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Zika Virus: Obstetric and Pediatric Anesthesia Considerations

Tutiven, Jacqueline L. MD*; Pruden, Benjamin T. MD; Banks, James S. MD; Stevenson, Mario PhD§; Birnbach, David J. MD, MPH

doi: 10.1213/ANE.0000000000002047
Obstetric Anesthesiology: Special Article
Continuing Medical Education

As of November 2016, the Florida Department of Health (FDH) and the Centers for Disease Control and Prevention have confirmed more than 4000 travel-related Zika virus (ZIKV) infections in the United States with >700 of those in Florida. There have been 139 cases of locally acquired infection, all occurring in Miami, Florida. Within the US territories (eg, Puerto Rico, US Virgin Islands), >30,000 cases of ZIKV infection have been reported. The projected number of individuals at risk for ZIKV infection in the Caribbean and Latin America approximates 5 million. Similar to Dengue and Chikungunya viruses, ZIKV is spread to humans by infected Aedes aegypti mosquitoes, through travel-associated local transmission, via sexual contact, and through blood transfusions. South Florida is an epicenter for ZIKV infection in the United States and the year-round warm climate along with an abundance of mosquito vectors that can harbor the flavivirus raise health care concerns. ZIKV infection is generally mild with clinical manifestations of fever, rash, conjunctivitis, and arthralgia. Of greatest concern, however, is growing evidence for the relationship between ZIKV infection of pregnant women and increased incidence of abnormal pregnancies and congenital abnormalities in the newborn, now medically termed ZIKA Congenital Syndrome. Federal health officials are observing 899 confirmed Zika-positive pregnancies and the FDH is currently monitoring 110 pregnant women with evidence of Zika infection. The University of Miami/Jackson Memorial Hospital is uniquely positioned just north of downtown Miami and within the vicinity of Liberty City, Little Haiti, and Miami Beach, which are currently “hot spots” for Zika virus exposure and transmissions. As the FDH works fervently to prevent a Zika epidemic in the region, health care providers at the University of Miami and Jackson Memorial Hospital prepare for the clinical spectrum of ZIKV effects as well as the safe perioperative care of the parturients and their affected newborns. In an effort to meet anesthetic preparedness for the care of potential Zika-positive patients and perinatal management of babies born with ZIKA Congenital Syndrome, this review highlights the interim guidelines from the Centers for Disease Control and Prevention and also suggest anesthetic implications and recommendations. In addition, this article reviews guidance for the evaluation and anesthetic management of infants with congenital ZIKV infection. To better manage the perioperative care of affected newborns, this article also reviews the comparative anesthetic implications of babies born with related congenital malformations.

From *Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, Florida; Jackson Memorial Hospital, Miami, Florida; Department of Radiology, University of Miami Miller School of Medicine, Miami, Florida; §Division of Infectious Diseases, Department of Medicine, University of Miami, Miami Miller School of Medicine, Miami, Florida; and UM-JMH Center for Patient Safety, Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, Florida.

Funding: None.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to David J. Birnbach, MD, MPH, UM-JMH Center for Patient Safety, Department of Anesthesiology, University of Miami Miller School of Medicine, 1611 NW 12th Ave, Miami, FL 33136. Address e-mail to dbirnbach@miami.edu.

Within the US territories, >30,000 cases of Zika virus (ZIKV) infection have been reported.1 ZIKV and other flaviviruses, including Dengue, West Nile Virus as well as the alphavirus Chikungunya, are single-stranded ribonucleic acid (RNA) viruses that are transmitted by mosquito vectors and cause disease in humans.2 Federal health officials are observing 899 confirmed Zika-positive pregnancies and the Florida Department of Health is currently monitoring 110 pregnant women with evidence of ZIKV infection.3 After its initial discovery in the Zika forest in Uganda in 1947, ZIKV did not receive much early attention; up until 2007, only 14 cases of human disease were known. In the past 10 years, ZIKV outbreaks have affected populations in the Yap Island (where since 2007, three-fourths of the Island’s residents have been infected), French Polynesia (2013), and Brazil (2015). As opposed to previous outbreaks, the latest outbreak has given rise to an epidemic that is sweeping across South and Central America and the Caribbean. The ZIKV has 2 lineages: African and Asian, with the Asian lineage being responsible for the recent outbreaks in the Americas.4 Infection by ZIKV usually presents itself clinically with a mild exanthematous rash, conjunctivitis, arthralgia, and fever. However, many infected persons are asymptomatic. Although typically self-limiting, studies now suggest an association between ZIKV infection and Guillain–Barré syndrome. Researchers are finding that symptoms of Guillain–Barré syndrome may appear contiguous with an active ZIKV infection (parainfectious).5,6 Documented modes of infection include transmission via sexual contact, mother to fetus, and blood. There have been no reports of transmission via breast milk, urine, or saliva.2 Even more alarming, maternal–fetal transmission of ZIKV has causally been linked to babies born with microcephaly, cerebral calcifications, and intrauterine growth restriction.7,8 There is no specific treatment for ZIKV infection. Rest, fluids, and acetaminophen are recommended for generalized symptoms and fever. However, because symptomatology from Zika is not distinct and can be seen with other flaviviruses including dengue, the use of nonsteroidal anti-inflammatory drugs and aspirin is generally contraindicated in these pregnant women until dengue is ruled out because of the high risk for hemorrhagic complications and the premature closure of the ductus arteriosus when >32 weeks’ gestation.9

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THE PARTURIENT

Perinatal Transmission

Studies in pregnant macaque monkeys using the Asian ZIKV strain have found prolonged persistence of ZIKV and have hypothesized a plausible “feedback loop” scenario to explain prolonged maternal–fetal infectivity.10 Animal studies have demonstrated placental infection with injury, findings suggestive of placental insufficiency. Pathologic evaluations of placentas from planned terminations of pregnancies and miscarriages of ZIKV-infected fetuses have also shown heterogeneous injury, inflammation, and calcification. Recent data from a cohort study of 88 symptomatic expectant mothers in Brazil revealed that 82% were positive for ZIKA RNA. Fetal lesions independent of gestational age on exposure and fetal growth restrictions were noted. In addition, as compared to other in utero infections, late gestational infections with Zika were at risk of placental insufficiency and fetal death.11

Table 1

Table 1

Serum and urine samples in symptomatic pregnant women were tested for evidence of acute ZIKV infection (within 2 weeks of illness) with the Centers for Disease Control and Prevention (CDC) trioplex real-time reverse transcription-polymerase chain reaction (rRT-PCR). Although a figure outlining anti-Zika virus immune responses (IgG, IgM, CD8 T-cell responses) would be informative, as of yet there are no published studies detailing how these responses develop after acute infection. Table 1 summarizes the CDC recommendations for managing pregnant women suspected of possible ZIKV infection. ZIKV RNA decreased in serum within the first week of illness but remained detectable in urine for at least 2 weeks after symptoms had subsided. It has therefore been recommended that asymptomatic pregnant women in risk “zones” or with exposure history should undergo ZIKV testing with rRT-PCR along with a Zika IgM antibody capture enzyme-linked immunosorbent assay (MAC-ELISA) test that is a qualitative screen for anti-Zika immunoglobulin M (IgM). IgM class antibodies to ZIKV are detectable in serum 3–5 days after appearance of symptoms and remain detectable for approximately 12 weeks. Therefore, monitoring for ZIKV infection should be part of the routine prenatal care for pregnant women living in active Zika zones, especially during the first and second trimesters. A positive Zika MAC-ELISA should be followed up with a rRT-PCR for presumptive diagnosis and direct perinatal care. Presumptive positive assays should be ultimately confirmed with a plaque reduction neutralization test, a gold standard for characterizing and quantifying serum levels of virus-specific neutralizing antibodies to ZIKV. A negative screening in pregnant women with a history of possible exposure should be followed up with a repeat Zika MAC-ELISA at 16–24 weeks’ gestation to confirm a maternal infection. There is, however, crossreactivity with other flaviviruses, especially dengue.9 Because false-positive results can occur in patients with a history of flavivirus infections, pregnant women with a positive or equivocal Zika virus IgM antibody test will need further confirmation by plaque reduction neutralization test. Of note, a negative rRT-PCR with a negative IgM in women with clinical and epidemiologic criteria, or who present more than 12 weeks from a possible exposure, does not rule out ZIKV infection and serial fetal ultrasounds are recommended.9 The CDC recommends that all pregnant women who have traveled to or live in endemic areas undergo Zika serology testing and serial fetal ultrasound screenings. In utero transmission exists throughout pregnancy, and therefore, the prolonged maternal viremia underscores the need for testing beyond disappearance of symptoms.

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Obstetric Outcomes and Anesthetic Implications

Case series from Brazil have determined that ZIKV infections in parturients have been associated with miscarriages, but the rate of preterm delivery has not been shown to differ from that of standard rates for preterm births in that country.12 Further investigation of stillbirths, spontaneous abortions, and preterm deliveries in relation to perinatal ZIKV infection are warranted. Virology studies on postmortem fetuses have reported the highest viral loads in fetal brain tissue followed by placenta, fetal membranes, umbilical cord, and amniotic fluid; reduced loads were found in solid organs.13 It can be inferred that viremia in newborns is high for a variable amount of time. Health care providers and workers can be at increased risk of occupational exposure to the virus in these settings.

Although somewhat controversial, neuraxial anesthesia or analgesia may be relatively contraindicated in ZIKV-infected parturients during active infection. The very nature of this neurotrophic virus suggests that iatrogenic crossing of the blood–brain barrier during neuraxial blockade is not a real problem. That said, the lack of clinical data as well as its possible link to increased central nervous system (CNS) inflammatory states with Guillain–Barré syndrome creates a potential risk that merits discussion when acquiring informed consent from the parturient. Regarding placement of epidurals in pregnant women with ZIKV infection or postponing cesarean delivery in an infected parturient, the CDC is not aware of any changes in obstetric–gynecologic practice in the United States. Existing policies may vary from hospital to hospital in relation to operational procedures in the face of a parturient with an active bloodborne pathogen in assuring that health care personnel adhere to The National Institute for Occupational Safety and Health standards.

Thrombocytopenia and leukopenia have also been noted in patients with coinfection by Dengue or Chikungunya virus along with elevation in liver transaminases; as such, preprocedural hematologic assay in a parturient with acute or subacute symptoms of Zika should be performed to provide risk assessment for placement of neuraxial blocks.14,15 Should a labor epidural catheter be offered to a symptomatic ZIKV-positive parturient with fever? Evidence of the probability for ZIKV viremia in a parturient is verified through serologic (IgM antibodies) and urine testing (RT-PCR). Unless markedly abnormal, elevated white blood cell count is irrelevant because this is a common finding in laboring women. While somewhat controversial, it has been reported that maternal inflammatory fevers have been associated with neonatal encephalopathies and neurocognitive effects; active infection or chorioamnionitis should be ruled out.16,17

The need for blood transfusion in the labor or peripartum period may arise, and it should be noted that there have been cases reported of ZIKV transmission through blood transfusions.18 To date, there is no Food and Drug Administration (FDA)-licensed assay to test for ZIKV in donated blood; there is, however, application of 2 investigational new tests being used on the supply of donated blood in the United States and Puerto Rico. Blood donations that test positive for ZIKV RNA with these are being removed from the blood supply.19 In view of the fact that ZIKV may be present in asymptomatic blood donors, measures are in place in high-risk areas to avoid the possibility of ZIKV transmission to recipients of blood transfusion. ZIKV can be transmitted postnatally in infants, and clinical guidance for their testing is offered by the CDC. A framework for the reporting, investigating, and tracking of all potential infectious disease transmission through a transfusion is facilitated by the Investigational Toolkit: Transfusion-Transmitted Infections overseen by the CDC. While blood collection centers comply with the AABB criteria to uphold transfusion safety for blood recipients, pathogen inactivation can be used to inactivate ZIKA in fresh frozen plasma and platelets. Amotosalen, commercially known as Psoralen, irreversibly blocks the replication of RNA and DNA of susceptible pathogens. When combined with ultraviolet A illumination, it promotes inactivation of ZIKV in plasma and platelets.20 This pathogen reduction treatment in blood components is currently deemed as an acceptable safety measure by the FDA. The FDA’s new recommendation for universal Zika risk reduction allows US blood centers a choice of testing blood donations for ZIKV RNA or adding an additional layer of safety by treating platelets and plasma with specialized pathogen inactivation technology. In Florida, OneBlood, a major distributor of blood products to >200 hospitals, acquired the pathogen inactivation technology in late 2015.20,21

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Perinatal Standard Precautions and Maintaining Infection Control

Olson et al22 detailed the importance of preventing ZIKV transmission in the labor and delivery suite.22 Anesthesia providers, who are at risk of exposure when performing neuraxial labor analgesia or anesthesia for cesarean delivery, should adhere to (1) strict hand hygiene; (2) use of double gloving; (3) proper handling of sharps; (4) surgical masks with eye shields; (5) impermeable gowns; and (6) wearing of knee-high impermeable shoe covers when participating in obstetric procedures. Although this list may appear obvious, they are not always performed by anesthesia personnel.23 To date, there has been no transmission of ZIKV in the health care setting; however, there has been 1 case of transmission in a laboratory worker in the United States.2 Occupational exposure to bloodborne pathogens is considered an urgent medical concern and prompt reporting and management of occupational exposure adheres to the National Institute of Occupational Safety and Health and state requirements (Appendix 1). No special precautions are recommended with other fluids such as breast milk, saliva, or urine, because no reports have been documented for its spread via these mechanisms.24

In vitro studies in mammalian cell culture assays for drug development platforms have demonstrated type I and II interferons, especially interferon-α, as having strong antiviral activity against ZIKV.25 Antiviral interferon-α for postexposure prophylaxis may be on the horizon along with a possible treatment option for high-risk groups. Contracting a bloodborne viral infection through needlesticks and laboratory exposure should be reported. ZIKV handling should conform to Biosafety level 2 guidelines and strict observation of basic standard precautions with the use of personal protective equipment during patient care and the transportation of laboratory specimens should be observed as per the Occupational Safety and Health Administration/The National Institute for Occupational Safety and Health guidelines.26,27 Splash exposure risks from maternal fluids and amniotic and placental tissue can be decreased with disposable absorbent material placed on tables and floors. This is important on labor and delivery and postpartum units because exposure risks are present even when the mother is asymptomatic.

There is very little known about the infectivity of a newborn with Zika Congenital Syndrome. ZIKV-exposed neonates maintain an active infection for >30 days and can continue to shed the virus until serologic markers return negative.28 There are case reports of infants who have shown continued viremia for up to 3 months. These cases will note positive RT-PCR and ZIKV-specific IgM in serum, urine, and saliva for up to 67 days.29 ZIKV RNA is no longer detected in 6–7 months. Since September 2016, health officials continue to warn that contact with a Zika patient’s body fluids such as tears, conjunctival discharge, saliva, urine, or stool might have been responsible for a “unique” case in Utah. This warning continues, because they are still unable to definitively identify how that person was infected.30

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Guillain–Barré Syndrome

Guillain–Barré syndrome (GBS) or acute inflammatory demyelinating polyradiculoneuropathy is currently linked to ZIKV-infected patients. This progressive motor weakness appears within 1–4 weeks of a susceptible patient’s exposure to an infectious trigger. Why ZIKV causes GBS is unknown, but immune susceptibility may play a role. Other infectious agents associated with this demyelinating inflammatory neuropathy are Mycoplasma pneumonia, Campylobacter jejuni, cytomegalovirus, and Epstein–Barr virus. Cases of GBS preceded by Dengue fever have also been reported from endemic areas.31 GBS is rare in pregnancy and may have a maternal mortality exceeding 10%.32 Chan et al reported on 30 parturients with GBS and noted that timing of disease onset was mostly in the third trimester and postpartum.33,34 Treatment is supportive along with IV immunoglobulins and plasmapheresis.35

Anesthetic risks are increased in patients with GBS. When affecting patients in their first and second trimesters, GBS usually has a stable prognosis and has been shown to allow gestation to term. Onset of GBS in the third trimester, however, may require admission to the intensive care unit for monitoring, possible intubation, and ventilator support with early prophylaxis for thromboembolism. These patients often require intubation or may even require tracheostomy for long-term care. Uterine contractions occur spontaneously, indiscriminate of the neurologic status of GBS. Elective induction of labor does not improve the neuropathy or respiratory failure and should be avoided when possible during active disease.36,37

Timely preparation for neuraxial or general anesthesia is important and goals are to reduce perioperative complications including aspiration, thromboembolism, and hypotension resulting from autonomic dysfunction. Although routinely used in healthy parturients receiving general anesthesia, the administration of succinylcholine for induction of general anesthesia is contraindicated in patients with GBS due to the upregulation of postsynaptic acetylcholine receptors that can precipitate hyperkalemia with potential cardiac arrest. Current availability of suggamadex for immediate reversal of the nondepolarizing muscle relaxant rocuronium makes for a potential path to safely securing an airway for rapid sequence induction of general endotracheal anesthesia in these patients. However, all neuromuscular-blocking agents should be used with caution in GBS to avoid prolongation of neuromuscular blockade.36–38

Table 2

Table 2

Neuraxial anesthesia or analgesia in parturients with GBS has been used with careful monitoring of any progressive or worsening of symptoms. There is no evidence that neuraxial anesthesia can cause or worsen GBS, and recovery from epidural analgesia/anesthesia without worsened postoperative neurologic symptoms has been reported in the literature.39,40 Table 2 summarizes the anesthetic considerations of ZIKV-infected parturients as detailed in the previous section.

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Naled

As of mid-September 2016, >58 countries and territories worldwide are actively reporting ZIKV transmission. Public health models of temperature and climate studies from the National Institute of Health have demonstrated how an ideal mosquito-thriving climate and conditions have continued to favor longer mosquito seasons in tropical and subtropical environments. The unprecedented spread of Zika in South Florida has officials determined to control the outbreak of these disease-carrying mosquitoes. Until Zika vaccine clinical trials are tested, aerial spraying and fumigation of Naled (Dibrom, AMVAC Chemical Corporation, Los Angeles, CA or Fly-Killer-D, Haco, Inc, Madison, WI) over Miami’s “hot zone” areas have begun along with the widespread use of a naturally occurring soil bacteria, bacillus thuringiensis israelensis, as a sprayed larvicide.

Registered since 1959, Naled is a fast-acting poison used as a short-term pest fumigant in agricultural settings, kennels, and food-processing plants. Used as an aerosolized ultra low volume (ULV) formulation, it has been applied for public health mosquito control programs without risks to humans in the past. Naled is currently being applied by air to approximately 16 million acres within the US mainland and is also deployed for mosquito control after hurricanes and floods. In small quantities, Naled has not shown to cause human health issues but is nonetheless prohibited for use in many countries. Tests at the CDC showed Naled to be 100% effective in killing female Aedes aegypti, but it is not a perfect approach. Naled degrades rapidly in environmental conditions, and at ULV particles do not kill the mosquito larvae. It degrades rapidly on exposure to ultraviolet sunlight, is insoluble in water, and resistant to being absorbed in soil particles. In addition, the ULV-aerosolized formulation needs to be sprayed weekly for an effective impact.41

Naled is an organophosphate. It interferes with cholinesterase activity at the neuromuscular motor-end plate and is moderate-to-high toxic with skin absorption if inhaled or ingested. Fumes are corrosive and will denature mucosal membranes of the mouth, throat, and lungs, ultimately affecting the CNS with untreated acute toxic exposures. Persons at risk may experience localized sweating, dermatitis, runny or bloody nasal discharges, ocular pain and excess tearing with blurred vision, chest discomfort, cough, and dyspnea. Studies by Duprey et al42 showed that Naled aerosolized fumigation did not increase risks for asthma. Naled breakdown products can be detected in serum and urine but only within a few hours of toxic exposure. Low cholinesterase levels in serum may indicate Naled exposure, but it is nonspecific.42,43 Chronic exposure to organophosphates produces a slow progressive impairment of memory and concentration, disorientation, headaches, and speech difficulty. Naled crosses the placenta, but no data are available at this time as to its teratogentic or carcinogenic effects, and the Environmental Protection Agency has classified this substance as Category E (“Evidence of noncarcinogenicity for humans”).44

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THE NEONATE

Zika Congenital Syndrome

The prevalence of CNS malformation and microcephaly in newborns was high during Zika outbreaks in French Polynesia; strong retrospective data support that there was a 1% risk of microcephaly in mothers infected with Zika during their first trimester.45 Brazil reports a 2015 overall incidence of microcephaly to be 5.7/100,000 births. The US CDC, however, believes this is an underestimation and that the incidence of microcephaly is between 10 and 20/100,000 births in Brazil. This includes those neonates affected by toxoplasma or cytomegalovirus infections.46

Zika Congenital Syndrome manifests patterns of neurologic findings that range in severity depending on the time of gestational exposure. Neuropathologic defects in the developing brain are observed as most severe in cases where exposure to the Zika virus occurred during the first trimester. Detection of Zika RNA in the amniotic fluid and findings on serial fetal ultrasonography correlate with fetal Zika infection.14,47 Hydrops fetalis has also been described as a postmortem finding, warning that other organ systems are being affected in addition to the CNS. Whether the teratogenic effects of the virus are directly caused by an infected sperm or by an infected developing placenta with compromised chorionic villi, Zika virus infiltrates neural primordial cells and the precursor to cortical neurons, radial glia cells. This compromises differentiation of neurons and astrocytes that will ultimately form the fetal cerebral cortex.48,49

Zika in utero inhibits neural cell growth. Early neural embryologic insults can result in abnormal gyrations (polymicrogyria) followed by extra-axial fluid, severe abnormalities of the midline structures, abnormality of the cerebellum, ventriculomegaly, mega cisterna magna, decreased brain parenchyma with cortical atrophy, and microcephaly as a late finding in the third trimester.48,49 Tropism of the Zika infection can affect upper and lower motor neurons, specialized ocular tissue, and auditory organs. This has been especially observed in specialized stem cells of the retina with macular neuroretinopathy on postnatal ophthalmic findings in Zika-affected infants in Brazil and in case series studies of arthrogryposis congenita seen in fetuses and newborns presumed Zika-positive.45 Although the spectrum of outcomes is not yet fully understood, these infants will need to be followed up for cognitive and CNS sequelae. Prolonged exposure in utero of the virus places the fetus at risk for sensorineural hearing loss, macular neuroretinal diseases, and neurologic defects with varying degrees of microcephaly.50

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Postnatal Findings and Anesthetic Implications

Perinatal Zika virus disease can be suspected if the mother has a history of exposure within the last 2 weeks of pregnancy and/or neonatal presence of clinical manifestations of the disease. The World Health Organization has published recommendations for the screening and management of newborns and infants born in Zika-susceptible areas (Table 3). Exposed newborns should be tested within the first 2 weeks of life with real-time serologic (rRT-PCR) and IgM tests for up to 12 weeks after symptoms.51 There have not been any reported cases of Zika infections transmitted through breast milk, and the CDC supports current evidence that defines the benefits of breast milk feeding outweighing the theoretical risk of acquiring the Zika virus.9

Table 3

Table 3

Characteristics resemble those found in the well-described congenital infections of the newborn such as those seen with TORCH syndrome (Toxoplasmosis, Other (syphilis, varicella-zoster, parvovirus B19), Rubella, Cytomegalovirus, and Herpes), maternal alcohol use, hypertensive disorders, and intrauterine infections with other flaviviruses. In these infections, congenital microcephaly is present at birth and can occur alone or accompanied with other abnormalities. This finding is associated with a reduction in brain volume, compromised neurocognitive outcomes, hearing and visual defects, and behavioral disabilities.52 Normal newborn head circumferences, on the 50th percentile range, can measure from 35 to 36 cm at birth for girls and 36 to 37 cm for boys.53 In its most distressing clinical presentation, neuroimaging of a baby with Zika Congenital Syndrome can reveal that head circumference is smaller than −2 standard deviations below the mean for sex and gestational age.53 Vasco-Aragao et al54 reported findings in 23 Zika-affected babies who also revealed premature closure of the anterior fontanelle. In addition, 78% presented dysmorphic craniofacial features, 30% had prominent occiputs, and 52% had redundant scalp skin (“cutis gyrata”) attributed to a lack of in utero brain and cranium development.54

Micrognathia, with a short submental thyroid distance, and craniocervical biomechanical limitations may compromise mask ventilation and hinder optimum visualization of the glottic opening with direct laryngoscopy. This may justify a videolaryngoscopic approach to securing an airway during neonatal resuscitation or induction of anesthesia. In emergent situations, placement of a laryngeal mask airway until the airway is appropriately secured avoids injury while supporting timely oxygen and ventilation.

Not all newborns with congenital Zika have microcephaly. Newborns might otherwise present with borderline head circumference along with hyperirritability, tremors, or seizures and congenital contractures of the joints, as those seen with arthrogryposis congenita.55 Archaic newborn reflexes are preserved, but they tend to have hyperreflexia and tremors with or without generalized seizures. Some feed without difficulty, but many are born with deglutition problems, dysphagia, and increased risks of aspiration. Mothers of Zika-affected babies report feeling that their babies are often in extreme pain. Researchers who have traveled to endemic areas have described these babies as having a high-pitched screeching cry. The description of an abnormal nonharmonic type of cry may be subjective, but cries with extreme values and unstable pitch may be reason to suspect dacrystic seizures, vocal cord abnormality, or asymmetry in a pathologic newborn.56,57 These issues may increase the difficulty of airway management. Imaging studies that clarify the impact on laryngoscopy are discussed subsequently.

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Radiologic Assessment

Radiologic (ultrasound, computed tomography, and magnetic resonance imaging) studies reveal common findings of generalized brain calcifications, especially between the cortex and subcortical white matter, cortical malformations, decreased brain volume, and ventriculomegaly.54 Malformations of this nature have been described among babies born with TORCH and pseudo-TORCH syndromes.

Figure 1

Figure 1

Figure 2

Figure 2

Figure 3

Figure 3

Figure 4

Figure 4

Fetal imaging can assess the severity of microcephaly and underlying structural anomalies within the brain in the mid- and late stages of pregnancy. In cases of ZIKV, there may often be occipitocervical biomechanical limitations because of occipital deformity, overlapping of cranial sutures, and flattening of the posterior fossa along with what most often is being described as thinning of the spinal cord at the craniocervical junction.54 This abnormal cervical spine curvature is expected to reduce the ability to place the head in a “sniffing” or Magill position for intubation. The occipital bone is typically flat with overriding sutures (premature closure), but there may be a superimposed protuberance. The protuberance could provide more depth to the posterior fossa, restoring normal sniffing positioning for airway management, but this is speculative. Head and neck imaging can be used to analyze airway abnormalities before intubation and should complement the clinical assessment for airway management. Figures 1–3 demonstrate radiologic findings of a neonate born with confirmed prenatal ZIKV infection. Figure 4 (a noninfected newborn) is presented for comparison. Further imaging studies evaluating the airways of Zika-infected patients are needed to identify whether there are airway abnormalities associated with the virus.

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Neonatal Resuscitation

The need for resuscitation of a newborn cannot always be predicted. One report has estimated that 1 in every 16 births will require some form of newborn resuscitation based on the American Heart Association guidelines.58 The prevalence of ZIKV-infected newborns requiring resuscitation has not been determined; however, one can assume that it will be greater than in healthy newborns. Health care providers need to manage resuscitative efforts and potential difficult airways in these newborns while observing basic standard precautions to avoid viral transmission. Primary resuscitation goals are to establish adequate ventilation and to reverse hypoxia and bradycardia.55,59 Congenital abnormalities associated with Zika virus may present challenges in bag-mask ventilation, laryngeal mask placement, and endotracheal intubation, even by those skilled in advanced airway management.60 Therefore, appropriate backup should be readily available. If possible preterm delivery or need for resuscitation is anticipated, additional skilled personnel and equipment (such as laryngeal mask airway, videolaryngoscope, or fiberoptic equipment) should be available before delivery.61 According to American Heart Association guidelines, initial steps are to provide warmth and position the head in the “sniffing” position to open the airway and stimulate breathing.62 In the event that these efforts are unsuccessful, a systematic approach to resuscitation as outlined by the 2015 American Heart Association Neonatal Resuscitation guidelines should be followed.

Newborn airways are grossly different from adults. Pediatric patients have larger heads and tongues; a more cephalad larynx; and a large, floppy epiglottis that can impede laryngoscopic views.62,63 Pediatric patients are also predisposed to hypoxemia secondary to greater oxygen consumption and lower functional residual capacity compared to adults, leading to more rapid desaturation.64,65 A review of pediatric closed claims cases found that the most common anesthesia-related deaths were related to inadequate ventilation.66 Anticipated difficult airways include congenital syndromes or anatomic abnormalities, temporomandibular joint dysfunction, and poor neck mobility.67 Because craniofacial distortions and microcephaly are common features in ZIKA-affected babies, one should plan for characteristics that interfere with spontaneous breathing, bag-mask ventilation, laryngoscopy, and intubation. A clear history should be obtained focusing on respiratory problems, feeding problems, and history of previous anesthetics if available. As much as possible, anesthetic providers should attempt to assess mouth opening, size of the tongue, presence of any masses, mandibular size, neck mobility, craniofacial distortions, and temporomandibular joint involvement.68 The Mallampati score is not practical in infants and young children as a result of poor cooperation.69

Table 4

Table 4

The American Society of Anesthesiologists task force on management of the difficult airway updated the practice guidelines for the management of the difficult airway in 2013 (Table 4). The task force outlines the basic preparation for difficult airway management to include (1) availability of equipment; (2) informing the parents of suspected difficult airway in preparation for birth; (3) assigning an individual to assist with airway; (4) preoxygenation by mask; and (5) administration of oxygen throughout airway management. The task force encourages the preparation for multiple airway interventions that may include (1) awake intubation; (2) video-assisted laryngoscopy; (3) intubation stylets; (4) supraglottic airways; (5) fiberoptic intubation; and (6) surgical airway. Capnography or end-tidal carbon dioxide should be used to confirm tracheal intubation. If multiple intubation attempts are made, it may be prudent to give 0.25–0.5 mg/kg of dexamethasone to decrease airway edema. In addition to planning for intubation, a strategy for extubation should also be established early to avoid loss of airway during this critical time.70

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Planning for Examination Under Anesthesia

While specific anesthetic guidelines for neonates and infants affected by the Zika virus have yet to be described in the literature, several recommendations can be inferred from the known clinical presentations and similar presentations of other congenital viral infections. A thorough preoperative evaluation is paramount in assessing the patient’s overall health status, optimizing medical needs before the procedure, identifying airway and physical abnormalities, educating the parents on expectations, and developing a perioperative plan.71,72 In nonemergency cases, a multidisciplinary approach with evaluation from infectious disease, neurology, pediatric, neonatal intensivists, and any other specialty based on patient presentation should be considered before arriving to the operating room. Special care should be focused on neurologic evaluation and motor function abnormalities. Arthrogryposis, defined as multiple congenital contractures affecting 2 or more areas of the body, is a common feature in Zika-affected babies.73 A recent retrospective imaging study of Zika-affected newborns with arthrogryposis suggests that the joint abnormalities may be neurogenic in origin with involvement of central and peripheral motor neurons.74 Large case series of presumed Zika-infected newborns with microcephaly have reported a higher incidence of clubfoot and hip dislocations.55 Difficult IV placement and positioning should be anticipated if arthrogrypotic features are present. Infants with arthrogryposis present with decreased subcutaneous tissue, tense skin, contractures, and decreased muscle mass.75 If peripheral IV access cannot be obtained, one should be prepared for interosseous or central access. Dysmorphic features should be assessed to anticipate the effect of perioperative complications. Particular attention should be given to the degree of microcephaly and craniofacial distortions that would predict difficulty with ventilation and intubation. Anesthesiologists should be prepared for a difficult airway before sedation, as outlined previously.

Table 5

Table 5

Pharmacologic considerations should include avoidance of specific medications that may have adverse effects in these patients. Drugs that have the potential to increase intracranial pressure (such as succinylcholine and ketamine) may be contraindicated, especially if the patient presents with craniosynostosis with overriding sutures. If craniosynostosis is present, the anesthesiologist should pay particular attention to minimizing hypoxia, hypercapnia, and increased venous pressure. Those with syndromic synostosis may also have proptosis, and special care should be made to avoid injury to the eyes.76 Because epileptic activity is associated with Zika, medications and anesthetic agents that lower the seizure threshold such as N2O, enflurane, sevoflurane, ketamine, and etomidate should be used with caution. If the child is taking antiepileptic drugs, the anesthesia provider should be familiar with side effects and drug interactions. For example, phenytoin, carbamazepine, and phenobarbital are especially known to inhibit release of acetylcholine resulting in increased sensitivity to nondepolarizing muscle relaxants.77 Table 5 summarizes the potential zika virus effects on neonates or infants and the anesthetic implications.

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CONCLUSIONS

Infection rates of ZIKV are increasing in the United States, and ZIKV has been declared a public health emergency of international concern by the World Health Organization. Until a vaccine becomes available, we should anticipate a growing number of infections and newborns affected by the ZIKV presenting to our operating rooms and clinics. While Miami is currently the epicenter in the United States, other locations will also see these patients. Together with our surgical colleagues, anesthesiologists will again be on the frontline for perioperative occupational safety and awareness in the guidance of managing these parturients and their newborns. Results of ongoing studies at various stages of gestation and abnormal brain development will position us to offer better care. The information presented in this review provides a reference for anesthesia care providers preparing for safe management of these patients while definitive treatment is developed and future clinical data evaluated. While we can prepare for difficult airway and IV placement, delineating specific neurodevelopmental clinical abnormalities in ZIKV-infected infants via imaging, behavioral, and clinical studies will benefit our patients’ outcomes and long-term care. Public health models from National Institute of Health environmental studies of this outbreak and its effects on newborns will anticipate future mental health issues, education, and further need for clinical trials. Given the unfortunate dilemma of this emerging disease and the effects on newborns, anesthesiologists are in the unique position to continuously advocate the importance of proper universal precautions to help prevent accidental transmission of this and other infectious diseases.

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DISCLOSURES

Name: Jacqueline L. Tutiven, MD.

Contribution: This author helped write the manuscript.

Name: Benjamin T. Pruden, MD.

Contribution: This author helped write the manuscript.

Name: James S. Banks, MD.

Contribution: This author helped write the manuscript.

Name: Mario Stevenson, PhD.

Contribution: This author helped write the manuscript.

Name: David J. Birnbach, MD, MPH.

Contribution: This author helped write the manuscript.

This manuscript was handled by: Jill M. Mhyre, MD.

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    Appendix 1 Interim Guidance for Protecting Workers From Occupational Exposure to Zika Virus

    Health care and laboratory workers78

    • Employers and workers in health care settings and laboratories should follow standard infection control and biosafety practices (including universal precautions) as appropriate to prevent or minimize the risk of Zika virus transmission.
    • Standard precautions include, but are not limited to, hand hygiene and the use of personal protective equipment (PPE) to avoid direct contact with blood and other potentially infectious materials, including laboratory specimens/samples. PPE may include gloves, gowns, masks, and eye protection.
    • Hand hygiene consists of washing with soap and water or using alcohol-based hand rubs containing at least 60% alcohol. Soap and water are best for hands that are visibly soiled. Hand hygiene must be performed before and after any contact with a patient, after any contact with potentially infectious material, and before putting on and removing PPE, including gloves.
    • Laboratories should ensure that their facilities and practices meet the appropriate biosafety level for the type of work being conducted (including the specific biologic agents—in this case, Zika virus) in the laboratory.
    • Employers should ensure that workers follow workplace standard operating procedures (eg, workplace exposure control plans) and use the engineering controls and work practices available in the workplace to prevent exposure to blood or other potentially infectious materials.
    • Employers should ensure workers do NOT bend, recap, or remove contaminated needles or other contaminated sharps. Properly dispose of these items in closable, puncture-resistant, leak-proof, and labeled or color-coded containers. Workers should use sharps with engineered sharps injury protection to avoid sharps-related injuries.
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