Clinical Effectiveness and Safety of Antivirals for Influenza in Pregnancy

Abstract

Seasonal influenza epidemics result in substantial health care burden annually. Early initiation of antiviral treatment of influenza has been shown to reduce the risk of complications and duration of illness. Pregnant and postpartum women may be at increased risk for influenza-associated complications; however, pregnant women have been generally excluded from clinical trials of antiviral treatment of influenza. In this review, we summarize the available evidence on the clinical effectiveness and safety of antiviral treatment of pregnant women with influenza. Observational data show a reduction of severe outcomes when pregnant and postpartum women are treated with oseltamivir and other neuraminidase inhibitors without increased risk of adverse maternal, fetal, or neonatal outcomes. Due to lack of safety and efficacy data for baloxavir treatment of pregnant and postpartum women, baloxavir is currently not recommended for use in these populations.

antiviral, influenza, neuraminidase inhibitor, pregnant women, postpartum

Influenza virus infection results in significant morbidity and mortality [1, 2], with increased risk of complications in those who are pregnant [3–8]. Due to normal changes of immunology, physiology, and anatomy during pregnancy [9–11], the body’s ability to balance oxidative stress [12, 13] and prevent progression of influenza is impaired, increasing the risk of pregnant women to develop disease complications [13–18]. Women who are up to 2 weeks postpartum may also be at increased risk of influenza-related complications as they transition back to normal physiology following pregnancy or pregnancy loss [4, 19]. Both observational data and animal models demonstrate that adverse birth outcomes may be increased following maternal influenza virus infection. This includes preterm delivery [20–23], low birth weight [13, 18, 21–24], congenital disease [25, 26], miscarriage [27], and infant death [21, 28]. Although influenza viral RNA has been detected in blood collected from severely ill patients [29–31], influenza viremia appears to be very uncommon, as recovery of live infectious virus from the blood or serum of patients with seasonal or pandemic influenza has rarely been reported [32, 33]. Transplacental influenza virus infection has also very rarely been reported [34–38], and most adverse birth outcomes associated with maternal influenza virus infection are thought to be related to the severity of maternal illness [39]. Due to the risk of severe maternal and fetal outcomes associated with influenza virus infection, women who are pregnant or who are up to 2 weeks postpartum are considered to be at high risk for influenza complications, particularly those in the second or third trimesters [40, 41].

The World Health Organization, American College of Obstetricians and Gynecologists, Infectious Disease Society of America, and US Centers for Disease Control and Prevention recommend antivirals, specifically neuraminidase inhibitors (NAIs), for treatment of pregnant and postpartum women with influenza [40, 42–44]. In the United States, available NAIs for treatment of influenza include oral oseltamivir, inhaled zanamivir, and intravenous peramivir (Table 1). The current recommended antiviral dosing in women who are pregnant and who are up to 2 weeks postpartum is based upon data derived from nonpregnant individuals because pregnant women have been excluded from randomized controlled trials (RCTs) of NAI treatment of influenza. Recommendations for antiviral treatment of influenza in pregnant women are based upon data from randomized controlled trials in nonpregnant outpatients and observational studies of antiviral treatment, predominantly oseltamivir, in outpatients and hospitalized patients that included pregnant women. In this review, we summarize the available evidence on the safety, pharmacokinetics, and effectiveness of antiviral treatment of influenza during pregnancy and the impact upon pregnancy and birth outcomes.

Table 1.

Influenza Antiviral Dosing for Treatment of Influenza A and B Virus Infections: Recommendations Including Pregnant Women and Women who Are up to 2 Weeks Postpartum^a

Antiviral Therapy	Route of Administration	Indication	Dose	Duration	Recommendations for Women who Are Pregnant or Postpartum	Adverse Events	Groups for Which Antiviral Is Not Recommended
Oseltamivirb	Oral	Treatment	Patients 1 y to 17 y: ≤15 kg – 30 mg twice daily >15–23 kg – 45 mg twice daily >23–40 kg – 60 mg twice daily >40 kg–75 mg twice daily Patients ≥18 y: 75 mg twice daily	5 d; longer treatment may be required for severely ill patients per clinical judgment	Pregnant women and women who are up to 2 wk postpartum (including after pregnancy loss) of any age	Nausea, vomiting, headache; postmarketing reports of serious skin reactions and sporadic, transient neuropsychiatric events	N/A
Zanamivirc	Inhaled	Treatment	Patients ≥7 y: 10 mg (two 5-mg inhalations) twice daily	5 d	Pregnant women and women who are up to 2 wk postpartum (including after pregnancy loss) of any age	Risk of bronchospasm, sinusitis, dizziness; postmarketing reports of serious skin reactions and sporadic, transient neuropsychiatric events	People with chronic respiratory disease including asthma and COPD and patients with a history of allergy to milk protein
Peramivird	Intravenous	Treatment	Patients 2–12 y of age: 12-mg/kg dose once; up to 600 mg maximum infused over a minimum of 15 min Patients ≥13 y: 600 mg infused once over a minimum of 15 min	1 d; longer treatment may be required for severely ill patients	Pregnant women and women who are up to 2 wk postpartum (including after pregnancy loss) of any age	Diarrhea; postmarketing reports of serious skin reactions and sporadic, transient neuropsychiatric events	N/A
Baloxavire	Oral	Treatment	Patients ≥12 y: 40–<80 kg: one 40-mg dose; ≥80 kg: one 80-mg dose	1 d; longer treatment may be required for severely ill patients	Not recommended for use in pregnant women due to lack of safety and efficacy data	None more common than placebo in clinical trials	Not recommended for children aged <12 y, pregnant women, or for chemoprophylaxis

Abbreviations: COPD, chronic obstructive pulmonary disease; FDA, Food and Drug Administration.

^aAdapted from the Centers for Disease Control and Prevention–recommended dosing for treatment and chemoprophylaxis of influenza in adults.

^bOseltamivir is FDA-approved for early treatment of uncomplicated influenza in persons aged 14 days and older.

^cZanamivir is FDA-approved for early treatment of uncomplicated influenza in persons aged 7 years and older.

^dPeramivir is FDA-approved for early treatment of uncomplicated influenza in persons aged 2 years and older.

^eBaloxavir is FDA-approved for the early treatment of uncomplicated influenza in people aged 12 years and older who are otherwise healthy or at high risk of developing influenza-related complications. Baloxavir is not currently recommended for chemoprophylaxis or for treatment of influenza in pregnant women due to lack of safety and effectiveness data in pregnant women. In rabbit animal models, baloxavir was associated with fetal skeletal variations resulting in 2 abortions out of 19 pregnancies [45]

METHODS

A literature search was performed using the PubMed database to identify English-language articles using the following Medical Subject Headings (MeSH) terms and keywords: “Antiviral agents” [MeSH], “Influenza, human” [MeSH], “Influenza, human/drug therapy” [MeSH], “Pregnant women” [MeSH], “Oseltamivir” [MeSH], “Oseltamivir/adverse effects” [MeSH], “Oseltamivir/metabolism” [MeSH], “Oseltamivir/pharmacokinetics” [MeSH], “Oseltamivir/pharmacology” [MeSH], “Oseltamivir/therapeutic use” [MeSH], “Oseltamivir/toxicity” [MeSH], “Zanamivir” [MeSH], “Zanamivir/adverse effects” [MeSH], “Zanamivir/metabolism” [MeSH], “Zanamivir/pharmacokinetics” [MeSH], “Zanamivir/pharmacology” [MeSH], “Zanamivir/therapeutic use” [MeSH], “Zanamivir/toxicity” [MeSH], “peramivir” [Supplementary Concept], “R125489” [Supplementary Concept]. Additional searches were also performed using the following non-MeSH terms: neuraminidase inhibitors, baloxavir, pregnant, pregnancy, placenta, influenza viremia, transplacental, and birth outcomes. Article titles were screened for relevant subject matter, and additional literature was identified through references and expert guidance. The search included literature published from January 1, 1999, through October 10, 2020.

Pharmacology of Oseltamivir in Pregnancy

The pharmacokinetics of medications can be impacted by the normal physiological changes of pregnancy. These changes, including increases in cardiac output, renal plasma flow, and glomerular filtration rate, can result in alterations of serum concentrations of medications with increased clearance from the body [46]. Furthermore, biological transport systems and cytochrome P450 activity are also known to experience changes during pregnancy and can affect the pharmacokinetics of medications differently depending on their interactions with these mechanisms [46]. In nonpregnant adults, the pharmacokinetics of NAIs differ (Table 2) and may be further impacted by the physiological changes of pregnancy. Available pharmacokinetic studies of NAIs in pregnant women have highlighted the potential effects on oseltamivir; however, pharmacokinetic data for other NAIs in pregnancy are lacking.

Table 2.

Pharmacokinetics of Influenza Antivirals in Nonpregnant Adults

Influenza Antiviral	Type	Mode of Administration	Kinetics	Time to Maximum Plasma Concentration	Half-life	Primary Elimination	Additional Information
Oseltamivir phosphate [47]	Neuraminidase inhibitor	Oral	Linear	OC: 3–4 h	OP: 1–3 h OC: 6–10 h	Renal	Absorbed in gastrointestinal tract and converted by the liver to the active metabolite OC
Zanamivir [48–51]	Neuraminidase inhibitor	Inhalation	Linear	2 h	3–4 h	Renal	Inhaled zanamivir is contraindicated in patients with prior lung disease including asthma and COPD; nebulized zanamivir is not recommended
Peramivir [52, 53]	Neuraminidase inhibitor	Intravenous	Linear	-	20 h	Renal	-
Baloxavir [54, 55]	Cap-dependent endonuclease inhibitor	Oral	Linear	4 h	79 h	Feces	Administration with food may lower peak plasma concentrations

Abbreviations: COPD, chronic obstructive pulmonary disease; OC, oseltamivir carboxylate; OP, oseltamivir phosphate.

Oseltamivir phosphate (OP) is an oral antiviral medication that is rapidly absorbed and metabolized to oseltamivir carboxylate (OC), the active metabolite of oseltamivir [47]. Maintaining OC concentration above the half maximal effective concentration (EC₅₀) level in the blood allows targeted action of oseltamivir to inhibit influenza viral neuraminidase, blocking the release of virions from infected cells. However, the changes in pregnancy may result in lower concentrations of oseltamivir and its metabolites. One oseltamivir study showed no difference in the time needed to reach maximum plasma concentration, but the maximum concentration (C_max) of OC was lower in pregnant women than nonpregnant patients [56]. The C_max of OC also differed by trimester. Women in the third trimester of pregnancy had an OC C_max that was higher than in their first and second trimesters [56]. Concentrations of OP showed no difference in C_max among trimesters but had a significantly longer half-life in the first trimester compared with others [56]. Other pharmacokinetic studies showed that pregnant women may experience a 30% reduction in exposure to OC when compared with nonpregnant patients [57, 58]. Pregnant women also experienced a higher oral clearance of OC than nonpregnant patients [57] that was highest in the first trimester [58]. These findings suggest that higher dosing of oseltamivir may be required in pregnant women to achieve the same bioavailability of oseltamivir compared with nonpregnant patients. However, there are currently very limited data on the safety of increased oseltamivir dosage or the frequency of dosage in pregnant women to inform recommendations.

Transplacental Transfer of Oseltamivir in Pregnancy

Studies using animal and human placenta models have been used to assess the transplacental transfer of oseltamivir. Both OP and OC were found to cross the placenta in animal models, with evidence of oseltamivir in both the amniotic fluids and the fetuses of pregnant rats [59]; however, preclinical studies using animal models showed no evidence of adverse effects of oseltamivir in either pregnancy or birth outcomes unless maternal levels of oseltamivir reached toxic levels [60]. Experiments using human placentas infused with oseltamivir demonstrated an extensive metabolism of OP to OC with only minimal levels of OC found on the fetal side of the placenta when supratherapeutic levels of oseltamivir were used [61]. Other placental studies found transfer of both OP and OC to fetal compartments at similar transfer rates [62, 63], with OC transferring in a bidirectional fashion [64]. One case report described evidence of OP and OC transplacental transfer in a pregnant woman treated with oseltamivir for influenza [65]. While there were no reported adverse events occurring with treatment, both OP and OC were detected in cord blood at higher concentrations than in previous ex vivo placental models [65]. It was unknown whether these higher concentrations were due to increased oseltamivir dosing (150 mg twice daily, or twice the recommended dose) used in response to a lack of clinical improvement or other factors. These studies suggest that fetal exposure to OP and OC with oseltamivir treatment during pregnancy is likely. While there are potential clinical benefits in rare instances of influenza viral transfer across the placenta, the longer-term effects of OP and OC exposure on the fetus are unknown [65].

Clinical Benefits of Neuraminidase Inhibitors in Pregnant Women

NAI treatment of pregnant women with influenza has been shown to reduce the risk of severe outcomes including hospital length of stay, intensive care unit (ICU) admission, and mortality. In a multicountry meta-analysis of individual patient-level observational data for hospitalized patients with influenza A(H1N1)pdm09 during 2009–2010, pregnant women who received NAI treatment (oseltamivir, zanamivir, or peramivir) during their illness experienced a significant reduction in mortality when compared with no treatment (adjusted odds ratio [aOR], 0.46; 95% CI, 0.23–0.89) [66]. Early initiation of NAI treatment (≤2 days after symptom onset) significantly reduced the risk of mortality when compared with later initiation of treatment (>2 days after symptom onset; aOR, 0.27; 95% CI, 0.11–0.63) and no treatment (aOR, 0.16; 95% CI, 0.04–0.67) [66].

Observational studies from the United States, France, and China have highlighted the importance of the timing of antiviral treatment in relationship to illness onset and clinical benefit. NAI treatment initiated more than 48 hours after influenza symptom onset has been found to increase the risk of ICU admission, use of mechanical ventilatory support, and mortality when compared with those who received NAIs earlier in their course of illness [4–6, 67]. Using US population-based data during 2010–2014, pregnant women who were treated early (≤2 days) with NAIs for severe or nonsevere influenza experienced shorter length of hospital stay than if they were treated later (>2 days) during their illness course [68]. These findings from observational studies suggest that early initiation of NAI treatment of pregnant women with influenza can reduce disease severity and that treatment should be initiated as soon as influenza is suspected or confirmed.

Despite the increased mortality observed in pregnant women with influenza during the 2009 H1N1 pandemic in other countries, there were no reports of influenza-associated maternal deaths in Japan [69]. One observational study reported that influenza-associated hospitalization rates were similar in pregnant women and the general population [70]. The Japan Society of Obstetrics and Gynecology published guidelines for pregnant women that recommended early antiviral treatment during the early spread of the pandemic in Japan, use of postexposure prophylaxis (PEP) with antivirals, and vaccination with 2009 H1N1 vaccine when available [71]. Some reports estimated that 85% [69] to 97% [70] of pregnant women in Japan received NAI treatment during their course of illness, with 92% receiving antivirals within 48 hours of symptom onset [70]. One review concluded that the high frequency of early initiation of NAI treatment in pregnant women with pandemic influenza, PEP, and 2009 H1N1 vaccination may all have contributed to reducing the risk of severe outcomes among pregnant women in Japan [71].

Pregnancy Outcomes With Maternal Neuraminidase Inhibitor Exposure

Overall, studies show that NAI use during pregnancy poses a low risk of adverse maternal or fetal outcomes. In 1 North American cohort study comparing 112 pregnant women with exposure to oseltamivir any time during pregnancy with 604 unexposed pregnant women, preterm delivery and small for gestational age (SGA) infants were similar between the 2 groups [72]. Rates of birth defects were similar among pregnant women with oseltamivir exposure during the first trimester of pregnancy and those who were unexposed [72]. A US case–control study of birth defects identified a higher risk estimate for intestinal malrotation in infants born to women exposed to oseltamivir during their pregnancy but only included 3 exposed cases [73]. One Swedish study comparing 86 pregnant women exposed to NAI (oseltamivir or inhaled zanamivir) during pregnancy with 860 women who were unexposed found no statistically significant risk of low 5-minute APGAR score (<7), low birth weight, SGA, moderate or very preterm birth, congenital malformations, or birth-related death in the exposed group [74]. An increase in risk for late transient hypoglycemia was reported when comparing NAI-exposed with unexposed patients, while other associations were not statistically significant [74]. A Brazilian case series of 31 NAI-treated pregnant women with suspected or confirmed influenza A (H1N1)pdm09 showed no association between adverse perinatal outcomes with either early or late oseltamivir exposure, nor was there an association between NAI use and serious maternal complications by trimester of pregnancy [15].

Studies using population-based data and prospectively enrolled cohorts have also found no association between NAI use in pregnancy and adverse maternal or fetal outcomes [75–78]. One Canadian-based study of 55 355 pregnant women, of whom 1237 were exposed to oseltamivir, reported no association between oseltamivir exposure and SGA, preterm births, or low 5-minute APGAR scores [75]. Pregnant women with influenza who were exposed to oseltamivir had a lower risk of having an SGA infant than those who were untreated [75]. Findings from a prospective cohort study of 782 pregnant women using national surveillance data in the United Kingdom examined associations of adverse outcomes with either oseltamivir (n = 27) or inhaled zanamivir use (n = 180). There were no differences in rates of adverse pregnancy outcomes in either group compared with untreated pregnant women with influenza [78]. In a manufacturer’s summary of reports of postmarketing safety data of oseltamivir use in 2128 pregnant women with known pregnancy outcome, no increased incidence of adverse pregnancy outcomes was found among those exposed to oseltamivir compared with background rates in the general population [79]. The manufacturer’s summary included reports of Category A birth defects, defined as drug exposure during the sensitive period for the defect. In the database, there were 11 cases of birth defects among 9 patients classified as Category A defects, and the rates of defects in these infants born to women with oseltamivir exposure during pregnancy were similar to background rates in the general population [79].

Other Neuraminidase Inhibitors and Baloxavir

Most published reports describe the use of oseltamivir in pregnant women and have shown clinical benefit and safety for both maternal and fetal outcomes. However, there are very few studies describing the use of other NAIs in pregnant women and associated safety data. In Japan, inhaled laninamivir is an approved long-acting NAI used to treat influenza. One study reported the use of laninamivir in 112 pregnant women at different doses (40-mg and 20-mg doses) and showed no increased risk of adverse pregnancy or fetal outcomes compared with the general population [80]. During the 2009 H1N1 pandemic, the US Food and Drug Administration issued an Emergency Use Authorization (EUA) for intravenous (IV) peramivir and allowed use of IV zanamivir through an Emergency Investigational New Drug (eIND) application for single-patient use in hospitalized patients with influenza A(H1N1)pdm09 for whom enterically administered oseltamivir would not be tolerated or when there was no clinical improvement with oseltamivir treatment [81–85]. A small number of pregnant women received IV peramivir or IV zanamivir. Due to small sample sizes and lack of an untreated comparison group, no conclusions were possible on the clinical benefit or safety of these intravenous NAIs for pregnant women or nonpregnant persons. While IV peramivir is Food and Drug Administration (FDA)–approved for early treatment of uncomplicated influenza in outpatients aged 2 years and older, no data are available from randomized controlled trials in pregnant women. IV zanamivir is not FDA-approved and is not available in the United States.

In 2018, baloxavir marboxil, a polymerase acidic endonuclease inhibitor, received FDA approval for early treatment of uncomplicated influenza in outpatients aged 12 years and older. Following oral administration, baloxavir marboxil is rapidly converted to the active drug baloxavir with a long half-life. Clinical trials demonstrated that a single dose of baloxavir had similar time to alleviation of influenza symptoms as 5 days of oseltamivir treatment [86]. However, as pregnant women have been excluded from controlled clinical trials of the safety and clinical efficacy of baloxavir treatment of influenza in outpatients and hospitalized patients, and as no published data from observational studies with pregnant women are available, the effects of baloxavir on maternal or birth outcomes are unknown. Animal reproduction data showed no adverse embryo-fetal effects except when levels of baloxavir reached a toxic maternal dose. Baloxavir use in rabbits was associated with fetal skeletal variations resulting in 2 abortions out of 19 pregnancies [45].

CONCLUSIONS

Pregnant women and women who are up to 2 weeks postpartum are at increased risk for severe maternal and fetal outcomes related to influenza virus infection. Observational data demonstrate a reduction of severe maternal outcomes when pregnant women with influenza are treated with oseltamivir or other NAIs early in their clinical course. While studies have demonstrated transplacental transfer of oseltamivir and its metabolites, no increased risk of adverse maternal, fetal, or neonatal outcomes has been identified with oseltamivir exposure during pregnancy, although long-term effects are unknown. Until safety and efficacy studies in pregnant women are available, baloxavir is not currently recommended for treatment of influenza in pregnant women. Given the abundant observational data that oseltamivir is safe and effective in pregnant women, oseltamivir is currently the preferred antiviral drug for treatment of influenza during pregnancy. Based upon limited pharmacokinetic data, additional studies are needed to determine the optimal dosing of oseltamivir for treatment of influenza during pregnancy.

Acknowledgments

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.

Potential conflicts of interest. Dr. Laura Riley has conflicts to declare, including an association with Up to Date and a previous consultation regarding a CMV vaccine with GSK. All other authors: no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.