Objective
To assess adverse fetal outcomes and short-term prognoses of infants exposed to oseltamivir or zanamivir in utero during pandemic (H1N1) 2009 in Japan.
Study Design
Case series study. We asked the 2611 obstetric facilities in Japan that are members of the Japan Society of Obstetrics and Gynecology to participate, and data were provided from 157 facilities. We evaluated the numbers of pregnancy complications and neonatal abnormalities.
Results
We evaluated 624 infants born to 619 women given oseltamivir and 50 infants born to 50 women given zanamivir. Of patients given oseltamivir before gestational week 22, 3 experienced miscarriage and 1 experienced induced abortion. The overall rate of congenital malformations was 2.1% (14/670). In infants exposed during the first trimester, the rate of malformations was 1.3% (2/156) with oseltamivir and 0.0% (0/15) with zanamivir, although in infants exposed during the second and third trimesters, this rate was 2.6% (12/464) with oseltamivir and 0.0% (0/35) with zanamivir. Increased rates of miscarriage in women given antiviral drugs before gestational week 22 (0.9% [3/322]), preterm delivery in women given antiviral drugs before gestational week 37 (5.5% [33/600]), stillbirth (0% [0/670]), neonatal death (0.15% [1/670]), birthweight <2500 g (8.7% [58/670]), small-for-gestational-age infants (8.4% [56/670]), necrotizing enterocolitis (0.0%), intraventricular hemorrhage (0.0%), seizures (0.15% [1/670]), and other transient abnormalities in the neonatal period (4.3% [29/670]) were not observed in those exposed to antiviral drugs before the corresponding episodes or complications.
Conclusion
Short-term prognoses of infants exposed to oseltamivir or zanamivir in utero were not adversely affected.
As high morbidity and mortality rates of pregnant women were expected in the beginning of pandemic (H1N1) 2009, the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) recommended the use of neuraminidase inhibitors such as oseltamivir or zanamivir in pregnant patients thought to be infected with the novel virus. The Japan Society of Obstetrics and Gynecology (JSOG) also recommended the use of oseltamivir or zanamivir for the treatment of pregnant patients or for prophylaxis in pregnant women in close contact with an infected person. It has been reported that early antiviral drug use and admission to an intensive care unit decreases the risk of maternal death because of pneumonia.
Vaccination against pandemic (H1N1) 2009 influenza during pregnancy had the benefits of reducing the risk of stillbirth and not increasing the risk of adverse fetal outcome. At that time, the safety of oseltamivir use in pregnancy was based on findings from 137 women who took oseltamivir during pregnancy, although 2 papers were published later. Pregnancy outcomes were available for only 9 women exposed to zanamivir during pregnancy. These data suggested oseltamivir is unlikely to cause adverse pregnancy or fetal outcomes, but the available data were limited. The safety of zanamivir in pregnancy was still unknown. Therefore, JSOG conducted this prospective study in collaboration with Chugai Pharmaceutical Co, Ltd, (Tokyo, Japan) to collect more information on pregnant women and fetuses exposed to antiviral drugs such as oseltamivir and zanamivir.
Materials and Methods
This prospective study was conducted after approval by the institutional review board at the University of Toyama (Toyama City, Japan). In August 2009, we asked all 2611 obstetric facilities in Japan that are members of JSOG to participate, and data were provided from 157 facilities. Pregnant women who visited physicians at these facilities to discuss prophylaxis or treatment of influenza were fully informed of the purpose of this study. When these women were given oseltamivir or zanamivir and consented to participate in this study during the 15-month period between Oct. 1, 2009, and Dec. 31, 2010, their obstetricians prospectively registered them at the Current Medical Information Center (CMIC) Co Ltd (Tokyo, Japan) registration center using an electronic data capture system or postal mail. A total 725 pregnant women were registered from 157 facilities and followed up. The registration center (CMIC Co Ltd) successively collected the following maternal and neonatal clinical data through the physicians who registered individual cases: maternal demographic characteristics such as maternal age; gestational week when contracting influenza and taking oseltamivir or zanamivir; vaccination against the novel H1N1 influenza and/or seasonal influenza; and pregnancy outcomes including gestational week at delivery, birthweight of infant, stillbirth, or live birth, neonatal death within 60 days after birth, congenital malformations, periventricular leukomalacia, respiratory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage, seizures, and other transient abnormalities such as febrile condition, hyperbilirubinemia (total bilirubin level; term infant ≥17 mg/dL, preterm infant ≥15 mg/dL), transient tachypnea of newborn, and hypoglycemia (blood sugar level; term infant <40 mg/dL, preterm infant <30 mg/dL). Intracranial hemorrhage and periventricular leukomalacia were diagnosed by ultrasonography and/or magnetic resonance imaging. Small for gestational age was defined as a birthweight below the 10th percentile for gestational age of Japanese infants. Congenital cardiac abnormalities in neonates were confirmed by neonatologists or cardiologists using echocardiography. The follow-up periods of these infants were 1 to18 months.
Of 725 registered women, 56 were excluded from this analysis on the basis of indeterminate neonatal information (n = 6), postpartum drug therapy (n = 5), administration of both oseltamivir and zanamivir (n = 1), administration of laninamivir (n = 2), administration of other treatment (n = 18), administration of unknown drugs (n = 4), unknown time of drug administration and maternal infection (n = 16), and administration of drugs at less than 4 weeks’ gestation (n = 4) ( Figure ). An influenza detection kit was used to diagnose 333 cases, and 84 cases were diagnosed by clinical symptoms.
Statistical analysis
The χ 2 test was used to compare patient baseline characteristics among the oseltamivir and zanamivir groups and the infected and noninfected groups. The unpaired Student t test was used to compare days from onset to treatment between oseltamivir and zanamivir. A P value of < .05 was considered statistically significant.
Results
A total 619 women took oseltamivir alone, with 624 fetuses (including 5 sets of twins) exposed to oseltamivir, and 50 women took zanamivir alone, with 50 fetuses exposed to zanamivir; 417 women, with 420 fetuses (including 3 sets of twins), contracted influenza. Of the 669 women, 37.7% (252) took antiviral drugs for prophylaxis after close contact with an infected person ( Figure and Table 1 ). We first studied whether influenza infection itself affects the maternal and fetal outcomes. Other risk factors for miscarriage, malformed infants, low-birthweight infants, and small-for-gestational-age infants, such as maternal age 35 and over, smoking, and alcohol use, were similar between infected and noninfected groups. In the infected group, 70% of patients developed a fever of 38°C or higher, although the frequency in the noninfected group was only 0.4%. The frequency of vaccination during pregnancy in the noninfected group was significantly higher than that in the infected group (49.2% vs 27.6%, P < .0001). There were no significant differences in frequencies of miscarriage, stillbirth, neonatal death, preterm delivery, low-birthweight infants, small-for-gestational-age infants, infants with congenital malformations, and other abnormalities in infants such as infection, hyperbilirubinemia, hypoglycemia, transient tachypnea, respiratory distress syndrome, pyrexia, hypothyroidism, necrotizing enterocolitis, intraventricular hemorrhage, convulsion, vomiting, periventricular leukomalacia, and hypernephroma between the infected and noninfected groups, suggesting that influenza infection did not induce miscarriage, stillbirth, neonatal death, preterm delivery, low-birthweight infants, small-for-gestational-age infants, or malformed infants in this study ( Table 2 ).
| Variable | Infected | Noninfected | P value |
|---|---|---|---|
| Number of women | 417 | 252 | |
| Age ≥35 y | 95 (22.8) 18.8–27.1 | 87 (34.5) 28.7–40.7 | .0009 |
| Multiple pregnancy | 3 (0.7) 0.1–2.1 | 2 (0.8) 0.1–2.8 | .9140 |
| Smoking, yes | 19 (4.6) 2.8–7.0 | 9 (3.6) 1.6−6.7 | .5376 |
| Alcohol use, yes | 10 (2.4) 1.2–4.4 | 4 (1.6) 0.4–4.0 | .4778 |
| Vaccination (during pregnancy), yes | 115 (27.6) 23.3–32.1 | 124 (49.2) 42.9–55.6 | < .0001 |
| Fever (≥38°C), yes | 292 (70.0) 65.4–74.4 | 1 (0.4) 0.0–2.2 | < .0001 |
| Timing of administration | |||
| 1st trimester | 120 (28.8) 24.5–33.4 | 54 (21.4) 16.5–27.0 | 0358 |
| 2nd trimester | 172 (41.2) 36.5–46.1 | 91 (36.1) 30.2–42.4 | .1876 |
| 3rd trimester | 125 (30.0) 25.6–34.6 | 107 (42.5) 36.3–48.8 | .0010 |
| Days from onset to treatment, mean ± SD (min, 25%, 50%, 75%, max) | 0.37 ± 0.81 day (0,0,0,1,9) |
| Variable | Infected | Noninfected | P value |
|---|---|---|---|
| Number of outcomes | 420 | 254 | |
| Miscarriage at <22 wks | 3 (1.3) 0.3–3.9 | 0 | .2521 |
| Induced abortion | 1 (0.2) 0.0–1.3 | 0 | .4364 |
| Stillbirth | 0 | 0 | — |
| Neonatal death | 1 (0.2) 0.0–1.3 | 0 | .4342 |
| Preterm delivery | |||
| <37 wks | 20 (5.2) 3.2–8.0 | 13 (5.9) 3.2–9.9 | .7069 |
| <28 wks | 1 (0.3) 0.0–1.9 | 0 | .4775 |
| Low birthweight <2500 g | 34 (8.2) 5.7–11.2 | 24 (9.4) 6.1–13.7 | .5689 |
| Small for gestational age | 29 (7.0) 4.7–9.9 | 27 (10.6) 7.1–15.1 | .0969 |
| Infants with congenital anomalies | 8 (1.9) 0.8–3.8 | 6 (2.4) 0.9–5.1 | .6998 |
| Congenital heart defect | 7 (1.7) 0.7–3.4 | 4 (1.6) 0.4–4.0 | .9151 |
| Deformity (excluding congenital heart defect) | 2 (0.5) 0.1–1.7 | 2 (0.8) 0.1–2.8 | .6172 |
| Minor skeletal change | 0 | 1 (0.4) 0.0–2.2 | .2003 |
| Other adverse birth outcomes | 23 (5.5) 3.5–8.2 | 6 (2.4) 0.9–5.1 | .0507 |
Characteristics of pregnant women in oseltamivir and zanamivir groups are shown in Table 3 . Baseline characteristics in both groups were similar.
| Variable | Oseltamivir | Zanamivir | P value |
|---|---|---|---|
| Number of women | 619 | 50 | |
| Age ≥35 y | 167 (27.0) 23.5–30.7 | 15 (30.0) 17.9–44.6 | .6443 |
| Maternal infection infected | 385 a (62.2) 58.2–66.0 | 32 (64.0) b 49.2–77.1 | .8002 |
| Multiple pregnancy | 5 (0.8) 0.3–1.9 | 0 | .5235 |
| Smoking, yes | 26 (4.2) 2.8–6.1 | 2 (4.0) 0.5–13.7 | .9458 |
| Alcohol use, yes | 12 (1.9) 1.0–3.4 | 2 (4.0) 0.5–13.7 | .3273 |
| Vaccination (during pregnancy), yes | 223 (36.0) 32.2–39.9 | 16 (32.0) 19.5–46.7 | .5677 |
| Treated | 363 (58.6) 54.6–62.6 | 30 (60.0) 45.2–73.6 | .8513 |
| Fever (≥38°C), yes | 272 (43.9) 40.0–48.0 | 21 (42.0) 28.2–56.8 | .7901 |
| Timing of administration | |||
| 1st trimester | 159 (25.7) 22.3–29.3 | 15 (30.0) 17.9–44.6 | .5036 |
| 2nd trimester | 239 (38.6) 34.8–42.6 | 24 (48.0) 33.7–62.6 | .1910 |
| 3rd trimester | 221 (35.7) 31.9–39.6 | 11 (22.0) 11.5–36.0 | .0502 |
| Days from onset to treatment mean ± SD (min, 25%, 50%, 75%, max) | 0.36 ± 0.81 day (0,0,0,1,9) | 0.39 ± 0.79 day (0,0,0,0,3) | .8181 |
a Infected patients comprised 304 patients diagnosed with a rapid test (type A, 298; type B, 3; and type A and B, 3) and 81 patients diagnosed with clinical symptoms.
b Infected patients comprised 26 patients diagnosed with a rapid test (type A, 25 and type B, 1) and 6 patients diagnosed with clinical symptoms.
The rates of neither miscarriage nor preterm deliveries appeared to be increased in either group ( Table 4 ). Only 3 (1.0%) of 294 women who took oseltamivir before gestational week 22 experienced miscarriage. There were no miscarriages in 27 women who took zanamivir before gestational week 22. These frequencies were lower than those reported by Nybo Andersen (13.5%) and in the report from the Ministry of Health and Welfare study of 827 Japanese cases from 1991 to 1993 (14.9%). Twenty-nine (5.2%; 95% confidence interval [CI], 3.5–7.4%) of 553 pregnant women who took oseltamivir and 4 (8.5%) of 47 pregnant women who took zanamivir before gestational week 36 experienced preterm delivery ( Table 4 ). The frequency of preterm delivery with oseltamivir was similar to that in Japanese national data from 2009 (5.70% [60.989/1,070,035]; 95% CI, 5.66–5.74%). The frequency with zanamivir was slightly higher than that in the 2009 Japanese national data; however, the 95% CI (2.4–20.4%) of preterm delivery in zanamivir did not exceed that in the national data ( Table 4 ).
| Variable | Oseltamivir | Zanamivir | P value |
|---|---|---|---|
| Number of outcomes | 624 | 50 | |
| Miscarriage at <22 wks | 3 (1.0) 0.2–3.0 | 0 | .5979 |
| Induced abortion | 1 (0.2) 0.0–0.9 | 0 | .7770 |
| Stillbirth | 0 | 0 | — |
| Neonatal death | 0 | 1 (2.0) 0.1–10.6 | .0004 |
| Preterm delivery | |||
| <37 wks | 29 (5.2) 3.5–7.4 | 4 (8.5) 2.4–20.4 | .3457 |
| <28 wks | 0 | 1 (2.6) 0.1–13.5 | .0015 |
| Low birthweight <2500 g | 53 (8.5) 6.5–11.0 | 5 (10.0) 3.3–21.8 | .7255 |
| Small for gestational age | 54 (8.7) 6.6–11.2 | 2 (4.0) 0.5–13.7 | .2471 |
| Infants with congenital anomalies | 14 (2.3) 1.2–3.8 | 0 | .2829 |
| Congenital heart defect | 11 (1.8) 0.9–3.2 | 0 | .3423 |
| Deformity (excluding congenital heart defect) | 4 (0.6) 0.2–1.6 | 0 | .5689 |
| Minor skeletal change | 1 (0.2) 0.0–0.9 | 0 | .7763 |
| Other adverse birth outcomes | 24 (3.9) 2.5–5.7 | 5 (10.0) 3.3–21.8 | .0405 |
The rates of neither convulsion nor other transient abnormalities such as transient tachypnea, respiratory distress syndrome, hypoglycemia, hyperbilirubinemia, infection with fever, hypothyroidism, and vomiting appeared to be increased compared with those that have been reported ( Table 5 ). In Japan, prevalence of infants with a birthweight <2500 g was 9.6% in 2009 and that of small-for-gestational-age infants was 10% in 1998. Therefore, the rates of birth weight <2500 g and small-for-gestational-age infants exposed to oseltamivir or zanamivir did not exceed those in Japanese national data ( Table 5 ). No infants developed necrotizing enterocolitis or intraventricular hemorrhage ( Table 5 ). Suspected periventricular leukomalacia was found on magnetic resonance imaging in one infant with a birthweight of 1794 g born at 31 weeks to a woman who contracted influenza at 15 weeks ( Table 6 ). However, periodic follow-up until 1 year of age revealed consistently normal neurologic development. Periventricular leukomalacia accounts for more than 50% of cerebral palsy cases among premature infants. The prevalence of moderately severe or severe cerebral palsy was approximately 2 per 1000 live births in 1994, and infants with birthweight <2500 g account for approximately a third of all infants with cerebral palsy. Thus, the case of suspected periventricular leukomalacia may have resulted from prematurity. One infant exhibited seizures and proved to have agenesis of corpus callosum ( Table 6 , case 26). One small-for-gestational-age infant with a birthweight of 776 g was stillborn at 28 weeks to a mother who contracted influenza at 8 weeks and developed placental abruption, which occurs in approximately 1 in 100 Japanese women. Another infant with a birthweight of 662 g was born at 24 weeks to a mother in the zanamivir treatment group who developed influenza 1 day before labor onset; the infant died 36 days after birth because of prematurity.
| Variable | Outcomes with oseltamivir exposure | Outcomes with zanamivir exposure | ||||
|---|---|---|---|---|---|---|
| 1st trimeste | 2nd trimester | 3rd trimester | 1st trimester | 2nd trimester | 3rd trimester | |
| Number of outcomes | 159 | 239 | 226 | 15 | 24 | 11 |
| Miscarriage at <22 wks | 2 (1.3) 0.2–4.5 | 1 (0.7) 0.0–4.1 | – | 0 | 0 | — |
| Induced abortion | 1 (0.6) 0.0–3.5 | 0 | – | 0 | 0 | — |
| Stillbirth | 0 | 0 | 0 | 0 | 0 | 0 |
| Neonatal death | 0 | 0 | 0 | 0 | 1 (4.2) 0.1–21.1 | 0 |
| Preterm delivery<37 wks | 6 (3.8) a 1.4–8.2 | 10 (4.2) b 2.0–7.6 | 13 (8.2) c 4.4–13.6 | 0 | 2 (8.3) 1.0–27.0 | 2 (25.0) 3.2–65.1 |
| Low birthweight <2500 g | 14 (9.0) 5.0–14.6 | 13 (5.5) b 2.9–9.2 | 26 (11.5) 7.7–16.4 | 1 (6.7) 0.2–31.9 | 3 (12.5) 2.7–32.4 | 1 (9.1) 0.2–41.3 |
| Small for gestational age | 12 (7.7) 4.0–13.1 | 17 (7.1) b 4.2–11.2 | 25 (11.1) 7.3–15.9 | 1 (6.7) 0.2–31.9 | 1 (4.2) 0.1–21.1 | 0 |
| Infants with congenital anomalies | 2 (1.3) | 6 (2.5) | 7 (3.1) | 0 | 0 | 0 |
| Congenital heart defect | 1 d (0.6) 0.0–3.5 | 5 (2.1) b 0.7–4.8 | 5 (2.2) 0.7–5.1 | 0 | 0 | 0 |
| Deformity (excluding congenital heart defect) | 1 e (0.6) 0.0–3.5 | 1 f (0.4) b 0.0–2.3 | 2 g (0.9) 0.1–3.2 | 0 | 0 | 0 |
| Infants with other adverse outcomes | 6 (3.8) 1.4–8.2 | 9 (3.8) b 1.7–7.1 | 9 (4.0) 1.8–7.4 | 0 | 1 (4.2) 0.1–21.1 | 4 (36.4) 10.9–69.2 |
| Infection | 2 (1.3) 0.2–4.6 | 1 (0.4) b 0.0–2.3 | 0 | 0 | 0 | 0 |
| Hyperbilirubinemia | 0 | 2 (0.8) b 0.1–3.0 | 1 (0.4) 0.0–2.4 | 0 | 0 | 2 (18.2) 2.3–51.8 |
| Hypoglycemia | 1 (0.6) 0.0–3.5 | 1 (0.4) b 0.0–2.3 | 1 (0.4) 0.0–2.4 | 0 | 0 | 1 (9.1) 0.2–41.3 |
| Transient tachypnea | 3 (1.9) 0.4–5.5 | 2 (0.8) b 0.1–3.0 | 4 (1.8) 0.5–4.5 | 0 | 0 | 0 |
| Respiratory distress syndrome | 0 | 0 | 0 | 0 | 1 (4.2) 0.1–21.1 | 0 |
| Pyrexia | 0 | 1 (0.4) b 0.0–2.3 | 1 (0.4) 0.0–2.4 | 0 | 0 | 0 |
| Hypothyroidism | 1 (0.6) 0.0–3.5 | 0 | 1 (0.4) 0.0–2.4 | 0 | 0 | 0 |
| Necrotizing enterocolitis | 0 | 0 | 0 | 0 | 0 | 0 |
| Intraventricular hemorrhage | 0 | 0 | 0 | 0 | 0 | 0 |
| Convulsion | 0 | 0 | 1 (0.4) 0.0–2.4 | 0 | 0 | 0 |
| Vomiting | 1 (0.6) 0.0–3.5 | 0 | 0 | 0 | 0 | 0 |
| Periventricular leukomalacia | 0 | 1 (0.4) b 0.0–2.3 | 0 | 0 | 0 | 0 |
| Hypernephroma | 0 | 0 | 0 | 0 | 0 | 1 (9.1) 0.2–41.3 |
a Excluding 3 patients with miscarriage or induced abortion.
b Excluding 1 patient with miscarriage.
c Excluding 67 patients taking oseltamivir after week 37.
d There were no cases of congenital heart defects or other deformities in infants exposed to oseltamivir or zanamivir during gestational weeks 4 to 7. In infants exposed during gestational weeks 8 to 14, the frequencies of congenital heart defects and other deformities were both 0.9% (1/113) with oseltamivir although there were no such defects or deformities with zanamivir. Details on congenital anomalies are shown in Table 5 .
g Agenesis of corpus collosum and Down syndrome complicated with VSD, AR, and PDA ( Table 7 ).
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