval between onset and death (days) | BMI | Comorbidities | Oseltamivir Treatment [Y/N, (days after onset)] | DOB of Infant | Infant outcome |
---|---|---|---|---|---|---|---|---|---|---|
30 | W-H | 5/28/09 | 6/4/09 | 11 | 25 | dk | obesity asthma | N | n/a | Fetal loss |
25 | B | 6/11/09 | 6/16/09 | 27 | 15 | 42.9 | obesity, diabetes | Y [ |
6/17/09 | Survived |
22 | W | 6/23/09 | 26 | 10 | dk | dk | 7/02/09 | D-7/2/09 | ||
25 | W | 7/17/09 | 35 | 11 | dk | asthma | Y [ |
7/19/09 | Survived | |
22 | W-H | 7/26/09 | 7/29/09 | 27 | 25 | dk | Y [ |
8/20/09 | Survived | |
31 | A | 8/4/09 | 8/8/09 | 13 | 9 | dk | Y [ |
n/a | Fetal loss | |
24 | W | 8/5/09 | 8/6/09 | 32 | 54 | 23.7 | Y [ |
8/07/09 | Survived | |
22 | W-H | 11/8/09 | 11/18/09 | 33 | 30 | dk | none | Y [ |
11/18/09 | D-11/22/09 |
B=Black, W=White, A=Asian, H=Hispanic, dk=don’t know, n/a=not applicable, D=Deceased, DOB=date of birth
To address the possibility that some pregnant women with pH1N1 illness during the study interval were not reported to FLDOH, we searched fields in the birth record for text strings containing “H1N1”. We identified 41 birth records with “H1N1” text appearing in the record. Of these 41 births, 9 were from confirmed cases of pH1N1 ascertained through surveillance, and 32 were from women not contained in the notifiable disease database. In 15 of the 32 records, the “H1N1” text appears to relate to provision of H1N1 vaccine or prophylaxis, leaving 17 remaining records which may represent pH1N1 infections among pregnant women which were not otherwise identified through routine surveillance and case reporting. We conducted additional analysis adding these 17 pregnant women and births to confirmed pH1N1 cases, and excluding the 15 pregnant women and births for which H1N1 may refer to vaccine or chemoprophylaxis. The results of these analyses were not substantially different from previous results, and did not alter any of our conclusions; therefore, we did not utilize this approach when presenting the primary results of our analysis. Similarly, results did not differ notably when excluding or including birth records from adopted children; therefore, results are presented for analyses following exclusion of these records.
Based on the available sample size and assuming an alpha-level of 0.05, the study analysis had 80% power to detect ORs of approximately 1.50 or greater for most of the risk factors presented in
We observed a consistent, and statistically significant association between pH1N1 illness during pregnancy and adverse neonatal and maternal outcomes, including low birth weight, preterm birth, neonatal ICU admission, infant death, and maternal ICU admission. The observed associations with pH1N1 illness remained significant after adjusting for other observed and known risk factors for adverse neonatal and maternal outcomes. As the disease surveillance data sources used for this analysis are more likely to detect case-patients with more severe influenza illness, our findings apply more toward outcomes associated with more severe influenza illness, rather than influenza infection in general.
While several previous case series have described neonatal outcomes of pH1N1 infected women [
In addition to the adverse neonatal outcomes we observed, the pandemic had a striking impact on maternal mortality in Florida, as elsewhere. Data from the Florida Pregnancy-Associated Mortality Review [
We identified younger age, racial and ethnic minorities, indicators of lower socio-economic status (SES), and obesity as risk factors for pH1N1 illness severe enough to be detected through our surveillance. Others have noted both an individual and ecological-level association between hospitalization for pH1N1 and indicators of low SES [
Obesity was both an observed risk factor for recognized and reported pH1N1 illness, as well as a risk factor for poor maternal outcomes among pregnant women, as indicated by ICU admission. Obesity may have important effects on immune response which leave obese individuals more susceptible to infection [
Others have previously identified obesity as a risk factor for severe illness with pH1N1 [
Pierce et al, used a similar approach to ours, however, the comparison cohort they used was smaller and taken exclusively from the pre-pandemic period [
By the end of 2009, an estimated 25% of residents in some areas of Florida were believed to have been infected with pH1N1, with the highest rates of infection noted among school-aged children 5-17 years, and infection rates approaching 50% among young adults 18-24 years [
The study is limited by imperfect disease surveillance and case ascertainment of all women with pH1N1 illness during pregnancy. Therefore, our findings are only generalizable to the more severe pH1N1 illness detected through our surveillance, not to pH1N1 infection in general. Imperfect disease surveillance may have led to both random and differential misclassification bias of pH1N1 illness, which was both an outcome and exposure variable in this analysis, possibly resulting in some bias in the risk estimates. This study was also limited by lack of comparative data for women without a live birth and missing data on pre-pregnancy BMI for approximately 6% of the women. Data available in the birth record regarding maternal morbidity, (e.g. ICU admission), also appears to be incomplete, somewhat limiting our conclusions regarding maternal outcomes. Prospective studies may help address all of these limitations. However, the advantages of our study over past reports include a very large comparison group with extensive information available from the birth record to facilitate control for confounding factors, as well as longer follow-up to allow ascertainment of child mortality, through the birth record, several months after birth.
The present study uses a population-based cohort design to add to and further characterize the previously described risk of adverse maternal and neonatal outcomes associated with pH1N1 illness. In conclusion, we found increased risk of severe adverse maternal and neonatal outcomes associated with pH1N1 illness during pregnancy. Pregnant women should continue to be regarded as a high risk group for adverse outcomes of influenza virus infection and should continue to be targeted for enhanced prevention activities through vaccination and appropriate chemoprophylaxis and treatment for influenza, consistent with current recommendations [
Disclaimer: 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 or other funding sources.
We gratefully acknowledge the many people working in the medical and public health sector in Florida who contributed to the data sources used in this analysis. We thank Richard Hopkins for advice regarding study design and critical review of the manuscript; Daniel Thompson for assistance with data matching; and Kristopher Arheart for statistical and programming advice. Finally we thank the anonymous peer-reviewers for volunteering their time to review and help strengthen the report.