Systematic Review of Lymphangioleiomyomatosis Outcomes in Pregnancy and a Proposed Management Guideline

Abstract

Objective Lymphangioleiomyomatosis (LAM) is a rare, multisystem disease that primarily affects women of reproductive age. Disease progression has been linked to estrogen exposure, and as such many patients are advised to avoid pregnancy. Data are limited regarding the interaction between LAM and pregnancy, and as such we performed a systematic review to summarize available literature reporting outcomes of pregnancies complicated by maternal LAM.

Study Design This was a systematic review including randomized controlled trials, observational studies, systematic reviews, case reports, clinical practice guidelines, and quality improvement studies with full-text manuscripts or abstracts in the English language with primary data on pregnant or postpartum patients with LAM. The primary outcome was maternal outcomes during pregnancy as well as pregnancy outcomes. Secondary outcomes were neonatal outcomes and long-term maternal outcomes. This search occurred in July 2020 and included MEDLINE, Scopus, clinicaltrials.gov, Embase, and Cochrane Central. Risk of bias was ascertained using the Newcastle–Ottawa Scale. Our systematic review was registered with PROSPERO as protocol number CRD 42020191402.

Results A total of 175 publications were identified in our initial search; ultimately 31 studies were included. Six (19%) studies were retrospective cohort studies and 25 (81%) studies were case reports. Patients diagnosed during pregnancy had worse pregnancy outcomes compared to those diagnosed with LAM prior to pregnancy. Multiple studies reported a significant risk of pneumothoraces during pregnancy. Other significant risks included preterm delivery, chylothoraces, and pulmonary function deterioration. A proposed strategy for preconception counseling and antenatal management is provided.

Conclusion Patients diagnosed with LAM during pregnancy generally experience worse outcomes including recurrent pneumothoraces and preterm delivery as compared to patients with a LAM diagnosis prior to pregnancy. Given that there are limited studies available, and that the majority are low-quality evidence and subject to bias, further investigation of the interaction between LAM and pregnancy is warranted to guide patient care and counseling.

Key Points

• Data are limited on the effects of lymphangioleiomyomatosis on pregnancy outcomes.

• We performed a systematic review to summarize pregnancy outcomes complicated by LAM.

• Patients diagnosed with LAM during pregnancy experience worse outcomes.

Keywords

pregnancy - maternal–fetal - lymphangioleiomyomatosis

Publication History

Received: 13 July 2022

Accepted: 24 February 2023

Accepted Manuscript online:
10 March 2023

Article published online:
18 April 2023

• References

• 1 Sullivan EJ. Lymphangioleiomyomatosis: a review. Chest 1998; 114 (06) 1689-1703
• 2 Johnson S. Lymphangioleiomyomatosis: clinical features, management and basic mechanisms. Thorax 1999; 54 (03) 254-264
• 3 Workshop Summary NHLBI. NHLBI Workshop Summary. Report of workshop on lymphangioleiomyomatosis. National Heart, Lung, and Blood Institute. Am J Respir Crit Care Med 1999; 159 (02) 679-683
• 4 Cohen MM, Freyer AM, Johnson SR. Pregnancy experiences among women with lymphangioleiomyomatosis. Respir Med 2009; 103 (05) 766-772
• 5 Ryu JH, Moss J, Beck GJ. et al; NHLBI LAM Registry Group. The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at enrollment. Am J Respir Crit Care Med 2006; 173 (01) 105-111
• 6 Cohen MM, Pollock-BarZiv S, Johnson SR. Emerging clinical picture of lymphangioleiomyomatosis. Thorax 2005; 60 (10) 875-879
• 7 Chebib N, Khouatra C, Lazor R. et al. Pulmonary lymphangioleiomyomatosis: From pathogenesis to management [in French]. Rev Mal Respir 2016; 33 (08) 718-734
• 8 Goncharova EA, Krymskaya VP. Pulmonary lymphangioleiomyomatosis (LAM): progress and current challenges. J Cell Biochem 2008; 103 (02) 369-382
• 9 Johnson SR, Tattersfield AE. Clinical experience of lymphangioleiomyomatosis in the UK. Thorax 2000; 55 (12) 1052-1057
• 10 Shen A, Iseman MD, Waldron JA, King TE. Exacerbation of pulmonary lymphangioleiomyomatosis by exogenous estrogens. Chest 1987; 91 (05) 782-785
• 11 Banner AS. Hormone receptors in lymphangioleiomyomatosis. Chest 1984; 85 (01) 3-4
• 12 Prizant H, Hammes SR. Minireview: lymphangioleiomyomatosis (LAM): the “other” steroid-sensitive cancer. Endocrinology 2016; 157 (09) 3374-3383
• 13 Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6 (07) e1000097
• 14 Taveira-DaSilva AM, Julien-Williams P, Jones A, Yao J, Moss J. Changes in lung function during pregnancy in patients with lymphangioleioimyomatosis. Am J Respir Crit Care Med 2017; 195 (Online Abstract): A7426
• 15 Seyama K, Goto N, Yoshimoto K. et al. Pregnancy and delivery after the establishment of the diagnosis of lymphangioleiomyomatosis. Am J Respir Crit Care Med 2011; 183: A1626
• 16 Ando K, Seyama K, Kobayashi E, Ebana H, Hoshika Y, Takahashi K. Pregnancy doesn't always cause deterioration of lymphangioleiomyomatosis. Respirology 2014; 19: 16-16
• 17 Hyslop A, Gupta N. Spontaneous pneumothoraces during pregnancy in patients with lymphangioleiomyomatosis. Chest 2019; 156 (04) A444
• 18 Creagh-Brown B, Cooke N, Corbishley C. Conservative management of an unusual cause of breathlessness during pregancy. Respiratory Medicine Extra 2006; 2 (04) 116-119
• 19 Gilbert E, Dilling D. Successful pregnancy without disease progression in an LAM patient. Chest 2011; 140 (04) 155A
• 20 Crawford TC, Grimm JC, Magruder JT. et al. A curious case of acute respiratory distress syndrome. J Surg Case Rep 2015; 2015 (11) rjv140
• 21 Pais F, Fayed M, Evans T. Lymphangioleiomyomatosis: an explosive presentation of a rare disease. Oxf Med Case Rep 2017; 2017 (06) omx023
• 22 Islam T, Birdwell A, Winsett R, Maselli D, Velez M, Habib SNO. Sirolimus? No problem: alternative management of lymphangioleiomyomatosis during pregnancy. Chest 2019; 156: A1941-A1942
• 23 Khaddour K, Shayuk M, Ludhwani D, Gowda S, Ward WL. Pregnancy unmasking symptoms of undiagnosed lymphangioleiomyomatosis: case report and review of literature. Respir Med Case Rep 2018; 26: 63-67
• 24 Weinans MJ, van Loon AJ. A diagnosis of lymphangioleiomyomatosis in a pregnant woman presenting with a retroperitoneal mass. Br J Obstet Gynaecol 1999; 106 (07) 747-748
• 25 McLoughlin L, Thomas G, Hasan K. Pregnancy and lymphangioleiomyomatosis: anaesthetic management. Int J Obstet Anesth 2003; 12 (01) 40-44
• 26 Hagan G, Lawford P. New diagnosis and subsequent post-partum radiological improvement of lymphangioleiomyomatosis. Thorax 2009; 64 (05) 460-460
• 27 Iruloh C, Keriakos R, Smith DJ, Cleveland T. Renal angiomyolipoma and lymphangioleiomyomatosis in pregnancy. J Obstet Gynaecol 2013; 33 (06) 542-546
• 28 Collins PD, McFerran SJ, Goldrick I, Cevallos-Morales J, Martin-Lazaro J. Postpartum bilateral tension pneumothoraces. Cureus 2019; 11 (06) e4856-e4856
• 29 Toyoda K, Matsumoto K, Inoue H. et al. A pregnant woman with complications of lymphangioleiomyomatosis and idiopathic thrombocytopenic purpura. Intern Med 2006; 45 (19) 1097-1100
• 30 Ogura K, Hosono A, Yoshida A, Beppu Y, Kawai A. A retroperitoneal mass, systemic lymphadenopathy, and pulmonary nodules in a pregnant woman. Diagnosis: lymphangioleiomyomatosis (LAM). Skeletal Radiol 2011; 40 (05) 631-632 , 657–658
• 31 Yamashita S, Nakamura K, Shinozaki H, Minegishi T. Lymphangioleiomyomatosis suspected to be a gynecologic disease. J Obstet Gynaecol Res 2011; 37 (03) 267-269
• 32 Ogawa R, Miyagawa M, Ide K, Akamune A, Ohtsuki Y, Mochizuki T. Exacerbation and remission of pulmonary micronodules with lymphangioleiomyomatosis around the time of childbirth. Jpn J Radiol 2013; 31 (09) 633-636
• 33 Nakanishi M, Okura N, Kashii T. et al. Case of lymphangioleiomyomatosis (LAM) discovered during cesarean section under spinal anesthesia [in Japanese]. Masui 2014; 63 (02) 191-194
• 34 Faehling M, Frohnmayer S, Leschke M, Trinajstic-Schulz B, Weber J, Liewald F. Successful pregnancy complicated by persistent pneumothorax in a patient with lymphangioleiomyomatosis (LAM) on sirolimus. Sarcoidosis Vasc Diffuse Lung Dis 2011; 28 (02) 153-155
• 35 Johnston CR, O'Donnell ME, Sayed Ahmed WA, Hunter A, Graham AN. Bilateral pneumothorax in pregnancy unmasking lymphangioleiomyomatosis. Ir J Med Sci 2011; 180 (04) 933-934
• 36 Saleh Gargari S, Hantoushzadae S, Mohamadi F, Jafar-Abadi M. Pregnancy complicated by lymphangioleiomyomatosis. Arch Iran Med 2009; 12 (02) 182-185
• 37 McCartney R, Facey N, Chalmers G. et al. Multiple pneumothoraces during second and third trimesters as first presentation of lymphangioleiomyomatosis. Obstet Med 2009; 2 (02) 84-86
• 38 Cho SY, Kim KH, Jeon WJ. Caesarean delivery under general anaesthesia for a woman with undiagnosed tuberous sclerosis complex and lymphangioleiomyomatosis. Anaesth Intensive Care 2009; 37 (01) 142-143
• 39 Mitra S, Ghosal AG, Bhattacharya P. Pregnancy unmasking lymphangioleiomyomatosis. J Assoc Physicians India 2004; 52: 828-830 (In eng)
• 40 Yigla M, Bentur L, Ben Izhak O, Rubin AH. Pulmonary lymphangioleiomyomatosis: prolonged survival despite multiple pregnancies and no hormonal intervention. Respirology 1996; 1 (03) 213-215
• 41 Brunelli A, Catalini G, Fianchini A. Pregnancy exacerbating unsuspected mediastinal lymphangioleiomyomatosis and chylothorax. Int J Gynaecol Obstet 1996; 52 (03) 289-290
• 42 Huang Y, Huang H, Li Q. et al. Approach of the treatment for pneumothorax. J Thorac Dis 2014; 6 (suppl 4): S416-S420
• 43 Cleary-Goldman J, Sanghvi AV, Nakhuda GS, Robinson JN. Conservative management of pulmonary lymphangioleiomyomatosis and tuberous sclerosis complicated by renal angiomyolipomas in pregnancy. J Matern Fetal Neonatal Med 2004; 15 (02) 132-134
• 44 McCormack FX, Inoue Y, Moss J. et al; National Institutes of Health Rare Lung Diseases Consortium; MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 2011; 364 (17) 1595-1606
• 45 Jankowska I, Oldakowska-Jedynak U, Jabiry-Zieniewicz Z. et al. Absence of teratogenicity of sirolimus used during early pregnancy in a liver transplant recipient. Transplant Proc 2004; 36 (10) 3232-3233
• 46 Sifontis NM, Coscia LA, Constantinescu S, Lavelanet AF, Moritz MJ, Armenti VT. Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mofetil or sirolimus. Transplantation 2006; 82 (12) 1698-1702
• 47 Framarino dei Malatesta M, Corona LE, De Luca L. et al. Successful pregnancy in a living-related kidney transplant recipient who received sirolimus throughout the whole gestation. Transplantation 2011; 91 (09) e69-e71
• 48 Faehling M, Wienhausen-Wilke V, Fallscheer S, Trinajstic-Schulz B, Weber J, Leschke M. Long-term stable lung function and second uncomplicated pregnancy on sirolimus in lymphangioleiomyomatosis (LAM). Sarcoidosis Vasc Diffuse Lung Dis 2015; 32 (03) 259-264
• 49 Barnes BT, Procaccini D, Crino J. et al. Maternal sirolimus therapy for fetal cardiac rhabdomyomas. N Engl J Med 2018; 378 (19) 1844-1845
• 50 Shen L, Xu W, Gao J. et al. Pregnancy after the diagnosis of lymphangioleiomyomatosis (LAM). Orphanet J Rare Dis 2021; 16 (01) 133
• 51 Wang Q, Luo M, Xiang B, Chen S, Ji Y. The efficacy and safety of pharmacological treatments for lymphangioleiomyomatosis. Respir Res 2020; 21 (01) 55
• 52 Goldberg HJ, Harari S, Cottin V. et al. Everolimus for the treatment of lymphangioleiomyomatosis: a phase II study. Eur Respir J 2015; 46 (03) 783-794
• 53 Corporation NP. . Afinitor prescribing information. 2021. Accessed March 22, 2023 at: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=2150f73a-179b-4afc-b8ce-67c85cc72f04&type=display
• 54 Veroux M, Corona D, Veroux P. Pregnancy under everolimus-based immunosuppression. Transpl Int 2011; 24 (12) e115-e117
• 55 Carta P, Caroti L, Zanazzi M. Pregnancy in a kidney transplant patient treated with everolimus. Am J Kidney Dis 2012; 60 (02) 329
• 56 Margoles HR, Gomez-Lobo V, Veis JH, Sherman MJ, Moore Jr J. Successful maternal and fetal outcome in a kidney transplant patient with everolimus exposure throughout pregnancy: a case report. Transplant Proc 2014; 46 (01) 281-283
• 57 Fiocchi R, D'Elia E, Vittori C. et al. First report of a successful pregnancy in an everolimus-treated heart-transplanted patient: neonatal disappearance of immunosuppressive drugs. Am J Transplant 2016; 16 (04) 1319-1322
• 58 Carta P, Zanazzi M, Minetti EE. Unplanned pregnancies in kidney transplanted patients treated with everolimus: three case reports. Transpl Int 2015; 28 (03) 370-372
• 59 Yamamura M, Kojima T, Koyama M, Sazawa A, Yamada T, Minakami H. Everolimus in pregnancy: case report and literature review. J Obstet Gynaecol Res 2017; 43 (08) 1350-1352
• 60 Taveira-DaSilva AM, Hedin C, Stylianou MP. et al. Reversible airflow obstruction, proliferation of abnormal smooth muscle cells, and impairment of gas exchange as predictors of outcome in lymphangioleiomyomatosis. Am J Respir Crit Care Med 2001; 164 (06) 1072-1076
• 61 Baldi BG, de Albuquerque AL, Pimenta SP, Salge JM, Kairalla RA, Carvalho CR. A pilot study assessing the effect of bronchodilator on dynamic hyperinflation in LAM. Respir Med 2013; 107 (11) 1773-1780
• 62 National Heart Lung and Blood Institute, National Asthma Education and Prevention Program Asthma and Pregnancy Working Group. Managing asthma during pregnancy: recommendations for pharmacologic treatment. NAEPP expert panel report 2004:1–57. Accessed March 22, 2023 at: https://www.nhlbi.nih.gov/files/docs/astpreg_qr.pdf
• 63 Schatz M, Zeiger RS, Harden KM. et al. The safety of inhaled beta-agonist bronchodilators during pregnancy. J Allergy Clin Immunol 1988; 82 (04) 686-695
• 64 Nishimura, Reproduction studies of iptratropium bromide (SCH 1000) on rats and rabbits. Iyakuhin Kenkyu 1978; [phone]
• 65 Niggeschulze A, Palmer AK. Reproductive toxicological investigations with iptratropium bromide. Arzneimittelforschung 1976; (26) 989-992