{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T21:05:31Z","timestamp":1770411931665,"version":"3.49.0"},"reference-count":55,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T00:00:00Z","timestamp":1770336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Influenza (flu) is a common respiratory virus with seasonal global spread. Zoonotic viruses can occasionally cross species, leading to pandemic-level spread, and for flu viruses, this is considered an \u201cantigenic shift\u201d. The flu can be particularly severe during pregnancy due to immune system adaptations that occur during pregnancy, with prior global pandemics causing excess hospitalizations, deaths, and other complications in the mothers and the neonates. We aim to review the current literature with respect to novel avian H5N1 and the potential impact of infection with flu during pregnancy. A systematic literature search was conducted. Here we provide a rapid summary of epidemiology and understanding of viral spread, published risks of H5N1 in pregnancy, the unique physiologic, cellular, and molecular adaptations making H5N1 infection unique in pregnancy, implementation of an effective vaccine program in event of a pandemic specific to pregnant individuals, optimizing peripartum care for infected individuals, and direction for future research to direct vaccine strategy and mitigate risks in a future flu pandemic.<\/jats:p>","DOI":"10.3390\/v18020212","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T10:05:47Z","timestamp":1770372347000},"page":"212","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Avian Influenza H5N1 Infection During Pregnancy: Preparing for the Next Flu Pandemic and Improving Perinatal Outcomes"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9856-694X","authenticated-orcid":false,"given":"Matthew J.","family":"Zuber","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Section of Maternal-Fetal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA"},{"name":"Center for Vaccines at the Extremes of Aging (CVEA), Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3060-5652","authenticated-orcid":false,"given":"Callie L.","family":"Brown","sequence":"additional","affiliation":[{"name":"Center for Vaccines at the Extremes of Aging (CVEA), Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA"},{"name":"Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cara B.","family":"Janusz","sequence":"additional","affiliation":[{"name":"Center for Vaccines at the Extremes of Aging (CVEA), Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA"},{"name":"Department of Implementation Science, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1097\/EDE.0000000000000340","article-title":"The Fraction of Influenza Virus Infections That Are Asymptomatic: A Systematic Review and Meta-analysis","volume":"26","author":"Leung","year":"2015","journal-title":"Epidemiology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/S0140-6736(09)61304-0","article-title":"H1N1 2009 influenza virus infection during pregnancy in the USA","volume":"374","author":"Jamieson","year":"2009","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e237149","DOI":"10.1001\/jamanetworkopen.2023.7149","article-title":"Severe Maternal Morbidity and Mortality of Pregnant Patients With COVID-19 Infection During the Early Pandemic Period in the US","volume":"6","author":"Matsuo","year":"2023","journal-title":"JAMA Netw. Open"},{"key":"ref_4","unstructured":"(2025, December 10). H5 Bird Flu: Current Situation, Available online: https:\/\/www.cdc.gov\/bird-flu\/situation-summary\/index.html."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/S0140-6736(22)00982-5","article-title":"Influenza","volume":"400","author":"Uyeki","year":"2022","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1002\/ijgo.14686","article-title":"Maternal influenza vaccination preferentially boosts hemagglutinin stem-specific antibody resulting in efficient transplacental transfer of stem-specific IgG","volume":"162","author":"Zuber","year":"2023","journal-title":"Int. J. Gynaecol. Obstet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/s41541-025-01317-4","article-title":"An influenza HA mRNA-LNP vaccine induces potent responses in newborn nonhuman primates that enhance protection from challenge","volume":"11","author":"Page","year":"2025","journal-title":"NPJ Vaccines"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/S1473-3099(19)30393-7","article-title":"Immunogenicity of chimeric haemagglutinin-based, universal influenza virus vaccine candidates: Interim results of a randomised, placebo-controlled, phase 1 clinical trial","volume":"20","author":"Bernstein","year":"2020","journal-title":"Lancet Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"70","DOI":"10.3201\/eid3113.250087","article-title":"Establishing Methods to Monitor Influenza (A)H5N1 Virus in Dairy Cattle Milk, Massachusetts, USA","volume":"31","author":"Stachler","year":"2025","journal-title":"Emerg. Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"50","DOI":"10.3201\/eid3101.241343","article-title":"Systematic Review of Avian Influenza Virus Infection and Outcomes during Pregnancy","volume":"31","author":"Purcell","year":"2025","journal-title":"Emerg. Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1002\/rmv.1884","article-title":"Avian influenza virus in pregnancy","volume":"26","author":"Liu","year":"2016","journal-title":"Rev. Med. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1016\/S0140-6736(07)61515-3","article-title":"H5N1 infection of the respiratory tract and beyond: A molecular pathology study","volume":"370","author":"Gu","year":"2007","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1097\/01.AOG.0000262051.71925.ac","article-title":"Pandemic influenza and pregnancy: A call for preparedness planning","volume":"109","author":"Beigi","year":"2007","journal-title":"Obstet. Gynecol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1016\/j.ajog.2011.04.010","article-title":"Pandemic influenza and pregnancy revisited: Lessons learned from 2009 pandemic influenza A (H1N1)","volume":"204","author":"Jamieson","year":"2011","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1097\/GRF.0000000000000880","article-title":"Influenza in Pregnancy: Maternal, Obstetric, and Fetal Implications, Diagnosis, and Management","volume":"67","year":"2024","journal-title":"Clin. Obstet. Gynecol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1111\/j.1600-0897.2010.00836.x","article-title":"The immune system in pregnancy: A unique complexity","volume":"63","author":"Mor","year":"2010","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"280","DOI":"10.3109\/15513815.2011.572956","article-title":"Placental transmission of novel pandemic influenza a virus","volume":"30","author":"Kanmaz","year":"2011","journal-title":"Fetal Pediatr. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1186\/1743-422X-8-342","article-title":"Highly pathogenic avian influenza H5N1 virus could partly be evacuated by pregnant BALB\/c mouse during abortion or preterm delivery","volume":"8","author":"Xu","year":"2011","journal-title":"Virol. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e29687","DOI":"10.1002\/jmv.29687","article-title":"Influenza A virus infection disrupts the function of syncytiotrophoblast cells and contributes to adverse pregnancy outcomes","volume":"96","author":"Wang","year":"2024","journal-title":"J. Med. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2532684","DOI":"10.1080\/22221751.2025.2532684","article-title":"Emerging highly pathogenic H5N1 influenza triggers fibrotic remodeling in human airway organoids","volume":"14","author":"Rothan","year":"2025","journal-title":"Emerg. Microbes Infect."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.cell.2020.11.025","article-title":"Synergism of TNF-alpha and IFN-gamma Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes","volume":"184","author":"Karki","year":"2021","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1086\/504690","article-title":"Differential expression of chemokines and their receptors in adult and neonatal macrophages infected with human or avian influenza viruses","volume":"194","author":"Zhou","year":"2006","journal-title":"J. Infect. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"(2017). Committee Opinion No. 723: Guidelines for Diagnostic Imaging During Pregnancy and Lactation. Obstet. Gynecol., 130, e210\u2013e216.","DOI":"10.1097\/AOG.0000000000002355"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1111\/irv.12745","article-title":"Medical masks vs N95 respirators for preventing COVID-19 in healthcare workers: A systematic review and meta-analysis of randomized trials","volume":"14","author":"Bartoszko","year":"2020","journal-title":"Influenza Other Respir. Viruses"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1001\/jama.2019.11645","article-title":"N95 Respirators vs Medical Masks for Preventing Influenza Among Health Care Personnel: A Randomized Clinical Trial","volume":"322","author":"Radonovich","year":"2019","journal-title":"JAMA"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Kobayashi, M., Nakagawa, S., Kamei, Y., Maenaka, T., Hiramatsu, K., Mimura, K., Kimura, T., Ueda, Y., Fujii, M., and Endo, M. (2025). Virtual telehealth visits for prenatal checkups during the COVID-19 pandemic in Japan: A nationwide survey and feasibility study. BMC Pregnancy Childbirth, 25.","DOI":"10.1186\/s12884-025-07598-w"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"American College of Obstetricians and Gynecologists (the College) and the Society for Maternal\u2013Fetal Medicine, Caughey, A.B., Cahill, A.G., Guise, J.M., and Rouse, D.J. (2014). Safe prevention of the primary cesarean delivery. Am. J. Obstet. Gynecol., 210, 179\u2013193.","DOI":"10.1016\/j.ajog.2014.01.026"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1056\/NEJMoa0910444","article-title":"Severe 2009 H1N1 influenza in pregnant and postpartum women in California","volume":"362","author":"Louie","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1093\/cid\/ciy874","article-title":"Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenzaa","volume":"68","author":"Uyeki","year":"2019","journal-title":"Clin. Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1097\/01.ede.0000152903.55579.15","article-title":"Maternal hyperthermia and the risk for neural tube defects in offspring: Systematic review and meta-analysis","volume":"16","author":"Moretti","year":"2005","journal-title":"Epidemiology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1001\/jama.2024.3172","article-title":"Acetaminophen Use During Pregnancy and Children\u2019s Risk of Autism, ADHD, and Intellectual Disability","volume":"331","author":"Ahlqvist","year":"2024","journal-title":"JAMA"},{"key":"ref_32","unstructured":"(2025, September 22). ACOG Affirms Safety and Benefits of Acetaminophen During Pregnancy. Available online: https:\/\/www.acog.org\/news\/news-releases\/2025\/09\/acog-affirms-safety-benefits-acetaminophen-pregnancy."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"(2018). ACOG Committee Opinion No. 741: Maternal Immunization. Obstet. Gynecol., 131, e214\u2013e217.","DOI":"10.1097\/AOG.0000000000002662"},{"key":"ref_34","unstructured":"(2025, December 26). Guidance for the Prevention and Control of Influenza in the Peri- and Postpartum Settings, Available online: https:\/\/www.cdc.gov\/flu\/hcp\/infection-control\/peri-post-settings.html#:~:text=Prompt%20antiviral%20treatment%20with%20oseltamivir,with%20confirmed%20or%20suspected%20influenza.&text=Pregnant%20women%20have%20been%20shown,are%20available%20in%20the%20future."},{"key":"ref_35","unstructured":"(2025, December 26). Influenza (Flu) and Breastfeeding, Available online: https:\/\/www.cdc.gov\/breastfeeding-special-circumstances\/hcp\/illnesses-conditions\/flu.html."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"500","DOI":"10.15585\/mmwr.mm7432a2","article-title":"Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices\u2014United States, 2025\u20132026Influenza Season","volume":"74","author":"Grohskopf","year":"2025","journal-title":"MMWR Morb. Mortal. Wkly. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"101427","DOI":"10.1016\/j.ajogmf.2024.101427","article-title":"Timing of influenza vaccination during pregnancy","volume":"6","author":"Olson","year":"2024","journal-title":"Am. J. Obstet. Gynecol. MFM"},{"key":"ref_38","unstructured":"(2025, December 29). Interim Updated Planning Guidance, Available online: https:\/\/www.cdc.gov\/pandemic-flu\/php\/planning-guidance\/index.html."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e20","DOI":"10.1016\/S2213-2600(25)00052-9","article-title":"An overview of influenza H5 vaccines","volume":"13","author":"Taaffe","year":"2025","journal-title":"Lancet Respir. Med."},{"key":"ref_40","unstructured":"(2025, December 29). Vaccines for Pandemic Influenza Preparedness and Response, Available online: https:\/\/www.fda.gov\/media\/182597\/download."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1111\/irv.12383","article-title":"An overview of the regulation of influenza vaccines in the United States","volume":"10","author":"Weir","year":"2016","journal-title":"Influenza Other Respir. Viruses"},{"key":"ref_42","unstructured":"(2025, December 29). Evaluation of the Immune Response After Vaccination. Available online: https:\/\/cdn.who.int\/media\/docs\/default-source\/consultation-rdb\/3.evaluation-of-the-immune-response-after-vaccination.pdf?sfvrsn=563d2574_3."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"The Lancet (2025). H5N1 avian influenza: Technical solutions, political challenges. Lancet, 405, 671.","DOI":"10.1016\/S0140-6736(25)00400-3"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1016\/j.vaccine.2009.11.077","article-title":"Exposure to MF59-adjuvanted influenza vaccines during pregnancy\u2014A retrospective analysis","volume":"28","author":"Tsai","year":"2010","journal-title":"Vaccine"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/s41541-025-01318-3","article-title":"Influenza mRNA vaccine reduces pathogenicity and transmission of A(H5N1) virus in a ferret model","volume":"10","author":"Hatta","year":"2025","journal-title":"NPJ Vaccines"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e70113","DOI":"10.1111\/irv.70113","article-title":"An Overview of the H5N1 mRNA Vaccine Pipeline","volume":"19","author":"Focosi","year":"2025","journal-title":"Influenza Other Respir. Viruses"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1097\/AOG.0000000000004166","article-title":"Evaluating the Association of Stillbirths After Maternal Vaccination in the Vaccine Safety Datalink","volume":"136","author":"Panagiotakopoulos","year":"2020","journal-title":"Obstet. Gynecol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1016\/j.jpeds.2014.01.037","article-title":"Maternal influenza vaccine and risks for preterm or small for gestational age birth","volume":"164","author":"Nordin","year":"2014","journal-title":"J. Pediatr."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1097\/AOG.0b013e3182a1118a","article-title":"Inactivated influenza vaccine during pregnancy and risks for adverse obstetric events","volume":"122","author":"Kharbanda","year":"2013","journal-title":"Obstet. Gynecol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1097\/AOG.0b013e318279f56f","article-title":"Trivalent inactivated influenza vaccine and spontaneous abortion","volume":"121","author":"Irving","year":"2013","journal-title":"Obstet. Gynecol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s40264-016-0482-1","article-title":"Surveillance of Adverse Events After Seasonal Influenza Vaccination in Pregnant Women and Their Infants in the Vaccine Adverse Event Reporting System, July 2010\u2013May 2016","volume":"40","author":"Moro","year":"2017","journal-title":"Drug Saf."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1016\/j.acap.2024.06.019","article-title":"Reflections on the Advisory Committee on Immunization Practices During the COVID-19 Pandemic","volume":"24","author":"Poehling","year":"2024","journal-title":"Acad. Pediatr."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"6456","DOI":"10.1016\/j.vaccine.2023.07.037","article-title":"A summary of the Advisory Committee for Immunization Practices (ACIP) use of a benefit-risk assessment framework during the first year of COVID-19 vaccine administration in the United States","volume":"41","author":"Wallace","year":"2023","journal-title":"Vaccine"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Cox, E., Sanchez, M., Taylor, K., Baxter, C., Crary, I., Every, E., Futa, B., and Adams Waldorf, K.M. (2023). A Mother\u2019s Dilemma: The 5-P Model for Vaccine Decision-Making in Pregnancy. Vaccines, 11.","DOI":"10.3390\/vaccines11071248"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e2459","DOI":"10.1002\/bdr2.2459","article-title":"Vaccines in Pregnancy: An Update on Recommendations From CDC\u2019s Advisory Committee on Immunization Practices","volume":"117","author":"Rasmussen","year":"2025","journal-title":"Birth Defects Res."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/18\/2\/212\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T10:12:22Z","timestamp":1770372742000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/18\/2\/212"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,6]]},"references-count":55,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["v18020212"],"URL":"https:\/\/doi.org\/10.3390\/v18020212","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,6]]}}}