http://orcid.org/0000-0003-1200-6242
Abstract
Alpha-1 Antitrypsin Deficiency (A1AD) is a hereditary condition characterized by low levels of circulating alpha-antitrypsin (AAT) in plasma. It is the best understood genetic risk factor for the development of chronic obstructive pulmonary disease (COPD). The diagnosis of A1AD is under-recognized. While there is a significant heterogeneity in disease presentation in relation to the severity of symptoms and prognosis, it is not uncommon for young individuals, including pregnant women to already have moderate to advanced lung disease at the time of diagnosis. Reductions in AAT levels may have unique implications for a gravid patient beyond that of lung disease. Care of the pregnant A1AD patient with chronic lung disease follows the principles of care for the management of airways disease in general with control of symptoms and reduction in exacerbation risk the main tenets of treatment. The effect of A1AD and augmentation in pregnancy has not been studied and thus care is reliant on expert opinion and clinical experience. Providers caring for pregnant patients with A1AD should consider referral to health care systems and providers with specific expertise in A1AD. Ultimately the decision is left to the individual patient and their physician to weigh the risk benefit of cessation or continuation of therapies. In this review, we present the perinatal course of a woman with A1AD and review the available literature pertaining to AAT and pregnancy and discuss the clinical implications.
Introduction
Alpha-1 Antitrypsin Deficiency (A1AD) is a hereditary condition characterized by low levels of circulating alpha-1 antitrypsin (AAT) in plasma. It is the best understood genetic risk factor for the development of chronic obstructive pulmonary disease (COPD) [Citation1,Citation2]. It is often under-recognized as there is significant heterogeneity in disease presentation in relation to the severity of symptoms and prognosis. It is not uncommon for young individuals and women of child bearing potential to already have moderate to advanced lung disease at the time of initial diagnosis [Citation1]. In this review, we present the perinatal course of a woman with A1AD induced lung disease and review the available literature pertaining to A1AD and pregnancy as well discuss the clinical implications of reduced AAT levels and potential impact for the pregnant patient.
Case
The patient is a 35 year old woman gravida 1 para 0 with a diagnosis of A1AD at 9 weeks gestation who presented to pulmonary clinic following her pregnancy diagnosis. Her A1AD was diagnosed in the context of a positive family history during a previous workup for angioedema and urticaria approximately 6 years prior to her current presentation. Her AAT phenotype was determined to be PiZZ with an initial level of 21 mg/dL. She had been previously diagnosed with asthma during early adulthood following the development of exertional dyspnea and cough with normal spirometry. A subsequent computed tomography (CT) scan of her chest revealed lower lobe bullae and emphysema as well as mild air trapping on expiratory images. Her airways disease was initially managed with maintenance budesonide/formoterol twice daily inhaler, oral montelukast and albuterol inhaler as needed for rescue. Augmentation therapy was initiated 3 years prior to her current presentation due to a combination of recurrent exacerbations and a declining forced expiratory volume in 1 s (FEV1) and diffusion capacity despite adherence to her maintenance regimen. Additional work up revealed positive PR3 antibodies at a low titer and she was clinically diagnosed with panniculitis based on a non-resolving rash that completely resolved within her 2nd week of augmentation. A superficial skin biopsy was equivocal for panniculitis.
On her current presentation to the clinic she reported a stable clinical course with no flares of her lung disease and adherence to her maintenance inhalers. She had not required the use of her rescue inhaler in several months. Review of systems was positive for weight gain. She did endorse mild orthopnea but no exertional symptoms or lower extremity swelling. She noted a recent emergency room visit secondary to vaginal spotting that resolved without specific intervention. Her exam revealed normal vital signs with a respiratory rate of 14, oxygen saturations 100% on room air and clear lung exam with normal excursion and effort. PFTs on her present visit were with normal limits (see ).
Table 1. Case spirometric trend.
Discussion
Alpha-1 antitrypsin
AAT is a broad spectrum protease inhibitor with immunomodulatory properties produced predominantly by the liver in both a constitutive and inducible fashion [Citation3]. It functions as the main inhibitor of neutrophil elastase (NE), a proteolytic enzyme elaborated by neutrophils. When unopposed, NE can induce structural damage in the respiratory tract. AAT has additional activity in neutralizing other serine proteases such as proteinase 3 (PR3), cathespin G, and myeloperoxidase from neutrophils, chymase and tryptase from mast cells, trypsin from the pancreas, granzyme-b from T lymphocytes and serine proteinases plasmin, thrombin, urokinase and factor Xa in the coagulation cascade [Citation4]. In total, AAT accounts for >90% of anti-protease activity in the human serum [Citation4]. The human body produces on average 34 mg/kg of AAT per day. Up to 80% of AAT diffuses into interstitial tissues, while 0.5–10% of AAT reaches biological fluids such as saliva, tears, milk, semen, bile, urine and Cerebrospinal Fluid (CSF) [Citation4]. Its expression is co-dominant, with plasma levels determined by both AAT alleles. There is marked variability in AAT levels within individuals, in part because of its induction as an acute phase reactant in response to acute tissue damage, tissue inflammation and estrogen [Citation4].
Abnormalities in the AAT protein as the result of allelic variation are risk factors for human disease. There are currently more than 100 known alleles that code for the AAT protein, with more than 30 alleles associated with deficiency or dysfunction [Citation1,Citation4]. The three most common allelic variants of AAT are the M, S and Z, account for 95–97% of the world’s population [Citation1,Citation5]. The M allele is the most common allele, and homozygous expression of two M alleles is the “wild type” form of the protein, with approximately 95% of the United States population MM homozygous [Citation1]. The most common deficient allele is Z which is found in 95% of individuals with clinically recognized A1AD, while the S allele is the most common allele worldwide that accounts for decreased circulating levels [Citation1].
While the protease/antiprotease imbalance has been the longstanding dogma in relation to development of clinically relevant lung disease, emerging laboratory and clinical studies in various autoimmune diseases, such as diabetes mellitus, multiple sclerosis and graft versus host disease, as well as the observation of elevated levels in the 3rd trimester of pregnancy, has illuminated the emerging biologic importance of this protein as a key immune modulator [Citation6]. AAT likely encompasses a broader role in the inflammatory process, acting to limit bystander cell injury during acute inflammation, influencing immune tolerance [Citation7], and performing roles in the transition between the innate and adaptive immune response [Citation6–8]. It is also now speculated to have important function in human gestation [Citation9].
Alpha-1 antitrypsin deficiency and clinical manifestations
A1AD is not itself a disease state, but rather a condition characterized by low circulating levels of AAT in plasma that can predispose affected individuals to certain conditions. It is most often biochemically associated with homozygosity of Z allele, frequently denoted as PiZZ, which predisposes an individual to developing obstructive lung disease. The development of early onset, severe, basilar predominant emphysema is the most common finding, though several additional phenotypes of chronic obstructive lung disease (chronic bronchitis, bronchiectasis and asthma) are also commonly reported. A presumed protective threshold of 11 µmol/L (or 80 mg/dL) of circulating AAT has come from historical observations; those individuals who are heterozygous for deficient alleles with circulating levels above this concentration are typically not at an increased risk of developing COPD. Additional clinical manifestations include liver disease due to polymerization of the malformed AAT proteins within the hepatocyte. Hepatic sequelae are best described in the PiZZ phenotype, although liver damage has been described to a lesser extent with other mutations and heterozygosity [Citation10]. Panniculitis is an uncommon finding resulting in inflammation of the panniculus, occurring predominantly in patients with PiZZ A1AD, possibly related to polymerization of the Z protein within soft tissues and promotion of a localized inflammatory process. Recent case reports indicate an increased risk of ANCA associated vasculitis (anti-Proteinase-3) in A1AD [Citation3,Citation11].
Alpha-1 antitrypsin’s role in pregnancy
AAT levels typically increase 4-6 fold during pregnancy and return to baseline pre-pregnancy levels post-partum [Citation12–15]. While AAT and its role in pregnancy has been studied for decades, its significance is only now emerging as recent studies have associated alterations in AAT levels and function in a variety of pregnancy related processes, from regulation of fertility to immune tolerance to obstetric complications [Citation9,Citation16–20].
The potential implications of reduced AAT levels in pregnancy are several-fold. Pre-eclampsia is the most studied obstetric complication that has been associated with reductions in AAT serum levels and inhibitory capacity [Citation16,Citation19,Citation21–24]. In addition, reductions in serum levels and inhibitory capacity have also been associated with recurrent and sporadic pregnancy loss where the reduced AAT level and activity was also accompanied by elevated circulating pro-inflammatory cytokines [Citation18]. Further small case reports have also identified severe AAT reductions in preterm premature rupture of membranes[Citation17] These findings are of particular relevance as the majority of studies showed that AAT levels while reduced, remained above the putative pulmonary protective threshold of 80 mg/dL (11 μMol/L) [Citation1,Citation2,Citation25].
Given the findings that higher circulating levels of AAT are seen in pregnancy and its function in mitigating inflammation and untoward immune activation [Citation16], individuals with A1AD with preexisting chronic lung disease may be at increased risk for loss of control or clinical worsening of their lung disease and/or obstetric complications secondary to either relative or absolute deficiencies. Secondly, individuals with even with minor reductions in levels or alterations in the AAT protein, while not at increased risk for lung disease, may be at increased risk for potential obstetric complications, particularly with continued smoking exposures, as it is known to inactivate the protein [Citation26].
Alpha-1 antitrypsin deficiency induced lung disease in pregnancy
Reports of A1AD and pregnancy are limited to case reports (see ). Two cases report significant drops in FEV1 of approximately 40% during pregnancy. Giesler et al. in 1977 first reported a 37 year old female smoker with PiZZ phenotype and severe obstruction [Citation27]. While the patient did exhibit a 43% drop in her FEV1 (nadir FEV1 0.75 L) at 35 weeks gestation compared to a pre-pregnancy FEV1 of 1.3 L (predicted 2.98 L), the majority of her volume loss occurred early on in her pregnancy. Her FEV1 remained relatively stable from gestational week 15 (FEV1 0.93 L) through 5 weeks post-partum (FEV1 0.75 L) despite the patient’s pregnancy being complicated by a significant pulmonary infection requiring hospitalization [Citation27]. This case report was notable at the time as it was the first described case of a patient with A1AD carrying a pregnancy to term. Per the authors’ review of the available obstetric literature, induced abortion was often recommended in A1AD as outcomes of pregnant patients with obstructive lung disease were thought to be generally poor, presumptively due to the “rapid deterioration in pulmonary function which follows even minor respiratory infections”. Thus, the authors’ conclusion was that A1AD associated obstructive lung disease was not “a contraindication to successful outcome of pregnancy for mother and child.” This initial case report was followed up with a report by Dempsey et al. 20 years later [Citation28]. They described a 27 year old woman with severe obstructive lung disease (FEV1 1.14L) initially with stable symptoms until 25 weeks gestation where a similar reduction in FEV1 ∼ 40% was described. Pregnancy was ultimately successful with planned Cesarean section at term.
TABLE 2 Summary of A1AD and pregnancy case reports.
Two case reports document complications of pregnancy in patients with A1AD. Kennedy et al. reported a 26 year old woman with PiZZ phenotype and no pulmonary symptoms in whom pregnancy was complicated by fetal growth retardation and pre-eclampsia [Citation29]. Kuller et al. reported a 40 year old woman with a history of pregnancies complicated by premature delivery, rupture of membranes, miscarriages and spontaneous abortion [Citation30]. After donating serum for a study she was found to have AAT levels at 15% of the normal value; phenotyping revealed lack of S or Z protein, and specific genotyping was unavailable at that time. The authors speculated that AAT deficiency may have played a role in her recurrent episodes of preterm labor [Citation30].
One case report of a woman with known A1AD reported by Atkinson et al. discusses a woman with bullous emphysema [Citation31]. She was diagnosed with A1AD after developing dyspnea during the third trimester of her first pregnancy; dyspnea persisted and a chest xray showed emphysema. AAT levels were significantly reduced, but phenotyping was unavailable. Although she was counseled against future pregnancies and elected to undergo tubal ligation, she was found to be 6 weeks pregnant after completion of the tubal ligation. At 21 weeks gestation she developed a pneumothorax requiring chest tube placement. She ultimately delivered a healthy infant at term [Citation31].
In terms of extra-pulmonary manifestations of A1AD, there are two case reports of patients with PiZZ related panniculitis in the post-partum period. One report by Yesudian et al. in 2004 was of a 31 year old woman with recurrent skin symptoms related to a prior cesarean section [Citation32]. She had initially been diagnosed with an abscess but further investigation found evidence of panniculitis without overt infection. She was ultimately diagnosed with A1AD with a PiZZ phenotype. Another report by Furey et al. described a 62 year old woman with A1AD PiZZ phenotype and panniculitis who reported similar skin findings 25 years earlier at 34 weeks gestation [Citation33]. Previous skin findings had resolved after several months, and although antibiotics and prednisone had been used neither was effective in treating the skin lesions. Her more recent episode was treated with augmentation therapy and she had rapid resolution of edema and skin findings.
Management of alpha-1 antitrypsin deficiency in pregnancy
The management of all patients with A1AD starts with medical and genetic counseling. As mentioned above, A1AD is not a disease itself per se, but rather a predisposition to developing lung disease in the setting of additional risk factors [Citation1,Citation2]. General counseling on absolute tobacco abstinence including vaping as well mitigating exposure to noxious potentially harmful inhalants is paramount as initial management. Prenatal testing and preimplantation genetic diagnosis is possible for A1AD however it is of no use in predicting prognosis or disease severity due to the multifactorial nature involved in the development of lung disease as well the heterogeneity and variability of expression of obstructive lung diseases. Fetal testing is similarly not recommended for similar reasons [Citation1,Citation2]. Despite this, referral to genetic counseling should be offered. Efforts to provide patients with information regarding inheritance patterns and risk to family members is useful in to facilitate an informed decision making process.
Recommendations for care of the pregnant A1AD patient with associated chronic obstructive lung disease is largely analogous to management of airways disease in general, where focus is placed decreasing symptoms and reducing exacerbation risk [Citation34,Citation35]. While the predominant pulmonary manifestation of A1AD is emphysema, there is limited data regarding emphysema and pregnancy for clinicians to inform their approach. Given the heterogeneity of obstructive lung disease expression and varying phenotypes guidance can be extrapolated from additional experience on non A1AD associated lung diseases (asthma, bronchitis, bronchiectasis and overlap syndromes).
Non-pharmacological therapies for chronic airways disease and COPD include trigger avoidance, supplemental oxygen if needed, vaccinations and pulmonary rehabilitation as mainstays of therapy [Citation36]. Smoking cessation and reduction of secondhand smoke exposure are a critical part of both COPD and obstetric counseling.
Pharmacological therapy in COPD as well as asthma and overlap syndromes have emphasized the use long acting maintenance inhalers.; either beta-adrenergic or anti-cholinergic inhaled bronchodilators as the mainstays of medical therapy based on step, stage and/or grade [Citation36]. In COPD patients with asthmatic features or overlap combination long acting beta-agonist and inhaled corticosteroid are recommended. Because there are more extensive safety data regarding budesonide, it is typically considered the preferred inhaled corticosteroid in pregnancy (Pulmicort Flexhaler prescribing information, AstraZeneca Pharmaceuticals LP, Wilmington DE 19850 rev 10/16). The overall safety profile of inhaled medications, including inhaled steroids, inhaled beta agonists and increasingly anticholinergics in asthma is reassuring, although specific Food and Drug Administration (FDA) labeling has generally identified these medications as having inconclusive evidence for use in pregnancy, with use in pregnancy left to the physician and patient to weigh the risk and benefits in the individual circumstance [Citation37]. The American Association of Allergy, Asthma and Immunology collects data from women who use medications for asthma in pregnancy through the Vaccines and Medications in Pregnancy Surveillance System (http://www.aaaai.org/about-aaaai/strategic-relationships/vampss/vampss-consumer, accessed 3/24/2020) and is a resource for women using a variety of different medications during pregnancy.
More recent evaluations suggest that many women discontinue their controller medications after becoming aware of the pregnancy[Citation38], which may result in worsening respiratory symptoms and control of their airways disease [Citation39,Citation40]. This is of particular concern as uncontrolled airways disease is associated with adverse pregnancy outcomes including low birthweight, preeclampsia and pre-term birth [Citation41]. Thus, pregnant A1AD patients with lung disease or even patients with reduced alpha-1 antitrypsin levels may be at a theoretically increased risk of adverse events, particularly with abrupt cessation of controller therapies.
Augmentation therapy and pregnancy
Administration of exogenous AAT is a therapy specific to A1AD. Indications for initiation of augmentation therapy include PiZZ or Null phenotypes with evidence of fixed, moderate airflow obstruction on spirometry [Citation42]. Other indications include rapid decline in FEV1, evidence of emphysema on CT scan and panniculitis [Citation2]. The effect of A1AD and augmentation in pregnancy has not been studied and thus guidance is reliant on expert opinion and clinical experience. Existing case reports of A1AD and pregnancy have focused primarily whether pregnancy can be tolerated in individual patients. Reports of successful pregnancies carried to term refute early recommendations for early termination [Citation27–30,Citation32,Citation33].
Augmentation therapy has been available in the US since 1988 after initial evaluation of weekly infusion of exogenous AAT (augmentation) revealed significantly higher trough values of AAT than placebo [Citation43]. With this data, augmentation therapy was approved and has been used extensively. Prospective and observational studies have largely suggested benefit of treatment. The National Heart, Lung and Blood Institute Registry enrolled participants with severe A1AD in an observational study and found a reduction in the rate of decline of FEV1 for participants with severe obstruction [Citation44]. A more recent double blind, placebo controlled trial enrolled patients with A1AD and randomized them to administration of augmentation therapy or placebo. Computed Tomography (CT) scans at total lung capacity (TLC) showed significantly greater lung density loss in the placebo compared to the control group per year [Citation45]. There are no known pregnancy-specific safety concerns with augmentation therapy. Alpha-1 antitrypsin proteinase augmentation is considered class C in pregnancy, as human and animal data establishing drug safety during first trimester of pregnancy is lacking. AAT has been detected in breast milk [Citation46], but it is unknown if intravenous augmentation therapy is eventually secreted into breast milk. The absolute contraindications for augmentation therapy include a hypersensitivity to AAT or absolute IgA deficiency [Citation3].
The clinical decision is ultimately left to the individual patient and their physician to weigh the risks and benefits of AAT augmentation and is dependent upon various individual factors including indication, preference and clinical circumstance. Referral to an Alpha-1 Antitrypsin Clinical Resource Center (CRC) for additional guidance and experience may be of interest.
Case follow-up
During the patient’s initial visit, the majority of time was spent discussing the risks and benefits of continued therapies versus withdrawal, with a collaborative decision to continue current therapies. This included continuing with augmentation, acknowledging the limited data to guide decision-making. She was also recommended to have post-natal screening for her child, we reviewed her COPD action plan regarding early recognition and treatment of symptoms to mitigate exacerbation severity.
She was seen in follow up on several occasions through her pregnancy. At 6 months parturient, she had complaints of worsening dyspnea in setting of 24 pound weight gain with decline in FVC and FEV1 (see ). Approximately 1 month later, she experienced an exacerbation but elected to “tough it out” and did not invoke her action plan nor call the clinic to notify of her worsening symptoms. A follow-up visit was conducted 3 weeks post-partum after term vaginal delivery of a girl. Her infant was noted with to have a patent ductus arteriosus but was otherwise healthy. Her pulmonary symptoms were stable, though she mentioned a prolonged recovery following her exacerbation, with a notable, but not significant, 12% reduction in her FEV1 from baseline. She acknowledged that her adherence to her maintenance inhaler regimen was inconsistent. She did endorse some minor flares of her prior rash during this time but symptoms resolved without specific intervention. She was seen again 4 months post-partum and asymptomatic from a pulmonary standpoint but without recovery of her FEV1 to her pre-pregnancy volume. A review of systems was notable for sleep deprivation.
One year later she again presented to clinic for routine follow-up after discovering she was pregnant for the second time. At 15 weeks gestation, she denied any pulmonary complaints or flares and was compliant with her maintenance inhalers. However, pulmonary function testing demonstrated a small decline in FEV1 (2.70 L). Augmentation therapy was again continued throughout her pregnancy with follow-up at 35 weeks showing stable spirometry. Increased dyspnea was attributed to her gravid state. She was then seen approximately 5 months post-partum following delivering of a healthy baby girl at approximately 40 weeks. At this time, she endorsed increased pulmonary symptoms which corresponded with a further decrease in her FEV1 (2.53L). She additionally endorsed increased lip swelling and rashes (similar to her initial presentation). She attributed this to caring for her infant and toddler at home with repeated “colds” but noted she had missed several doses of her augmentation secondary to social issues and relocating. She had remained compliant with her maintenance inhaler but again declined intervention for an exacerbation.
Conclusion
Care of the pregnant A1AD patient follows the principles of care for the management of airways disease in general. Control of symptoms and reduction in exacerbation risk are main tenets of treatment. Lower levels of AAT have been associated with adverse pregnancy outcomes in small studies. The effect of A1AD and augmentation in pregnancy has not been studied and thus care is reliant on expert opinion and clinical experience. Providers caring for pregnant patients with A1AD should consider referral to health care systems and providers with specific expertise in A1AD. Ultimately the decision is left to the individual patient and their physician to weigh the risk benefit of cessation or continuation of therapies.
Declaration of interest
The authors report no conflict of interest.
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