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 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 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 (<37 gestational weeks) occurred in 14 (8.3%) zanamivir-exposed infants, three (15.0%) oseltamivir-exposed infants and 46 (10.3%) infants in the reference group, with no significant differences between the groups (zanamivir aOR 0.95, 95% CI 0.45–1.89, oseltamivir aOR 1.68, 95% CI 0.38–5.38). One infant was delivered by emergency caesarean at 30 weeks' gestation. Hydrops fetalis had been detected and investigated antenatally, with a final diagnosis of non-isoimmune haemolytic disease. Placental abnormalities suggestive of chorioangioma were also observed; however, autopsy was not performed. The 36-year-old mother had tested positive for A/H1N1 and had been treated with zanamivir at 25 weeks' gestation. The baby subsequently died in the neonatal period. Reported maternal co-morbidities were gestational diabetes mellitus, polycystic ovary syndrome, chronic pain, vitamin D deficiency, endometriosis and irritable bladder. It is noteworthy that her two previous children had required neonatal blood transfusion in the neonatal period.
Birth weight was reported for 150 live-born infants exposed to neuraminidase inhibitors and 368 live-born infants in the reference group. Low birth weight (<2500 g) at term affected four (2.9%) zanamivir-exposed, two (14.3%) oseltamivir-exposed and 16 (4.3%) reference group infants, with no significant differences in incidence between the groups (zanamivir aOR 0.94, 95% CI 0.25–2.90, oseltamivir aOR 4.12, 95% CI 0.59–17.99).