Sophie Carra

MD Michael Schatz

PhD Paul-Michel Mertes

PhD Maria Jose Torres

Florent Fuchs

MD PhD Gianenrico Senna

PhD Mariana C Castells

PhD Pascal Demoly

Luciana Kase Tanno
email: luciana.tanno@gmail.com

PhD Florence Fuchs

MD PhD Luciana Kase Tanno

Anaphylaxis and Pregnancy: A Systematic Review and Call for Public Health Actions

Keywords: anaphylaxis, epidemiology, management, perioperative anaphylaxis, pregnancy, prevention

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Anaphylaxis is a generalized hypersensitivity reaction with an acute onset after exposure (minutes to several hours) to a triggering factor [START_REF] Cardona | World Allergy Organization Anaphylaxis Guidance[END_REF][START_REF] Anaphylaxis | The American Academy of Allergy, Asthma & Immunology[END_REF]. The lifetime prevalence of anaphylaxis is currently estimated at 0.05-2 % in the USA and about 3 % in Europe [START_REF] Yu | The Epidemiology of Anaphylaxis[END_REF]. In fact, it can occur at any time of the life cycle, and it requires special attention when it happens in pregnant women because it implies a potential risk of fatality to both mother and fetus/newborn and can lead to sequelae in newborns related to brain anoxia and encephalopathies [START_REF] Mccall | The incidence, characteristics, management and outcomes of anaphylaxis in pregnancy: a population-based descriptive study[END_REF].

Although anaphylaxis during pregnancy is a known life-threatening reaction involving two lives at the same time, there are only a paucity of articles addressing this critical condition.

In pregnant women, clinical signs of anaphylaxis can be different from non-pregnant women, which may hinder the recognition of this condition [START_REF] Simons | Anaphylaxis during pregnancy[END_REF]. For instance, blood pressure values in pregnant women tend to be lower than non-pregnant women, which could lead to the delayed diagnosis of an initial anaphylactic shock. Cutaneous signs could be absent in about 35% of cases [START_REF] Mccall | The incidence, characteristics, management and outcomes of anaphylaxis in pregnancy: a population-based descriptive study[END_REF]. These are reasons why clear definition of anaphylaxis during pregnancy and guidelines would be helpful to identify the reaction and avoid risk to two patients.

Management of anaphylaxis in pregnant women has been controversial over the past decades due to doubts regarding the safety of epinephrine use in pregnant women [START_REF] Edmondson | Anaphylaxis in pregnancy--the right treatment?[END_REF][START_REF] Entman | Anaphylaxis in pregnancy[END_REF]. Consensus guidelines among different specialists involved in the care of pregnant women, such as obstetricians, anesthetists, pediatricians, and allergists would harmonize the management of this health problem and facilitate optimal patient care. The lack of collaboration between specialties makes the identification of patients at-risk difficult and increases the risk for both the mother and the newborn.

This systematic review evaluates published data related to anaphylaxis during pregnancy and the potential risk factors in order to identify key issues in the diagnosis and management of this condition.

Evidence-based data may support prevention strategies and certainly are the first step towards guidelines production.

METHODS

PROTOCOL AND ETHICS

This systematic review was performed using the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines (PRISMA 15) [START_REF] Shamseer | Preferred reporting items for systematic review and metaanalysis protocols (PRISMA-P) 2015: elaboration and explanation[END_REF].

No ethical approval was required for the performance of this work.

STRATEGY OF SEARCH

We searched for all published data to identify articles related to anaphylaxis during pregnancy in Pubmed, Science Direct, Cochrane, Scielo and Lilacs websites, with no language restrictions. The search was performed on the 1st of August 2020. The MeSH terms used were: "anaphylaxis" AND "pregnancy" or "anaphylaxis during pregnancy". All the articles were screened in parallel by two independent authors. In all cases, disagreements were openly discussed among the co-authors. The Cohen's kappa coefficient demonstrated high agreement between the two reviewers (Kappa = 0.82).

Inclusion and exclusion criteria

As exclusion criteria we considered publications related to: in-vitro studies, animal studies, case reports, conference abstracts only, articles older than 1992, and articles without clear relation to our subject (Figure 1).

Studies were reviewed by two independent authors who screened full-text selected articles, and included studies were approved by all co-authors. In all cases, disagreements were openly discussed among the co-authors.

Data analysis and outcomes

Data abstracted from eligible studies were related to study design, population characteristics, rates of anaphylaxis morbidity (Table 1), triggers, clinical patterns, and management (Table 2). From a total of 733 initially identified articles, 12 reports describing epidemiological data, diagnostic features, triggers, and risk factors for anaphylaxis during pregnancy were selected to undergo the qualitative assessment of the study (Figure 1). Articles included in the final review are summarized in tables 1 and 2

RESULTS

Of the 12 articles, 5 (42%) are original articles, 4 (33%) are reviews, and the others are each of an editorial, case series, and correspondence. Only one original article is mentioned in 3 reviews, none of the others were cited in the reviews. Six (50%) of these articles were published in anesthesia journals, 5 (42%) in allergy journals, and 1 (8%) in a gynecological journal. From overall 12 articles, 6 were published by anesthesiologists, 5 by allergists, 1 by gynecologists. Seven articles were studies focused on diagnosis and management of anaphylaxis during pregnancy (58%). Seventeen percent of articles (2) were written by anesthesiologists and allergists together but no international consensus between specialties about anaphylaxis in pregnant women is provided excepted for the French recommendations, endorsed by the European Network of Drug Allergy (ENDA) in 2011 [START_REF] Mertes | Reducing the risk of anaphylaxis during anesthesia: 2011 updated guidelines for clinical practice[END_REF]. Nine of the 12 articles were published after 2012 (75%), two articles between 2000 and 2006 (17%), and one in 1992 (8%). Half of the studies were carried out in Europe, 1 study including many European countries (8%), 2 studies in the United Kingdom (16%), 2 studies in Italy (16%) and one in France (8%). 25% of studies were carried out in USA.

Most of articles (7/12, 58%) did not mentioned any definition of anaphylaxis. A definition of anaphylaxis was mentioned in 2 articles (16%) but did not provide the references. The Ring and Messmer anaphylaxis degree of severity was used in 3/12 articles, but the remainder of the publications simply described the clinical manifestations.

From the 4 epidemiological articles covering a total of 483 cases of anaphylaxis in pregnancy, three used national databases as the source of data, and two utilized the International Classification of Diseases (ICD)-9 CM to access the data. Three covered morbidity statistics (including the incidence, causative agents, frequency of triggers of anaphylaxis, management and associated outcomes of this condition) and one included mortality data.

Frequency of anaphylaxis during pregnancy was estimated to be 1.5 to 3.8 per 100 000 maternities, depending on the populations studied [START_REF] Mccall | The incidence, characteristics, management and outcomes of anaphylaxis in pregnancy: a population-based descriptive study[END_REF][START_REF] Mccall | Anaphylaxis in pregnancy: a population-based multinational European study[END_REF][START_REF] Mccall | Anaphylaxis in Pregnancy in the United States: Risk Factors and Temporal Trends Using National Routinely Collected Data[END_REF].

The mortality rate in pregnant women with anaphylaxis varied from 0% to 5% [START_REF] Mccall | The incidence, characteristics, management and outcomes of anaphylaxis in pregnancy: a population-based descriptive study[END_REF][START_REF] Mccall | Anaphylaxis in pregnancy: a population-based multinational European study[END_REF][START_REF] Mccall | Anaphylaxis in Pregnancy in the United States: Risk Factors and Temporal Trends Using National Routinely Collected Data[END_REF][START_REF] Mulla | Anaphylaxis in the obstetric patient: analysis of a statewide hospital discharge database[END_REF]. Forty-nine to 74% of anaphylaxis cases were described during caesarean sections [START_REF] Mccall | The incidence, characteristics, management and outcomes of anaphylaxis in pregnancy: a population-based descriptive study[END_REF][START_REF] Mccall | Anaphylaxis in pregnancy: a population-based multinational European study[END_REF][START_REF] Mccall | Anaphylaxis in Pregnancy in the United States: Risk Factors and Temporal Trends Using National Routinely Collected Data[END_REF]. In the only article reporting mortality of pregnant women due to anaphylaxis [START_REF] Tacquard | Anaphylaxis-related mortality in the obstetrical setting: analysis of the French National Confidential Enquiry into Maternal Deaths from 2001 to 2012[END_REF], all of the five deaths were during cesarean section. In 7 articles, differences regarding causative agents between vaginal versus cesarean delivery were not detailed. Four articles described detailed causative agents across terms of pregnancy and time in relation to delivery (pre, during and post), remaining articles covered broader list of possible triggers (Table 3). Among women presenting with anaphylaxis during pregnancy, 12% with a suspected or proven allergy prior to the pregnancy received the same molecule during the pregnancy, leading to a clinical allergic reaction (12.5% -11.7%) [START_REF] Mccall | The incidence, characteristics, management and outcomes of anaphylaxis in pregnancy: a population-based descriptive study[END_REF][START_REF] Mccall | Anaphylaxis in pregnancy: a population-based multinational European study[END_REF].

The most common causative agent of anaphylaxis during pregnancy was not different across time in relation to delivery (pre, during and post).

Beta-lactam antibiotics (58%), latex (25%) and anaesthetic agents (17%) were the main culprit agents in the reviewed studies. In 2/12 studies an allergy work-up was performed, while in the remainder, no etiological investigation was performed. In the study focusing on mortality, the main causative agent was neuromuscular blocking agents.

For anaphylaxis occurring during a general anesthesia (usually used for emergency cesarean section or due to a suspicion of allergy to the local anesthetics) general anesthetics are by far the most frequently involved and the mortality rate is higher because they are often urgent cesarean sections. [START_REF] Tacquard | Anaphylaxis-related mortality in the obstetrical setting: analysis of the French National Confidential Enquiry into Maternal Deaths from 2001 to 2012[END_REF] Frequent triggers and differential diagnosis according to the period of pregnancy (before or during/after the delivery) are shown in Table 3. In general, before labor and delivery, the causative agents and differential diagnosis of anaphylaxis are the same as in non-pregnant women. During labor and delivery, the most frequent differential diagnoses are amniotic fluid embolism, preeclampsia/eclampsia-associated symptoms, laryngopathy gravidarum and seizures.

Although without proper statistical calculation, 1 article (16%) mentioned specific cofactors: cesarean delivery, clinical past history of allergic reaction, and black race. Five articles (42%) identified latex allergy or antecedent clinical reaction to latex as a risk factor for anaphylaxis during pregnancy.

Most of the articles (among articles proposing a management strategy, 71%) proposed the same management and treatment for a clinical episode of anaphylaxis during pregnancy as in non-pregnant patients, and, all of the articles in which management guidelines were available (n =7, 58%) recommend the use of epinephrine in the patient's care during anaphylaxis in pregnancy. However, no details regarding dose of epinephrine or position of the patient were detailed. No details regarding serum tryptase were available in any of the reports. Epinephrine has been administered in 125 (25.8%) cases of all 483 anaphylaxis reported in the selected articles.

DISCUSSION

We here present the first systematic review on the management of anaphylaxis during pregnancy. We were able to identify key issues related to this specific condition, and the outcomes of our manuscript supports the identification of potential phenotypes at risk for developing anaphylaxis, who should be the target for preventive measures. We could also highlight the need for strengthening the collaboration between specialists involved in the care of these patients, both during the acute phase and in the follow-up.

It is rather surprising to find so few articles specifically related to anaphylaxis during pregnancy, which is concerning, considering the potentially negative consequences of gestational anaphylaxis to both mothers and newborns. The majority of reports were descriptive and reviews. The restricted number of clinical trials in this population is expected due to logistical and ethical considerations [START_REF] Allesee | Pregnancy and Protection: The Ethics of Limiting a Pregnant Woman's Participation in Clinical Trials[END_REF]. However, epidemiological studies were also very limited, with only two populational-based studies. In the two manuscripts using national databases, the ICD-9 (or modifications) was the basis of the search. All of the guidelines were specialty-centered. Although it seems that anaphylaxis during pregnancy is a field of interest of many specialists, namely allergists, anesthesiologists, and gynecologists/obstetricians, there are very few manuscripts authored by different specialists in collaboration.

The frequency of anaphylaxis during pregnancy is estimated to be 1.5 to 3.8 per 100 000 maternities [START_REF] Mccall | Anaphylaxis in pregnancy: a population-based multinational European study[END_REF], depending on the populations studied. Although with limited epidemiological studies, the data may have been influenced by changes over the period of the study, such as the decline of latex allergy after 2000, the lack of availability of serum tryptase measurement in most areas prior to 2005-2010, or the identification of Mast Cell Activation Syndrome (MCAS) only after 2010. Only one study included anaphylaxis mortality data in pregnant women, and the incidence of anaphylaxis-related maternal mortality is estimated at 0.05 per 100 000 live births [START_REF] Tacquard | Anaphylaxis-related mortality in the obstetrical setting: analysis of the French National Confidential Enquiry into Maternal Deaths from 2001 to 2012[END_REF]. Data show that the mortality is higher when a general anesthesia has to be used, most often for an emergency cesarean section. In this case, muscle relaxants are the substances most often involved [START_REF] Tacquard | Anaphylaxis-related mortality in the obstetrical setting: analysis of the French National Confidential Enquiry into Maternal Deaths from 2001 to 2012[END_REF].

Mortality rate in women experiencing anaphylaxis during pregnancy was estimated at 5% [START_REF] Mccall | The incidence, characteristics, management and outcomes of anaphylaxis in pregnancy: a population-based descriptive study[END_REF]. The mortality rate is low, and the morbidity data is in need of information regarding hospitalization duration, intensive care unit admissions and sequalae.

Only 25% of articles mentioned the negative impact in newborns, notably, encephalopathies, transfer to intensive care unit, and preterm births [START_REF] Mccall | The incidence, characteristics, management and outcomes of anaphylaxis in pregnancy: a population-based descriptive study[END_REF][START_REF] Simons | Anaphylaxis during pregnancy[END_REF]. Although two negative fatal outcomes of anaphylaxis (maternal deaths, newborn deaths) are possible, very few articles describe data related to the postpartum period [START_REF] Mccall | The incidence, characteristics, management and outcomes of anaphylaxis in pregnancy: a population-based descriptive study[END_REF][START_REF] Mccall | Anaphylaxis in pregnancy: a population-based multinational European study[END_REF][START_REF] Tacquard | Anaphylaxis-related mortality in the obstetrical setting: analysis of the French National Confidential Enquiry into Maternal Deaths from 2001 to 2012[END_REF].

Physiological characteristics of pregnancy such as the baseline blood pressure can delay the diagnosis of anaphylaxis. Lack of consensus regarding the definition of anaphylaxis in the studies may reflect the difficulties in clinical practice of the prompt recognition of anaphylaxis during pregnancy. In order to standardize the definition of anaphylaxis, allergy academies propose clear definitions of anaphylaxis, such as the WAO recent definition [START_REF] Cardona | World Allergy Organization Anaphylaxis Guidance[END_REF].

A broader method to increase the accuracy of anaphylaxis data is through international classifications.

The WHO eleventh edition of international classification of diseases (ICD-11) could be used to determine uniform morbidity and mortality rates of anaphylaxis during pregnancy in different countries and by distinguished medical specialties. This classification is more precise, sensitive and accurate for anaphylaxis than the previous ICD editions [START_REF] Tanno | Global implementation of the world health organization's International Classification of Diseases (ICD)-11: The allergic and hypersensitivity conditions model[END_REF]. Data from milder anaphylactic reactions are generally missing. Isolated cutaneous signs, itching in the valvular or vaginal areas, low back pain, fetal distress and preterm labor are specific manifestations of potential allergic reactions in this population [START_REF] Simons | Anaphylaxis during pregnancy[END_REF]. Reminders for practitioners in the delivery room or operating room could be placed to red flag signs of a potential allergic reaction.

Although the majority of studies discuss possible culprit triggers for anaphylaxis, in only 17% of papers were causative agents proven by allergy testing [START_REF] Mulla | Anaphylaxis in the obstetric patient: analysis of a statewide hospital discharge database[END_REF][START_REF] Draisci | Anaphylactic reactions during cesarean section[END_REF]. In fact, "unknown cause" is considered a risk factor for severe anaphylaxis and biphasic anaphylaxis. In practice, the non-confirmed trigger increases the risk of developing another anaphylactic reaction in the future. Our data demonstrated that 12 % of women with a suspected or proven past allergy have been exposed to the same agent during the pregnancy, leading to a new reaction [START_REF] Mccall | The incidence, characteristics, management and outcomes of anaphylaxis in pregnancy: a population-based descriptive study[END_REF][START_REF] Simons | Anaphylaxis during pregnancy[END_REF]. The nature of the initial clinical reaction is not specified in the two of studies providing these data. Precise diagnosis, written recommendations, and correct label of allergy in electronic health records should be able to decrease this risk. After treating the acute phase, we recommend that all cases of anaphylaxis should be referred to allergists for etiological confirmation, risk stratification and specific guidance in relation to the need of epinephrine autoinjectors or information regarding the possible cross-reactivity between allergens. This is the case, for example, of perioperative anaphylaxis (cesarean delivery) in which the patient is exposed to many agents simultaneously. Similar actions should be applied to cases of personal history of anaphylaxis seen by general practitioners, gynecologists, anesthesiologists. We emphasize that premedication with anti-histamine and/or systemic corticosteroids is insufficient to prevent immune-mediated anaphylaxis.

During the first trimester of pregnancy, the most frequent causes of anaphylaxis are the same as in non-pregnant women (food, venom, drugs) [START_REF] Simons | Anaphylaxis during pregnancy[END_REF]. However, during the second and third trimesters, antibiotics are the most commonly reported cause of anaphylaxis, in particular beta-lactams used to prevent infection during cesarean section and to treat streptococcal B infections. The patterns of prescriptions for the treatment of Streptococcal B infections vary among countries. For instance, in USA, a routine bacteriological screening is performed before delivery [START_REF] Doare | Intrapartum Antibiotic Chemoprophylaxis Policies for the Prevention of Group B Streptococcal Disease Worldwide: Systematic Review[END_REF], but in the UK the antibiotic is used as risk prevention strategy. Routine use of antibiotics can increase sensitization and antibiotic resistance [START_REF] Frieri | Antibiotic resistance[END_REF][START_REF] Lee | Strategies to Minimize Antibiotic Resistance[END_REF]. Currently there is an international effort by the allergy community to facilitate delabelling of allergy to beta lactams [START_REF] Moussa | De-labeling of βlactam allergy reduces intraoperative time and optimizes choice in antibiotic prophylaxis[END_REF][START_REF] Trubiano | Antimicrobial allergy « labels » drive inappropriate antimicrobial prescribing: lessons for stewardship[END_REF][START_REF] Trubiano | Antimicrobial stewardship's new weapon? A review of antibiotic allergy and pathways to « de-labeling[END_REF]. Therefore, accurate diagnosis of drug allergy is key.

In general, pregnancy has been considered as a relative contraindication of allergy testing [START_REF] Heinzerling | The skin prick test -European standards[END_REF]. The indication has been restricted to cases in which the utilization of a molecule is absolutely necessary without any alternatives [START_REF] Hepner | Should local anesthetic allergy testing be routinely performed during pregnancy?[END_REF]. This is the case of suspected allergy to local anesthetics [START_REF] Mertes | Reducing the risk of anaphylaxis during anesthesia: 2011 updated guidelines for clinical practice[END_REF]. In order to minimize risks to both mother and fetus, allergy work-up should be performed in early pregnancy. We would also recommend routine surveillance at periodic pre-natal visits with a specific question about any noticed sign of reaction to latex during examination or with casual contacts.

The second most frequent cause of anaphylaxis during pregnancy is natural rubber latex, probably due to the frequent exposure of pregnant women to latex gloves during gynecological and/or obstetric procedures [START_REF] Draisci | Latex sensitization: a special risk for the obstetric population?[END_REF]. During delivery, causative agents are different between spontaneous or cesarean delivery [START_REF] Mccall | The incidence, characteristics, management and outcomes of anaphylaxis in pregnancy: a population-based descriptive study[END_REF][START_REF] Simons | Anaphylaxis during pregnancy[END_REF][START_REF] Doare | Intrapartum Antibiotic Chemoprophylaxis Policies for the Prevention of Group B Streptococcal Disease Worldwide: Systematic Review[END_REF].

During spontaneous delivery, the most common causative agents of anaphylaxis are anesthetic agents followed by antibiotics [START_REF] Mccall | The incidence, characteristics, management and outcomes of anaphylaxis in pregnancy: a population-based descriptive study[END_REF][START_REF] Simons | Anaphylaxis during pregnancy[END_REF]. Local anesthetics are used during spontaneous delivery in order to decrease pain of the mother as major components of an epidural/spinal anesthesia [START_REF] Silva | Epidural analgesia for labor: Current techniques[END_REF]. However, they are rarely implicated in true IgE-mediated anaphylaxis [START_REF] Speca | Allergic reactions to local anesthetic formulations[END_REF], and the rates observed in publications may probably be due to non-confirmed allergies. A study from the UK recently showed that the rate of proven allergy caused by local anesthetic agents is lower than 1% [START_REF] Bhole | IgE-mediated allergy to local anaesthetics: separating fact from perception: a UK perspective[END_REF].

During cesarean delivery under local anesthesia, rates of causatives agents of anaphylaxis are relatively equally distributed between antibiotics and natural rubber latex. For cesarean deliveries under general anesthesia the main responsible agents are muscle relaxants [START_REF] Mccall | Anaphylaxis in Pregnancy in the United States: Risk Factors and Temporal Trends Using National Routinely Collected Data[END_REF].

This could be explained by the need for antibiotic therapy during surgical procedures and the utilization of sterile gloves composed of natural rubber latex. Latex allergy is mentioned as a risk factor for anaphylaxis during pregnancy [START_REF] Mccall | Anaphylaxis in pregnancy: a population-based multinational European study[END_REF]. Latex allergic clinical reactions occur usually less than one hour after contact [29]. Identifying latex allergy risk factors and history related to a possible latex allergy during the pregnancy is fundamental to prevention by advising a latex free environment [START_REF] Frieri | Antibiotic resistance[END_REF]29,[START_REF] Gawchik | Latex allergy[END_REF]. Some countries are currently trying to reduce latex utilization for professional use. In some countries such as the UK and Germany, latex gloves have been replaced by synthetic ones, and in other countries such as in France, gloves are no longer powdered, which has been shown to substantially decrease the risk of latex sensitization and allergy [START_REF] Henry | The benefits of latex-free gloves in the operating room environment[END_REF].

Although a personal history of allergy or anaphylaxis is considered a risk factor for another episode during pregnancy [START_REF] Draisci | Anaphylactic reactions during cesarean section[END_REF], there are no data related to the increased risk of anaphylaxis according to the number of pregnancies. However, it is known that increased number of procedures can promote the sensitization to allergens [START_REF] Caffarelli | Perioperative allergy: risk factors[END_REF]. Multiple pregnancies could be considered as a risk factor for anaphylaxis during pregnancy. Cesarean delivery and personal history of allergic reaction have been identified as two main co-factors for anaphylaxis during pregnancy [START_REF] Mccall | Anaphylaxis in pregnancy: a population-based multinational European study[END_REF].

With these cofactors clearly established, one could identify a phenotype at risk for anaphylaxis during pregnancy, represented by a second or third trimester pregnant woman with history of multiple pregnancies/cesareans/procedures, personal history of anaphylaxis and/or allergic reaction to medication without allergy work-up, with additional risk factors for natural rubber latex allergy and with indication to a new cesarean delivery. Risk factors for latex allergies include health care workers and others who frequently wear latex gloves, people who have had multiple surgeries (for example 10 or more) such as children with spina bifida, people who are often exposed to latex including rubber industry workers, and people with other allergies such as hay fever or allergy to certain foods [START_REF] Draisci | Latex sensitization: a special risk for the obstetric population?[END_REF]29,[START_REF] Gawchik | Latex allergy[END_REF]. Although decreased exposure to NRL has reduced the general risk of anaphylaxis and perioperative anaphylaxis overall, no decreased trends were observed specifically in anaphylaxis related to pregnancy over the time after the application of preventive measures for latex allergy in hospital, probably because of the rarity of this phenomena. Populations at-risk are the key target of prevention strategies aimed to decrease morbidity/mortality. Two thirds of the selected articles propose clear management guidance for anaphylaxis during pregnancy.

The French recommendations, endorsed by the European Network of Drug Allergy (ENDA), insisted in 2011 on the need to use adrenaline and give precision about emergency treatment of pregnant women with anaphylaxis [START_REF] Mertes | Reducing the Risk of Anaphylaxis During Anesthesia: 2011 Updated Guidelines for Clinical Practice[END_REF].

Fetal extraction should be done as soon as possible if the anaphylaxis occurs during labor, otherwise maternal resuscitation could fail due to compression of the vena cava by the fetus [START_REF] Mertes | Reducing the risk of anaphylaxis during anesthesia: 2011 updated guidelines for clinical practice[END_REF]. Conversely, in other situations in the operating room, the surgical procedure will not be undertaken in case of anaphylaxis at anesthetic induction [START_REF] Mertes | Reducing the risk of anaphylaxis during anesthesia: 2011 updated guidelines for clinical practice[END_REF].

Although recommended management measures are quite similar in the majority of articles, there is no mention of the dose of epinephrine to be used in the pregnant women, the position to place the woman in during the acute phase, nor the utility of evaluating blood tryptase levels.

If anaphylaxis during pregnancy is suspected, serum tryptase levels should be measured [34 , 35]. The serum tryptase level is a marker used to support the diagnosis of an anaphylactic episode in situations where clinical manifestations are not clear and made the diagnosis is uncertain, but no article in our review mentioned serum tryptase.

The presence of mast cell activation disorders, including mastocytosis, is one of the most important risk factors for anaphylaxis in pregnancy, but are not discussed in any of the articles.

In systemic mastocytosis, the pregnancy itself and/or delivery can be a trigger to mast cells degranulation, leading to significant maternal and fetal complications [START_REF] Watson | Systemic mastocytosis complicating pregnancy[END_REF][START_REF] Matito | Clinical impact of pregnancy in mastocytosis: a study of the Spanish Network on Mastocytosis (REMA) in 45 cases[END_REF]. Treatment with H1 blockers, and when indicated, steroids and epinephrine, can reduce these complications [START_REF] Lei | Management of Mastocytosis in Pregnancy: A Review[END_REF]. Ideally, the diagnosis of mast cell activation disorder should be made before the pregnancy and all health professionals involved should be aware to promptly recognize and treat anaphylactic manifestations and treat. This study presents some limitations. Although with careful selection of the documents, we had a limited sample of articles probably due to the total number of publications in the field. Due to the limited epidemiological data, it was not possible to follow the changes overtime. Most of the studies were published by authors from Europe or USA; these data about anaphylaxis may reflect the situation in more wealthy countries, including the causative agents. Rather than common tendency for all medical publications having higher number of publications from higher incoming countries, these regions have easier access to investigations and treatments. Data from low-incoming countries are missing. It was also not possible to follow the differences in epidemiological trends due to the ICD editions cause only two articles were population-based studies based on ICD-9 (or modifications), in which anaphylaxis were under represented. Besides, the widespread availability of laboratory measurement of serum tryptase did not occur until the early 2000's in Europe and after 2010 in the US. This may have limited reporting in many of the studies. Similarly, MCAS was not really recognized widely or defined until about 2010. The risk factors mentioned have been identified from very limited available literature, and other yet unidentified factors may influence risks.

CONCLUSION

Anaphylaxis during pregnancy is still a rare but a life-threatening phenomenon for the mother and the newborn. This first systematic review focused on diagnosis and management of anaphylaxis during pregnancy identifies the main risk factors for anaphylaxis during each trimester, and during delivery or caesarean section, stressed specific gaps and reinforces future public health strategies. The evidence presented highlights the need for better investigation and risk stratification to avoid negative outcomes. A national or multi-national registry of anaphylaxis in pregnancy would begin to answer many questions despite some of the inherent reporting biases. Also a collaboration between different specialists involved in the care of pregnant women should be established in order to support preventive strategies and reduce avoidable deaths due to anaphylaxis during pregnancy.

3 ABREVIATIONSEAACI:

 3 European Academy of Allergy and Clinical Immunology ENDA : European Network of Drug Allergy ICD-9-CM : International classification of diseases, ninth revision, clinical modification ICD-11 : International classification of diseases 11th Revision NMBA : Neuromuscular blocking agents NRL : Natural rubber latex SPT : Skin prick test UK : United Kingdom USA : United States of America INTRODUCTION:

Figure 1 :

 1 Figure 1: Flow diagram showing the stages of selection for the systematic review analysis.

Table 1 .

 1 Summary of characteristics of the included publications regarding anaphylaxis during pregnancy.

	Author,	Region	Type	of	Database	Study aim	Specific	Triggers	Number	of	Mortality	History of	Severity of	Risk
	(year)		study				population		women with	rate	previous	anaphylaxi	factors/
									anaphylaxis			anaphylaxi	s	co-factors
												s
	S. J. McCall	Europe	Descriptive	Data register:	Estimation of	51% had	The most	Sixty-five		Case/fatali	7 cases	No data	Multiple
	et al. (2020)		multination	UK Obstetric	the incidence,	cesarean	common causes:	cases were		ty rate:	(11.1%)	available	pregnancy
	[10]		al study: combinatio n of	Surveillance System / Netherlands	causative agents, management	section Separation	-Antibiotics (43%) -Anesthetic agents (17%)	identified among maternities 4,446,120		3.2% (95% 11.0), CI 0.4-			4 cases (6.3%)
			retrospectiv	Obstetric	and outcomes	between				2 deaths:			Drug
			e and		Surveillance	of anaphylaxis	antenatal /		1.5 per 100		-one from			allergy
			prospective	System /	in pregnancy	intrapartum		000		suxametho			known
			population-	Finnish Medical	across	/ post -		maternities		nium and			19 cases
			based study	Birth Registry /	Europe.	delivery				one from			(30.6%)
					UKOSS data		anaphylaxis				amoxicillin			-14 cases
					collection						/			allergy to
											clavulanic			penicillin
											acid			(22.6%)
														Atopic
														status
														20 cases
														(32.3%)
														Clinical
														history of
														allergy
														34 cases
														(54.1%)
														Clinical
														history of
														allergy or
														atopy

Table 2 .

 2 Anaphylaxis during obstetrics: causative agent and differential diagnosis(4,5,10-13,17,39- 43)

		Pregnancy			Delivery		Post
							delivery
	Stage r of	Trimester 1 Trimester	Trimester 3 Spontaneous	Cesarean
	the		2		delivery	section
	pregnancy
	Global	General	1)Antibiotics (58%)	1)Anesthetics	1)Antibiotics	1 article:
	triggers of	population:	2)Natural rubber latex	(43%)	(50%)	hormonal
	anaphylaxis	food,	(43%)		2)Antibiotics	2)Latex	sensitivity
		venom,	3)Anesthetic agents	(14%)	(50%)	1 article:
		drugs,	(14%)				blood
		biological					products
		agents
		such as
		immunothe
		rapy,
		natural
		rubber
		latex
	Risk factor	clinical past history of allergic reaction;		Cesarean
	for	risk factors for latex allergy (health care		section
	anaphylaxis	workers and other people frequently
		wearing latex gloves, people who have
		had multiple surgeries (10 or more)
		such as children with spina bifida,
		people who are often exposed to
		natural rubber latex (including rubber
		industry workers) and people with
		other allergies such as hay fever or
		allergy to certain foods)

Table 3 .

 3 Differential diagnosis for anaphylaxis during obstetrics.[START_REF] Simons | Anaphylaxis during pregnancy[END_REF]

		Before Labor and Delivery	Labor and Delivery
	Differential	Common diagnostic dilemmas:	Pulmonary embolism
	diagnosis	-acute asthma	(thrombotic) and pulmonary
		-acute generalized urticaria	edema
		-acute angioedema
		-syncope/fainting	Cardiac conditions (acquired
		-panic attack	and congenital)
		Postprandial syndromes:	Hypotension caused by spinal
		-scrombroid	block, local anesthetic, or
		-pollen-food allergy syndrome (oral	hemorrhage,
		allergy syndrome)	secondary to abruptio
		-monosodium glutamate reaction	placentae or uterine rupture
		-sulfite reaction
		-food poisoning	Cerebrovascular accident
		Upper airway obstruction (other	Amniotic embolism fluid
		forms):
		-nonallergic angioedema including	Preeclampsia/eclampsia-
		hereditary angioedema types I, II and III	associated symptoms, such as
			laryngopathia gravidarum and
		Shock (other forms):	seizures
		-hypovolemic
		-septic
		-cardiogenic
		Nonorganic diseases:
		-vocal cord dysfunction
		-hyperventilation
		-psychosomatic episode
		-Munchausen stridor
		Common diagnostic:
		-excess endogenous histamine:
		mastocytosis/clonal mast cell disorder
		-flush syndromes
		-carcinoid syndrome
		-certain tumors
		-systemic capillary leak syndrome

received an unrestricted Novartis and MEDA/Mylan Pharma grants through CHUM administration. LKT received a research AllerGOS grant. The other