Management of hereditary angioedema type I and homozygous MTHFR mutation during pregnancy

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Amanda Ribeiro Batlle
Ana Paula Possar do Carmo
Nirelcio Galao
Anete S Grumach


Hereditary Angioedema; MTHFR mutation; Pregnancy; Thrombosis; Thrombophilia


Hereditary angioedema (HAE) is an autosomal dominant disease, characterized by edema
attacks resulting from quantitative and/or functional deficiency of the C1 inhibitor (C1-INH),
which acts in controlling the complement, coagulation, fibrinolysis, and contact systems. The
exacerbation of these systems results in decreased circulating levels of kallikrein and conversion
of bradykinin. In addition, thrombophilia is related to the deficiency of methylenetetrahydrofolate
reductase (MTHFR) enzyme, causing an increase in homocysteine, accumulation
of atheromatous plaques, and arterial and venous thrombosis. The association of these conditions
in related systems brings greater clinical risks to the patient. We report a female patient,
aged 23 years, with HAE and homozygous MTHFR mutation, G2A1, carrier of HAE with crises
since early childhood. The first pregnancy terminated with abortion due to gestational sac
detachment. In the second pregnancy, at 5.1 weeks, she had bleeding and partial detachment
of gestational sac. Thrombophilia tests confirmed homozygosity for the MTHFR enzyme. At the
beginning of gestation, she had attacks of angioedema treated with fresh plasma, and at one
occasion, she received treatment with a plasma-derived C1-INH esterase. During breastfeeding,
she received prophylaxis with plasma-derived C1-INHdp. The course of HAE during pregnancy
worsened. There are studies that discuss the occurrence of abortion due to attacks of
angioedema. The patient’s disease was associated with a homozygous MTHFR mutation, which
probably caused the miscarriage. The control of both clinical situations is important for the
success of pregnancy, so a combined action plan between obstetricians and HAE treatment
specialists is essential.

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1. Cicardi M, Aberer W, Banerji A, et al. Classification, diagnosis,
and approach to treatment for angioedema: Consensus report from the Hereditary Angioedema International
Working Group. Allergy. 2014 May;69(5):602–16.
2. Zuraw BL, Bork K, Binkley KE, et al. Hereditary angioedema with normal C1 inhibitor function: Consensus of an international expert panel. Allergy Asthma Proc. 2012 Nov–Dec;33(Suppl 1):S145–56.
3. Machado AM, Pires RM, Martins RO, Grumach AS. Pregnancy and Postpartum in hereditary angioedema with C1 inhibitor deficit in women who have no access to therapy. J Investig Allergol Clin Immunol. 2017;27(5):322–3.
4. Czaller I, Visy B, Csuka D, Fust G, Toth F, Farkas H. The natural history of hereditary angioedema and the impact of
treatment with human C1-inhibitor concentrate during pregnancy: A long-term survey. Eur J Obstet Gynecol Reprod Biol.
5. Martinez-Saguer I, Rusicke E, Aygoren-Pursun E, Heller C, Klingebiel T, Kreuz W. Characterization of acute hereditary
angioedema attacks during pregnancy and breast-feeding and their treatment with C1 inhibitor concentrate. Am J
Obstet Gynecol. 2010;203(131): el–7.
6. Chinniah N, Katelaris CH. Hereditary angioedema and pregnancy. Aust N Z J Obstet Gynaecol. 2009;49:2–5. https://doi.
7. Caballero T, Farkas H, Bouillet L, et al. International consensus and practical guidelines on the gynecologic and obstetric
management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol.
9. Moll S, Varga EA. Homocysteine and MTHFR mutations. Circulation. 2015 Jul 7;132(1):e6–9.
8. Saguer IM, Ettingshausen CE. Successful management of hereditary angioedema during pregnancy in a patient with
heterozygous MTHFR mutation. Ann Allergy Asthma Immunol. 2017;118(6):734–5.
10. Deol PS, Barnes TA, Dampier K, John Pasi K, Oppenheimer C, Pavord SR. The effects of folic acid supplements on coagulation status in pregnancy. Br J Haematol. 2004 Oct;127(2):204– 8.
11. Van der Put NM, Steegers-Theunissen RP, Frosst P, Trijbels FJ, Eskes TK, Van der Heuvel LP, et al. Molecular genetic analysis in mild hyperhomocysteinemia: A common mutation in the methylenetetrahydrofolate reductase gene is a genetic factor for cardiovascular disease. Am J Hum Genet. 1996;58(1):35–41.
12. Toma TS, Louvison MCP, Bersusa AAS, Bonfim JRA, Prado MF. Low molecular weight heparins for prophylaxis and treatment of deep venous thrombosis in pregnancy. Bol Inst. Saúde (BIS). 2013;14(2):229–36. Available from:
13. Brown NM, Pratt VM, Buller A, et al. Detection of 677CT/1298AC “double variant” chromosomes: Implications for interpretation of MTHFR genotyping results. Genet Med. 2005;7(4):278–
82. 14. Majluf-Cruz A, Nieto-Martínez S. Long-term follow-up analysis
of nadroparin for hereditary angioedema. A preliminary report. Int Immunopharmacol. 2011 Aug;11(8):1127–32. https://
15. Weiler JM, Quinn SA, Woodworth GG, Brown DD, Layton TA, Maves KK. Does heparin prophylaxis prevent exacerbations
of hereditary angioedema? J Allergy Clin Immunol. 2002 Jun;109(6):995–1000.
16. Poppelaars F, Damman J, de Vrij EL, et al. New insight into the effects of heparinoids on complement inhibition by
C1-inhibitor. Clin Exp Immunol. 2016;184(3):378–88.