H1N1 Influenza in Pregnancy
WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers.
Educational grant provided by Women's Health and Education Center (WHEC).
Current data from World Health Organization (WHO) suggests that the influenza A/H1N1 (swine flu) pandemic is now inevitable and unstoppable. Evidence shows the new H1N1 virus spread occurred in less than six weeks rather than six months as in past pandemics. Centers for Disease Control and Prevention (CDC) first identified cases of respiratory infection with a novel influenza A (H1N1) virus in the United States on April 15 and 17, 2009. During seasonal influenza epidemics and previous pandemics, pregnant women have been at increased risk for complications related to influenza infection. In addition, maternal influenza virus infection and accompanying hyperthermia place fetuses at risk for complications such as birth defects and preterm birth. As part of surveillance for infection with the novel influenza A (H1N1) virus, CDC initiated surveillance for pregnant women who were infected with the novel virus. As of 10 May 2009, a total of 20 cases of novel influenza A (H1N1) virus infection had been reported among pregnant women in the United States, including 15 confirmed cases and five probable cases. Among the 13 women from seven states for whom data are available, the median age was 26 years (range: 15-39 years); three women were hospitalized, one of whom died. The challenge these viruses present to the healthcare community is that they are virtually impossible to distinguish from one another based solely on symptoms. Correct diagnosis is dependent on a laboratory test, in most cases.
This document provides review of novel influenza A (H1N1) virus infection in pregnant women. Pregnant women with confirmed, probable, or suspected influenza A (H1N1) virus infection should receive antiviral treatment. Given the potential for rapidly worsening disease, close follow-up is recommended. The healthcare provider prescribing treatment should plan to contact patients on treatment within the first 24 hours of therapy to evaluate response. This review adds to a growing body of data that supports the notion that pregnant women may be both susceptible to and exhibit more severe symptoms with H1N1 influenza than is seen in non-pregnant patients (1).
Human infections with a novel influenza A (H1N1) virus that is easily transmissible among humans were first identified in April 2009. Severe illnesses among pregnant women and infants have been reported in this outbreak. Although the epidemiology and spectrum of illness among pregnant woman and infants are not fully understood at this time and are under investigation. However, evidence that influenza can be more severe in pregnant women is available from observations during previous pandemics and from studies among pregnant women who had seasonal influenza (2). An excess of influenza-associated deaths among pregnant women were reported during the pandemics of 1918--1919 and 1957--1958. Adverse pregnancy outcomes have been reported following previous influenza pandemics, with increased rates of spontaneous abortion and preterm birth reported, especially among women with pneumonia. Case reports and several epidemiologic studies conducted during inter-pandemic periods also indicate that pregnancy increases the risk for influenza complications for the mother and might increase the risk for adverse perinatal outcomes or delivery complications.n
The H1N1 influenza pandemic is having far-reaching effects, with a wide range of disease presentations. Influenza-like illness is defined as fever and cough or sore throat. Other common symptoms include rhinorrhea, headache, shortness of breath, and myalgias, with vomiting and diarrhea (3). Although many patients will fall into this category, especially if presumptively treated. Moderately ill patients with influenza may rapidly worsen. Influenza A infections in pregnancy have been associated with adverse maternal and neonatal outcomes, including preterm labor, preterm birth, pneumonia, adult respiratory distress syndrome, and most seriously, overwhelming maternal illness and death. The rate of hospital admission for H1N1 in pregnant women is much higher than for non-pregnant women.
Given the highly infectious nature of H1N1, our recommendation is to evaluate symptomatic patients, and isolate them from other pregnant patients. Safe telephone triage is highly dependent on this patient population, their access to healthcare, and their ability to reliable follow up. Telephone triage should be used quite cautiously with a low-threshold for in-person evaluation, preferably in a general medical clinic or urgent care or emergency department with obstetric consult. Any patient with obstetric complaints should be evaluated on labor and delivery unit; a mask should be worn by the patient and immediate respiratory droplet precautions should be taken. Risk factors for severe disease, which also have been noted in non-pregnant patients include: obesity, low socioeconomic status, active or past tobacco use, third-trimester gestation, and underlying cardiac disease (4). In contrast to previous influenza epidemics, children, young adults, and obese patients have been widely reported to bear a disproportionate burden of disease caused by H1N1 influenza. Pregnant women, however, have been known to be at increased risk with previous influenza epidemics, as is being seen this pandemic of H1N1 disease.
Viruses are, if anything else, unpredictable. The 2008-2009 cold and flu season was tracking to be a relatively mild one -- pretty uneventful except for the circulation of the oseltamivir (Tamiflu)-resistant strain of influenza. And then the month of April introduced us to 2009 influenza A H1N1, or swine flu. With the emergence of new pathogens, such as the new H1N1 and antiviral-resistant viruses, it is increasingly important for us to accurately diagnose patients so we can better monitor the viruses circulating throughout our healthcare facilities and communities. Benefits of accurate detection of respiratory viruses include: improved patient care; reduced unnecessary use of medication; decreased medical procedures and expenses; prevention of hospital-acquired infection.
During influenza season, testing should occur in the following persons if the result will influence clinical management (5):
- Outpatient immunocompetent persons of any age at high risk of developing complications of influenza (e.g., hospitalization or death) presenting with acute febrile respiratory symptoms, within 5 days after illness onset, when virus is usually being shed;
- Outpatient immunocompromised persons of any age presenting with febrile respiratory symptoms, irrespective of time since illness onset, because immunocompromised persons can shed influenza viruses for weeks to months;
- Hospitalized persons of any age (immunocompetent or immunocompromised) with fever and respiratory symptoms, including those with a diagnosis of community-acquired pneumonia, irrespective of time since illness onset;
- Elderly persons and infants presenting with suspected sepsis or fever of unknown origin, irrespective of time since illness onset;
- Children with fever and respiratory symptoms presenting for medical evaluation, irrespective of time since illness onset;
- Persons of any age who develop fever and respiratory symptoms after hospital admission, irrespective of time since illness onset;
- Immunocompetent persons with acute febrile respiratory symptoms who are not at high risk of developing complications secondary to influenza infection may be tested for purposes of obtaining local surveillance data.
At any time of the year, testing should occur for the following persons:
- Health care personnel, residents, or visitors in an institution experiencing an influenza outbreak who present with febrile respiratory symptoms, within 5 days after illness onset;
- Persons who are epidemiologically linked to an influenza outbreak (e.g., household and close contacts of persons with suspected influenza, returned travelers from countries where influenza viruses may be circulating, participants in international mass gatherings, and cruise ship passengers), who present within 5 days after illness onset.
Today, we have a wealth of tools at our disposal to identify respiratory viruses. Until recently, methods available to detect and identify respiratory viruses were too slow and cumbersome to make them valuable tools. In the last couple of years, however, more timely and accurate tests have been introduces. The available testing methods include the following:
- Cell Culture: it is the most traditional approach to identifying respiratory viruses where cells are grown under controlled conditions. Although proven to be accurate, the test can require up to 14 days for results.
- Direct Fluorescent Antibody (DFA): it is a laboratory test that uses antibodies with fluorescent dye to detect the presence of viruses. This test does not detect the full range of viruses that commonly cause respiratory illness, lacks great sensitivity, and cannot indentify dual infections. However, it can have a sensitivity equivalent to viral culture (98%) when an adequate sample is collected (6).
- Enzyme Immunoassay (EIA): these techniques are traditional methods that work to detect the viral antigen; however, EIA methods are available for only a limited number of pathogens.
- Rapid Pathogen Test: rapid flu test are the most common of the rapid tests. Widely available and usually easy to use, rapid tests use antibodies to detect protein from the virus. These tests can give results in a matter of minutes and are inexpensive; without using great care in performing the test, particularly to diagnose H1N1, the results can be skewed. The sensitivity of rapid antigen testing has been reported as low as 30% with specificity as low as 58% in some studies (6).
- Polymerase Chain Reaction (PCR): it is a technique that reproduces and analyzes a short sequence of DNA in order to detect viruses. Sensitive and specific, PCR-based tests can detect respiratory viruses and can accurately identify a number of respiratory viruses as well as detect dual and triple infections (6). These tests can take several hours to run, but most can provide results in less than 24 hours.
There is no evidence that repeat testing to indicate the presence or absence of continued viral shedding is indicated if the patient is clinically improving. Given these test characteristics and the potential for aggressive and severe disease, our recommendation is, an increased index of suspicion for H1N1 influenza in women with influenza-like illness in pregnancy, even with negative rapid antigen or direct fluorescence antibody testing. During the coming influenza season, when the incidence of H1N1 is anticipated to be high, patients with influenza-like illness in pregnancy should be diagnosed and treated presumptively on the basis of symptoms alone.
Influenza Vaccination during Pregnancy:
Influenza vaccination is an essential element of prenatal care. The American College of Obstetricians and Gynecologists (ACOG) Committee on Obstetric Practice supports the Centers for Disease Control and Prevention (CDC)'s expanded recommendation that women who will be pregnant during the influenza season (October through mid May) should be vaccinated (7). The ideal time to administer the vaccine is October and November; however, it is appropriate to vaccinate patients throughout the influenza season as long as the vaccine supply lasts. This intramuscular, inactivated vaccine may be used in all 3 trimesters. One study of influenza vaccination of more than 2,000 pregnant women demonstrated no adverse fetal effects associated with influenza vaccination (7). Any theoretical risk of the vaccination is out-weighted by its benefits. Likewise, the benefits of the vaccine outweigh any unproven potential concerns about traces of thimerosal preservative, which exist only in the multidose vials. It should be noted that the intranasal vaccine spray contains a live, attenuated virus and should not be used during pregnancy.
The CDC has listed pregnant women as a priority group for vaccination, along with children and healthcare workers. Public health authorities are working to make the vaccine available for distribution and administration in October 2009. Practitioners should implement vaccination programs for their patients as vaccine for H1N1 strain of influenza becomes available. Immunizing pregnant women also confers protection to their infants; this is important consideration because infants' aged 0-6 months do not respond to the influenza vaccine. Breastfeeding is not a contraindication for vaccination. Antiviral agents should not be used as a substitute for influenza vaccination.
In all clinical settings, including settings that provide care for pregnant women, patients should be screened for signs and symptoms of febrile respiratory illness at the initial point of contact, and these patients should be promptly segregated and assessed. Outpatient clinical settings and labor and delivery units should develop and implement procedures for handling patients with respiratory illness and friends or family members who might accompany them. Pregnant women who are in close contact with a person who has a confirmed, probable, or suspected case should receive a 10-day course of chemoprophylaxis with zanamivir or oseltamivir. For chemoprophylaxis in pregnant patients, a preferred anti-influenza medication has not been determined. Although zanamivir might have the benefit of more limited systemic absorption, respiratory symptoms such as coughing or severe nasal congestion might limit its usefulness because of its inhaled route of administration.
Oseltamivir is the preferred treatment for pregnant women, and the drug regimen should be initiated within 48 hours of symptom onset, if possible (8). Pregnant women who are in close contact with a person with confirmed, probable, or suspected novel influenza A (H1N1) infection should receive a 10-day course of chemoprophylaxis with zanamivir or oseltamivir. The novel influenza A (H1N1) virus that is circulating is susceptible to the neuraminidase inhibitor antiviral medications, oseltamivir and zanamivir. In randomized, placebo-controlled trials among outpatients, these medications have reduced the severity and duration of symptoms of seasonal influenza if started within 48 hours of illness onset, and limited data from observational studies among hospitalized patients with seasonal influenza indicate that oseltamivir can reduce mortality, even when started >48 hours after illness onset. In addition, oseltamivir and zanamivir have been highly effective in preventing seasonal influenza if used shortly after exposure to the disease. Little information is available on the safety or effectiveness of these medications when used during pregnancy. However, considering the limited information available and the known risks for influenza complications during pregnancy, any potential risk to a fetus likely is outweighed by the expected benefits of influenza antiviral treatment for this novel virus. Thus, CDC interim guidance indicates that pregnant women with confirmed, probable, or suspected novel influenza A (H1N1) virus infection should receive antiviral treatment for 5 days.
Oseltamivir, a neuraminidase inhibitor, prohibits progeny virions from being released from infected cells (9). The standard adult dose for influenza A is 75 mg twice daily for 5 days. Additional considerations for the dosing of oseltamivir in pregnancy include the increased glomerular filtration rate normally seen in pregnancy. Few data exist regarding the effect of normal physiology of pregnancy on plasma concentrations of this drug. However, because this drug is cleared by the kidney, it is plausible that lower circulating concentrations of the drug may be seen in pregnant women. In acutely ill patients requiring assisted ventilation, these data have helped guide the practice to increase oseltamivir dosing to 150 mg twice daily, orally for a total of 10 days. This increased dosing regimen is only being used for patients presenting with or developing severe disease (9).
The current CDC guidelines are:
|75-mg capsule twice per day for 5 days||75-mg capsule once per day for 10 days|
|Two 5-mg inhalations (10 mg total) twice per day for 5 days||Two 5-mg inhalations (10 mg total) once per day for 10 days|
Although zanamivir can be used in pregnancy, oseltamivir is preferred for treatment of pregnant women because of its systemic absorption. Theoretically, higher systemic absorption might suppress influenza viral loads more effectively in sites other than the respiratory system (e.g., placenta) and might provide better protection against mother-child transmission. Similar to the recommendation for non-pregnant personswho are treated, oseltamivir treatment should be initiated as soon as possible, ideally within 48 hours of onset of symptoms (1)(3). In addition, any pregnant woman hospitalized with confirmed, probable, or suspected novel influenza A (H1N1) virus infection should receive oseltamivir, even if >48 hours have elapsed since illness onset. Beginning treatment as early as possible is critical. In addition, treating fevers in pregnant women with acetaminophen is important because maternal hyperthermia has been associated with various adverse fetal and neonatal outcomes.
Maternal and Fetal Complications from Influenza:
In acutely ill pregnant patients the following complications have been reported: adult respiratory distress syndrome, super-imposed bacterial pneumonia, renal failure, pulmonary embolus, and maternal death. The increased minute ventilation, reduced tidal volumes, and decreased functional residual capacity of normal pregnancy physiology leave less reserve capacity for significant stress on pulmonary function. Although the immune system perturbations in pregnancy that may account for increased severity of disease are poorly understood, recent research posits that cyto-toxic T-cells and dendritic cell changes may help explain the observed alterations in the maternal systemic immune response (10). Significant volume overload can contribute to worsening of respiratory status. The decreased colloidal oncotic pressure in the third trimester of normal gravid patients when compared with normal non-gravid patients supports the increased propensity for severe respiratory complications during the third trimester. Decreased oncotic pressure predisposes gravid women to develop pulmonary edema. Careful attention to fluid status and aggressive diuresis significantly improves the respiratory status in patients. Venous thromboembolism events have also been reported in the case reports and deserve special attention in pregnant and postpartum critically ill patients as physiologic hypercoagulability compounded by immobilization predisposes these patients to this complication (3).
At this time there have been no reported cases of placental transmission of the virus. Fetal complications are related to the perturbations in maternal physiology and the accompanied fetal stress response. These can include preterm premature rupture of membranes, preterm labor, and preterm birth. Acute pyrexia and hypoxia can be associated with fetal tachycardia, minimal variability, and late decelerations of the fetal heart rate. In acutely ill patients, early administration of steroids for fetal lung maturity is recommended, because the potential for preterm birth is high (9). For patients with mild disease, antipyretics and close follow-up to ensure response to treatment are recommended.
Infant feeding considerations:
Infants who are not breastfeeding are more vulnerable to infection and hospitalization for severe respiratory illness than infants who are breastfeeding. Women who are not ill with influenza should be encouraged to initiate breastfeeding early and feed frequently. Ideally, babies should receive most of their nutrition from breast milk. Eliminate unnecessary formula supplementation, so the infant can receive as much maternal antibodies as possible. Infants are thought to be at higher risk for severe illness from novel influenza A (H1N1) infection and very little is known about prevention of novel H1N1 flu infection in infants (1)(3). If possible, only adults who are not sick should care for infants, including providing feedings. The risk for novel influenza A (H1N1) transmission through breast milk is unknown. However, reports of viremia with seasonal influenza infection are rare, which suggests that the risk of virus crossing into breast milk is also probably rare. Sick women who are able to express their milk for bottle feedings by a healthy family member should be encouraged to do so. Antiviral medication treatment or prophylaxis is not a contraindication for breastfeeding. Careful adherence to hand hygiene and cough etiquette is critical, especially for sick women who do not have anyone to help with infant care while they are ill. Women with influenza-like illness are recommended to use facemasks when providing infant care and feedings. Instruct parent and caretakers on how to protect their infant from the spread of germs, like influenza A (H1N1) virus, that cause respiratory illnesses:
- Practice hand hygiene and cough etiquette at all times
- Keep the infant away from persons who are ill and out of crowded areas.
- Limit sharing of toys and other items that have been in infants' mouths. Wash thoroughly with soap and water any items that have been in infants' mouths.
H1N1 Influenza and Public Health Preparedness:
In December 2009, the Department of Health and Human Services will present to Congress, its first-ever national health security strategy, outlining high-priority activities and areas of investment for strengthening the capability of the United States to prepare for, respond to, and recover from large-scale public health emergencies. Fortunately the strategy is being developed in parallel with a national debate over health care reform, since national health security will not be achievable without key elements of reform. These elements include: an effective focus on prevention and wellness, universal access to needed care, widespread deployment of health information technology, changes in organization of and payment for care, and research on comparative effectiveness. Early detection of a new infectious disease -- and potentially the survival of those who are infected -- requires that sick people have access to health care system and receive early treatment. Delays in seeking care can lead to delays in the recognition and control of epidemic and in the treatment of patients. Indeed, experts have hypothesized that one reason the mortality associated with the current epidemic of swine-origin influenza A (H1N1) virus (S-OIV) was so high in Mexico is that, many people were delayed in seeking care, in part because of its cost (11). In the United States, lack of health insurance is a key reason for delays in seeking care; health care reform that results in universal coverage would facilitate earlier detection of new diseases, enable disease-control efforts to be efforts to be instituted, and alleviate the population's vulnerability that is attributable to delayed care.
In the event of a large-scale health emergency such as an influenza pandemic, the health care system will experience unprecedented demand. Determining how to retain, and pay for the capacity to "surge" in such an event is a critical aspect of health preparedness; it is particularly challenging, however, because one way to achieve the cost-containment goal of health care reform is to shift care from expensive inpatient settings to less expensive outpatient setting (12). New approaches, including self-triage guidelines, remote monitoring devices, and telemedicine, support such shifts in the delivery of care. Research suggests that building excess emergency-department and inpatient capacity as a sort of insurance policy may not be a sound approach and will only increase health care expenditures. Currently, we are far from allocating our resources with maximum efficiency, even in the absence of a large-scale emergency. A U.S. health security strategy will need to build on, and take full advantage of core components of a reformed health care system.
Viral respiratory infections are important causes of maternal morbidity and mortality. Missed infections can cause additional medical complications, nosocomial infections, and prolonged hospital stays, contributing to unnecessary healthcare costs as well as increased patient morbidity and mortality. Inaccurate diagnosis resulting in overuse of medications is also of particular concern. Accurate identification of the pathogen -- or pathogens -- infecting a patient is essential in order to take effective clinical action, contain the spread of infection, and contribute to public health surveillance efforts. The influenza vaccination may be used in all 3 trimesters. The paucity of data regarding the safety profile of oseltamivir in pregnancy and lactation makes over-treatment of pregnant and nursing women unappealing. However, in the light of the severity of disease and serious morbidity and mortality complicating severe cases, we suggest to follow the Center for Disease Control and Prevention (CDC)'s recommendations and feel that the benefits outweigh the theoretical harms of treatment in this population. Ideally, treatment should be initiated within the first 48 hours of influenza symptoms for maximal benefit. Neither negative rapid test results nor mild initial presentations should delay the treatment. All pregnant women with suspected influenza should be prescribed treatment with oseltamivir. Treatment should not be withheld in gravid patients who represent with febrile illness consistent with influenza outside of the 48 hours window, because treatment even at a later stage may prevent more serious complications such as bacterial pneumonia. With the right approach, health care reform could facilitate vast improvements in our ability to respond to and recover from large-scale health emergencies, such as H1N1 flu pandemic.
- World Health Organization (WHO)
Pandemic influenza vaccines: current status
- Centers for Disease Control and Prevention (CDC)
Pregnant Women and Novel Influenza A (H1N1) Virus: Consideration for Clinicians
- National Institutes of Health (NIH)
H1N1 Flu (Swine Flu)
- Centers for Disease Control and Prevention (CDC). Intensive-care patients with severe novel influenza A (H1N1) virus infection -- Michigan, June 2009. MMWR Morb Mortal Wkly Rep 2009;58:749-752
- Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003; 289:179-186
- Centers for Disease Control and Prevention. H1N1 flu. Available at: http://www.cdc.gov/h1n1flu/surveillanceqa.htm Accessed on September 30, 2009
- Jamieson DJ, Honein MA, Rasmussen SA et al. H1N1 influenza virus infection during pregnancy in USA. Lancet 2009;374:451-458
- Fiore AE, Shay DK, Broder K, et al. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008. MMWR Recomm Rep 2008; 57(RR-7):1--60
- Ruest A, Michaud S, Deslandes S et al. Comparison of the Directigen flu A+B test, the QuickVue influenza test, and clinical case definition to viral culture and reverse transcription-PCR for rapid diagnosis of influenza virus infection. J Clin Microbiol 2003;41:3487-3493
- ACOG Committee on Obstetric Practice. ACOG committee opinion number 305, November 2004. Influenza vaccination and treatment during pregnancy. Obstet Gynecol 2004;104:1125-1126
- Ward P, Small I, Smith J et al. Oseltamivir (Tamiflu) and its potential for use in the event of influenza pandemic. J Antimicrob Chemother 2005;55suppl:5-21
- Saleeby E, Chapman J, Morse J et al. H1N1 influenza in pregnancy; cause for concern. Obstet Gynecol 2009;114:885-891
- Gonzalez JM, Ofori E, Burd I et al. Maternal mortality from systemic illness: unraveling the contribution of the immune response. Am J Obstet Gynecol 2009;200:430.e1-8
- Lacy M, Malkin E. First flu death provides clues to Mexico toll. New York Times April 30, 2009
- Lurie N. H1N1 influenza, public health preparedness, and health care reform. N Engl J Med 2009;361:843-845
Dedicated to Women's and Children's Well-being and Health Care Worldwide