Greer, Laura G. MD; Sheffield, Jeanne S. MD; Rogers, Vanessa L. MD; Roberts, Scott W. MD, MS; McIntire, Donald D. PhD; Wendel, George D. Jr MD
The emergence of pandemic influenza A H1N1 in early 2009 raised awareness of the morbidity and mortality influenza can inflict. In an average influenza season, influenza results in approximately 226,000 hospital admissions and 36,000 deaths in the United States.1 Although most people infected with influenza experience an acute but self-limited febrile respiratory syndrome, certain groups, including pregnant women, are at increased risk of severe disease or death secondary to influenza infection.2–4
Vaccination programs are the cornerstone to preventing influenza-related illness and complications in high risk groups. The Centers for Disease Control and Prevention (CDC) and the American College of Obstetricians and Gynecologists both recommend seasonal influenza vaccination in pregnant patients.5,6 When vaccination fails, antiviral therapies play an important role in both postexposure prophylaxis and the treatment of influenza.2,4
There are two classes of antiviral therapies. The first is the M2 ion channel inhibitors, amantadine and rimantadine. The M2 ion channel inhibitors are only effective for the treatment and prophylaxis of influenza A. This class of medication has not been used as the primary therapy for influenza since the 2005–2006 influenza season because of the development of resistance to these medications. In the 2008–2009 influenza season, however, increasing rates of oseltamivir resistance led to the use of the M2 ion channel inhibitors in conjunction with oseltamivir as two-drug therapy for influenza A.7 The second class of influenza antiviral therapy is the neuraminidase inhibitors, oseltamivir and zanamivir. These are effective against both influenza A (including novel H1N1) and B, and they have been the first-line drugs for treatment and prophylaxis of influenza since 2006.7,8 Because influenza viruses continue to mutate, all of these medications remain important tools in influenza treatment and prevention.
Historically, because of limited safety data, both the CDC and the American College of Obstetricians and Gynecologists left use of influenza antiviral therapy in pregnancy to the discretion of the provider to determine whether the potential benefit justified the potential risk to the fetus.6,8 In spring 2009, however, with concern for the potentially devastating consequences of a novel H1N1 strain, the CDC recommended that pregnant women with influenza A H1N1 be treated with antiviral medication and that pregnant women with close contact with a person with H1N1 receive antiviral prophylaxis.4 There is limited safety data regarding the use of antiviral medications for the treatment of influenza during pregnancy in humans.9 Amantadine, rimantadine, oseltamivir, and zanamivir all have U.S. Food and Drug Administration Pregnancy Category C ratings because there are no clinical trials designed to assess their safety during pregnancy.4
To provide some guidance on the risk, if any, of antiviral medication during pregnancy, we reviewed the maternal and neonatal outcomes of pregnant women treated at our hospital for influenza with amantadine, rimantadine, or oseltamivir during five influenza seasons.
MATERIALS AND METHODS
This was a retrospective cohort study examining maternal and fetal outcomes after antepartum maternal treatment of influenza with antiviral medications during five influenza seasons at Parkland Hospital between October 2003 and March 2008. During these pre-H1N1 influenza seasons, pregnant patients from our prenatal clinics with suspected influenza were referred to our obstetrics–gynecology emergency department or labor and delivery triage for evaluation. Rapid influenza tests were performed with optical immunoassay, direct fluorescent antibody testing, or both. Patients who tested positive for influenza and who had had symptoms for less than 48 hours were given antiviral therapy with an M2 ion channel inhibitor or oseltamivir. The medications given varied by influenza season, and pharmacy prescribing restrictions for antiviral medications during the study period limited treatment to confirmed cases of influenza. Patients with sustained tachycardia (110 or more beats per minute), fever 38.0°C or higher, pneumonia, threatened preterm labor, or an inability to tolerate oral therapy were admitted to the hospital.
Patients eligible for inclusion in the study were first identified using the pharmacy prescribing records database. This is a centralized hospital pharmacy database used to enter all medication orders filled in and dispensed from the centralized pharmacy. The entries are made by the pharmacist filling the prescription before releasing the medications. We identified all female patients to whom the antiviral drugs amantadine, rimantadine, or oseltamivir were dispensed from the hospital pharmacy as an inpatient or outpatient during the five influenza seasons between October 2003 and March 2008.
Next, these medical records were linked to our obstetric database to identify women who received antiviral medication during pregnancy. Selected obstetric and neonatal outcomes for all women delivering neonates at Parkland Hospital are routinely entered into a computerized database. Nurses attending each delivery complete an obstetric data sheet, and research nurses assess the data for consistency and completeness before electronic storage. Data on neonates' outcomes are abstracted from discharge records. Periodically, the stored data are audited by reviewing trends using control chart methods as well as reevaluation of randomly selected records. The obstetrics database was used to identify patients who delivered at Parkland Hospital within 38 weeks after receiving antiviral medication for influenza. The only exclusion criteria were patients who did not deliver at Parkland Hospital and, therefore, did not have outcome data available for review. Using the estimated gestational age at delivery and the date the medication was dispensed, we calculated the gestational age at the time of exposure and sorted the exposure by first, second, or third trimester.
During the study period, there were differences in availability of the M2 ion channel inhibitors between our inpatient and outpatient pharmacy, and some patients received one M2 ion channel inhibitor while hospitalized but received the other M2 ion channel inhibitor from the outpatient pharmacy to complete their course of therapy. We, therefore, analyzed amantadine and rimantadine together as a class, M2 ion channel inhibitors, rather than by individual medication.
We evaluated maternal characteristics, including age, race, parity, gestational age at delivery; medical conditions, including obesity and overt diabetes; and pregnancy outcomes, including preterm birth (delivery less than 37 weeks of gestation), premature rupture of membranes, development of preeclampsia or gestational diabetes, fever in labor, and duration of hospital stay. We also evaluated fetal outcomes, including stillbirth, major and minor malformations, birth weight, need for intubation or neonatal intensive care unit admission, grade 3 or 4 intraventricular hemorrhage, necrotizing enterocolitis, hyperbilirubinemia, seizures, neonatal death, and duration of hospital stay. In our institution, anomalies that are not life threatening and do not require surgical repair (such as accessory nipples, extra digits, and nevi) are considered minor malformations. Major malformations are malformations that do not meet the definition of a minor malformation.10 Malformations in liveborn neonates were identified or confirmed by neonatology fellows and faculty in the Department of Pediatrics at University of Texas Southwestern Medical Center.
Each medication was compared with our overall obstetric patient population during the same time period to examine whether there were increased rates of adverse outcomes in the patients receiving the M2 ion channel inhibitors or oseltamivir antiviral treatment during pregnancy. For the M2 ion channel inhibitors and for oseltamivir, we analyzed outcomes by exposure at any gestational age and by exposure in each trimester.
Statistical analysis was performed with the use of χ2, Student t test, analysis of variance, Kruskal-Wallis test, and Wilcoxon rank sum test using SAS 9.1 (SAS Institute, Cary, NC). This population based, retrospective cohort study includes a fixed sample size dependent on the time period of the study. Consequently, an a priori sample size was not developed. Under this consideration, negative associations are to be viewed as associations not demonstrated rather than as definitive evidence of lack of association. For reference purposes, under the sample sizes observed of 80,000 women in the control group and 100 in the comparison groups, our data provides 80% power to recognize a doubling of the frequency of occurrence from 10% to 20% for a two-sided χ2 test with a significance level of .05.
This study was approved by the Internal Review Board at University of Texas Southwestern Medical Center, Dallas, Texas. The study was conducted by the Department of Obstetrics and Gynecology at University of Texas Southwestern. No outside funding was received for this study.
From October 2003 to March 2008, we had 239 pregnant patients with influenza who received antepartum antiviral therapy as indicated by the pharmacy prescribing records database and who subsequently delivered at our hospital. A total of 207 patients (87%) initiated treatment as inpatients, and 32 patients (13%) initiated treatment as outpatients. Of these, 104 received an M2 ion channel inhibitor (amantadine, rimantadine, or both) and 135 received oseltamivir. Fifty-five percent of the exposures were third trimester, 32% were second trimester, and 13% were first trimester. Other patients delivering at our hospital during the same time period are described as the comparison control group.
Looking first at the characteristics of the women who received antiviral therapy for influenza, there were no significant differences in age, race, nulliparity, estimated gestational age at delivery, or preexisting medical problems of overt diabetes or obesity between the groups (Table 1). There was, however, an increase in the number of patients with a multiple gestation who were treated with the M2 ion channel inhibitors (Table 1). There was no significant increased risk of preeclampsia, preterm birth, gestational diabetes, premature rupture of membranes, prolonged hospital stay, or occurrence of fever in labor in the mothers exposed to antiviral therapy antepartum (Table 1).
There were 108 fetuses exposed to M2 ion channel inhibitors and 137 exposed to oseltamivir. There were no significant differences in the incidence of stillbirth, major malformations, or minor malformations in the fetuses exposed to antiviral medication (Table 2). The one major malformation reported from the antiviral exposure group was in a neonate with trisomy 21. The neonate was exposed to an M2 ion channel inhibitor during the second trimester of pregnancy and was diagnosed with a patent foramen ovale and clinodactyly after delivery.
Considering only singleton, liveborn neonates without major malformations, there were no significant differences in fetal weight or rates of small or large for gestational age neonates. There were also no significant differences in the number of neonates who required intubation or intensive care nursery admission or who had grade 3 or 4 intraventricular hemorrhage, hyperbilirubinemia, or seizures. There were no differences in the incidence of neonatal death (Table 3).
There was a significant increased rate of necrotizing enterocolitis in neonates exposed to antiviral medications (P<.001). Two neonates in the study developed necrotizing enterocolitis. One was exposed to amantadine during the second trimester. The mother was infected with HIV and was also taking multidrug antiviral therapy. She developed severe preeclampsia at 32 weeks of gestation, and the fetus was growth restricted. She underwent a cesarean delivery for fetal distress, and the neonate weighed 844 g. The neonate subsequently developed necrotizing enterocolitis, underwent surgery, and was hospitalized for 126 days. The second neonate with necrotizing enterocolitis was exposed to oseltamivir during the second trimester. The mother underwent a cesarean delivery for severe preeclampsia and transverse lie at 29 weeks of gestation. The neonate weighed 1,200 g, developed necrotizing enterocolitis, required surgery, and was hospitalized for 37 days.
When liveborn singleton neonate outcomes were analyzed by trimester of exposure to the M2 ion channel inhibitors or to oseltamivir, the only significant finding was the increased rate of necrotizing enterocolitis compared with those in the control group (Tables 4 and 5).
In this study, we found that pregnant women treated with antiviral therapy for influenza were not dissimilar to those who did not have influenza antiviral exposure. The outcomes of patients with influenza treated with antiviral therapy during pregnancy were similar to our control patient population in the rates premature rupture of membranes, preeclampsia, gestational diabetes, preterm birth, fever in labor, and duration of hospital stay. There were, however, more pregnancies with multiple gestations among women who received antepartum antiviral treatment. Because twinning occurs at or within the first week after conception, the increased rate of multiple gestations cannot be attributed to antiviral exposure. Instead, it raises the question of whether women with a multiple gestation and influenza infection are more likely to seek treatment or to have a more severe infection.
It is reassuring to see that fetuses exposed to antiviral therapy for the treatment of influenza did not have increased rates of stillbirth, major malformations, or minor malformations. Similarly, liveborn singletons without major malformations with in utero exposure to antivirals for the treatment of influenza had birth weights similar to those of unexposed neonates and did not have an increased incidence of hyperbilirubinemia, seizures, intraventricular hemorrhage, intensive care nursery admission, or neonatal death.
We observed a significant increase in the rate of necrotizing enterocolitis in the group receiving antiviral medications. One neonate was exposed to an M2 ion channel inhibitor, and the other was exposed to oseltamivir. Both were delivered preterm, at 29 and 32 weeks of gestation, respectively, and one was growth restricted. Necrotizing enterocolitis affects up to 10% of very low birth weight neonates. The exact cause of necrotizing enterocolitis is unknown, but epidemiologic studies show prematurity and feeding with nonhuman milk to be consistent precursors of necrotizing enterocolitis.11 Because these patients received different medications with different mechanisms of action, it seems more probable that necrotizing enterocolitis was the result of prematurity rather than medication exposure or maternal influenza during pregnancy.
There are several limitations to this study. First, it is important to recognize that because all women treated with antiviral therapy had influenza, it is not possible to separate the risks arising from febrile viral illness or influenza from the potential risk of antiviral therapy. Second, we cannot confirm that all patients completed outpatient therapy as directed. Third, we cannot rule out the possibility that some women could have received antiviral treatment before knowing they were pregnant, could have been diagnosed with and treated for influenza outside our hospital system, or could have used a pharmacy outside our hospital system to get their prescriptions filled. Any of these situations could have resulted in a patient's being analyzed in the control group despite having received antiviral medication during pregnancy. Given the large control group, however, any statistical effect of the potential unidentified patients would likely be very small. Finally, this analysis is subject to the limitations of a retrospective study with a fixed sample size. Although the sample size is adequate to evaluate many of the outcomes, it is underpowered to detect significant differences in some of the outcomes provided. Specifically, although the data regarding malformations are encouraging, the overall number of patients treated is small, especially in the first trimester. Accordingly, this subgroup analysis may be underpowered to detect an increased risk of major malformations, and the data presented in Tables 4 and 5, analyzing outcomes by trimester, may be underpowered.
In conclusion, as obstetricians face an influenza season that promises increased rates of influenza infection resulting from the concurrent circulation of both seasonal influenza and 2009 influenza A H1N1, our study provides some reassuring safety data about commonly used medications for practitioners treating pregnant patients with influenza infection.