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Effects of influenza on pregnant women and infants

      Influenza vaccination during pregnancy has been shown to decrease the risk of influenza and its complications among pregnant women and their infants up to 6 months old. To adequately assess the benefits and potential risks that are associated with the use of influenza vaccine during pregnancy, it is necessary to examine the influenza-associated complications that occur among pregnant women and their children. Pregnant women have been shown to be at increased risk for morbidity and death with influenza illness during seasonal epidemics and pandemics. Newborn infants born to mothers with influenza during pregnancy, especially mothers with severe illness, are at increased risk of adverse outcomes, such as preterm birth and low birthweight. Infants <6 months old who experience influenza virus infection have the highest rates of hospitalization and death of all children. Here we review the risks for influenza-associated complications among pregnant women and infants <6 months old.

      Key words

      Informed decisions regarding the use of influenza vaccine during pregnancy must include consideration of both the benefits and the potential risks of the vaccine. To fully understand the benefits of influenza vaccine during pregnancy, we must examine the complications that are associated with influenza virus infection during pregnancy that include those in the woman and her infant. In addition, because observational studies and 1 randomized trial have shown that influenza vaccination protects infants <6 months old from influenza,
      • Zaman K.
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      Influenza vaccine given to pregnant women reduces hospitalization due to influenza in their infants.
      the influenza-associated disease burden among young infants also must be considered. Here, we review data on the effects of influenza virus infection on pregnant women and infants <6 months old.

      Effects of influenza during pregnancy on the pregnant woman

      Pregnant women are more likely to experience severe complications that are associated with influenza compared with the general population, based on data from seasonal influenza epidemics and pandemics.
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      During pregnancy, immunologic alterations and physiologic changes that affect respiratory, cardiovascular, and other organ systems place women at increased risk for certain infections and associated complications. A woman's immune system adapts during pregnancy to tolerate a genetically foreign fetus. How this adaptation occurs is not well understood, but it appears that a shift away from cell-mediated immunity and toward humoral immunity occurs. This immunologic adaptation results in increasing the risk for complications that are associated with certain infections, which includes infection with influenza viruses.
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      Changes in the cardiovascular and respiratory systems that include increased heart rate, stroke volume, oxygen consumption, and decreased lung capacity also put women at increased risk for severe influenza illness.
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      Data suggest that pregnant women are at increased risk of hospitalization related to complications from seasonal influenza compared with nonpregnant women. Using data from the Tennessee Medicaid program for the years 1974-1993, Neuzil et al
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      Impact of influenza on acute cardiopulmonary hospitalizations in pregnant women.
      showed that pregnant women were more likely to be hospitalized with an acute cardiopulmonary illness during seasonal influenza epidemics compared with postpartum women. The highest rate of hospitalization was during the third trimester of pregnancy, at which time pregnant women were 3-4 times more likely to be hospitalized with a cardiopulmonary illness during influenza season compared with postpartum women.
      Cox et al
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      examined data from a nationally representative hospital discharge database for the years 1998-2002 and showed that the proportion of hospitalizations among pregnant women with respiratory illness was substantially higher during influenza season (3.4 per 1000 pregnancy hospitalizations, compared with 1.8 per 1000 during the rest of the year). Pregnant women with comorbid conditions (ie, chronic cardiac disease, chronic pulmonary disease, diabetes mellitus, chronic renal disease, malignancies, and immunosuppressive disorders) were >3 times more likely to be hospitalized for respiratory illness during influenza season than women without these comorbid conditions.
      A study from Nova Scotia also demonstrated an increased risk for influenza-associated complications during pregnancy.
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      • McNeil S.A.
      • Fell D.B.
      • et al.
      Impact of influenza exposure on rates of hospital admissions and physician visits because of respiratory illness among pregnant women.
      Compared with the year before pregnancy, pregnant women without comorbid conditions were 1.7 (95% confidence interval [CI], 1.0–2.8), 2.1 (95% CI, 1.3–3.3), and 5.1 (95% CI, 3.6–7.3) times more likely to be hospitalized for respiratory illness during the influenza season during the first, second, and third trimesters, respectively. Pregnant women with ≥1 comorbid conditions (defined as preexisting diabetes mellitus, pulmonary disease that included asthma, heart disease, renal disease, and anemia) were at substantially higher risk of hospitalization during all 3 trimesters, with rate ratios of 2.9 (95% CI, 1.5–5.4) in the first trimester, 3.4 (95% CI, 1.9–6.0) in the second trimester, and 7.9 (95% CI, 5.0–12.5) in the third trimester of pregnancy, compared with the year before pregnancy.
      Among a case series of pregnant women with laboratory-confirmed influenza A at Parkland Memorial Hospital in Dallas, Texas, during the 2003-2004 influenza season,
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      • Sheffield J.S.
      • Roberts S.W.
      • et al.
      Presentation of seasonal influenza A in pregnancy: 2003-2004 influenza season.
      62% of the women were hospitalized, and 1 in 8 experienced pneumonia. Symptoms of influenza among pregnant women were similar to those in nonpregnant adults, except that pregnant women were more likely to have nausea and vomiting. A substantial proportion of women in this cohort experienced a profound tachycardia that failed to respond to hydration or antipyretic medications.
      Human infections with highly pathogenic avian influenza (HPAI) A (H5N1) virus were first identified in Hong Kong during 1997
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      Outbreak of avian influenza A(H5N1) virus infection in Hong Kong in 1997.
      and again in early 2003 in family members who had traveled to southern China.
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      • Yu W.C.
      • Leung C.W.
      • et al.
      Re-emergence of fatal human influenza A subtype H5N1 disease.
      HPAI H5N1 virus has received considerable attention in recent years because of high mortality rates among human cases and extensive spread among poultry populations of many countries since 2005; concern about the virus prompted extensive pandemic preparedness activities worldwide. As of May 2, 2012, 603 laboratory-confirmed human cases of HPAI H5N1 virus infection have been reported to the World Health Organization since November 2003, with a 59% cumulative case fatality proportion.

      World Health Organization. Cumulative number of confirmed human cases for avian influenza A(H5N1) reported to WHO, 2003–2012, 2012 (vol 2012).

      Published information on the effects of HPAI H5N1 virus infection in pregnant women is limited. A review paper that was published in 2008 noted that 4 of 6 pregnant women with HPAI H5N1 virus infection died and that the 2 women who survived had spontaneous abortions.
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      • Chotpitayasunondh T.
      • et al.
      Update on avian influenza A (H5N1) virus infection in humans.
      Detailed clinical and pathologic data have been reported on 1 of the women who died.
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      • et al.
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      • Shu Y.
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      • Li D.
      Lethal avian influenza A (H5N1) infection in a pregnant woman in Anhui Province, China.
      Her illness progressed rapidly to multiorgan failure and death, despite intensive supportive care. Pathologic analysis demonstrated widespread extrapulmonary dissemination of HPAI H5N1 virus in several tissues, including in fetal lung cells, that documented transplacental transmission to her fetus.
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      • et al.
      H5N1 infection of the respiratory tract and beyond: a molecular pathology study.
      Data from previous pandemics (which includes the pandemics of 1918, 1957, and 2009) suggest that pregnant women have higher rates of morbidity and mortality. In one report from the 1918 H1N1 influenza pandemic (n = 1350), one-half of all pregnant patients had pneumonia; approximately one-half of these patients died, which yielded a case fatality proportion among pregnant women of 27%.
      • Harris J.W.
      Influenza occurring in pregnant women.
      Among a case series of 86 pregnant women who were hospitalized with pandemic influenza in Chicago during 1918, 41 women (45.5%) died.
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      • Bonar B.E.
      Pandemic influenza and pneumonia in a large civilian hospital.
      Pregnancy was also identified as a risk factor for severe disease during the 1957 H2N2 influenza pandemic. In a study in Minnesota in 1957-1958, pandemic influenza was the leading cause of death during pregnancy; nearly 20% of deaths that occurred during pregnancy were due to influenza. During this time period, one-half of the women of reproductive age who died from pandemic influenza were pregnant.
      • Freeman D.W.
      • Barno A.
      Deaths from Asian influenza associated with pregnancy.
      More recently, the influenza A(H1N1)pdm09 (2009 H1N1) pandemic provided further evidence that pregnant women are at high risk for severe influenza complications. When the data for pregnant women were compared with nonpregnant women of reproductive age or with the general population, several studies demonstrated that pregnant women were at increased risk of hospitalization, admission to an intensive care unit, death, and other severe outcomes related to 2009 H1N1. Data from the first month after emergence of 2009 H1N1 in the United States showed that pregnant women were >4 times more likely to be hospitalized than the general population.
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      • et al.
      H1N1 2009 influenza virus infection during pregnancy in the USA.
      Although pregnant women comprise 1% of the population in the United States, they accounted for approximately 5% of all 2009 H1N1-related deaths in the United States.
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      • Honein M.A.
      • et al.
      Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States.
      In pooled data from a systematic review, pregnant women accounted for 6.3% of hospitalizations, 5.9% of intensive care unit admissions, and 5.7% of deaths that were associated with 2009 H1N1.
      • Mosby L.G.
      • Rasmussen S.A.
      • Jamieson D.J.
      2009 Pandemic influenza A (H1N1) in pregnancy: a systematic review of the literature.
      The highest risk for severe complications appeared to be in the second and especially the third trimesters of pregnancy, although intensive care unit admissions and deaths occurred in all 3 trimesters.
      • Siston A.M.
      • Rasmussen S.A.
      • Honein M.A.
      • et al.
      Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States.
      • Louie J.K.
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      Severe 2009 H1N1 influenza in pregnant and postpartum women in California.
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      • Graitcer S.B.
      • et al.
      Severity of 2009 pandemic influenza A (H1N1) virus infection in pregnant women.
      Observational data suggest that pregnant women who received antiviral treatment that was initiated within 2 days of onset of 2009 H1N1-associated symptoms were less likely to die or to be admitted to an intensive care unit.
      • Siston A.M.
      • Rasmussen S.A.
      • Honein M.A.
      • et al.
      Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States.
      As reviewed by Mosby et al,
      • Mosby L.G.
      • Rasmussen S.A.
      • Jamieson D.J.
      2009 Pandemic influenza A (H1N1) in pregnancy: a systematic review of the literature.
      5 observational studies showed that neuraminidase inhibitor treatment of pregnant women with 2009 H1N1 when started within 48 hours of symptom onset was associated with a lower risk of severe disease. Some clinical benefit was observed when antiviral treatment was started 3-4 days after symptom onset compared with the initiation of treatment >4 days after symptom onset.
      • Mosby L.G.
      • Rasmussen S.A.
      • Jamieson D.J.
      2009 Pandemic influenza A (H1N1) in pregnancy: a systematic review of the literature.
      Data that were collected during the 2009 H1N1 pandemic also demonstrated an increased risk for influenza-associated complications among postpartum women.
      • Louie J.K.
      • Jamieson D.J.
      • Rasmussen S.A.
      2009 pandemic influenza A (H1N1) virus infection in postpartum women in California.
      Based on 15 case reports of women up to 6 months after delivery in California, severe illness was often reported: 9 postpartum women with 2009 H1N1 were admitted to the intensive care unit; 3 of these died. The risk appeared to be highest during the first postpartum week, although an appropriate comparison group was not included.
      Although treatment with antiviral medications appears to decrease the risk of severe influenza outcomes among pregnant women, limited data are available on the effects of antiviral medications on the embryo or fetus when used during pregnancy.
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      • Jamieson D.J.
      • Bresee J.S.
      Pandemic influenza and pregnant women.
      • Rasmussen S.A.
      • Kissin D.M.
      • Yeung L.F.
      • et al.
      Preparing for influenza after 2009 H1N1: special considerations for pregnant women and newborns.
      Available information on antiviral medications during pregnancy is reassuring; however, adequate well-controlled studies of pregnant women are not available, and these medications are considered to be pregnancy category C by the United States Food and Drug Administration.
      • Rasmussen S.A.
      • Kissin D.M.
      • Yeung L.F.
      • et al.
      Preparing for influenza after 2009 H1N1: special considerations for pregnant women and newborns.
      Therefore, pregnant women might be reluctant to take antiviral medications, and health care providers might be reluctant to prescribe such treatment for influenza during pregnancy. Delayed or lack of antiviral treatment of pregnant women with 2009 H1N1 was observed, particularly early in the pandemic, despite clear public health recommendations for treatment. Treatment delay often was associated with adverse outcomes in pregnant women.
      • Siston A.M.
      • Rasmussen S.A.
      • Honein M.A.
      • et al.
      Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States.
      • Louie J.K.
      • Acosta M.
      • Jamieson D.J.
      • Honein M.A.
      Severe 2009 H1N1 influenza in pregnant and postpartum women in California.

      Effects of influenza during pregnancy on the newborn infant

      Limited information is available on risks to the embryo or fetus that are associated with seasonal or pandemic influenza virus infection. Viremia appears to occur very infrequently during influenza illness
      • Zou S.
      Potential impact of pandemic influenza on blood safety and availability.
      ; therefore, transplacental (vertical) transmission of influenza virus from mother to the embryo or fetus is expected to be rare.
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      • Stephenson T.
      • et al.
      Influenza virus infection in the second and third trimesters of pregnancy: a clinical and seroepidemiological study.
      • Kanmaz H.G.
      • Erdeve O.
      • Ogz S.S.
      • et al.
      Placental transmission of novel pandemic influenza A virus.
      • Lieberman R.W.
      • Bagdasarian N.
      • Thomas D.
      • Van De Ven C.
      Seasonal influenza A (H1N1) infection in early pregnancy and second trimester fetal demise.
      • Yawn D.H.
      • Pyeatte J.C.
      • Joseph J.M.
      • Eichler S.L.
      • Garcia-Bunuel R.
      Transplacental transfer of influenza virus.
      As previously noted, transplacental virus transmission has been well-documented in a pregnant woman who was infected with HPAI H5N1 virus, which has been shown to cause extrapulmonary infection, which includes viremia.
      • Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human Infection with Avian Influenza A.V.
      • Abdel-Ghafar A.N.
      • Chotpitayasunondh T.
      • et al.
      Update on avian influenza A (H5N1) virus infection in humans.
      • De Jong M.D.
      • Bach V.C.
      • Phan T.Q.
      • et al.
      Fatal avian influenza A (H5N1) in a child presenting with diarrhea followed by coma.
      • Buchy P.
      • Mardy S.
      • Vong S.
      • et al.
      Influenza A/H5N1 virus infection in humans in Cambodia.
      This report described a fatal case of H5N1 virus infection in a pregnant woman; on pathologic evaluation, H5N1 viral genomic sequences and antigens were detected in placental tissue and fetal lung cells.
      • Gu J.
      • Xie Z.
      • Gao Z.
      • et al.
      H5N1 infection of the respiratory tract and beyond: a molecular pathology study.
      Transplacental transmission of 2009 H1N1 virus was suspected in some cases, but definitive evidence was not available.
      • Dulyachai W.
      • Makkoch J.
      • Rianthavorn P.
      • et al.
      Perinatal pandemic (H1N1) 2009 infection, Thailand.
      • Patel M.
      • Dennis A.
      • Flutter C.
      • Thornton S.
      • D'mello O.
      • Sherwood N.
      Pandemic (H1N1) 2009 influenza: experience from the critical care unit.
      • Valvi C.
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      2009H1N1 Infection in a 1-day-old neonate.
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      Human 2009 influenza A (H1N1) virus infection in a premature infant born to an H1N1-infected mother: placental transmission?.
      • Vasquez R.D.
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      • Gamio I.E.
      • et al.
      [Probable vertical transmission of the influenza virus A (H1N1): apropos of a case].
      Therefore, the limited evidence to date suggests that vertical transmission of influenza viruses can occur but is likely to be very rare.
      Even in the absence of transplacental transmission of influenza virus, the embryo or fetus might be affected adversely by influenza in the mother during pregnancy, especially when the mother is severely ill. Data from the 1918 H1N1 influenza pandemic demonstrated an increased risk for pregnancy loss that is associated with influenza illness.
      • Harris J.W.
      Influenza occurring in pregnant women.
      In Harris's series, approximately one-quarter of pregnancies with uncomplicated influenza ended in pregnancy loss; among those mothers whose influenza that was complicated by pneumonia, more than one-half of pregnancies ended in pregnancy loss. A recent analysis of birth rates during the time period surrounding the 1918 H1N1 pandemic showed a decline in the birth rate in the spring of 1919; the authors concluded that this decline could be consistent with influenza causing first-trimester pregnancy losses in approximately 1 in 10 women during the peak of the pandemic.
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      • Simonsen L.
      • Viboud C.
      • et al.
      Natality decline and miscarriages associated with the 1918 influenza pandemic: the Scandinavian and United States experiences.
      An analysis of data from Japan during the 1918-1920 H1N1 influenza pandemic demonstrated a significantly increased risk for stillbirths (risk ratios ranged from 1.1–1.3).
      • Nishiura H.
      Excess risk of stillbirth during the 1918-1920 influenza pandemic in Japan.
      Studies from the 1957 H2N2 influenza pandemic showed a possible increase in the risk for pregnancy loss and preterm delivery among women who had influenza during pregnancy.
      • Hardy J.M.
      • Azarowicz E.N.
      • Mannini A.
      • Medearis Jr, D.N.
      • Cooke R.E.
      The effect of Asian influenza on the outcome of pregnancy, Baltimore, 1957-1958.
      Seasonal influenza in pregnant women also may increase the risk for adverse infant outcomes. Based on data from a 13-year population-based cohort study in Nova Scotia, infants born to women who were hospitalized for respiratory illness during influenza season (a proxy for influenza illness) at any time during pregnancy were more likely to be born small for gestational age (adjusted relative risk, 1.66; 95% CI, 1.11–2.49) and to have lower mean birthweight (P < .009) than infants born to women who were not hospitalized.
      • McNeil S.A.
      • Dodds L.A.
      • Fell D.B.
      • et al.
      Effect of respiratory hospitalization during pregnancy on infant outcomes.
      In contrast, in a study that used data from the Tennessee Medicaid program, infants born to pregnant women with a respiratory hospitalization during influenza season did not differ with regard to prevalence of preterm birth or low birthweight from infants born to women without a respiratory hospitalization, matched on gestational age and the presence of maternal comorbidity.
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      • et al.
      Maternal morbidity and perinatal outcomes among pregnant women with respiratory hospitalizations during influenza season.
      Data from the H1N1 pandemic indicate that influenza during pregnancy increases the risk for adverse pregnancy outcomes. A study of 256 women who were hospitalized in the United Kingdom with 2009 H1N1 virus infection during pregnancy reported a significantly increased perinatal mortality rate (39 per 1000 total births [95% CI, 19–71] among women with prenatal influenza), compared with a rate of 7 per 1000 (95% CI, 3–13) among the comparison group without 2009 H1N1. This was primarily due to an increase in the rate of stillbirths (27 vs 6 per 1000 total births; P = .001). In this study, preterm birth was also more likely with 2009 H1N1 (adjusted odds ratio, 4.0; 95% CI, 2.7–5.9). Risk factors for preterm delivery were third-trimester infection, admission to an intensive care unit, and secondary pneumonia that accompanied 2009 H1N1.
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      Yates et al
      • Yates L.
      • Pierce M.
      • Stephens S.
      • et al.
      Influenza A/H1N1v in pregnancy: an investigation of the characteristics and management of affected women and the relationship to pregnancy outcomes for mother and infant.
      also identified an increased risk for preterm delivery, based on an examination of 241 pregnant women who were hospitalized with laboratory-confirmed 2009 H1N1 (odds ratio, 3.1; 95% CI, 2.4–4.5). In addition, several case series of pregnant women with 2009 H1N1 demonstrated an increased frequency of preterm delivery, particularly among women with severe illness.
      • Mosby L.G.
      • Rasmussen S.A.
      • Jamieson D.J.
      2009 Pandemic influenza A (H1N1) in pregnancy: a systematic review of the literature.
      A recent follow-up study of severely ill women (defined as women who were admitted to an intensive care unit or who died) with 2009 H1N1 during pregnancy in the United States reported to the Centers for Disease Control showed an increased risk of adverse infant outcomes. Among infants born to women who delivered while hospitalized for 2009 H1N1 illness, 63.6% (95% CI, 51.8–74.3) were born preterm (compared with 12.3% of all US births), 69.4% (95% CI, 57.5–79.8) were admitted to a neonatal intensive care unit (compared with 6.1% of all US births), and 29.2% (95% CI, 19.1–41.1) had 5-minute Apgar scores that were ≤6 (compared with 1.6% of all US births). Among infants born to mothers who delivered after their hospital discharge for 2009 H1N1, 25% (95% CI, 14.0–39.0) were small for gestational age (compared with 10% of all US births), and 22% (95% CI, 11.5–36.0) were admitted to a neonatal intensive care unit (compared with 6.1% of all US births).
      Centers for Disease Control and Prevention
      Maternal and infant outcomes among severely ill pregnant and postpartum women with 2009 pandemic influenza A (H1N1)–United States, April 2009-August 2010.
      In a prospective study in Rhode Island, infants born to 16 women with 2009 H1N1 during pregnancy had a lower mean birthweight than those born to 25 women with influenza-like illness (defined as fever and cough and/or sore throat in the absence of other known causes of illness) who tested negative for 2009 H1N1.
      • Mendez-Figueroa H.
      • Raker C.
      • Anderson B.L.
      Neonatal characteristics and outcomes of pregnancies complicated by influenza infection during the 2009 pandemic.
      However, in that study, no differences in gestational age, Apgar scores, or cord blood gas pH values were noted.
      Other adverse outcomes among children have also been postulated after seasonal or pandemic influenza during pregnancy, but data are limited. For example, some studies suggested that the risk of congenital anomalies was increased among infants born to pregnant women with pandemic H2N2 influenza in 1957.
      • Hardy J.M.
      • Azarowicz E.N.
      • Mannini A.
      • Medearis Jr, D.N.
      • Cooke R.E.
      The effect of Asian influenza on the outcome of pregnancy, Baltimore, 1957-1958.
      • Coffey V.P.
      • Jessop W.J.
      Maternal influenza and congenital deformities: a follow-up study.
      • Saxen L.
      • Hjelt L.
      • Sjostedt J.E.
      • Hakosalo J.
      • Hakosalo H.
      Asian influenza during pregnancy and congenital malformations.
      • Wilson M.G.
      • Stein A.M.
      Teratogenic effects of Asian influenza: an extended study.
      Seasonal influenza during pregnancy has been associated with congenital anomalies (in particular, cleft lip with or without cleft palate and neural tube and congenital heart defects) in limited studies.
      • Acs N.
      • Banhidy F.
      • Puho E.
      • Czeizel A.E.
      Pregnancy complications and delivery outcomes of pregnant women with influenza.
      • Acs N.
      • Banhidy F.
      • Puho E.
      • Czeizel A.E.
      Maternal influenza during pregnancy and risk of congenital abnormalities in offspring.
      Associations between maternal influenza (seasonal or pandemic influenza) and other adverse outcomes that included childhood leukemia, schizophrenia, and Parkinson disease have also been suggested.
      • Kwan M.L.
      • Metayer C.
      • Crouse V.
      • Buffler P.A.
      Maternal illness and drug/medication use during the period surrounding pregnancy and risk of childhood leukemia among offspring.
      • Ebert T.
      • Kotler M.
      Prenatal exposure to influenza and the risk of subsequent development of schizophrenia.
      • Takahashi M.
      • Yamada T.
      A possible role of influenza A virus infection for Parkinson's disease.
      Fever that often accompanies influenza virus infection has been shown to increase the risk for several adverse infant outcomes and might be responsible for some of the observed associations between maternal influenza and adverse outcomes.
      • Edwards M.J.
      Review: hyperthermia and fever during pregnancy.
      For example, a 2-fold risk was suggested by a metaanalysis of the association between maternal hyperthermia and neural tube defects.
      • Moretti M.E.
      • Bar-Oz B.
      • Fried S.
      • Koren G.
      Maternal hyperthermia and the risk for neural tube defects in offspring: systematic review and meta-analysis.
      An association between maternal fever and other congenital anomalies (eg, congenital heart defects and orofacial clefts) has also been observed.
      • Oster M.E.
      • Riehle-Colarusso T.
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      • National Birth Defects Prevention S.
      Maternal fever during early pregnancy and the risk of oral clefts.
      • Wang W.
      • Guan P.
      • Xu W.
      • Zhou B.
      Risk factors for oral clefts: a population-based case-control study in Shenyang, China.
      Several studies have reported that maternal influenza vaccination reduces adverse outcomes in infants born to pregnant women with influenza. Zaman et al
      • Zaman K.
      • Roy E.
      • Arifeen S.E.
      • et al.
      Effectiveness of maternal influenza immunization in mothers and infants.
      conducted a clinical trial in Bangladesh in which pregnant women were assigned randomly to receive either inactivated influenza or pneumococcal vaccines to assess their effectiveness during pregnancy. Infants born to pregnant women who received influenza vaccine during a time period when influenza virus was circulating were compared with infants born to women who received pneumococcal vaccine during the same time period. Infants born to women who received influenza vaccine had significantly higher birthweights (3178 vs 2978 g; P = .02) and were less likely to be born small for gestational age (25.9% vs 44.8%; P = .03) than infants born to women who received pneumococcal vaccine, which suggests that prevention of influenza through prenatal vaccination results in improved intrauterine growth.
      • Steinhoff M.C.
      • Omer S.B.
      • Roy E.
      • et al.
      Neonatal outcomes after influenza immunization during pregnancy: a randomized controlled trial.
      A cohort analysis that used surveillance data from the Georgia Pregnancy Risk Assessment Monitoring System showed that infants born to mothers who received influenza vaccine during pregnancy were less likely to be born preterm (adjusted odds ratio, 0.60; 95% CI, 0.38–0.94) and less likely to be small for gestational age (adjusted odds ratio, 0.31; 95% CI, 0.13–0.75), compared with infants born to women who did not receive the influenza vaccine.
      • Omer S.B.
      • Goodman D.
      • Steinhoff M.C.
      • et al.
      Maternal influenza immunization and reduced likelihood of prematurity and small for gestational age births: a retrospective cohort study.

      Effects of influenza on infants <6 months old

      Many studies have shown that young children are at increased risk for influenza-associated complications,
      • Nair H.
      • Brooks W.A.
      • Katz M.
      • et al.
      Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis.
      • Thompson W.W.
      • Shay D.K.
      • Weintraub E.
      • et al.
      Influenza-associated hospitalizations in the United States.
      • Neuzil K.M.
      • Zhu Y.
      • Griffin M.R.
      • et al.
      Burden of interpandemic influenza in children younger than 5 years: a 25-year prospective study.
      • Kim H.W.
      • Brandt C.D.
      • Arrobio J.O.
      • Murphy B.
      • Chanock R.M.
      • Parrott R.H.
      Influenza A and B virus infection in infants and young children during the years 1957-1976.
      • O'Brien M.A.
      • Uyeki T.M.
      • Shay D.K.
      • et al.
      Incidence of outpatient visits and hospitalizations related to influenza in infants and young children.
      • Izurieta H.S.
      • Thompson W.W.
      • Kramarz P.
      • et al.
      Influenza and the rates of hospitalization for respiratory disease among infants and young children.
      but only a few of these studies have focused specifically on infants <6 months old. Using data from the Tennessee Medicaid program for the years 1973-1993, Neuzil et al
      • Neuzil K.M.
      • Mellen B.G.
      • Wright P.F.
      • Mitchel Jr, E.F.
      • Griffin M.R.
      The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children.
      showed a high rate of excess hospitalization for cardiopulmonary conditions when influenza viruses were circulating compared with noninfluenza periods. The average rate of influenza-associated excess hospitalizations was highest in infants <6 months old (104 per 10,000 children per year), compared with 50 per 10,000 in infants 6-12 months old, 19 for children 1-3 years old, 9 for children 3-5 years old, and 4 for children 5-15 years old. Other studies of laboratory-confirmed influenza provide stronger evidence that young infants are at high risk for severe complications from influenza. A study of children during 2 influenza seasons (2002-2003 and 2003-2004) showed that infants <6 months old had the highest rates of hospitalization for laboratory-confirmed influenza among children who were 0-59 months old. The average annual rate of hospitalization because of influenza was 4.5 per 1000 children (95% CI, 3.4–5.5) for infants <6 months old, compared with 0.9 per 1000 (95% CI, 0.7–1.2) for children 6-23 months old and 0.3 per 1000 (95% CI, 0.2–0.5) for children 24-59 months old.
      • Poehling K.A.
      • Edwards K.M.
      • Weinberg G.A.
      • et al.
      The underrecognized burden of influenza in young children.
      In a population-based study from 2003-2008, the highest hospitalization rates among children with laboratory-confirmed influenza were in infants <6 months old and ranged from 9–30 per 10,000 children.
      • Dawood F.S.
      • Fiore A.
      • Kamimoto L.
      • et al.
      Burden of seasonal influenza hospitalization in children, United States, 2003 to 2008.
      In a study of laboratory-confirmed influenza-associated deaths among children during a severe seasonal influenza epidemic in 2003-2004, the highest mortality rate was observed among children <6 months old (0.88 per 100,000 children; 95% CI, 0.52–1.39).
      • Bhat N.
      • Wright J.G.
      • Broder K.R.
      • et al.
      Influenza-associated deaths among children in the United States, 2003-2004.
      Several studies suggested that children who were infected with 2009 H1N1 influenza virus were at increased risk of complications.
      • Belongia E.A.
      • Irving S.A.
      • Waring S.C.
      • et al.
      Clinical characteristics and 30-day outcomes for influenza A 2009 (H1N1), 2008-2009 (H1N1), and 2007-2008 (H3N2) infections.
      • Gilca R.
      • De Serres G.
      • Boulianne N.
      • et al.
      Risk factors for hospitalization and severe outcomes of 2009 pandemic H1N1 influenza in Quebec, Canada.
      • Van Kerkhove M.D.
      • Vandemaele K.A.
      • Shinde V.
      • et al.
      Risk factors for severe outcomes following 2009 influenza A (H1N1) infection: a global pooled analysis.
      • Halasa N.B.
      Update on the 2009 pandemic influenza A H1N1 in children.
      However, only a few studies included data for infants <6 months old. In a study from Argentina, infants <6 months old with laboratory-confirmed 2009 H1N1 were at increased risk for hospitalization and death.
      • Libster R.
      • Bugna J.
      • Coviello S.
      • et al.
      Pediatric hospitalizations associated with 2009 pandemic influenza A (H1N1) in Argentina.
      In that study, infants <6 months old with 2009 H1N1 had the highest rate of hospitalizations and the second highest rate of death (infants who were 6-12 months old had the highest rate of death). In a study of children who were hospitalized with 2009 H1N1 in California, the highest hospitalization rate was in infants <6 months old.
      • Louie J.K.
      • Gavali S.
      • Acosta M.
      • et al.
      Children hospitalized with 2009 novel influenza A(H1N1) in California.
      In a case series from California of 82 infants who were admitted to an intensive care unit with 2009 H1N1, 27 infants (35%) were born preterm (<37 weeks' gestation), and 46 infants (60%) had at least 1 reported chronic medical condition (eg, chronic lung disease associated with preterm birth, congenital heart defects, and cerebral palsy).
      • Yen C.J.
      • Louie J.K.
      • Schechter R.
      Infants hospitalized in intensive care units with 2009 H1N1 influenza infection, California, 2009-2010.
      In a study of 2009 H1N1 patients that used data from a national hospital discharge database from Japan, infants were 2 times more likely to be hospitalized than children 12-24 months old.
      • Takeuchi M.
      • Yasunaga H.
      • Horiguchi H.
      • Matsuda S.
      Clinical features of infants hospitalized for 2009 pandemic influenza A (H1N1) in Japan: analysis using a national hospital discharge database.
      Although infants <6 months old are at increased risk of complications that are associated with influenza, their options for antiviral treatment and chemoprophylaxis options are limited. The neuraminidase inhibitors oral oseltamivir and inhaled zanamivir are not approved by the US Food and Drug Administration for use in children <1 year old, although oseltamivir was made available under an Emergency Use Authorization during the 2009 H1N1 pandemic for this age group
      • Halasa N.B.
      Update on the 2009 pandemic influenza A H1N1 in children.
      and continues to be recommended for use in this age group by the Advisory Committee on Immunization Practices.
      • Fiore A.E.
      • Fry A.
      • Shay D.
      • Gubareva L.
      • Bresee J.S.
      • Uyeki T.M.
      Antiviral agents for the treatment and chemoprophylaxis of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP).
      In addition, influenza vaccines are not approved for use in children <6 months old. Thus, influenza vaccination during pregnancy and influenza vaccination of household contacts and caregivers of infants <6 months old can help prevent influenza in these vulnerable infants who are too young to receive influenza vaccination.
      Centers for Disease Control and Prevention
      Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2011.

      Comment

      In summary, pregnant women and infants <6 months old are at increased risk for adverse consequences that are related to influenza, based on data from seasonal and pandemic influenza. Infants born to women who experienced 2009 H1N1 influenza virus infection during pregnancy, especially women who had severe illness, were more likely to have adverse infant outcomes (eg, low birthweight and preterm birth). In addition, influenza vaccination during pregnancy has been shown to decrease the frequency of influenza or its complications in infants up to 6 months old. Thus, influenza vaccination during pregnancy is a key strategy to prevent influenza and influenza-related complications in pregnant women and their infants.

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