Pregnancy and immunology: selected aspects

Review article Supported by a grant from AstraZeneca LP

Pregnancy and immunology: selected aspects G. William Palmer, MD and Henry N. Claman, MD

Learning Objectives: This article reviews current concepts of the immunology of pregnancy and of the diagnosis and management of certain allergic conditions in the pregnant woman: asthma, rhinitis, immunotherapy, and hereditary angioedema (HAE). Data Sources: Current texts, reviews, and individual studies were picked from the National Library of Medicine database. Results and Conclusions: Knowledge concerning the immunologic paradox of pregnancy continues to evolve. Although the answer is not definitive, attention is being paid to the role of a Th-2 shift in the pregnant uterus. Extensive studies, both epidemiologic and therapeutic, are clarifying the influence of pregnancy on asthma and rhinitis (and vice versa) and the best methods for treatment of these conditions in the pregnant woman. A brief guideline to the handling of hereditary angioedema in pregnancy is presented. Ann Allergy Asthma Immunol 2002;89:350–359.

INTRODUCTION The allergist/immunologist frequently sees patients who are pregnant or who are planning a pregnancy. The interface between allergy/immunology and pregnancy is fascinating and presents special challenges to the physician. This review covers only selected aspects of the subject. IMMUNOLOGY OF PREGNANCY The Immunologic Paradox of Pregnancy: Fetus as Allograft To the allergist/immunologist, the most intriguing fact about human pregnancy is that it occurs and is usually terminated by the delivery of a live baby. This 9-month long event flies in the face of what we know about transplantation immunology. The baby is an allogeneic (more properly, a hemiallogeneic) allograft. Half of its transplantation antigens, histocompatibility leukocyte antigen (HLA)-class I (A, B, and C) and HLA-class II (DR, DP, and DQ), come from the father and should cause the fetus to be rejected by the mother’s immune system well before the end of the first month. How does the fetus not only survive, but thrive? It is a fascinating question, and it was brought into sharp focus by the late immunologist, Sir Peter Medawar, winner of the Nobel Prize in Medicine or Physiology. Medawar1 outlined his thoughts in a paper with the rather forbidding title, “Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates.” Medawar postulated that the survival of the fetus was made possible by one (or more) of the following three mechanisms. Division of Allergy and Clinical Immunology, University of Colorado Health Sciences Center, Denver, Colorado. Received for publication April 25, 2002. Accepted for publication in revised form May 21, 2002.

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1) The anatomic separation of the fetus from its mother, ie, there is no significant contact between the mother’s immune system and the foreign antigens of the fetus, namely those antigens contributed by the father’s genes (see below). 2) The antigenic immaturity of the fetus. By this, Medawar meant that the immature fetal tissues would not express the paternal foreign transplant antigens, and so would not be regarded as a foreign immunogenic graft. 3) The immunologic inertness of the mother. This vivid phrase implied that the state of pregnancy was associated with a temporary form of immunodeficiency in which the mother’s immune system would not be able to recognize and react to the paternal antigens on the fetus. Recent research has made major gains in exploring the immunologic paradox of pregnancy. As is turns out, no one of Medawar’s three postulates provides exactly the right answer— but he certainly asked the right questions! In 1971, 18 years later, immunology had a different landscape. Alan Beer et al2 updated and expanded the Medawar approach, and considered that the following five concepts, not alone but in concert, might explain the survival of the fetal allograft. 1) Complete separation of maternal and fetal blood circulations. 2) Afferent blockade in the feto-maternal complex, analogous to the concept of the uterus as an immunologically privileged site. 3) An immunologic barrier at the feto-maternal interface because of: a) failure of the trophoblast to express paternal alloantigens, or b) masking of expressed paternal alloantigens. 4) Endocrinologically mediated local (decidual) inhibition of alloreactivity.

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5) Production of immunosuppressive cells, antibodies, and/or factors, specific and/or nonspecific, by a) fetus and b) mother. Immunology has moved even further since 1971, and many advances have provided further insight into the paradox. We know that immunologic recognition of the fetus does occur, but there are multiple (perhaps redundant) mechanisms which interfere with possible immune rejection of the fetus.3 The main maternal immunologic mechanisms that could mediate maternal rejection of the fetal allograft are 1) alloantibodies against paternal HLA; 2) classical cytotoxic T cellmediated allograft responses against paternal HLA; 3) complement and antibody-mediated attack; and 4) natural killer (NK) cell-directed injury. It appears that all of these are blunted or evaded in normal pregnancy, but mainly in the uterus itself. Most women make immunoglobulin (Ig)G and IgM antibodies against paternal HLA I and II antigens, if not in the first pregnancy, then in later ones. If the antibodies gained access to the fetus they could produce grave, if not fatal, damage. The IgM antibodies do not cross the placenta, and the IgG antibodies are absorbed in the “placental sink.” Thus, neither of these reagents reaches the embryo, and thus can not harm it. There has been speculation that high levels of maternal antifetal antibodies might actually be helpful in pregnancy. Although this concept has not been proven, it comes from the fact that, for years, the standard commercial antiHLA sera used for tissue typing (eg, anti-A1 or anti-B27) came from multiparous women. If a woman had six children and had high titers of antibodies to her husband’s HLA antigens, such antibodies could hardly be called deleterious to successful pregnancy.4 Nevertheless, the fact that women with common variable hypogammaglobulinemia can have normal pregnancies indicates that the maternal antibody response to paternal antigens is not necessary for a successful pregnancy. The most important mechanisms protecting the fetus involve the fact that the fetally derived membranes in contact with the maternal circulation and immune systems, namely the trophoblast, do not express the HLA I and II antigens of the fetus. Not only are the gene products of these histocompatibility antigens not expressed, but instead there are substitute truncated class I antigens, (HLA-E, F, and G), which are present on the trophoblast. HLA-E, F, and G (of which G seems to be the most important) are called nonclassical class I HLA antigens to distinguish them from classical HLA-I molecules (HLA-A, B, and C). These pregnancy-associated nonclassical HLA-I molecules show little polymorphism in the population.5 This fact, and the lack of expression of classical HLA I and II, mean that maternal T cells do not see the paternal histocompatibility antigens of the fetus in the uterus. Further, the machinery which might attack any allogenic paternal HLA antigens, namely the maternal T cells (CD4 and CD8), are sparse in the endometrium. The complement system is also abnormal in the decidua. Although complement proteins are present, there are unusu-

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ally high amounts of complement regulatory proteins such as CD46, decay accelerating factor, and CD65. These proteins actually interfere with complement activation, ensuring that this mechanism does not operate efficiently. Finally, there are increased percentages of macrophages and large granular cells in the decidua. The latter carry 1 of the 2 main NK cell markers (CD56) but not the other (CD16). These are often called uterine NK cells. The increased numbers of NK cells in the decidua might make one think that they could carry out non–HLA-linked immune damage against foreign cells (considering fetal cells in that light). It is of great interest that the nonclassical HLA-E, F, and G gene products are potent inhibitors of NK activity. Maternal Immunocompetence in Pregnancy One of the possible mechanisms invoked by Medawar1 to explain the survival of the hemiallogeneic fetus was that pregnancy involved a temporary state of immunologic “inertness,” ie, of immunodeficiency. I have discussed that topic previously, and will summarize it here.4 If the pregnant female were immunodeficient to any significant degree, one would expect to see evidence of that deficiency in an increased susceptibility to infection. There are data showing that certain viral infections, eg, hepatitis B, variola, and influenza (but not varicella), may be more severe in pregnancy. Some latent virus infections, such as cytomegalovirus and Epstein-Barr virus, become reactivated. In general, however, most pregnant women react normally to most microbes. The immunologic machinery–T and B cells, complement and antibody responses to immunization–are generally normal in pregnancy. Plasma IgG (but not IgA or IgM) falls, probably because of transfer to the fetus and trapping in the placental sink. All in all, systemic immunocompetence is either normal in pregnancy, or is impaired only to a degree which would not account for the fetal allograft’s survival. Local Immunocompetence in the Pregnant Uterus: A “Tilt” to Th-2? The past few decades have shown that there is great compartmentalization in the immune system. We understand the special features of the mucosal, bronchial, skin, and other local immune venues. What about the pregnant uterus? Earlier work indicated that to some extent, the decidua of the pregnant uterus had some features of an immunologically privileged site. This term has been applied to certain areas such as the brain, the cornea, and the anterior chamber of the eye, places where the immunologic machinery and responses are greatly dampened. Experiments to demonstrate this point in the pregnant uterus are difficult to execute and to interpret. In general, they show that primary allograft immunity is hard to induce in the pregnant uterus, but preexisting systemic allograft immunity can be expressed. It is doubtful if these experiments are relevant to the human situation.

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The 1980s and 1990s comprised the era in which scientists explored the concept of immune deviation: the balance (or better, often the reciprocal relation between) antibody production and Type I delayed hypersensitivity. These two kinds of reactions appear to be promoted by two types of T helper cells: Th-1 for delayed hypersensitivity and Th-2 for antibody production (in very approximate terms). In 1993, the late Tom Wegmann et al6 put forward the provocative hypothesis that pregnancy involved a shift to the Th-2 side of the immune response. They indicated that Th1– driven delayed hypersensitivity (including cell-mediated allograft rejection) would be deleterious to a successful pregnancy, but antibody-mediated responses (provided they did not cross the placenta) might be helpful. Although they believed that the Th-2 bias was systemic, it is likely that the intrauterine milieu is even more important in this respect. More recently, interest has returned to the question of maternal T cell tolerance and the infamous suppressor T cell, but the roles of these processes remain unclear.7 ALLERGY AND PREGNANCY Medications in Pregnancy–General Considerations Many physicians and patients rely heavily on the U.S. Food and Drug Administration’s (FDA) use-in-pregnancy rating system (ie, the A, B, C, D, X system) in making decisions regarding treatment for such conditions as asthma and allergic rhinitis. Unfortunately, this system has severe limitations, and the physician must look beyond the current labeling system to make informed prescribing decisions. Only 40% of drugs currently in the Physicians’ Desk Reference have pregnancy labeling, and more than 60% of these are rated category C (“Risk can not be ruled out”).8 The default assignment to category C is misleading to many clinicians, who may think this indicates a degree of risk, rather than lack of information.9 In addition, the current system does not take into account the timing of drug exposure. In a study comparing the risk classification system from the FDA to similar systems used in Australia and Sweden (the latter being the model for the U.S. system), only 26% of drugs common to all three systems were placed in the same risk category.10 The Teratology Society9 recommended abandoning the current system in favor of narrative statements that summarize and interpret available data. This seems to be the goal of the FDA Pregnancy Labeling Task Force, which was given the assignment in 1997 to revise the current system to make it more clinically useful.8 The model currently under development attempts to address the above concerns and would not use letter categories. Therefore, in this review, the letter categories of medications will not be emphasized. Instead, general guidelines of medication use will be given based on the best available evidence. Asthma and Pregnancy Asthma in pregnancy may increase the risk of both maternal and fetal complications. The exact mechanisms involved are still

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poorly understood, but appear to be related to the disease process itself and not to the medications used to treat asthma.11,12 Several studies have looked at how pregnancy affects the course of chronic asthma. Individual studies have a broad range of results, but taken together, the commonly quoted generalization seems to be true: one-third of pregnant women have improvement in their asthma; one-third experience worsening; and one-third have no change.13 There are additional important generalizations suggested by other studies. The more severe the asthma is before pregnancy, the more likely it is to worsen during pregnancy.14 Also, most patients whose asthma changes pattern during pregnancy go back to their prepregnancy status within 3 months postpartum.15 Exacerbations are most likely to occur between weeks 24 and 36, with exacerbations unlikely beyond week 37, including during delivery.11 An equally important issue is how asthma affects pregnancy. Several studies have attempted to address this question. Findings are not always consistent from study to study, suggesting a possible role for a future meta-analysis. However, several studies have found an approximate two- to threefold increased risk of pregnancy-induced hypertension (preeclampsia) among asthmatic mothers. A smaller number of studies have suggested an increase in perinatal mortality, preterm births, and low birth weight infants.11,12,16 Several studies have shown these adverse outcomes to be a function of asthma severity as evaluated by steroid dependency.11,16 What then is the cause of the complications: the asthma itself; the medications, including steroids, used to treat asthma; or other factors associated with asthma? Schatz11 addressed the question of cause by examining pregnancy outcomes in studies in which asthma was managed by specialists compared with studies in which asthma was managed by nonspecialists. The assumption of this comparison is that specialists will be more aggressive in treating asthma during pregnancy. Disease control will be increased, as will medication use. In this comparison, patients in studies with specialist care did have decreased likelihood of perinatal mortality, preterm birth, and low birth weight. This does not seem to hold true for preeclampsia, suggesting that this complication might be related to medication or some factor other than asthma control.11 Another study has shown significantly lower birth weights in infants from asthmatic mothers who required hospitalization for asthma during pregnancy compared with infants from asthmatic mothers not requiring hospitalization.17 Finally, Schatz et al18 demonstrated a correlation between forced expiratory volume in 1 second (FEV1) and intrauterine growth in an asthmatic population. These studies then also support the concept of poor asthma control as a major cause of the associated pregnancy complications. Studies regarding the safety of medications during pregnancy are usually limited by their retrospective methodology and lack of long-term followup to look for late sequelae. With these limitations in mind, asthma medications appear to be relatively safe for use during pregnancy. The Michigan Medicaid Surveillance Study observed no increase in expected

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number of congenital malformations among users of many different types of ␤-agonists and among users of inhaled beclomethasone, cromolyn, or prednisone. Theophylline use was associated with a possible increase in heart defects, oral clefts, and urinary tract defects. The risk appeared to be small and may have arisen by chance in such a surveillance study.19 In addition, a multivariate analysis from Schatz et al20 supported the safety of ␤-agonists, cromolyn, beclomethasone, and theophylline. The data regarding the safety of beclomethasone are very important, as two studies have shown inhaled steroids decrease the number of acute exacerbations among pregnant asthmatic patients.21,22 The effect of oral steroids on pregnancy complications is more difficult to sort out. As mentioned above, several studies have correlated oral steroid use with pregnancy complications, but the steroid use may have simply been a marker for asthma severity/lack of control. In the multivariate analysis from Schatz et al,20 oral corticosteroids were independently associated with a doubling of preeclampsia, but not with lower birth weight or preterm births. Schatz11 also makes reference to a nonasthma study in which pregnant women were exposed to prednisone 10 mg daily throughout pregnancy as a treatment for recurrent miscarriage. The infants born to these individuals had significantly lower birth weights. Another explanation for the association between asthma and pregnancy complications could be a common pathophysiologic mechanism leading to both asthma and adverse pregnancy outcomes. One example might be an abnormality that leads to vascular and uterine smooth muscle dysfunction in addition to bronchial smooth muscle dysfunction.11 Such a concept is supported by a recent study demonstrating reduced Doppler ultrasound placental blood flow in moderate and severe asthmatic patients at 18 weeks gestation. In vitro studies on the delivered placentae demonstrated significantly less vasodilatory response in the placentae from moderate and severe asthmatic patients.23 The issues of asthma management during pregnancy were addressed in 1993 by the Working Group on Asthma and Pregnancy established by the National Asthma Education and Prevention Program.24 The Working Group emphasized the importance of objective measures for evaluation and monitoring, including frequent spirometry and early sonography to evaluate fetal growth. Stepwise pharmacotherapy was recommended to achieve full control of symptoms and maintenance of pulmonary function. The Working Group also performed an extensive review of data regarding medication safety and concluded that the risks of uncontrolled asthma are greater than any known risks from medication. Some specific recommendations included cromolyn as first-line anti-inflammatory therapy. If inhaled corticosteroids are required, beclomethasone is preferred because of studies supporting its safety. Oxytocin is the drug of choice for both labor induction and postpartum hemorrhage, as both prostaglandin F2 (for labor induction) and ergonovine (for hemorrhage) can induce asthma. A position statement regarding the use of newer asthma medications during pregnancy was developed by a joint com-

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mittee of the American College of Obstetricians and Gynecologists (ACOG) and the American College of Allergy, Asthma, and Immunology (ACAAI) in 2000.25 Because there are no controlled human data regarding salmeterol in pregnancy, the committee recommended using salmeterol only as continuation therapy if the patient has demonstrated very good response to the drug before pregnancy. The committee also recognized the potential role of salmeterol as add-on therapy if the patient is not adequately controlled on inhaled steroids. The committee expanded the recommended inhaled steroids to include budesonide, as there have been reassuring studies regarding its use. The position statement also concluded that “it would not be unreasonable” to continue a different inhaled steroid, such as fluticasone, if the patient was well controlled with the drug before pregnancy. After reviewing the data on oral steroids in pregnancy, the committee concluded that the benefits of the drug for severe asthma during pregnancy “still outweigh the risks.” Finally, with regard to leukotriene modifiers, the committee recommended avoiding zileuton because of concerning animal data. In contrast, the animal data for zafirlukast and montelukast have been reassuring. The latter two agents are only recommended for those patients who have shown a “uniquely favorable response before becoming pregnant.” Despite the recommendations calling for aggressive treatment of asthma during pregnancy, a study of pregnant women presenting with asthma exacerbations to the emergency department showed that they were less likely than nonpregnant asthmatic patients to be treated with corticosteroids (38% vs 64%, P ⫽ 0.002) and were almost three times more likely to report an ongoing exacerbation 2 weeks later.26 This is just one more example of how some physicians are reluctant to use steroids even when they are indicated. Rhinitis during Pregnancy The hormonal changes of pregnancy are often invoked to explain an apparent association between rhinitis symptoms and pregnancy. But rhinitis of pregnancy is a controversial disorder. A more appropriate description is rhinitis during pregnancy, as both pregnancy and rhinitis are very common and may intersect without a strict cause-and-effect relationship. Estrogen administration to animals has been shown to cause swelling of nasal mucosa, possibly mediated through increased levels of acetylcholine.27,28 The increased blood volume of pregnancy and progesterone-induced vascular smooth muscle relaxation may also lead to increased nasal vascular pooling manifesting as nasal congestion.28,29 More recently, estrogen has been shown to increase the level of H1-receptor mRNA in nasal epithelial cells30 and to enhance eosinophil adhesion to mucosal microvascular endothelial cells in vitro.31 Despite the possible hormonal effects on the nasal mucosa and the marked increase of these hormones in pregnancy (100- to 1,000-fold), only 20 to 30% of pregnant women have significant nasal symptoms.27,32 Rhinitis in nonpregnant women has been reported to occur in up to 20% of the

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population.28 Therefore, rhinitis solely attributable to pregnancy may not be a distinct entity. Despite lack of hard data, some authors assert that allergic rhinitis, bacterial rhinosinusitis, and rhinitis medicamentosa are much more common causes of nasal symptoms in pregnancy than any specific vasomotor rhinitis of pregnancy.28 Mabry27 looked at this issue more formally. He interviewed 66 random pregnant women about nasal symptoms. He found that the occurrence of new onset nasal symptoms during pregnancy was no greater than might be explained by chance in a similar nonpregnant population, although he recognized the need for a prospective study to validate this finding. There might be a temptation to attribute nasal symptoms during pregnancy to a possible estrogenic effect on the nasal mucosa, but a proper workup is still indicated. Allergic rhinitis is common in both pregnant and nonpregnant women.28 For diagnosis of allergic etiologies in the pregnant patient, radioallergosorbent testing is preferred to skin testing, because of the risk, albeit small, of systemic reactions during skin testing.28,29 Rhinitis medicamentosa appears to be particularly common in pregnancy, perhaps attributable to the desire to avoid systemic medications. Mabry27 found rhinitis medicamentosa in an amazing 62.5% of pregnant women with rhinitis symptoms. As topical decongestants are available over-thecounter, it is difficult for the physician to monitor their appropriate use. The patient history must always include directed questions about the use of these medications. Bacterial rhinosinusitis has been reported to be six times more common in pregnant than nonpregnant women and may be the underlying cause of new-onset nasal symptoms.33 Many of these patients will lack the classic signs and symptoms of sinusitis, making diagnosis difficult. Limited sinus radiography, with appropriate fetal shielding, may be required on occasion.29 The underlying cause of increased sinusitis in pregnancy is unclear, although it is more likely related to local factors than any systemic immunodeficiency.28 Hormone-induced changes in nasal mucosa and sinus ciliary activity may result in stagnation of secretions, predisposing to infection.27 Ellegard and Karlsson34 have attempted to define a distinct entity of pregnancy rhinitis and its possible causes and treatment. They defined pregnancy rhinitis as new-onset subjective nasal congestion in the last 6 weeks or more of pregnancy, without signs of infection or known allergic disease, which resolves completely within 2 weeks after delivery. Of 23 women initially followed through pregnancy, 5 (22%) met the definition of pregnancy rhinitis. Although the subjective nasal symptoms were significantly lower after delivery than during pregnancy, the mean values of nasal peak expiratory flow rates were unchanged. One explanation the authors give for the discrepancy between the subjective and objective measures is a psychologic one: the new mothers minimized their symptoms once the baby had arrived. But if this is a distinct entity attributable to pregnancy, resolution after delivery should be more than just imagined. There may also

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have been overlap among patients with rhinitis medicamentosa and pregnancy rhinitis. In a separate report with the same patients, Ellegard et al found that the five women with pregnancy rhinitis had significantly higher levels of placental growth hormone than the women who did not meet the definition. There was no association between pregnancy rhinitis and the levels of estradiol or progesterone. Placental growth hormone is similar in structure to human growth hormone, but is released in continuous fashion after the first trimester, unlike the normal episodic release of human growth hormone. Placental growth hormone is felt to play a role in regulating nutrients available to the fetus. Interestingly, acromegaly is associated with hypertrophy of the sinus mucosa. The elevated levels of placental growth hormone may have a similar effect.35 In later studies, Ellegard and Karlsson also found pregnancy rhinitis to be associated with significantly higher levels of specific IgE to house-dust mites36 and with smoking.32 But these latter associations would argue against pregnancy rhinitis being solely attributable to pregnancy. Their latest study37 examined the efficacy of topical fluticasone in pregnancy rhinitis. In a double-blind, placebo-controlled, randomized, adequately powered study, fluticasone treatment was no better than placebo for both subjective and objective outcomes. As most confounding forms of rhinitis would be expected to respond to fluticasone, the lack of a steroid effect may be evidence for pregnancy rhinitis as a distinct entity. If pregnancy rhinitis is characterized by noninflammatory nasal congestion, it would not be surprising that fluticasone has no effect. It might also explain why topical decongestants are so popular among pregnant women, as they would be more effective than alternatives at treating the primary congestion. The Joint Task Force on Practice Parameters from the American Academy of Allergy, Asthma and Immunology33 published treatment recommendations for allergic rhinitis in 1998, including treatment during pregnancy. For allergic rhinitis in pregnancy, avoidance of allergens and irritants (eg, cigarette smoke) must be stressed. First-line therapy should be nasal cromolyn, because it is applied topically and has reassuring human and animal data. If this is inadequate, intranasal beclomethasone would be the nasal steroid of choice because of reassuring data with beclomethasone in asthma. Topical beclomethasone may also be used to overcome rhinitis medicamentosa. For vasomotor rhinitis of pregnancy, the task force recommends intranasal saline, exercise appropriate for pregnancy (exercise has documented vasoconstrictive effects in the nose), and pseudoephedrine in the second and third trimesters (first trimester use of decongestants has been linked to infant gastroschisis).33 Other decongestants, should phenylpropanolamine (no longer available) and phenylephrine, should be avoided altogether, as they have been linked with malformations.28 If an antihistamine is used, chlorpheniramine is preferred because of its long history of safe use. Diphenhydramine was linked with infant cleft palate in one case-control study. Because there are too little data and experience with

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the second generation of antihistamines, chlorpheniramine is still preferred over others.38 Antibiotics with a long history of safe use in pregnancy, such as amoxicillin with or without clavulanate, erythromycin, or cephalosporins, should be used to treat sinusitis.33 Immunotherapy in Pregnancy The clinical efficacy of allergen immunotherapy (IT) has been established for both allergic rhinitis and asthma.39 But there is a long history of concern about using IT in the pregnant patient. As early as 1922, Cooke40 reported on two cases of uterine contractions caused by IT. In 1940 Francis41 reported that a systemic reaction to a grass injection caused an abortion in a pregnant woman. The concern of systemic reactions leading to pregnancy complications has led some allergists/immunologists to discontinue this form of therapy during pregnancy. In contrast, current practice guidelines for allergic rhinitis state that IT may continue during pregnancy if it is benefiting the patient without causing systemic reactions. The guidelines further discourage starting IT anew or escalating the dose during pregnancy given the greater risk of systemic reactions with increasing doses of allergen.33 The same approach may be applied to the pregnant asthmatic patient already on IT, with the understanding that patients with asthma are at increased risk for adverse reactions from IT.42 There are two retrospective studies that support the general position of the practice guidelines. In the 1978 study by Metzger et al,43 121 pregnancies from 90 women being treated with high- or moderate-dose IT were reviewed for incidence of pregnancy complications and reactions to IT. The IT-treated group was compared with a group of 147 untreated pregnancies in women with similar atopic diseases (asthma, rhinitis). The incidence of pregnancy complications was similar in both groups and less than or equal to that expected in the general population. In fact, there was a trend toward less risk of abortion in the treated group compared with the untreated group (5% vs 18%, P ⬍ 0.10). More than 1,000 months of IT were represented in this study, during which only 7 generalized reactions in 6 different mothers were recorded. None of the systemic reactions resulted in abortion. The authors concluded that “IT can be cautiously continued during pregnancy without significant risk to either mother or fetus.” A more recent study by Shaikh44 in 1993 came to the same conclusion. He reviewed 109 pregnancies in 81 women treated with IT and compared them to 82 untreated pregnancies in an atopic control group. Seven of the IT-treated patients started the therapy after becoming pregnant. There were only three systemic reactions in the IT-treated group, including one in a patient started on IT during the pregnancy. All three reactions required epinephrine, which was well tolerated. There were no subsequent complications in these three patients. The IT-treated group had pregnancy complications far below that expected in the general population. Further, the incidence of abortion was significantly lower in the treated group compared with the untreated control group

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(3.67% vs 24.4%, P ⬍ 0.05). The seven women who started IT for the first time during pregnancy had no associated pregnancy complications. IT in a pregnant woman does not seem to protect her child from allergic disease, nor does it increase the child’s risk for allergic sensitization. The offspring from the IT-treated patients in the two preceding studies did not appear to have any greater or lesser tendency for allergic sensitivity compared with that expected in children born into allergic families. Even in a well controlled study with long-term followup of offspring, Settipane et al45 found that allergen IT during pregnancy had no effect on the development of asthma, rhinitis, or positive skin tests in the children. Insect venom allergy in the pregnant patient requires special consideration. An anaphylactic event from an insect sting could cause morbidity or mortality in both mother and fetus. Using both earlier epidemiologic data and a physician survey, Schwartz et al46 have estimated the risk of Hymenoptera reactions during pregnancy, the effect of venom IT (VIT) on this risk, and the safety of VIT in pregnant women. The chance of being stung during a pregnancy is approximately 10%. If the patient is allergic to the insect, there is a 40 to 60% chance of anaphylaxis. The resultant risk of anaphylaxis in any pregnancy is therefore approximately 4 to 6%. This is similar to the 5% risk of systemic reaction during the induction phase of VIT, which is likely offset by the reaction occurring in front of the physician. Once at maintenance, the risk for systemic reaction from VIT falls to less than 1%. VIT is 98 to 99% protective if the patient is stung. The surveys returned by practicing allergists/immunologists yielded 43 pregnancies in 26 women treated with VIT. Only two minor adverse reactions to the VIT were reported in this group (large local swelling and mild worsening of asthma). There had been five field stings during the 43 pregnancies. Only one sting resulted in a mild systemic cutaneous reaction that did not require any therapy. The pregnancy complication rate in this group receiving VIT was no higher than expected in the general population, although there was no control group of venom-sensitive pregnant patients who had refused VIT. The authors conclude that maintenance VIT is relatively safe and effective in the pregnant patient. Initiating VIT during pregnancy must be weighed against the risk of systemic reactions from the therapy. Drug Desensitization during Pregnancy A drug desensitization should only be performed after weighing the risks of the procedure with the expected benefits from the drug. The pregnant patient is no different. Penicillin is the drug of choice for treating syphilis. In the pregnant patient with syphilis and a documented allergy to penicillin, a desensitization procedure must be performed. The alternative therapy of erythromycin is less effective and may not cross the placenta to treat the fetus. Wendel et al47 reported their experience with 15 pregnant women requiring penicillin desensitization after sensitivity was documented by positive penicillin skin testing. Thirteen of the patients had syphilis, 1

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had listeria sepsis, and 1 Streptococcus viridans endocarditis. An oral desensitization protocol was used. Five of the patients developed either mild urticaria or pruritus during the desensitization or treatment period. There were no systemic reactions. All infections were successfully treated, although the patient with listeria sepsis aborted before parenteral ampicillin therapy could begin. The infants born to the patients with syphilis had no evidence of neonatal syphilis. Thus, oral penicillin desensitization during pregnancy is safe and allows for effective treatment of serious infections. Intravenous Ig (IVIG) in Pregnancy Hypogammaglobulinemia can be diagnosed for the first time during pregnancy.48 A much more likely scenario for the allergist/immunologist, however, is to have a patient with known common variable immunodeficiency (CVID) who then becomes pregnant. Adequate IVIG replacement therapy in the mother is important for both mother and fetus, as the newborn’s humoral immunity is dependent upon transplacental transfer of antibody from the mother. If the mother has adequate replacement throughout pregnancy (measured by trough levels ⬎500 mg/dL), this should suffice for the offspring as well. There will be no need to increase the frequency of IVIG administration during the third trimester.49 There have been case reports of adequate placental transfer with IVIG doses ranging from 300 mg/kg monthly to 400 mg/kg every 3 weeks.48,49 Rapid subcutaneous Ig replacement therapy at home at a dose of 100 mg/kg/week throughout pregnancy has also resulted in adequate cord blood IgG concentrations in four women with CVID.50 In all of these reports, the replacement therapy was well tolerated with no systemic reactions. Pregnancy Complications and Atopic Disease in the Offspring A number of recent studies have examined the possible link between pregnancy complications and later development of atopic illnesses in the offspring. A case-control study from the United Kingdom found an association between respiratory tract infections during pregnancy and childhood asthma (odds ratio 1.69, P ⫽ 0.03). Also, the more such infections the mother had during pregnancy, the higher the likelihood of asthma in the offspring (P ⫽ 0.02 for trend).51 Two studies from Finland suggested an association between Cesarean section and risk of asthma in both childhood52 and adulthood.53 Other endpoints of atopy were not associated with Cesarean section delivery, suggesting that the mechanism for increased asthma was independent of overall atopic risk. A Norwegian study found that uterus-related complications, such as hemorrhage or preterm contractions, were associated with a threefold increased risk of both asthma and allergic rhinitis at age 4. Cesarean delivery did not convey increased risk for these diagnoses by age 4.54 All of these studies are limited by their retrospective methodology, with potential for uncontrolled confounders and recall bias. Nonetheless, if the link between Cesarean delivery and asthma holds up under

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further study, it would be another good reason to minimize the number of Cesarean sections that are currently performed. Prematurity and low birth weight are risk factors for recurrent wheezing and hospital admission for asthma in the preschool years,55,56 but it is not clear if this effect persists. In 1985 Bertrand et al57 found that premature infants (approximately 33 weeks gestation and 2,000 g) had significantly decreased peak expiratory flow rate when evaluated at ages 7 to 12 years. The finding was strongest in patients with respiratory distress syndrome (mean FEV1 70% compared with 86% in controls). Other studies have reproduced these findings in preterm infants with low birth weight at a similar period of followup (7 to 9 years of age),58,59 although in one study,60 the reduction in peak expiratory flow rate was only seen in those children who had had bronchopulmonary dysplasia in the newborn period. Still other studies have suggested an increased incidence of bronchial hyperreactivity later in childhood in low birth weight61 and premature62 children. In a recent cohort study from Australia, characterized by longer followup (14 years) and smaller and more premature infants than the earlier studies, there was a significant reduction in FEV1 compared with normal controls (95% vs 105% predicted), especially in those with a history of bronchopulmonary dysplasia. However, overall lung function at age 14 years was mostly normal in these patients, and they were no more likely than the control group to have a diagnosis of current asthma or to require hospitalization.63 Thus, the increased risk of wheezing episodes and hospital admissions in early childhood in premature children may not persist into adolescence. Hereditary Angioedema (HAE) and Pregnancy Although it is reasonably rare, the allergist must be aware of HAE with regard to diagnosis and management because the disease may be fatal if not properly handled, and most physicians are unaware of the illness. There are particular hazards of HAE when it exists during pregnancy. This is not the place to review HAE in general. The reader is referred to standard texts, a recent review by Nzeako et al,64 and the website for the Hereditary Angioedema Association.65 There are a few points which should be emphasized, however. 1) HAE does not itch, nor is urticaria a part of the syndrome. Epinephrine, antihistamines, and corticosteroids are not indicated for treatment. 2) Attacks of edema (often painful) may be obvious, as in the face, hands, and upper airways. However, severe crampy abdominal pain is frequent, and reflects edema in the gut. 3) The family history may be negative in 50% of HAE cases. With regard to pregnancy: 1) In view of the fact that trauma is a frequent trigger for acute HAE attacks, it is surprising that the trauma of decidual separation, labor, and delivery are not more devastating when pregnancy ends. Nevertheless, the end of a successful pregnancy is frequently benign from the HAE standpoint.

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2) The effect of pregnancy on HAE varies from patient to patient.66 Many women are no worse or even better in pregnancy. Some, however, get more frequent attacks, and the postpartum period may be dangerous. Thus, it is important to educate and counsel the pregnant patient, and to be vigilant. 3) Attacks of abdominal pain in the pregnant woman must be carefully considered. They may reflect the HAE, be a pregnancy complication, or be unrelated to either. A careful diagnostic workup of this complaint is mandatory. 4) The usual prophylaxis of HAE using impeded androgens (eg, Stanozolol, Sanofi-Synthelabo, New York, NY) is contraindicated in pregnancy because of the danger of virilizing the fetus. Androgens have been used in the last month or two with no apparent effect on the mother and only transient virilization of the baby. 5) Acute attacks of HAE in the pregnant woman are probably best treated by fresh frozen plasma (FFP). (As of the writing of this article, the FDA has not approved BaxterMarion’s product, C1 INH concentrate). There is a theoretical risk in the use of FFP for acute attacks, as it may provide relatively more substrate (in the form of complement components) than C1 INH. This has prompted some authors to recommend against its use.67,68 However, there are no known case reports of FFP worsening symptoms in pregnant patients, and others have favored its use.69 6) Prophylaxis against HAE attacks raises difficult questions during pregnancy. FFP has been used, as have tranexamic acid and epsilon aminocaproic acid. FFP is probably the safest reagent, but experience is limited.68 Many physicians do not use routine prophylaxis but reserve it for acute attacks, unless it is quite clear that pregnancy is aggravating the HAE to an unacceptable level. CONCLUSION The immunologic aspects of pregnancy are vast. This review has covered topics that are of importance to the practicing allergist/immunologist. Despite the fetus being a hemiallogeneic allograft, there are multiple mechanisms that prevent immunologic rejection of the fetus in the uterus, including a possible uterine tilt toward Th-2 responses. Interestingly, these mechanisms protect the fetus without significantly jeopardizing systemic immunocompetence of the mother. Asthma has been linked to both maternal and fetal complications and should be treated aggressively during pregnancy. Rhinitis solely attributable to pregnancy may not be a distinct entity. If it does exist, it is probably less common than other causes of rhinitis symptoms during pregnancy, such as allergic rhinitis, bacterial sinusitis, and rhinitis medicamentosa. IT should be continued during pregnancy if it is benefiting the patient without causing reactions. Antibiotic desensitization can be performed safely during pregnancy to treat serious infections. There are some preliminary data suggesting a link between certain pregnancy complications, such as respiratory tract infections, Cesarean section, and uterus-related complications, and the later development of atopic illnesses in the offspring. Prematurity and low birth weight appear to be risk

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factors for asthma in early childhood, but this effect may not persist into adolescence. Finally, the allergist/immunologist should be aware of special considerations for HAE in the pregnant patient. REFERENCES 1. Medawar PB. Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates. Symp Soc Exp Biol 1953;11:320 –338. 2. Beer AE, Billingham RE. Immunobiology of mammalian reproduction. In: Dixon FJ, Kunkel HG, editors. Advances in Immunology. New York: Academic Press, 1971:1– 84. 3. Norwitz ER, Schust DJ, Fisher SJ. Implantation and the survival of early pregnancy. N Engl J Med 2001;345:1400 –1408. 4. Claman HN. The Immunology of Human Pregnancy. Totowa, NJ: Humana Press, 1993. 5. Carosella ED, Paul P, Moreau P, Rouas-Freiss N. HLA-G and HLA-E: fundamental and pathophysiological aspects. Immunol Today 2000;21:52–53. 6. Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH-2 phenomenon? Immunol Today 1993; 14:353–356. 7. Mellor AL, Munn DH. Immunology at the maternal-fetal interface: lessons for T cell tolerance and suppression. Annu Rev Immunol 2000;18:367–391. 8. Boothby LA, Doering PL. FDA labeling system for drugs in pregnancy. Ann Pharmacother 2001;35:1485–1489. 9. Teratology Society Public Affairs Committee. FDA classification of drugs for teratogenic risk. Teratology 1994;49:446 – 447. 10. Addis A, Sharabi S, Bonati M. Risk classification systems for drug use during pregnancy: are they a reliable source of information? Drug Saf 2000;23:245–253. 11. Schatz M. Interrelationships between asthma and pregnancy: a literature review. J Allergy Clin Immunol 1999;103:S330 — S336. 12. Liu S, Wen SW, Demissie K, et al. Maternal asthma and pregnancy outcomes: a retrospective cohort study. Am J Obstet Gynecol 2001;184:90 –96. 13. Juniper EF, Newhouse MT. Effect of pregnancy on asthma: a systematic review and meta-analysis. In: Schatz M, Zeiger RS, Claman HN, editors. Asthma and Immunological Diseases in Pregnancy and Early Infancy. New York: Marcel Dekker, 1993: 401– 427. 14. Gluck JC, Gluck PA. The effects of pregnancy on asthma: a prospective study. Ann Allergy 1976;37:164 –168. 15. Schatz M, Harden K, Forsythe A, et al. The course of asthma during pregnancy, post partum, and with successive pregnancies: a prospective analysis. J Allergy Clin Immunol 1988;81:509 –517. 16. Tan KS, Thomson NC. Asthma in pregnancy. Am J Med 2000;109:727–733. 17. Greenberger PA, Patterson R. The outcome of pregnancy complicated by severe asthma. Allergy Proc 1988;9:539 –543. 18. Schatz M, Zeiger RS, Hoffman CP. Intrauterine growth is related to gestational pulmonary function in pregnant asthmatic women. Chest 1990;98:389 –392. 19. Rosa F. Databases in the assessment of the effects of drugs during pregnancy. J Allergy Clin Immunol 1999;103:S360 — S361. 20. Schatz M, Zeiger RS, Harden K, et al. The safety of asthma and

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allergy medications during pregnancy. J Allergy Clin Immunol 1997;100:301–306. Stenius-Aarniala BS, Hedman J, Teramo KA. Acute asthma during pregnancy. Thorax 1996;51:411– 414. Wendel PJ, Ramin SM, Barnett-Hamm C, et al. Asthma treatment in pregnancy: a randomized controlled study. Am J Obstet Gynecol 1996;175:150 –154. Clifton VL, Giles WB, Smith R, et al. Alterations of placental vascular function in asthmatic pregnancies. Am J Respir Crit Care Med 2001;164:546 –553. Luskin AT. An overview of the recommendations of the Working Group on Asthma and Pregnancy. J Allergy Clin Immunol 1999;103:S350 —S353. The American College of Obstetricians and Gynecologists (ACOG) and The American College of Allergy, Asthma and Immunology (ACAAI). The use of newer asthma and allergy medications during pregnancy. Ann Allergy Asthma Immunol 2000;84:475– 480. Cydulka RK, Emerman CL, Schreiber D, et al. Acute asthma among pregnant women presenting to the emergency department. Am J Respir Crit Care Med 1999;160:887– 892. Mabry RL. Rhinitis of pregnancy. South Med J 1986;79: 965–971. Schatz M, Zeiger RS. Diagnosis and management of rhinitis during pregnancy. Allergy Proc 1988;9:545–554. Incaudo GA. Diagnosis and treatment of rhinitis during pregnancy and lactation. Clin Rev Allergy 1987;5:325–337. Hamano N, Terada N, Maesako K, et al. Expression of histamine receptors in nasal epithelial cells and endothelial cells–the effects of sex hormones. Int Arch Allergy Immunol 1998;115: 220 –227. Hamano N, Terada N, Maesako K, et al. Effect of sex hormones on eosinophilic inflammation in nasal mucosa. Allergy Asthma Proc 1998;19:263–269. Ellegard E, Hellgren M, Toren K, Karlsson G. The incidence of pregnancy rhinitis. Gynecol Obstet Invest 2000;49:98 –101. Dykewicz MS, Fineman S, Skoner DP, et al. Diagnosis and management of rhinitis: complete guidelines of the Joint Task Force on Practice Parameters in Allergy, Asthma and Immunology. American Academy of Allergy, Asthma, and Immunology. Ann Allergy Asthma Immunol 1998;81:478 –518. Ellegard E, Karlsson G. Nasal congestion during pregnancy. Clin Otolaryngol 1999;24:307–311. Ellegard E, Oscarsson J, Bougoussa M, et al. Serum level of placental growth hormone is raised in pregnancy rhinitis. Arch Otolaryngol Head Neck Surg 1998;124:439 – 443. Ellegard E, Karlsson G. IgE-mediated reactions and hyperreactivity in pregnancy rhinitis. Arch Otolaryngol Head Neck Surg 1999;125:1121–1125. Ellegard EK, Hellgren M, Karlsson NG. Fluticasone propionate aqueous nasal spray in pregnancy rhinitis. Clin Otolaryngol 2001;26:394 – 400. Schatz M, Petitti D. Antihistamines and pregnancy. Ann Allergy Asthma Immunol 1997;78:157–159. Nelson HS. The use of standardized extracts in allergen immunotherapy. J Allergy Clin Immunol 2000;106:41– 45. Cooke RA. Studies in specific hypersensitiveness. J Immunol 1922;7:119. Francis N. Abortion after grass pollen injection. J Allergy 1941;12:559. Lockey RF, Benedict LM, Turkeltaub PC, Bukantz SC. Fatal-

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ities from immunotherapy (IT) and skin testing (ST). J Allergy Clin Immunol 1987;79:660 – 677. Metzger WJ, Turner E, Patterson R. The safety of immunotherapy during pregnancy. J Allergy Clin Immunol 1978;61: 268 –272. Shaikh WA. A retrospective study on the safety of immunotherapy in pregnancy. Clin Exp Allergy 1993;23:857– 860. Settipane RA, Chafee FH, Settipane GA. Pollen immunotherapy during pregnancy: long-term follow-up of offsprings. Allergy Proc 1988;9:555–561. Schwartz HJ, Golden DB, Lockey RF. Venom immunotherapy in the Hymenoptera-allergic pregnant patient. J Allergy Clin Immunol 1990;85:709 –712. Wendel GD Jr, Stark BJ, Jamison RB, et al. Penicillin allergy and desensitization in serious infections during pregnancy. N Engl J Med 1985;312:1229 –1232. Olatunbosun OA. Hypogammaglobulinemia associated with pregnancy. Int J Gynecol Obstet 1993;40:162–163. Schaffer FM, Newton JA. Intravenous gamma globulin administration to common variable immunodeficient women during pregnancy: case report and review of the literature. J Perinatol 1994;14:114 –117. Gardulf A, Andersson E, Lindqvist M, et al. Rapid subcutaneous IgG replacement therapy at home for pregnant immunodeficient women. J Clin Immunol 2001;21:150 –154. Hughes CH, Jones RC, Wright DE, Dobbs FF. A retrospective study of the relationship between childhood asthma and respiratory infection during gestation. Clin Exp Allergy 1999;29: 1378 –1381. Xu B, Pekkanen J, Jarvelin MR. Obstetric complications and asthma in childhood. J Asthma 2000;37:589 –594. Xu B, Pekkanen J, Hartikainen AL, Jarvelin MR. Caesarean section and risk of asthma and allergy in adulthood. J Allergy Clin Immunol 2001;107:732–733. Nafstad P, Magnus P, Jaakkola JJ. Risk of childhood asthma and allergic rhinitis in relation to pregnancy complications. J Allergy Clin Immunol 2000;106:867– 873. Kitchen WH, Ford GW, Doyle LW, et al. Health and hospital readmissions of very-low-birth-weight and normal-birth-weight children. Am J Dis Child 1990;144:213–218. Schaubel D, Johansen H, Dutta M, et al. Neonatal characteristics as risk factors for preschool asthma. J Asthma 1996;33: 255–264. Bertrand JM, Riley SP, Popkin J, Coates AL. The long-term pulmonary sequelae of prematurity: the role of familial airway hyperreactivity and the respiratory distress syndrome. N Engl J Med 1985;312:742–745. Chan KN, Noble-Jamieson CM, Elliman A, et al. Lung function in children of low birth weight. Arch Dis Child 1989;64: 1284 –1293. McLeod A, Ross P, Mitchell S, et al. Respiratory health in a total very low birthweight cohort and their classroom controls. Arch Dis Child 1996;74:188 –194. Gross SJ, Iannuzzi DM, Kveselis DA, Anbar RD. Effect of preterm birth on pulmonary function at school age: a prospective controlled study. J Pediatr 1998;133:188 –192. Wjst M, Popescu M, Trepka MJ, et al. Pulmonary function in children with initial low birth weight. Pediatr Allergy Immunol 1998;9:80 –90. MacLusky IB, Stringer D, Zarfen J, et al. Cardiorespiratory status in long-term survivors of prematurity, with and without

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hyaline membrane disease. Pediatr Pulmonol 1986;2:94 –102. 63. Doyle LW, Cheung MM, Ford GW, et al. Birth weight ⬍ 1501 g and respiratory health at age 14. Arch Dis Child 2001; 84:40 – 44. 64. Nzeako UC, Frigas E, Tremaine WJ. Hereditary angioedema: a broad review for clinicians. Arch Intern Med 2001;161: 2417–2429. 65. Hereditary Angioedema Association resource page. Available at: http://www.hereditaryangioedema.com. Accessed June 2002. 66. Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema: the clinical syndrome and its management. Ann Intern Med 1976;4:580 –593. 67. White GM, Zeiger RS. Cutaneous diseases during pregnancy. In: Schatz M, Zeiger RS, Claman HN, editors. Asthma and Immunological Diseases in Pregnancy and Early Infancy. New York: Marcel Dekker, 1998:355.

68. Galan HL, Reedy MB, Starr J, Knight AB. Fresh frozen plasma prophylaxis for hereditary angioedema during pregnancy. J Reprod Med 1996;41:541–544. 69. Hsieh FH, Sheffer AL. Episodic swelling in a pregnant woman from Bangladesh: evaluation and management of angioedema in pregnancy. Allergy Asthma Proc 2002;23:157–161. Requests for reprints should be addressed to: Henry Claman, MD Allergy and Clinical Immunology Mail Stop B164, Room 4627D University of Colorado Health Sciences Center 4200 East 9th Avenue Denver, CO 80262 E-mail: [email protected]

CME Examination 1–5, Palmer GW, Claman HN. 2002;89:350 –359. CME Test Questions 1. All of the following are true regarding the survival of the fetal allograft EXCEPT: a. The decidua contains high amounts of complement regulatory proteins that interfere with complement activation. b. HLA-E, F, and G present on the trophoblast are potent inhibitors of NK cell activity. c. The trophoblast expresses high levels of paternally derived HLA-A, B, and C. d. Maternal IgM antibodies directed against paternally derived antigens do not cross the placenta. 2. Which of the following is NOT true regarding the interaction of asthma and pregnancy? a. Asthma exacerbations during delivery are very common. b. The more severe the asthma is before pregnancy, the more likely it is to worsen during pregnancy. c. Asthmatic mothers seem to have an increased risk of preeclampsia. d. In an asthmatic population, FEV1 in the mother has correlated directly with intrauterine growth of the fetus. 3. Which of the following answers regarding rhinitis symptoms in pregnancy is true? a. Rhinitis symptoms affect the majority of pregnant women.

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b. Vasomotor rhinitis of pregnancy is the most common cause of rhinitis symptoms during pregnancy. c. Bacterial sinusitis is more common in pregnant women than nonpregnant women. d. Fluticasone nasal spray is an effective treatment for pregnancy rhinitis. 4. Which of the following treatments or procedures can be safely used in pregnancy? a. Continuation of maintenance IT for aeroallergens. b. Continuation of maintenance VIT. c. Desensitization procedure for penicillin allergy. d. IVIG therapy for CVID. e. All of the above. 5. All of the following are true regarding HAE and pregnancy EXCEPT: a. Epinephrine, antihistamines, and corticosteroids are not indicated for treatment of HAE. b. The family history may be negative in a patient with HAE. c. Most patients with HAE get more frequent attacks during pregnancy. d. FFP is preferred over androgens for HAE prophylaxis during pregnancy. Answers found on page 428.

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