Maternal medicine
DOI: 10.1111/1471-0528.12640 www.bjog.org
Pregnancy outcome following maternal use of zanamivir or oseltamivir during the 2009 influenza A/H1N1 pandemic: a national prospective surveillance study HJ Dunstan,a AC Mill,b S Stephens,a LM Yates,a,c SHL Thomasa,d a United Kingdom Teratology Information Service, Wolfson Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK b School of Biology, Newcastle University, Newcastle upon Tyne, UK c Institute of Human Genetics, International Centre for Life, Newcastle upon Tyne, UK d Wolfson Unit of Clinical Pharmacology, Institute of Cellular Medicine and Medical Toxicology Centre, Newcastle University, Newcastle upon Tyne, UK Correspondence: L Yates, UKTIS, Wolfson Unit, Newcastle upon Tyne, NE2 4HH, UK. Email [email protected]
Accepted 2 December 2013. Published Online 7 March 2014.
Objective To conduct enhanced surveillance for signals of
Main outcome measures Rates of major congenital malformation,
teratogenesis following use of the neuraminidase inhibitors zanamivir and oseltamivir in the treatment or post-exposure prophylaxis of 2009 A/H1N1 influenza during pregnancy.
preterm delivery and low birth weight.
Design Prospective cohort study, using national surveillance data
collected by the UK Teratology Information Service (UKTIS) during the 2009 A/H1N1 pandemic. Setting United Kingdom. Population Pregnant women who were reported to UKTIS
by healthcare professionals seeking advice about exposure to zanamivir and oseltamivir or to other non-teratogenic drugs. Methods Pregnancy outcomes were collected for prospectively
reported pregnancies exposed to zanamivir (n = 180) or oseltamivir (n = 27), and compared with a reference group of 575 prospectively reported pregnancies exposed to non-teratogenic drugs over the same period.
Results No significant differences in overall rates of major malformation in live-born infants [adjusted odds ratios (aOR): zanamivir 0.37 (95% confidence interval 0.02–2.70); oseltamivir aOR 0.81 (0.05, 14.15)], preterm delivery [aOR: zanamivir 0.95 (0.45, 1.89); oseltamivir aOR 1.68 (0.38, 5.38)] or low birth weight [aOR: zanamivir 0.94 (0.25, 2.90); oseltamivir aOR 4.12 (0.59, 17.99)] were observed following exposure at any gestation. No major malformations were reported in 37 zanamivir or eight oseltamivir first trimester exposures. Conclusion These surveillance data do not provide a signal that
use of zanamivir or oseltamivir in pregnancy is associated with an increased risk of the adverse pregnancy outcomes studied but the data are too limited to state conclusively that there is no increase in risk. Keywords A/H1N1 influenza, neuraminidase inhibitors, oseltamivir, pregnancy, zanamivir.
Please cite this paper as: Dunstan HJ, Mill AC, Stephens S, Yates LM, Thomas SHL. Pregnancy outcome following maternal use of zanamivir or oseltamivir during the 2009 influenza A/H1N1 pandemic: a national prospective surveillance study. BJOG 2014;121:901–906.
Introduction Influenza infection in pregnancy has been associated with an increased risk of adverse maternal and fetal outcomes, including maternal death, miscarriage and stillbirth,1,2 and less conclusively with congenital malformation in the offspring.3 Pregnant women were therefore identified as a high risk group requiring early treatment or post-exposure antiviral prophylaxis with the neuraminidase inhibitors
ª 2014 Royal College of Obstetricians and Gynaecologists
zanamivir or oseltamivir during the 2009 Influenza A/ H1N1 pandemic.1,4 Oseltamivir is administered orally and is readily absorbed from the gastrointestinal tract, whereas zanamivir is an inhaled preparation and as such has lower systemic and subsequent transplacental bioavailability. For this reason, zanamivir was recommended in the UK as the preferred antiviral during the 2009 pandemic for prophylaxis in the pregnant patient where active illness had not been
901
Dunstan et al.
confirmed, especially during the first trimester, when organogenesis occurs. Oseltamivir was advised where A/H1N1 infection was suspected or confirmed in pregnancy on the basis that zanamivir may be less effective in the treatment of systemic illness. Other countries opted for the use of oseltamivir for first line use for in both scenarios. Data on the fetal safety of neuraminidase inhibitor use during pregnancy was very limited at the onset of the 2009 pandemic, particularly for zanamivir, and consisted mainly of incomplete information from unpublished sources. To address the need to collect information on maternal and fetal outcome during the 2009 pandemic, the UK Teratology Information Service (UKTIS) collected fetal outcome details from health care professionals, the vast majority of whom were general practitioners, who contacted the service for case-specific advice and information about the safety of oseltamivir or zanamivir use in a particular patient who was pregnant. In this report, these pregnancy outcome data are compared with information collected over the same period from enquiries relating to other drug treatments considered non-teratogenic.
Methods Data collection was performed as surveillance on behalf of the Health Protection Agency and was covered by Section 251 of the NHS Act 2006. Because this data collection was conducted as enhanced surveillance activity by the UK Teratology Information Service during the pandemic, separate ethical approval was not required. For part of the study period, UKTIS was also involved in a study funded by the National Institute of Health Research investigating the characteristics and management of women with or at risk of A/H1N1 virus infection and the relationship to pregnancy outcomes.4 The study was approved by the County Durham and Tees Valley Research Ethics Committee (REC reference number: 09/H0905/66). All participants provided informed consent. The study sponsor was the Newcastle upon-Tyne Hospitals NHS Foundation Trust (NUTH). Data collected during this study for women exposed to neuraminidase inhibitor antiviral agents were also included in the current analysis.
Data collection Information was collected for singleton pregnancies reported between January 2009 and December 2010 with outcome data collected until October 2012. Exposed pregnancies were defined as women who received the neuraminidase inhibitors zanamivir or oseltamivir in pregnancy. The reference group comprised women about whom UKTIS received enquiries during the same time period regarding exposure to other medications that are considered not to be teratogenic. These include topical preparations, cyclizine, amoxicillin and
902
paracetamol. Women also exposed to confirmed teratogens (e.g. oral retinoids, sodium valproate, methotrexate and mycophenolate mofetil) were excluded from the comparison group. This method of comparison is internationally accepted among Teratogen Information Services.5 Women in the neuraminidase inhibitor or reference groups were identified to UKTIS by healthcare professionals when clinical advice was sought from the service. Patient data was ascertained prospectively where the outcome of the pregnancy and the results of prenatal diagnosis were not already known at the time of the enquiry. Details of exposures were collected at the initial contact with the service. Immediately following this, a questionnaire was sent to the enquirer requesting confirmation of information including maternal demographics, obstetric and medical history, social or illicit drug exposure and smoking status. Details of pregnancy outcome were requested by a further questionnaire administered approximately 1 month after the expected date of delivery. These included details of any additional exposures, pregnancy complications and outcome, gestational age, birth weight, gender, APGAR scores, congenital malformations and neonatal problems. Up to two reminder letters and questionnaires were sent out to health professionals who did not respond. The primary outcome analysed was the rate of major congenital malformation in live born singleton infants following first trimester exposure to a neuraminidase inhibitor. Rates of preterm delivery and low birth weight in term infants were also investigated for exposure at any stage of pregnancy. Rate of live birth, miscarriage, elective termination, late fetal death, and minor congenital malformation are also reported to contextualise the primary outcomes for these cohorts.
Data analysis To compare apparent risk of specific pregnancy outcomes between the neuraminidase inhibitor and reference group, odds ratios (ORs) were calculated using logistic regression. Where a zero cell was present in a table, ORs were estimated using a zero-cell correction of 0.5 in the epiR package in R.6 Confidence intervals were calculated using exact methods and P < 0.05 was considered evidence for significant effect. Adjusted ORs were calculated for a reduced data set, adjusting for maternal age and week of exposure, where data were available. Data available were insufficient to allow for adjustment of other maternal factors that could potentially impact on the pregnancy outcomes studied, such as smoking, alcohol use, body mass index (BMI) and socioeconomic status.
Definitions Prematurity was defined as gestational age less than 37 weeks. Miscarriage was defined as the spontaneous loss
ª 2014 Royal College of Obstetricians and Gynaecologists
Neuraminidase inhibitors in pregnancy
of a pregnancy before 24 weeks’ gestation. Late fetal death was defined as an intrauterine death or stillbirth at or after 24 weeks’ gestation. Malformations were classified according to the EUROCAT classification system (revised July 2011) by an experienced observer who was blinded to maternal exposure status.7 The congenital anomaly rate includes live births only.
Results The outcomes of 782 pregnancies were available for analysis, including 180 exposed to zanamivir, 27 to oseltamivir and 575 exposed to other drugs. Of the 207 women exposed to neuraminidase inhibitors, 17 were recruited as part of the NIHR-funded study and the remainder via routine surveillance. Nine women included in the study also underwent vaccination for A/H1N1 influenza, six receiving zanamivir and three receiving oseltamivir. Details of maternal age, trimester of exposure, and indication for antiviral therapy for the study populations, are shown in Table 1.
Pregnancy outcomes Pregnancy outcomes are provided as Supporting Information (Table S1). Because of missing data, the number of observations reported for each outcome differs between the adjusted and unadjusted analysis, therefore the number of observations for each factor has been reported separately for each analysis. The incidence of major malformation in first trimester neuraminidase inhibitor-exposed live-born infants was not significantly higher than that in the reference group (all first trimester neuraminidase-exposed 0/45 [0.0%] versus reference 4/281 [1.4%], aOR 0.73, 95% confidence interval [CI] 0.04–13.30; zanamivir 0/34 [0.0%] versus reference 4/281 [1.4%], aOR 0.89, 95% CI 0.05–16.96; oseltamivir 0/ 8 [0.0%] versus reference 4/281 [1.4%], aOR 3.63, 95% CI 0.18–72.89). Overall major and minor malformation rates
were also not increased in live-born infants exposed at any stage of pregnancy (Table S1). The single reported major malformation (absent right kidney) occurred in an infant exposed to zanamivir at 27 weeks’ gestation. This timing of exposure makes causality implausible if this is a case of true renal agenesis, but does not exclude the possibility of renal regression as a consequence of the exposure. The four minor malformations reported were a small paraumbilical hernia, positional talipes, hydronephrosis and spina bifida occulta, all in infants exposed to zanamivir during the second or third trimesters, with no malformations reported in the 45 live-born infants exposed to zanamivir or oseltamivir during the first trimester. A fetal cloacal abnormality was detected on antenatal scan following maternal treatment of suspected A/H1N1 infection with oseltamivir from day 10 to day 15 of pregnancy (periconceptually). The pregnancy was terminated electively at 23 weeks. Postmortem examination was declined and no further details are available. Exposure to external agents in the weeks prior to implantation (often referred to as the ‘all-or-nothing’ period) is thought unlikely to result in major congenital malformation in the fetus. There were three (3.3%) elective terminations of pregnancy in the zanamivir-exposed group, two (11.1%) in the oseltamivir-exposed group including the case described, and 30 (6.6%) in the reference group. Other than the cloacal abnormality described above, none was known to have a diagnosis of fetal malformation. Three miscarriages were reported in the neuraminidase-exposed groups, all to women who had been treated for influenza. These occurred (i) at 7 weeks’ gestation, to a 24-year-old woman treated with oseltamivir at 4 weeks’ gestation; (ii) at 9 weeks gestation to a 44-year-old woman with depression and a BMI of 31 kg/m2, treated with oseltamivir for influenza symptoms at 5 weeks’ gestation. No other medication use was reported; (iii) at 21 weeks’ gestation, 6 weeks after zanamivir treatment in a 22-year-old
Table 1. Maternal demographics Group n Mean maternal age (range) Trimester of exposure 1 2 3 Unknown Antiviral treatment Antiviral prophylaxis Indication unknown
Reference
Zanamivir
Oseltamivir
575 30.2 (16–46 years)
180 27.5 (17–42 years)
27 28.9 (17–44 years)
371 136 58 10 N/A N/A N/A
40 66 69 5 118 5 57
12 9 5 1 16 0 11
(64.5%) (23.7%) (10.1%) (1.7%)
ª 2014 Royal College of Obstetricians and Gynaecologists
(22.2%) (36.7%) (38.3%) (2.8%) (65.6%) (2.8%) (31.6%)
(44.4%) (33.3%) (18.5%) (3.7%) (59.3%) (40.7%)
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Dunstan et al.
woman with asthma who was a smoker. Statistical comparison of the miscarriage rates was not undertaken, as the data was underpowered to perform a left truncated Cox analysis. Gestational age at delivery was reported for 168 zanamivir-exposed, 20 oseltamivir-exposed and 445 unexposed live-born infants. Preterm delivery (
DOI: 10.1111/1471-0528.12640 www.bjog.org
Pregnancy outcome following maternal use of zanamivir or oseltamivir during the 2009 influenza A/H1N1 pandemic: a national prospective surveillance study HJ Dunstan,a AC Mill,b S Stephens,a LM Yates,a,c SHL Thomasa,d a United Kingdom Teratology Information Service, Wolfson Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK b School of Biology, Newcastle University, Newcastle upon Tyne, UK c Institute of Human Genetics, International Centre for Life, Newcastle upon Tyne, UK d Wolfson Unit of Clinical Pharmacology, Institute of Cellular Medicine and Medical Toxicology Centre, Newcastle University, Newcastle upon Tyne, UK Correspondence: L Yates, UKTIS, Wolfson Unit, Newcastle upon Tyne, NE2 4HH, UK. Email [email protected]
Accepted 2 December 2013. Published Online 7 March 2014.
Objective To conduct enhanced surveillance for signals of
Main outcome measures Rates of major congenital malformation,
teratogenesis following use of the neuraminidase inhibitors zanamivir and oseltamivir in the treatment or post-exposure prophylaxis of 2009 A/H1N1 influenza during pregnancy.
preterm delivery and low birth weight.
Design Prospective cohort study, using national surveillance data
collected by the UK Teratology Information Service (UKTIS) during the 2009 A/H1N1 pandemic. Setting United Kingdom. Population Pregnant women who were reported to UKTIS
by healthcare professionals seeking advice about exposure to zanamivir and oseltamivir or to other non-teratogenic drugs. Methods Pregnancy outcomes were collected for prospectively
reported pregnancies exposed to zanamivir (n = 180) or oseltamivir (n = 27), and compared with a reference group of 575 prospectively reported pregnancies exposed to non-teratogenic drugs over the same period.
Results No significant differences in overall rates of major malformation in live-born infants [adjusted odds ratios (aOR): zanamivir 0.37 (95% confidence interval 0.02–2.70); oseltamivir aOR 0.81 (0.05, 14.15)], preterm delivery [aOR: zanamivir 0.95 (0.45, 1.89); oseltamivir aOR 1.68 (0.38, 5.38)] or low birth weight [aOR: zanamivir 0.94 (0.25, 2.90); oseltamivir aOR 4.12 (0.59, 17.99)] were observed following exposure at any gestation. No major malformations were reported in 37 zanamivir or eight oseltamivir first trimester exposures. Conclusion These surveillance data do not provide a signal that
use of zanamivir or oseltamivir in pregnancy is associated with an increased risk of the adverse pregnancy outcomes studied but the data are too limited to state conclusively that there is no increase in risk. Keywords A/H1N1 influenza, neuraminidase inhibitors, oseltamivir, pregnancy, zanamivir.
Please cite this paper as: Dunstan HJ, Mill AC, Stephens S, Yates LM, Thomas SHL. Pregnancy outcome following maternal use of zanamivir or oseltamivir during the 2009 influenza A/H1N1 pandemic: a national prospective surveillance study. BJOG 2014;121:901–906.
Introduction Influenza infection in pregnancy has been associated with an increased risk of adverse maternal and fetal outcomes, including maternal death, miscarriage and stillbirth,1,2 and less conclusively with congenital malformation in the offspring.3 Pregnant women were therefore identified as a high risk group requiring early treatment or post-exposure antiviral prophylaxis with the neuraminidase inhibitors
ª 2014 Royal College of Obstetricians and Gynaecologists
zanamivir or oseltamivir during the 2009 Influenza A/ H1N1 pandemic.1,4 Oseltamivir is administered orally and is readily absorbed from the gastrointestinal tract, whereas zanamivir is an inhaled preparation and as such has lower systemic and subsequent transplacental bioavailability. For this reason, zanamivir was recommended in the UK as the preferred antiviral during the 2009 pandemic for prophylaxis in the pregnant patient where active illness had not been
901
Dunstan et al.
confirmed, especially during the first trimester, when organogenesis occurs. Oseltamivir was advised where A/H1N1 infection was suspected or confirmed in pregnancy on the basis that zanamivir may be less effective in the treatment of systemic illness. Other countries opted for the use of oseltamivir for first line use for in both scenarios. Data on the fetal safety of neuraminidase inhibitor use during pregnancy was very limited at the onset of the 2009 pandemic, particularly for zanamivir, and consisted mainly of incomplete information from unpublished sources. To address the need to collect information on maternal and fetal outcome during the 2009 pandemic, the UK Teratology Information Service (UKTIS) collected fetal outcome details from health care professionals, the vast majority of whom were general practitioners, who contacted the service for case-specific advice and information about the safety of oseltamivir or zanamivir use in a particular patient who was pregnant. In this report, these pregnancy outcome data are compared with information collected over the same period from enquiries relating to other drug treatments considered non-teratogenic.
Methods Data collection was performed as surveillance on behalf of the Health Protection Agency and was covered by Section 251 of the NHS Act 2006. Because this data collection was conducted as enhanced surveillance activity by the UK Teratology Information Service during the pandemic, separate ethical approval was not required. For part of the study period, UKTIS was also involved in a study funded by the National Institute of Health Research investigating the characteristics and management of women with or at risk of A/H1N1 virus infection and the relationship to pregnancy outcomes.4 The study was approved by the County Durham and Tees Valley Research Ethics Committee (REC reference number: 09/H0905/66). All participants provided informed consent. The study sponsor was the Newcastle upon-Tyne Hospitals NHS Foundation Trust (NUTH). Data collected during this study for women exposed to neuraminidase inhibitor antiviral agents were also included in the current analysis.
Data collection Information was collected for singleton pregnancies reported between January 2009 and December 2010 with outcome data collected until October 2012. Exposed pregnancies were defined as women who received the neuraminidase inhibitors zanamivir or oseltamivir in pregnancy. The reference group comprised women about whom UKTIS received enquiries during the same time period regarding exposure to other medications that are considered not to be teratogenic. These include topical preparations, cyclizine, amoxicillin and
902
paracetamol. Women also exposed to confirmed teratogens (e.g. oral retinoids, sodium valproate, methotrexate and mycophenolate mofetil) were excluded from the comparison group. This method of comparison is internationally accepted among Teratogen Information Services.5 Women in the neuraminidase inhibitor or reference groups were identified to UKTIS by healthcare professionals when clinical advice was sought from the service. Patient data was ascertained prospectively where the outcome of the pregnancy and the results of prenatal diagnosis were not already known at the time of the enquiry. Details of exposures were collected at the initial contact with the service. Immediately following this, a questionnaire was sent to the enquirer requesting confirmation of information including maternal demographics, obstetric and medical history, social or illicit drug exposure and smoking status. Details of pregnancy outcome were requested by a further questionnaire administered approximately 1 month after the expected date of delivery. These included details of any additional exposures, pregnancy complications and outcome, gestational age, birth weight, gender, APGAR scores, congenital malformations and neonatal problems. Up to two reminder letters and questionnaires were sent out to health professionals who did not respond. The primary outcome analysed was the rate of major congenital malformation in live born singleton infants following first trimester exposure to a neuraminidase inhibitor. Rates of preterm delivery and low birth weight in term infants were also investigated for exposure at any stage of pregnancy. Rate of live birth, miscarriage, elective termination, late fetal death, and minor congenital malformation are also reported to contextualise the primary outcomes for these cohorts.
Data analysis To compare apparent risk of specific pregnancy outcomes between the neuraminidase inhibitor and reference group, odds ratios (ORs) were calculated using logistic regression. Where a zero cell was present in a table, ORs were estimated using a zero-cell correction of 0.5 in the epiR package in R.6 Confidence intervals were calculated using exact methods and P < 0.05 was considered evidence for significant effect. Adjusted ORs were calculated for a reduced data set, adjusting for maternal age and week of exposure, where data were available. Data available were insufficient to allow for adjustment of other maternal factors that could potentially impact on the pregnancy outcomes studied, such as smoking, alcohol use, body mass index (BMI) and socioeconomic status.
Definitions Prematurity was defined as gestational age less than 37 weeks. Miscarriage was defined as the spontaneous loss
ª 2014 Royal College of Obstetricians and Gynaecologists
Neuraminidase inhibitors in pregnancy
of a pregnancy before 24 weeks’ gestation. Late fetal death was defined as an intrauterine death or stillbirth at or after 24 weeks’ gestation. Malformations were classified according to the EUROCAT classification system (revised July 2011) by an experienced observer who was blinded to maternal exposure status.7 The congenital anomaly rate includes live births only.
Results The outcomes of 782 pregnancies were available for analysis, including 180 exposed to zanamivir, 27 to oseltamivir and 575 exposed to other drugs. Of the 207 women exposed to neuraminidase inhibitors, 17 were recruited as part of the NIHR-funded study and the remainder via routine surveillance. Nine women included in the study also underwent vaccination for A/H1N1 influenza, six receiving zanamivir and three receiving oseltamivir. Details of maternal age, trimester of exposure, and indication for antiviral therapy for the study populations, are shown in Table 1.
Pregnancy outcomes Pregnancy outcomes are provided as Supporting Information (Table S1). Because of missing data, the number of observations reported for each outcome differs between the adjusted and unadjusted analysis, therefore the number of observations for each factor has been reported separately for each analysis. The incidence of major malformation in first trimester neuraminidase inhibitor-exposed live-born infants was not significantly higher than that in the reference group (all first trimester neuraminidase-exposed 0/45 [0.0%] versus reference 4/281 [1.4%], aOR 0.73, 95% confidence interval [CI] 0.04–13.30; zanamivir 0/34 [0.0%] versus reference 4/281 [1.4%], aOR 0.89, 95% CI 0.05–16.96; oseltamivir 0/ 8 [0.0%] versus reference 4/281 [1.4%], aOR 3.63, 95% CI 0.18–72.89). Overall major and minor malformation rates
were also not increased in live-born infants exposed at any stage of pregnancy (Table S1). The single reported major malformation (absent right kidney) occurred in an infant exposed to zanamivir at 27 weeks’ gestation. This timing of exposure makes causality implausible if this is a case of true renal agenesis, but does not exclude the possibility of renal regression as a consequence of the exposure. The four minor malformations reported were a small paraumbilical hernia, positional talipes, hydronephrosis and spina bifida occulta, all in infants exposed to zanamivir during the second or third trimesters, with no malformations reported in the 45 live-born infants exposed to zanamivir or oseltamivir during the first trimester. A fetal cloacal abnormality was detected on antenatal scan following maternal treatment of suspected A/H1N1 infection with oseltamivir from day 10 to day 15 of pregnancy (periconceptually). The pregnancy was terminated electively at 23 weeks. Postmortem examination was declined and no further details are available. Exposure to external agents in the weeks prior to implantation (often referred to as the ‘all-or-nothing’ period) is thought unlikely to result in major congenital malformation in the fetus. There were three (3.3%) elective terminations of pregnancy in the zanamivir-exposed group, two (11.1%) in the oseltamivir-exposed group including the case described, and 30 (6.6%) in the reference group. Other than the cloacal abnormality described above, none was known to have a diagnosis of fetal malformation. Three miscarriages were reported in the neuraminidase-exposed groups, all to women who had been treated for influenza. These occurred (i) at 7 weeks’ gestation, to a 24-year-old woman treated with oseltamivir at 4 weeks’ gestation; (ii) at 9 weeks gestation to a 44-year-old woman with depression and a BMI of 31 kg/m2, treated with oseltamivir for influenza symptoms at 5 weeks’ gestation. No other medication use was reported; (iii) at 21 weeks’ gestation, 6 weeks after zanamivir treatment in a 22-year-old
Table 1. Maternal demographics Group n Mean maternal age (range) Trimester of exposure 1 2 3 Unknown Antiviral treatment Antiviral prophylaxis Indication unknown
Reference
Zanamivir
Oseltamivir
575 30.2 (16–46 years)
180 27.5 (17–42 years)
27 28.9 (17–44 years)
371 136 58 10 N/A N/A N/A
40 66 69 5 118 5 57
12 9 5 1 16 0 11
(64.5%) (23.7%) (10.1%) (1.7%)
ª 2014 Royal College of Obstetricians and Gynaecologists
(22.2%) (36.7%) (38.3%) (2.8%) (65.6%) (2.8%) (31.6%)
(44.4%) (33.3%) (18.5%) (3.7%) (59.3%) (40.7%)
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Dunstan et al.
woman with asthma who was a smoker. Statistical comparison of the miscarriage rates was not undertaken, as the data was underpowered to perform a left truncated Cox analysis. Gestational age at delivery was reported for 168 zanamivir-exposed, 20 oseltamivir-exposed and 445 unexposed live-born infants. Preterm delivery (
