Thirteen clinical cases of immediate hypersensitivity occurring before or during the course of labor have been reported since 2000 (Table 2).7,9–13,15,16,19–22,36 No neuraxial analgesia was performed in these cases. Drug-induced immediate hypersensitivity (n = 11)10–13,15,16,19–22,36 was the most frequently reported, followed by latex (n = 2).7,9 β-lactam antibiotics including amoxicillin, ampicillin, penicillin G, cefazolin, ceftriaxone, and cefotaxime were the most common drugs (n = 8).10,13,15,19–22,36 Other agents included ranitidine (n =1) and colloid solutions (n =2) (pentastarch and dextran).11,12,16 Clinical features of drug-induced reactions were moderate (grade II, n = 4) or severe (grade III, n = 6 and grade IV, n = 1) and appeared within the first few minutes after drug administration. Latex-induced reactions were graded as moderate and appeared within minutes after latex contact.7,9
Fourteen cases of immediate hypersensitivity have been reported during cesarean delivery under spinal (n = 11)17,18,37–41 and general anesthesia (n = 3)8,14,36 (Table 3). In this clinical setting, cardiovascular signs of immediate hypersensitivity may have been aggravated by caval compression and the cardiovascular effects of anesthesia (i.e., either spinal or general anesthesia), causing negative inotropic effects and/or vasodilation.
Type of Anesthesia
Latex was frequently involved in cases of immediate hypersensitivity occurring during the course of cesarean delivery performed under spinal anesthesia (n = 10)17,18,37,38,40,41 (Table 3). Clinical features were either moderate (grade I: n = 3; grade II: n = 1) or severe (grade III: n = 5; grade IV: n = 1) and appeared within 10 to 30 minutes after the start of the cesarean delivery17,37,38 or within minutes of administering exogenous oxytocin (4 cases).18,37,40,41 Following uterine manipulation, oxytocin-induced uterine contractions may favor the absorption of latex particles. These particles were most likely derived from latex gloves and released into the systemic circulation.38,42 A severe (grade III) immediate hypersensitivity reaction was reported after IV administration of a gelatin-based colloid.39
No immediate hypersensitivity reactions attributed to local anesthetics administered during labor, or cesarean delivery were reported during the last decade. Allergy to local anesthetics is frequently reported by patients, but it is rare to encounter an IgE-mediated allergic reaction to local anesthetics.2–4 Reports of an anxiety attack, a vasovagal episode, and the intravascular injection of epinephrine were associated with reactions after local anesthetic injection.2–4 The vast majority of adverse effects to local anesthetics are because of systemic absorption of local anesthetic or epinephrine.
Only 3 cases of succinylcholine-induced immediate hypersensitivity reactions have been reported (Table 3).8,14,36 Clinical features were always severe (grade III: n = 2; grade IV: n = 1) and occurred within minutes after succinylcholine administration. Patients exhibited severe cardiovascular signs associated with bronchospasm. No cutaneous signs were observed in these 3 cases.
Maternal and Fetal Outcomes After Maternal Anaphylaxis
No maternal morbidity or mortality was observed when maternal anaphylaxis occurred during labor. Neonatal neurological abnormalities, including rigidity of the extremities, seizure-like movements, brain damage, hypoxic encephalopathy, and neonatal death were reported in 46% of these cases.9,11,13,19,20,22 Parturients experiencing anaphylaxis had a delayed cesarean delivery after anaphylaxis onset9,20–22 or did not receive epinephrine despite undetectable arterial blood pressure.13 Others received excess IV epinephrine for the grade of the reaction11 or received delayed epinephrine.22 Epinephrine was the first drug injected in only one-third of grade III reactions,19,36 while other vasoconstrictors such as ephedrine or etilefrine were injected as first-line therapy in the remaining two-third of cases.11,13,15,22 A 2008 review found that in most cases of severe anaphylaxis, permanent damage occurred in the neonate.22 There were 9 cases common to our series in that review.7,10,13,15,17,19
Neonatal deaths and neurological abnormalities were associated with maternal anaphylaxis (grade II and III reactions) during labor. Inappropriate doses or delayed epinephrine may have contributed to these poor outcomes. Cesarean delivery was delayed in many cases. In contrast, fetal outcome was uneventful when appropriate doses of epinephrine were given according to the severity of the reaction, and cesarean delivery was performed promptly (within 10–15 minutes) after the onset of anaphylaxis, even in cases of severe reactions (grade III and IV).15,16,19,36
No neonatal neurological abnormalities or death were reported when maternal anaphylaxis occurred during cesarean delivery.8,14,17,18,36–41 In contrast, maternal morbidity, including severe hypertension associated with pulmonary edema, acute respiratory distress syndrome with acute renal failure,8 acute respiratory distress syndrome with disseminated intravascular coagulation,37 and increased liver enzymes with abnormal renal function40 were reported in 20% of cases. Epinephrine was the first drug injected in 60% of severe reactions (grade III or IV),8,17,37,39 while other vasoconstrictors such as ephedrine or phenylephrine were injected as first-line therapy in 40% of the cases.14,18,36,40 Maternal morbidity was likely because of the excess dose of epinephrine for the grade of the reaction in 2 cases,8,40 and the cause of morbidity was inconclusive in another case in the absence of details.37 In 1 case, maternal death was because of unrecognized latex-induced anaphylaxis.38
In summary, maternal morbidity was mainly reported when anaphylaxis occurred during cesarean delivery and may be attributable to delayed recognition and/or inappropriate management of maternal anaphylaxis. No neonatal neurological damage and/or death were observed in this clinical setting, probably because fetal extraction was concurrently performed during maternal resuscitation. Neonatal morbidity was reported primarily if anaphylaxis occurred during labor. Thus, anaphylaxis may be catastrophic to the mother and/or fetus. Review of these cases suggests that poor maternal and/or neonatal outcomes are likely because of inappropriate management of maternal anaphylaxis.
Management of Anaphylaxis During the Third Trimester of Pregnancy
The management steps for the treatment of an immediate hypersensitivity reaction during pregnancy are listed in Table 4.
Epinephrine is the first-line therapy for perioperative anaphylaxis management.1–4,28 Early use of epinephrine, dosed according to the clinical presentation, must be the rule after a severe immediate hypersensitivity reaction (i.e., grades III and IV).2–4,43 Previous reports demonstrated poor outcomes, including deaths, associated with either inadequate or excessive epinephrine doses during anaphylaxis.44 Absent or late administration of epinephrine was also associated with significant morbidity and mortality.44 Garvey et al.45 investigated the use of epinephrine in 270 patients experiencing perioperative anaphylaxis. Epinephrine was the first drug injected in only 24% of patients with grade III reactions; ephedrine and phenylephrine were commonly used as first-line therapy. These authors point out that “treatment with epinephrine can be delayed because of difficulties in diagnosing anaphylaxis and reluctance to administer epinephrine, even if the correct diagnosis has been made.” Some authors have expressed concerns regarding the use of epinephrine during pregnancy because of its potential to reduce uteroplacental blood flow.22 Although epinephrine increases uterine vascular resistance through its α-adrenergic-mediated blood vessel vasoconstriction, an appropriate dose of an alpha-adrenergic agonist, being titrated to response, will increase systemic vascular resistance, cardiac output, and uteroplacental perfusion.46 During attempted resuscitation of a pregnant woman, the best hope for fetal survival is maternal survival.43 Therefore, epinephrine should be the treatment of choice for anaphylaxis during pregnancy, as recognized by the latest French Guidelines4 and the Eighth Report of the Confidential Enquiries into Maternal Deaths in the United Kingdom.26 Although the latest Scandinavian2 and British3 guidelines, as well as the American practice parameter,32 on perioperative anaphylaxis highlight the important role of epinephrine for the treatment of anaphylaxis during anesthesia, they do not specifically discuss the use of epinephrine in the parturient. The therapeutic range of epinephrine plasma concentrations necessary for successful anaphylaxis treatment remains unknown. Therefore, epinephrine should be used with careful titration according to the hemodynamic response2–4,28 (Table 5). Epinephrine should not be injected during grade I reactions; small titrated boluses may sometimes be necessary during grade II reactions. Titrated IV bolus administration is required during grade III reactions; repeated doses may be required. A continuous infusion may be initiated to minimize the need for repeated bolus injections.1,4,28 Grade IV reactions (cardiac arrest) require cardiopulmonary resuscitation and high doses of epinephrine.47 Advanced Cardiovascular Life Support guidelines for cardiac arrest during pregnancy recommend the use of the same dosages used during resuscitation of adults.43
Desensitization of adrenergic receptors may be one of the factors contributing to catecholamine failure during anaphylaxis; thus, arginine vasopressin (AVP) may be an alternative treatment. AVP works through its vasoconstrictive effects mediated by nonadrenergic vascular V1 receptors. Increased nitric oxide synthesis contributes to the hypotension and resistance to vasopressors during vasodilatory shock48 and is another factor that may contribute to catecholamine failure.28 AVP directly decreases intracellular concentrations of the nitric oxide second messenger, guanosine 3′, 5′-cyclic monophosphate, and thus might act during anaphylaxis as an anti-inflammatory agent.49 Accordingly, several case reports suggest that AVP might be considered a potential rescue therapy during anaphylaxis refractory to epinephrine, norepinephrine, and/or phenylephrine.50–55 Further studies are necessary to clarify the use of AVP during anaphylaxis. There are no data available regarding the use of AVP during pregnancy.
Fluid therapy initiated with either crystalloid or colloid solutions is essential to compensate for the peripheral vasodilatation and interstitial capillary leakage.2–4,34 Changes in vascular permeability may cause more than half of the intravascular fluid to translocate into the interstitial space within 15 minutes after onset of anaphylactic shock.56 Therefore, a large volume of crystalloids and/or colloids should be administered via large-bore IV access from the early stage of anaphylaxis.1–4 While the French guidelines recommend that colloids be used after the crystalloid dose exceeds 30 mL/kg,1,4 others estimate that there is no evidence that one is better than the other.2,3 Although these guidelines indicate that large volumes of fluid may be required, they do not indicate the dose to be used.1–4 The dose requirement for fluid therapy during anaphylaxis remains unknown.
Emergent cesarean delivery should be considered early in cases of persistent maternal hemodynamic instability despite resuscitation.4,43 Since a stable maternal hemodynamic status during anaphylaxis does not guarantee appropriate placental perfusion and fetal oxygenation, normal fetal heart rate variability provides reassurance about fetal status.57 Persistent nonreassuring fetal heart rate patterns despite aggressive medical management are an indication for emergency delivery.58
Treatment with inhaled β2-agonist (salbutamol or albuterol) is recommended for isolated bronchospasm.1–4,28 Epinephrine remains the first-line therapy when cardiovascular collapse and bronchospasm occur together.2–4,28 α1- and β1-adrenergic receptors activation by epinephrine counteracts the vasoplegic component of anaphylaxis, while its β2-effect is effective in relieving bronchoconstriction. Glucocorticoid therapy (i.e., methylprednisolone 1 mg/kg) is considered a secondary treatment to decrease airway inflammation.1–4,28,59 H1- and/or H2-receptor antagonists may be administered as the second line of treatment, but never before epinephrine.1–4,28 However, their effects have never been evaluated.
The 2010 Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care from the American Heart Association make it clear that there should be no delay in delivering the usual treatment during the management of cardiac arrest in pregnancy, including standard drug doses.43 Cesarean delivery should be initiated within 4 minutes of the arrest if the resuscitation has not been successful with the goal of delivering the fetus within 5 minutes of the arrest.43 Emptying the uterus removes aortocaval compression, resulting in 60% to 80% increase in cardiac output, thereby increasing the likelihood of maternal survival.60 Unfortunately, very few cases of perimortem cesarean delivery are within the recommended time period. Survival of the mother has been reported with perimortem cesarean delivery performed up to 15 minutes after the onset of maternal cardiac arrest.60,61 The Eighth Report of the Confidential Enquiries into Maternal Deaths in the United Kingdom reported the death of a woman after suffering an anaphylactic reaction to an antibiotic given during labor.26 A careful review demonstrates that “the failure to initiate perimortem caesarean section on the labor ward within 4 minutes of cardiac arrest to deliver the fetus may have contributed to the unsuccessful maternal resuscitation,” and adds that “acute anaphylaxis requires an immediate medical response including treatment with epinephrine.”26
Etiological Diagnosis of Immediate Hypersensitivity
While the initial diagnosis of peripartum immediate hypersensitivity relies on the clinical symptoms and the chronology of events, the etiological diagnosis is based on serologic and skin tests.2–4,28 The interpretation of the allergological assessment should be done in the context of the clinical history. This analysis helps to ensure an accurate diagnosis necessary to determine the pathophysiological mechanism, to identify the culprit agent, and to provide subsequent recommendations for further anesthetic procedures.2–4,28
The diagnosis of IgE-mediated allergic hypersensitivity was proven in 44% of the reported cases in this review (confirmation by the clinical history and positive skin tests to the culprit agent) (Tables 2 and 3).8,14,17,18,36,37,39 If measured, serum tryptase was always elevated. Serum-specific IgE measured during documented latex-induced reactions was always positive. The diagnosis of IgE-mediated anaphylaxis remained presumptive in the remaining 56% of cases.7,9–13,15,16,19–22,38,40,41 Although the clinical history was suggestive of immediate allergic hypersensitivity, tryptase was not measured in most of these cases, and skin tests were not performed. Therefore, it is difficult to draw conclusions from these uninvestigated cases because the evidence is quite limited.
Biochemical Tests and In Vitro Assays Measurements
Plasma histamine is an inflammatory mediator stored in mast cell and basophil granules. An increased concentration of plasma histamine indicates in vivo release and is observed during both allergic and nonallergic immediate reactions. The peak of plasma histamine is immediate, and its plasma half-life is short, approximately 15 to 20 minutes.4 However, serum histamine is not a good marker following anaphylaxis after the first trimester of pregnancy, because it is metabolized by the histamine-degrading diamine oxidase enzyme; this enzyme is released by the placenta.62 The balance between histamine and the diamine oxidase seems to be crucial for an uncomplicated course of pregnancy.63 Plasma histamine measurement is therefore not helpful in the diagnosis of anaphylaxis after the first trimester of pregnancy because of false negative results.4
Tryptases are neutral serine proteases stored predominantly in mast cells. Two major forms can be measured in vivo: pro-α tryptase that reflects the mast cell burden and is increased in mastocytosis,64 and mature β-tryptase preferentially stored in mast cells granules and released during mast cell activation, such as during IgE-mediated anaphylaxis.65 The total tryptase level, measured in serum by fluoroimmunoassay, measures mature β-tryptase in addition to pro-α tryptase.66 The median serum tryptase level was reported to be 5.1 µg/L (range: 1–30.7 µg/L) in a general adult population.67 Serum total tryptase concentrations reach a peak at 1 hour after the onset of the immediate reaction, decline under first-order kinetics with a half-life of approximately 2 hours, and correlate with the clinical severity of the reaction.2–4 While an increase in tryptase can be measured 30 to 60 minutes after onset of symptoms in cases of mild reactions, sampling is recommended between 30 minutes and 2 hours in cases of grade III and IV reactions.4 Tryptase may not be increased in mild reactions. An increase in tryptase is highly suggestive of mast cell activation as seen in IgE-mediated anaphylaxis, but its absence does not preclude the diagnosis. To compare the concentrations during an immediate reaction with baseline levels, a tryptase measurement may be performed after >24 hours following a reaction or when the patient is referred for investigation.1–4
Specific Serum IgE Measurement
IgE-antibody testing may be performed at the time of the reaction or later.1–4 Specific serum IgE measurement is available for some drugs including β-lactam drugs (e.g., ampicillin and amoxicillin, penicillins G and V), succinylcholine, morphine, chlorhexidine and protamine, but the test sensitivity is low.1–4 IgE-antibody assay is also commercially available for latex and has a similar sensitivity as a skin prick test.68 In the United States, Food and Drug Administration-approved specific serum IgE measurements are only available for penicillins G, V and latex. Identification of serum IgE provides possible evidence of IgE sensitization; this result should be correlated with clinical symptoms at the time of contact or administration of the allergen.
Skin tests should be performed as suggested by the clinical history. All drugs and substances (e.g., latex, chlorhexidine) to which the patient was exposed before the reaction should be tested. Skin testing should be performed at least 4 to 6 weeks after an anaphylactic reaction to avoid false negative results.3,4 Skin test can be performed at any point during the pregnancy, especially for local anesthetics, latex, and neuromuscular-blocking drugs.4
A suggestive clinical history with a mild reaction without an increase in tryptase and a negative skin test is indicative of a nonallergic reaction, such as histamine release.1–4 Conversely, immediate hypersensitivity reactions requiring emergency treatment, and associated with an increased tryptase and positive skin tests to the suspected drug/agent, constitute evidence of an IgE-mediated mechanism.1–4 In this latter condition, the identified drug/agent should be avoided in the future. The sensitivity of skin tests for neuromuscular-blocking drugs in patients having experienced anaphylaxis after a neuromuscular-blocking drug injection is >95%, and their reproducibility is excellent.1,69 Therefore, negative skin-tested drugs can be used for further procedures (i.e., negative skin-tested neuromuscular-blocking drugs during the diagnostic approach of a documented neuromuscular-blocking drug-induced IgE-mediated anaphylaxis).4 In selected cases, drug challenges are the “gold standard” after a negative skin test to address drug hypersensitivity to certain drugs such as penicillins.70,71
As no prospective randomized studies evaluating the use of a specific protocol of premedication for the prevention of perioperative anaphylaxis have been published, it is critical to identify at-risk patients before any surgical procedure.2–4,28 A careful and complete review of the clinical history is essential before any procedure in patients with previous uninvestigated perioperative immediate reactions because they are at increased risk of a recurrence during subsequent anesthetics.2–4,28 An allergological assessment linked to the clinical history should then be considered to identify and avoid the culprit drug or latex.2–4,28 Therefore, it is quite important that health care facilities have institutional guidelines for precautions used during management of patients with latex allergy, including the use of latex-free gloves and medical equipment.
Even though anaphylaxis is not common during pregnancy, it is important to recognize it rapidly and treat it effectively, because the cardiovascular disturbances may be catastrophic to both mother and fetus. Causes of anaphylaxis include drugs and environmental agents to which obstetric patients are commonly exposed. Accordingly, the most common triggers are penicillin administered for prophylaxis against neonatal group B streptococcal infection, other β-lactam antibiotics (e.g. cephalosporins) administered for surgical prophylaxis, and latex. No anaphylaxis to local anesthetics has been reported during the past decade. The vast majority of adverse effects to local anesthetics are because of systemic absorption of local anesthetic or epinephrine. The management of anaphylaxis occuring during the third trimester of pregnancy may be challenging. As stated in the latest report of the Confidential Enquiries into Maternal Deaths in the United Kingdom, a formal anaphylaxis protocol should be immediately available for all clinical staff.26 The use of cognitive aids, such as anaphylaxis checklists, have been demonstrated to improve medical care in a simulated clinical environment.72,73 Treatment with epinephrine should be grade specific, and cesarean delivery should be considered in cases of severe reactions. Finally, patients who experience anaphylaxis during pregnancy should have a follow-up assessment from an allergy/immunology specialist to confirm the trigger for anaphylaxis, prevent recurrences, and propose alternatives for further procedures.
Name: David L. Hepner, MD, MPH.
Contribution: This author helped conduct the study and prepare the manuscript.
Attestation: David Hepner approved the final manuscript.
Name: Mariana Castells, MD, PhD.
Contribution: This author helped prepare the manuscript.
Attestation: Mariana Castells approved the final manuscript.
Name: Claudie Mouton-Faivre, MD.
Contribution: This author helped conduct the study, analyze the data, and prepare the manuscript.
Attestation: Claudie Mouton-Faivre approved the final manuscript.
Name: Pascale Dewachter, MD, PhD.
Contribution: This author helped design and conduct the study, collect and analyze the data, and prepare the manuscript.
Attestation: Pascale Dewachter approved the final manuscript.
This manuscript was handled by: Cynthia A. Wong, MD.
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