ACIP Recommendations and Pregnancy (Flu)
This webpage contains information relevant to maternal vaccination originally from “Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices—United States, 2017-18 Influenza Season” (MMWR Recomm Rep 2017;66[no.RR-2]:1-20).
Background and Epidemiology
Pregnant women are vulnerable to severe symptoms and illness attributable to influenza. Physiologic changes associated with pregnancy, such as altered cardiopulmonary mechanics and changes in cell mediated immunity, might contribute to enhanced susceptibility (54). In a case-cohort study of 1,873 pregnant women conducted over the 2010–11 and 2011–12 seasons, among 292 women with acute respiratory illnesses, those with influenza reported greater symptom severity than those with non-influenza acute respiratory illness (55). Case reports and some observational studies suggest that pregnancy increases the risk for hospitalization and serious maternal medical complications (56-58). Most of these studies have measured changes in excess hospitalizations or outpatient visits for respiratory illness during influenza season rather than LCI. A retrospective cohort study of pregnant women conducted in Nova Scotia during 1990–2002 compared medical record data for 134,188 pregnant women to data from the same women during the year before pregnancy. During the influenza seasons, the rate ratio of hospital admissions during the third trimester compared with admissions in the year before pregnancy was 7.9 (95% confidence interval [CI] = 5.0–12.5) among women with comorbidities and 5.1 (95% CI = 3.6–7.3) among those without comorbidities (58).
Increased severity of influenza among pregnant women was reported during the pandemics of 1918–19, 1957–58, and 2009–10 (59-64). During the 2009(H1N1) pandemic, severe infections among postpartum (delivered within previous 2 weeks) women also were observed (60, 63, 65). In a case series conducted during the 2009(H1N1) pandemic, 56 deaths were reported among 280 pregnant women admitted to intensive care units. Among U.S. deaths due to pandemic influenza reported to CDC, five percent of all US deaths from pandemic influenza involved pregnant women, even though they represented <1% of the population (66, 67). Among the deaths, 36 (64%) occurred in the third trimester. Pregnant women who were treated with neuraminidase inhibitor antivirals >4 days after symptom onset were more likely to be admitted to an intensive care unit (57% versus 9%; relative risk [RR]: 6.0; 95% CI = 3.5–10.6) than those treated within 2 days after symptom onset (66).
Some studies of pregnancy outcomes have suggested increased risk for pregnancy complications attributable to maternal influenza illness; others have not. A review of data from the National Inpatient Sample (a publically available hospital discharge database) covering the 1998–99 through the 2001–02 seasons and including over 6.2 million hospitalizations of pregnant women, reported increased risk for fetal distress, preterm labor, and cesarean delivery among those women with respiratory illness during influenza seasons, compared with women without respiratory illness (68). A study of 117,347 pregnancies in Norway during the 2009–10 pandemic noted an increased risk for fetal death among pregnant women with a clinical diagnosis of influenza (adjusted hazard ratio [aHR]: 1.91; 95% CI = 1.07–3.41) (69). A cohort study conducted among 221 hospitals in the United Kingdom observed an increased risk for perinatal death, stillbirth, and preterm birth among women admitted with confirmed 2009(H1N1) infection (70). However, other studies of infants born to women with LCI during pregnancy have not shown higher rates of prematurity, preterm labor, low birth weight, or lower Apgar scores compared with infants born to uninfected women (71-73).
Influenza symptoms often include fever, which during pregnancy might be associated with neural tube defects and other adverse outcomes (74). A meta-analysis of 22 observational studies of congenital anomalies following influenza exposure during the first trimester of pregnancy noted associations with several types of congenital anomalies, including neural tube defects, hydrocephaly, heart and aortic valve defects, digestive system defects, cleft lip, and limb reduction defects. However, many of the included studies were conducted during the 1950s through 1970s, and a nonspecific definition of influenza exposure was used (any reported influenza, ILI, or fever with influenza, with or without serological or clinical confirmation) (75). A 2005 meta-analysis of fifteen observational studies noted an association between maternal fever and neural tube defects (76). Associations between maternal fever and congenital heart defects (77) and orofacial cleft (78) have been reported in some studies; in one study of congenital anomalies such as orofacial clefts, congenital heart defects, and omphalocele, the association with maternal fever was ameliorated among those mothers who had taken multivitamins (79).
Immunogenicity, Efficacy, and Effectiveness of Influenza Vaccines
Passive transfer of anti-influenza antibodies from vaccinated women to neonates has been documented (180-182). Protection of infants though maternal vaccination has been observed in several studies. In a randomized controlled trial conducted in Bangladesh, vaccination of pregnant women during the third trimester resulted in a 36% reduction in respiratory illness with fever among these women, as compared with women who received pneumococcal polysaccharide vaccine. In addition, influenza vaccination of mothers was 63% effective (95% CI = 5 to 85) in preventing LCI in their breastfed infants during the first 6 months of life (183). A randomized placebo-controlled trial of IIV3 among HIV-infected and uninfected women in South Africa reported efficacy against RT-PCR–confirmed influenza of 50.4% (95% CI = 14.5 to 71.2) among the HIV-uninfected mothers and 48.8% (95% CI = 11.6 to 70.4) among their infants (184). In a study conducted in Mali in which pregnant women were randomized to receive either IIV3 or quadrivalent meningococcal vaccine during the third trimester and infants were followed to detect LCI through 6 months of age, vaccine effectiveness against LCI among the infants was 67.9% (95%CI 35.2 to 85.3) through 4 months and 57.3% (95%CI 30.6 to 74.4) through 5 months; by six months of follow up effectiveness was 33.1% (95%CI 3.7 to 53.9) (185). A randomized placebo-controlled trial of year-round influenza vaccination in Nepal (where influenza circulates throughout the year, rather than seasonally), vaccine effectiveness against LCI among infants 0–6 months of age was 30% (95%CI = 5 to 48) for the full study period. Vaccines with two different compositions were used during this period; vaccine effectiveness for the vaccine used during the first period was 16% (95%CI -19 to 41) while that for the latter was 60% (95%CI = 26 to 88) (186).
Among observational studies, in a matched case-control study of infants admitted to a large urban hospital in the United States during 2000–2009, investigators found that maternal vaccination was associated with significantly lower likelihood of hospitalization for LCI among infants aged <6 months (91.5%; 95% CI = 61.7 to 98.1) (187). A prospective cohort study among Native Americans reported that infants aged <6 months of vaccinated mothers had a 41% reduction of the risk for LCI in the inpatient and outpatient settings (RR: 0.59; 95% CI = 0.37 to 0.93) and a 39% reduction in risk for ILI-associated hospitalization (RR: 0.61; 95% CI = 0.45 to 0.84) (188). In a study of 1,510 infants aged <6 months, those of vaccinated mothers were less likely to be hospitalized with LCI than those of nonvaccinated mothers (aOR: 0.55; 95% CI = 0.32 to 0.95) (189). In a case control study covering the 2010-11 and 2011-12 influenza seasons, vaccination of pregnant women reduced their risk of laboratory-confirmed influenza by approximately half (190).
Safety of Influenza Vaccines
IIVs: Substantial data have accumulated which do not indicate fetal harm associated with inactivated influenza vaccines administered during pregnancy. However, data specifically concerning administration of these vaccines during the first trimester are limited (480). This can contribute to imprecision in estimates for risk of outcomes such as fetal death, spontaneous abortion and congenital malformations (481).
A matched case-control study of 225 pregnant women who received IIV3 within the 6 months before delivery determined that no serious adverse events occurred after vaccination and that no difference in pregnancy outcomes was identified among these pregnant women compared with 826 pregnant women who were not vaccinated (482). A review of health registry data in Norway noted an increased risk for fetal death associated with clinically diagnosed (not laboratory-confirmed) influenza A(H1N1) pdm09 infection, but no increased risk for fetal mortality associated with vaccination (69). Reviews of VAERS reports during 1990–2009 (483) and 2010-2016 (484), concerning pregnant women after receipt of IIV3 did not find any new or unexpected pattern of adverse pregnancy events or fetal outcomes
Background rates of spontaneous abortion vary from 10.4% in women aged <25 years to 22.4% in women aged >34 years (485). Considering the number of pregnant women vaccinated, miscarriage following (but not attributable to) influenza vaccination would therefore not be an unexpected event. However, data on the use of influenza vaccines are more limited during the early first trimester, when spontaneous abortions are more likely to occur. Among 7 observational studies summarized in a 2015 systematic review, none reported an increased risk of spontaneous abortion associated with influenza vaccination (481). A cohort study from the Vaccines and Medications in Pregnancy Surveillance System (VAMPSS) of vaccine exposure during the 2010-11 through 2013-14 seasons found no significant association of spontaneous abortion with influenza vaccine exposure in the first trimester or within the first 20 weeks of gestation (486). A case-control analysis of data from six health care organizations participating in VSD found no significant increase in the risk for pregnancy loss in the 4 weeks following seasonal influenza vaccination during the 2005–06 and 2006–07 seasons (487). However, results of a later VSD study using similar methods suggested an increased risk for spontaneous abortion in some pregnant women in the 1 to 28 days after receiving IIV3 during either the 2010–11 or the 2011–12 seasons; the increased risk was seen primarily in women who had also received a H1N1pdm09-containing vaccine in the previous season (488).
A systematic review and meta-analysis of seven published observational studies (four involving unadjuvanted A[H1N1]pdm09 monovalent vaccine, two involving adjuvanted A[H1N1]pdm09 monovalent vaccine, and one involving A/New Jersey/8/76 monovalent vaccine) found decreased risk for stillbirth among women who were vaccinated (for all studies, RR: 0.73; 95% CI = 0.55–0.96; for studies of influenza A(H1N1)pdm09 vaccines RR: 0.69; 95% CI = 0.52–0.90); there was no significant difference in risk for spontaneous abortion between vaccinated and unvaccinated women (RR: 0.91; 95% CI = 0.68–1.22) (489). Several reviews of studies involving seasonal and 2009(H1N1) IIV in pregnancy concluded that no evidence exists to suggest harm to the fetus from maternal vaccination (490-492).
A systematic review and meta-analysis of studies of congenital anomalies after vaccination including data from 15 studies (14 cohort studies and one case-control study), eight of which reported data on first-trimester immunization showed that risk for congenital malformations was similar for vaccinated and unvaccinated mothers: in the cohort studies, events per vaccinated versus unvaccinated were 2.6% versus 3.1% (5.4% versus 3.3% for the subanalysis involving first-trimester vaccination); in the case-control study, the percentage vaccinated among cases versus controls was 37.3% versus 41.7% (493). There was no association between congenital defects and influenza vaccination in any trimester (OR: 0.96; 95% CI = 0.86–1.07) or specifically in the first trimester (OR: 1.03; 95% CI = 0.91–1.18). With respect to major malformations, there was no increased risk after immunization in any trimester (OR: 0.99; 95% CI = 0.88–1.11) or in the first trimester (OR: 0.98; 95% CI = 0.83–1.16). A case-control analysis from VAMPSS of data from the 2011-12 through 2013-14 seasons noted an elevated OR for omphalocele (5.16, 95%CI 1.44—18.7) during the 2011-12 season; no other significant associations were found (494).
Assessments of any association with influenza vaccination and preterm birth and small for gestational age infants have yielded inconsistent results, with most studies reporting no association or a protective effect against these outcomes (495-500). Protective effects observed in some studies may be due to biases arising from temporal variability in access to vaccine, timing of exposure to vaccination in pregnancy, and confounding due to differences in the study populations at baseline (501). A VSD study of 46,549 pregnancies during the 2009-2010 season found a strong protective effect against preterm birth of monovalent H1N1pdm09 vaccination when these potential effects were ignored, but no effect with adjustment for them (502). In a retrospective cohort study of 57,554 women, influenza vaccination was not associated with increased or decreased risk for preterm birth or small for gestational age birth (497).
Few studies have assessed infant health outcomes outside the neonatal period, among infants born to mothers receiving IIV during pregnancy. A retrospective cohort study of electronic medical record data including nearly 197,000 women noted no association between receipt of IIV in any trimester and diagnosis of an autism spectrum disorder (ASD) in the child. When data were analyzed by trimester, an increased risk was noted following vaccination during the first trimester (adjusted hazard ratio 1.20, 95%CI 1.04—1.39) (503). This association was no longer statistically significant after adjusting for multiple comparisons.
RIVs: Experience with the use of RIVs in pregnancy is limited, as these vaccines have been available only since the 2013-14 influenza season. In two pre-licensure studies of RIV3, 23 pregnancies occurred among participants who received RIV3. Complete follow-up was available for 18 pregnancies. Outcomes included 11 pregnancies which ended in uneventful, normal, term births; two in which the recipients experienced pregnancy-related AEs but delivered healthy infants; four elective terminations, and one spontaneous abortion (452). VAERS has received 3 RIV3 reports involving pregnant women. A pregnancy registry has been established for RIV3 and RIV4 (241, 354).
LAIV: As a live virus vaccine, LAIV has not been recommended for use during pregnancy. However, occasional reports of its use for pregnant women are reported to VAERS. Among 27 reports to VAERS involving inadvertent administration of LAIV3 to pregnant women during 1990–2009, no unusual patterns of maternal or fetal outcomes were observed (483). Of 127 reports of administration of LAIV3/4 to pregnant women submitted to VAERS from July2010 through May 2016, no adverse event was reported in 112 instances; the remaining 15 included two reports each of spontaneous abortion, elective termination, and nasal congestion and one report each of transverse myelitis, abdominal pain, preterm delivery, chest pain with dyspnea secondary to trauma, pure cell aplasia, headache, common cold, pulmonary hypertension in a newborn infant, and one unspecified pregnancy complication. Only the instance of pulmonary hypertension in the infant was reported as a serious event (484). Among 138 reports noted in a health insurance claims database, all outcomes occurred at similar rates to those observed in unvaccinated women (504).
Under the previous FDA labeling regulations, influenza vaccines were classified as either Pregnancy Category B or Category C on the basis of risk of reproductive and developmental adverse effects and on the basis of such risk weighed against potential benefit. In 2014, new regulations updated the format and content requirements of labeling for human prescription drugs and biological products, including vaccines. Under the new regulations, the previous pregnancy risk categories are replaced with a narrative summary of risk based on human and animal data for the specific product. In accordance with a defined implementation plan, many influenza vaccines are now labeled using the new format.