Objective
This study was undertaken to examine the association between maternal oseltamivir treatment for influenza and infant outcomes during the 2009 HINI influenza pandemic.
Study Design
This was a retrospective cohort study using a population-based maternal newborn database including women who gave birth to a singleton infant in the Canadian province of Ontario from November 2009 through April 2010. Risks of small for gestational age (SGA) (10th percentile and 3rd percentile), preterm birth (<37 weeks of gestation), very preterm birth (<32 weeks of gestation), and 5-minute Apgar score <7 associated with maternal exposure to oseltamivir were analyzed by multivariable regression.
Results
A total of 55,355 women with a singleton birth were included in this study. Among them, 1237 (2.2%) women received oseltamivir for treatment or prevention of influenza during pregnancy. Women who took oseltamivir during pregnancy were less likely to have a SGA infant based on the 10th percentile for growth (adjusted risk ratio, 0.77; 95% confidence interval, 0.60–0.98). No association between maternal use of oseltamivir with SGA on 3rd percentile, preterm birth, very preterm birth, and low Apgar score was observed.
Conclusion
There is no evidence of an association between maternal use of oseltamivir for influenza and early birth, low Apgar at birth, and poor fetal growth.
In March 2009, a novel H1N1 influenza A virus was identified in Mexico and spread rapidly across many countries. Compared with nonpregnant women, pregnant women are at increased risk for related hospital admission and death associated with influenza pandemic. During seasonal influenza epidemics and previous pandemics, pregnant women have been at increased risk for complications related to influenza infection. The mechanical, immunological, and hormonal changes during pregnancy are likely the reasons that pregnant women are more vulnerable to viral respiratory infections such as influenza than nonpregnant women.
Oseltamivir (Tamiflu; F. Hoffmann-La Roche Ltd., Basel, Switzerland) is an antiviral drug of the neuraminidase inhibitor class used for the treatment and prophylaxis of influenza. It is hydrolyzed by the liver to its active metabolite, with an elimination half-life of about 6-10 hours. The H1N1 virus is susceptible to neuraminidase inhibitors such as oseltamivir. The efficacy and safety of oseltamivir in children aged ≥1 year and in adults has been well established, and it was used extensively for the treatment and prevention of 2009 H1N1 influenza. Only a few studies have examined the association between maternal use of oseltamivir and pregnancy outcomes ; however, these studies were based on small samples or self-reports from pregnant women. The benefit of treatment of pregnant women with antiviral medications is presumed to outweigh its risk; however, the limited availability of information on risk and benefits of antiviral medication during pregnancy is challenging for both health care providers and pregnant women. The aim of this study was to assess the effect of maternal oseltamivir use for treatment or prevention of influenza on infant outcomes.
Materials and Methods
This was a population-based retrospective cohort study. All hospital birth records from November 2009 through April 2010 from Better Outcomes Registry and Network (BORN) Ontario, an Internet-based birth record system, were abstracted. The BORN Ontario database contains information on maternal and prenatal characteristics, health services, obstetric information, as well as birth outcomes. Starting on Nov. 2, 2009, at the time of admission for labor or elective cesarean section, health care staff collected additional information via patient interview or from antenatal records and hospital charts regarding influenza illness, use of antiviral medications, or influenza vaccination during pregnancy using standardized questions and data collection forms. These data were entered directly into the BORN birth record system at each hospital or electronically uploaded to the BORN system in hospitals with this capability.
Statistics Canada software (PCCF+ version 5E; Statistics Canada, Ottawa, Ontario, Canada) was used to create neighborhood information on education and income based on the long form 2006 Canadian Census (administered to a 20% random sample of the population). Neighborhood family income and level of education were linked by dissemination areas using maternal postal code. These variables were presented as quintiles for analysis. Each quintile contains about one-fifth of the total Ontario population, but may not necessarily contain one fifth of the births in our study population.
We restricted our analysis to singleton, live births ≥20 weeks of gestation and ≥500 g in weight. Pregnancies that ended in miscarriage <20 weeks’ gestation and terminations of pregnancy for fetal anomalies at any gestational age were excluded from the database.
Adverse infant outcomes examined in the study included small-for-gestational-age (SGA) infant (<10th percentile for birthweight) and severe SGA infant (<3rd percentile) by sex and gestational week strata using a Canadian growth standard, preterm delivery (live birth at <37 gestational weeks), very preterm delivery (live birth at <32 gestational weeks), and Apgar score <7 at 5 minutes.
We first compared the distribution of baseline characteristics between women who were exposed to oseltamivir during pregnancy and those women who were not. We then analyzed risk of each adverse infant outcome associated with maternal exposure to oseltamivir by calculating unadjusted risk ratios (RRs) along with 95% confidence intervals (CIs) using logistic regression. Odds ratios with 95% CI approximate the RR for rare outcomes, and will thus be interpreted as RR. Subsequently, adjusted RR with 95% CI were estimated using multiple logistic regression. Two sets of logistic regression models were developed. In the first set of models, we adjusted for maternal age (<20, 20-24, 25-34, 35-39, and ≥40 years), parity (defined as number of previous live births and stillbirths, with values 0, 1, and ≥2), vaccination (vaccination for influenza, yes vs no), preexisting comorbidities (asthma, chronic hypertension, insulin-dependent diabetes, noninsulin-dependent diabetes, or heart disease, present vs absent), maternal smoking (yes vs no), occurrence of influenza-like illness (yes vs no), and neighborhood education and income levels (in quartiles). In the second sets of models, influenza vaccination during pregnancy was added to the model. The confounding factors to be adjusted for were selected by an expert panel consisting of obstetricians, epidemiologists, statisticians, and nursing researchers, after integrating information from a literature review and preliminary results of the data. Supplemental analyses were performed in pregnant women who reported influenza.
All analyses were conducted using SAS software, version 9.2 (SAS Institute Inc, Cary, NC). Research ethics board approval was obtained from the Ottawa Hospital.
Results
A total of 55,355 pregnant women who gave birth to a singleton infant from November 2009 through April 2010 in hospitals in Ontario were included in the analysis. Among them, 1237 (2.2%) women had received oseltamivir therapy at some time during their pregnancy. Women who received oseltamivir therapy were more likely to have no previous live birth and be smokers, were younger, were more likely to come from low education and higher income neighborhoods, and were less likely to have high-risk medical comorbidities ( Table 1 ).
| Characteristics | Total n = 55,355 | Antiviral use during pregnancy | P value | ||||
|---|---|---|---|---|---|---|---|
| None n = 54,118 | Oseltamivir n = 1237 | ||||||
| n | % | n | % | n | % | ||
| Maternal age, y | |||||||
| <20 | 2066 | 3.7 | 2007 | 3.7 | 59 | 4.8 | |
| 20-24 | 7423 | 13.4 | 7225 | 13.4 | 198 | 16.0 | |
| 25-34 | 34,070 | 61.5 | 33,331 | 61.6 | 739 | 59.7 | .0128 |
| 35-39 | 9625 | 17.4 | 9427 | 17.4 | 198 | 16.0 | |
| ≥40 | 2170 | 3.9 | 2127 | 3.9 | 43 | 3.5 | |
| Missing | 1 | 0.0 | 1 | 0.0 | 0 | 0.0 | |
| Parity | |||||||
| 0 | 24,223 | 43.9 | 23,738 | 44.0 | 485 | 39.3 | |
| 1 | 19,581 | 35.5 | 19,123 | 35.4 | 458 | 37.1 | .0023 |
| ≥2 | 11,415 | 20.7 | 11,124 | 20.6 | 291 | 23.6 | |
| Missing | 136 | 0.2 | 133 | 0.2 | 3 | 0.2 | |
| Month of delivery | |||||||
| November 2009 | 9404 | 17.0 | 9196 | 17.0 | 208 | 16.8 | |
| December 2009 | 8702 | 15.7 | 8497 | 15.7 | 205 | 16.6 | |
| January 2010 | 9928 | 17.9 | 9699 | 17.9 | 229 | 18.5 | .0597 |
| February 2010 | 9421 | 17.0 | 9244 | 17.1 | 177 | 14.3 | |
| March 2010 | 8883 | 16.0 | 8694 | 16.1 | 189 | 15.3 | |
| April 2010 | 9017 | 16.3 | 8788 | 16.2 | 229 | 18.5 | |
| Smoking | |||||||
| No | 47,005 | 88.4 | 46,040 | 88.5 | 965 | 82.8 | |
| Yes | 6190 | 11.6 | 5989 | 11.5 | 201 | 17.2 | < .0001 |
| Missing | 2160 | 3.9 | 2089 | 3.9 | 71 | 5.7 | |
| Had influenza | |||||||
| No | 53,105 | 96.8 | 52,610 | 98.0 | 495 | 43.2 | |
| Yes | 1734 | 3.2 | 1083 | 2.0 | 651 | 56.8 | < .0001 |
| Missing | 516 | 0.9 | 425 | 0.8 | 91 | 7.4 | |
| Vaccinated for influenza | |||||||
| No | 31,640 | 58.1 | 30,997 | 58.2 | 643 | 53.6 | |
| Yes | 22,779 | 41.9 | 22,223 | 41.8 | 556 | 46.4 | .0014 |
| Missing | 936 | 1.7 | 898 | 1.7 | 38 | 3.1 | |
| Medical comorbidities a | |||||||
| No | 49,998 | 92.6 | 48,942 | 88.1 | 1056 | 92.7 | |
| Yes | 3969 | 7.4 | 3826 | 11.9 | 143 | 7.3 | < .0001 |
| Missing | 1388 | 2.5 | 1350 | 2.5 | 38 | 3.1 | |
| Income quartiles | |||||||
| 1 (Lowest) | 13,515 | 25.0 | 13,231 | 25.1 | 284 | 23.5 | |
| 2 | 13,600 | 25.2 | 13,256 | 25.1 | 344 | 28.5 | |
| 3 | 13,601 | 25.2 | 13,335 | 25.3 | 266 | 22.0 | .0066 |
| 4 (Highest) | 13,285 | 24.6 | 12,972 | 24.6 | 313 | 25.9 | |
| Missing | 1354 | 2.4 | 1324 | 2.4 | 30 | 2.4 | |
| Education quartiles | |||||||
| 1 (Lowest) | 13,743 | 25.4 | 13,350 | 25.3 | 393 | 32.6 | |
| 2 | 13,585 | 25.2 | 13,278 | 25.2 | 307 | 25.4 | |
| 3 | 13,500 | 25.0 | 13,228 | 25.1 | 272 | 22.5 | < .0001 |
| 4 (Highest) | 13,173 | 24.4 | 12,938 | 24.5 | 235 | 19.5 | |
| Missing | 1354 | 2.4 | 1324 | 2.4 | 30 | 2.4 | |
a High-risk medical comorbidities include: mothers with asthma, chronic hypertension, insulin-dependent diabetes, noninsulin-dependent diabetes, and heart disease.
The risks and RR for birth outcomes are shown in Table 2 . The risk of SGA <10th percentile was significantly lower among women who used oseltamivir at some time during pregnancy compared with those who did not (6.9% vs 9.2%; adjusted RR, 0.77; 95% CI, 0.60–0.98). No association between maternal use of oseltamivir with SGA <3rd percentile, preterm birth <37 weeks, very preterm birth <32 weeks, and Apgar score <7 was observed, after adjusting for potential confounding factors. Results from models with or without influenza vaccination were almost identical. Supplemental analyses restricting to pregnant women who reported influenza yielded similar findings, although reduced number of study subjects resulted in statistical instability (data available upon request).
| Outcome a | No antiviral use (n = 53,875) | Oseltamivir use (n = 1232) |
|---|---|---|
| Small for gestational age (<10th percentile) | ||
| n (%) | 4975 (9.2) | 85 (6.9) |
| Unadjusted RR (95% CI) | 1.00 (Reference) | 0.75 (0.61–0.92) |
| Adjusted RR (95% CI) | 1.00 (Reference) | 0.77 (0.61–0.98) |
| Adjusted RR (95% CI) b | 1.00 (Reference) | 0.77 (0.60–0.98) |
| Small for gestational age (<3rd percentile) | ||
| n (%) | 1287 (2.39) | 27 (2.2) |
| Unadjusted RR (95% CI) | 1.00 (Reference) | 0.92 (0.63–1.34) |
| Adjusted RR (95% CI) | 1.00 (Reference) | 0.86 (0.54–1.38) |
| Adjusted RR (95% CI) b | 1.00 (Reference) | 0.83 (0.51–1.35) |
| Preterm birth (<37 wk) | ||
| n (%) | 3306 (6.1) | 86 (7.0) |
| Unadjusted RR (95% CI) | 1.00 (Reference) | 1.14 (0.93–1.40) |
| Adjusted RR (95% CI) | 1.00 (Reference) | 1.24 (0.97–1.58) |
| Adjusted RR (95% CI) b | 1.00 (Reference) | 1.26 (0.99–1.61) |
| Very preterm birth (<32 wk) | ||
| n (%) | 379 (0.7) | 8 (0.7) |
| Unadjusted RR (95% CI) | 1.00 (Reference) | 0.92 (0.50–1.86) |
| Adjusted RR (95% CI) | 1.00 (Reference) | 1.39 (0.62–3.11) |
| Adjusted RR (95% CI) b | 1.00 (Reference) | 1.46 (0.65–3.27) |
| 5-min Apgar score <7 | ||
| n (%) | 637 (1.2) | 16 (1.3) |
| Unadjusted RR (95% CI) | 1.00 (Reference) | 1.10 (0.67–1.79) |
| Adjusted RR (95% CI) | 1.00 (Reference) | 1.20 (0.67–2.12) |
| Adjusted RR (95% CI) b | 1.00 (Reference) | 1.22 (0.68–2.16) |
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