Pregnant women have long been noted to be at an increased risk of serious illness as a result of influenza, particularly in the later stages of pregnancy. This risk is further increased in pregnant women with underlying comorbidities such as diabetes mellitus, asthma, and multifetal gestation. Influenza during pregnancy has also been associated with an increased risk of pregnancy complications including preterm delivery and fetal distress.1,2 Vaccination with the trivalent inactivated influenza vaccine is the cornerstone of prevention of influenza in pregnant women and their newborn offspring. In a randomized controlled trial, vaccination with the trivalent inactivated influenza vaccine was shown to reduce all febrile respiratory illnesses by approximately one third in vaccinated mothers and their newborns.3 Since 2004, the Centers for Disease Control and Prevention and the Advisory Committee on Immunization Practice has recommended vaccination of all women who will be pregnant during the influenza season regardless of gestational age.2 This recommendation is supported by the American College of Obstetricians and Gynecologists.4
Despite these recommendations, the majority of pregnant women are not vaccinated. During the last two decades, only 10–24% of pregnant women in the United States received an influenza vaccine.2,5 After the H1N1 influenza pandemic, vaccination rates for seasonal influenza increased. A survey of women pregnant in the 2010–2011 influenza season found self-reported vaccination rates of 49%. It is yet to be determined, however, if these higher vaccination levels will be maintained.6 Concerns about the safety of influenza vaccination in pregnancy among patients and health care workers have been cited as one of the major barriers to vaccination.7,8
To date, no study has found an association between vaccination with the inactivated influenza vaccine in pregnancy and adverse maternal or neonatal outcomes,9 – 11 but few of these studies include data from women vaccinated in the first trimester. In this study, we compare neonatal outcomes in women who received the influenza vaccination in the first trimester of pregnancy with those who received the vaccine in the second and third trimesters and with unvaccinated women.
MATERIALS AND METHODS
This was a retrospective cohort study examining neonatal outcomes after antepartum maternal influenza vaccination during five influenza seasons between October 2003 and March 2008. During the study period, all pregnant women receiving prenatal care in our clinic system were offered the annual trivalent inactivated influenza vaccine. From October 2003 through March 2004, women were offered vaccination only in the second and third trimesters. In 2004, the Advisory Committee of Immunization Practices of the Centers for Disease Control and Prevention changed the pregnancy vaccination recommendations to include women in the first trimester. Accordingly, from October 2004 through March 2008, vaccination was offered in all three trimesters.
Demographic information was entered into a vaccination log in each of our prenatal clinics. The vaccination record was then linked to our obstetric database. Selected obstetric and neonatal outcomes for all women delivering neonates at Parkland Health and Hospital System 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 neonatal outcomes are abstracted from discharge records. Information on malformations for all live births and stillbirths was abstracted from the newborn nursery hospital record at the time of discharge or death. In addition, monthly committee reviews of all stillbirths delivered at our hospital were also collected. Stillbirths were limited to a fetal death 500 g or more. Malformations in live births were confirmed by neonatology fellows and faculty of the Department of Pediatrics at the University of Texas Southwestern Medical Center. Major malformations were categorized as those causing significant functional or cosmetic impairment or those that were life-limiting. Examples of major malformations include neural tube defect, hypoplastic left heart, ventral wall defect, and craniofacial cleft.
Women receiving an influenza vaccination and who delivered at our institution were compared with women who received prenatal care during the months of October through March for each of the 5 years of the study. Neonatal outcomes were then assessed. Statistical analysis was performed using SAS 9.1 and included Student's t test, χ2, and logistic regression. We adjusted for race and diabetes in specific analyses. 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. This study was approved by the institutional review board at the University of Texas Southwestern Medical Center, Dallas, Texas.
From October 2003 to March 2008, 10,225 women received the trivalent inactivated influenza vaccine and 8,690 delivered at our institution, 439 in the first trimester and 8,251 in the second and third trimesters. Demographic characteristics are listed in Table 1, comparing the women accepting an influenza vaccine with those who declined. Women receiving the vaccine antepartum were significantly older, with a higher parity. They were also more likely to have a pregnancy complication requiring them to be seen at our Obstetrics Complications Clinic (72% compared with 48%, respectively). Multiple gestations were more common in those women receiving vaccinations, and body mass index (calculated as weight (kg)/[height (m)]2)was higher. Women vaccinated in the first trimester had the highest medical complications rate at 81%, significantly higher than those women receiving vaccination in the second or third trimester (71%) (P<.001).
Table 2 details the delivery and neonatal outcomes for the entire cohort. Although the overall mean estimated gestational age at delivery was not significantly different between the two groups, preterm delivery was decreased in those women receiving the influenza vaccine. Birth weight was not affected by vaccination. There was no increase in major malformation rates in the two groups and, interestingly, the stillbirth and the neonatal death rates were significantly decreased in those women receiving influenza vaccination.
There were 447 neonates exposed to the influenza vaccine in the first trimester. Table 3 compares selected neonatal outcomes by trimester of exposure and with women who declined vaccination. First-trimester exposure to the annual influenza vaccine did not result in an increase in major malformations. The significant decrease in stillbirths was seen in the second and third trimesters of vaccination compared with the nonvaccinated group. Neonatal pneumonia rates were highest in neonates born to women receiving the flu vaccine in the second or third trimester. There was no statistical difference between the first-trimester exposure and the nonvaccinated group. Neonatal intensive care unit (NICU) admissions were higher in the neonates exposed to influenza vaccination in the first trimester; after adjusting for race and diabetes, the odds ratio was 1.890 (1.3–2.8) compared with the no-vaccination group. The NICU admissions were lower in those women vaccinated in the second and third trimesters.
In this study, we found that neonates exposed to the seasonal trivalent inactivated influenza vaccine in the first trimester of pregnancy did not have an increased risk of major fetal malformations. In fact, vaccination in any trimester was associated with a decrease in the overall stillbirth rate, neonatal death, and preterm delivery 36 or less and less than 32 weeks of gestation.
The high morbidity and mortality during pregnancy from influenza infection (pandemic and nonpandemic) has been reported for almost a century, starting with the 1918 influenza epidemic.12 – 14 Influenza vaccination has been administered in pregnancy for over 50 years to improve maternal health and fetal and neonatal outcomes. Influenza vaccination of the pregnant woman results in protective antibody titers, comparable to levels in the nonpregnant adult. These maternal antibodies then transmit transplacentally and provide protection to the newborn during the first few months of life.15 – 17 Several recent studies have reported a decrease in influenza viral infection in infants born to mothers who received the trivalent inactivated influenza vaccine during pregnancy.3,18,19 Influenza vaccine of the pregnant woman has been shown to also benefit the fetus.20 Omer and colleagues21 using surveillance data from the Georgia Pregnancy Risk Assessment Monitoring System noted a decrease in prematurity and small-for-gestational-age rates (as defined as less than 10%) in the cohort of women receiving the seasonal influenza vaccine during the period of widespread influenza activity. Although vaccine effectiveness varies each year depending on how well the vaccine strains match to circulating virus and the incidence of influenza that year, there is little doubt that maternal vaccination during pregnancy is warranted for the health of the mother–infant pair.22
These improvements in health outcomes, however, have to take vaccine safety into account. As early as 1973 when a report of a population-based collaborative perinatal project (1959–1965) with over 2,000 pregnant women receiving the trivalent inactivated influenza vaccine was presented, vaccine safety has been demonstrated.23 There is now a number of papers reporting on the safety of trivalent inactivated influenza vaccine during pregnancy, recently reviewed by Tamma and colleagues.9 Although no harmful effects were reported in either the mother or fetus or neonate, there is a paucity of contemporary data from vaccination in the first trimester.3,10,24 The U.S. Vaccine Adverse Event Reporting System database from 1990–2009 was recently reviewed.11 Adverse events in the mother are rare and no universal patterns of pregnancy complications or fetal outcomes were observed. Although these data are reassuring, the Food and Drug Administration continues to classify the trivalent inactivated influenza vaccine as a pregnancy category B, indicating that reproductive animal studies have not shown a fetal risk, but there are no controlled studies in pregnancy.
Despite the fact that the trivalent inactivated influenza vaccine is considered effective and safe in pregnancy, and is, in fact, recommended by the Centers for Disease Control and Prevention and American College of Obstetricians and Gynecologists, seasonal vaccination rates are historically dismal. Although these rates did increase in the setting of the recent pandemic outbreak, it remains to be seen if this increase can be sustained. Numerous reports have been presented in recent years to try to determine why vaccination rates are so low in this high-risk population. When patients were surveyed, a prevailing theme was concern for maternal and fetal safety.6,8,25 – 29 When obstetric health care providers were queried, a surprising number of respondents did not vaccinate in the first trimester30 or felt that influenza vaccines were not safe in pregnancy.7 Safety concerns were a major issue for both patients and health care providers despite impressive efforts by the Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists to educate the public regarding vaccine safety. One of the limitations to education has been the limited data available regarding first-trimester vaccination. Our study contributes to the available safety literature and supports early vaccination.
The increase in NICU admissions in neonates whose mothers were vaccinated in the first trimester was an unexpected finding. This remained true even when prematurity and a diagnosis of insulin-dependent diabetes was accounted for. This may reflect the fact that there was a higher preponderance of women in the vaccination group with other comorbid conditions followed in our Obstetrics Complications Clinic, possibly leading to an NICU admission. This NICU admission did not, however, result in an increase in neonatal death or prolonged length of stay.
There are several limitations to this study. Women listed in the nonvaccinated group may have received the trivalent inactivated influenza vaccine at another location. Financial restrictions in our patient population should have kept this number low because the vaccine was offered free of charge at all of our prenatal clinics. Furthermore, the potential addition of some vaccinated women to the nonvaccinated group would only serve to dilute the population, lessening the significant differences. Given the large control group, any statistical effect would likely be small. Finally, there was a higher percentage of women in the vaccinated group that was seen in our obstetric complication clinic, possibly reflecting our policy assuring that patients with comorbid conditions receive the influenza vaccine. This concentration of patients with comorbid conditions in the vaccination group did not result in worse outcomes, however, strengthening the argument that the vaccine is safe in pregnancy. These women may have also had high compliance rates for medical care, resulting in a higher vaccination rate.
The 2009 influenza pandemic has focused new attention on influenza in high-risk groups, including pregnancy. Efforts to improve vaccination rates in pregnancy have been escalated and much research has gone into determining potential pitfalls and hurdles to overcome to increase this rate, safety being one of the greatest concerns. Vaccine safety in the second and third trimesters has been well described. Our report describes the effect of influenza vaccination in the first trimester. There was no evidence of increased major malformations diagnosed in the cohort of neonates born to mothers vaccinated in the first 13 weeks of pregnancy. Immunization benefited the entire cohort of women by its association with a lower stillbirth and neonatal death rate as well as preterm delivery. These effects are likely secondary to the decrease in maternal influenza infection in women who were vaccinated. In light of these findings, patients and health care providers concerned about the safety of influenza vaccination in the first trimester of pregnancy should be reassured, which will hopefully lead to vaccination rates continuing to improve.
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