Obstetrics Case Reports 89
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but did not find nerves associated with spiral arterioles in eight abnormal placental beds in the 3rd trimester of pregnancy (Khong et al. 1997). Uterine nerves are sparse in the second half of pregnancy, owing to marked increases in uterine size associated with hyperplasia and hypertrophy; muscle cells proliferate and enlarge, whereas the nerves are relatively fixed (Wikland et al. 1984). It may not be possible to identify abnormal nerves near uterine spiral arterioles in the 3rd trimester of pregnancy, owing to the enlargement of the uterus and lengthening of injured blood vessels. The level of the section in the placental bed and the original source of the neural injury may also be significant in this context. In contrast to recent theories of pre-eclampsia, the ‘uterine reinnervation’ view imputes a pre-pregnancy injury to the uterus (Quinn 2014). Neural signals from the uterus to the kidneys result in vasoconstriction in the renal cortex, hypertension and proteinuria, and varying phenotypes of the hypertensive disorders of pregnancy. Further studies to identify neural cytokines in thickened, uterine spiral arterioles in the first half of pregnancy may be helpful. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References Atwal GSS, Du Plessis D, Armstrong G et al. 2005. Uterine innervation after hysterectomy for chronic pelvic pain with, or without, endometriosis. American Journal of Obstetrics and Gynecology 193:1650–1655. Brosens I, Pijnenborg R, Vercryusse L et al. 2011. The “Great Obstetrical Syndromes” are associated with disorders of deep placentation. American Journal of Obstetrics and Gynecology 204:193–201. Brosens JJ, de Souza NM, Barker FG. 1995. Uterine junctional zone: function and disease. Lancet 346:558–560. Dixon HG, Robertson WB. 1958. A study of the vessels of the placental bed in normotensive and hypertensive women. Journal of Obstetrics and Gynaecology of the British Empire 65:803–809. Heaton KW, Cripps HA. 1993. Straining at stool and laxative taking in an English population. Digestive Diseases and Sciences 38:1004–1008. Khong TY, Tee JH, Kelly AJ. 1997. Absence of innervation of the uteroplacental arteries in normal and abnormal human pregnancies. Gynecologic and Obstetric Investigation 43:89–93. Page NM, Woods RJ, Gardiner SM et al. 2000. Excessive placental secretion of neurokinin B during the third trimester causes pre-eclampsia. Nature 405:797–800. Pijnenborg R, Dixon HG, Robertson WB et al. 1980. Trophoblastic invasion of human decidua from 8 to 18 weeks of pregnancy. Placenta 1:3–19. Quinn M. 2007a. Perivascular nerve fibre proliferation; the consequence of prolonged straining. Journal of Obstetrics and Gynaecology 27:185–188. Quinn M. 2007b. Uterine innervation in adenomyosis. Journal of Obstetrics and Gynaecology 27:287–291. Quinn MJ. 2014. Preeclampsia: 2 placental phenotypes, 1 etiology? American Journal of Obstetrics and Gynecology [Epub ahead of print]. Savitskii GA, Morozov VV, Svechnikova FA et al. 1981. Pathogenesis of uterine myoma development. Akusherstvo I Ginekologiia (Moskva) 4:13–15. Stephansson O, Kieler H, Granath F et al. 2009. Endometriosis, assisted reproduction technology, and risk of adverse pregnancy outcome. Human Reproduction 24:2341–2347. Wikland M, Lindblom B, Dahlström A et al. 1984. Structural and functional evidence for the denervation of human myometrium during pregnancy. Obstetrics and Gynecology 64:503–509. Wu XQ, Chen HY, Li W et al. 2014. Abnormal innervation of narrowed uterine vessels in cornual ectopic pregnancy. Journal of Obstetrics and Gynaecology (in press).
Management of pregnancies in a hereditary angioedema patient after treatment with attenuated androgens since childhood H. Farkas1, N. Veszeli1, D. Csuka1, G. Temesszentandrási1, F. Tóth2, L. Kőszegi3 & L. Varga1
13rd Department of Internal Medicine, 2Department of Obstetrics
and Gynecology, Semmelweis University, Budapest and 3Department of Obstetrics and Gynecology, ‘Balassa János’ Hospital, Szekszárd, Hungary DOI: 10.3109/01443615.2014.925860 Correspondence: H. Farkas, 3rd Department of Internal Medicine, Faculty of Medicine, Semmelweis University, H-1125 Budapest, Kútvölgyi út 4, Hungary. E-mail: [email protected]
Introduction We wish to describe the course of pregnancies in a patient with severe hereditary angioedema due to C1 inhibitor deficiency (HAEC1-INH). This autosomal dominant disorder belongs to the group of bradykinin-mediated angioedemas, characterised by episodic oedema-formation involving the skin and the mucous membranes (Longhurst and Cicardi 2012).
Case report A 34-year-old woman with type I HAE-C1-INH had severe and frequent oedematous episodes and danazol prophylaxis (100 mg/day) had started at 9 years of age. This attenuated androgen reduced the number and severity of oedematous episodes, but caused irregular menstruation. No other adverse effects were observed, and the patient was satisfied with this therapy. While taking the danazol, she experienced four unplanned pregnancies. All were recognised during the danazol treatment and resulted in miscarriages. The role of the danazol treatment in the miscarriages could not be ruled out. The patient planned a fifth pregnancy and therefore, her treatment had to be modified. Danazol was substituted by tranexamic acid. After conception, the patient received long-term prophylaxis (LTP) with plasma-derived, nanofiltrated C1-INH concentrate (pnfC1-INH, Berinert, Marburg, Germany) every 2 days (500 IU per occasion); it prevented the recurrence of attacks. Pre-procedural prophylaxis with pnfC1-INH concentrate (1,000 IU) was administered before caesarean section, which was uneventful, and a healthy baby was delivered. The patient received pnfC1-INH concentrate, administered on demand during breast-feeding (Farkas et al. 2012). She was switched to LTP after breast-feeding of the first child had ended. Tranexamic acid (TXA) 1,500 mg/day was chosen, because the patient wished to have one more child. She conceived again, but miscarried on Week 9. However, spontaneous pregnancy occurred 3.5 months after the miscarriage (Table I). Because the frequency of oedematous episodes had increased, we administered pnfC1INH concentrate twice a week for LTP during the 1st trimester. The patient continued on TXA, because minor vaginal bleeding kept recurring. Ultrasound confirmed a twin pregnancy with one viable and one ‘vanishing’ fetus. Oedematous episodes recurred despite treatment with 1,000–1,500 IU ⫻ 2/week. Therefore, we recommended switching to an on-demand treatment regimen and individualised replacement therapy (IRT) (Kreuz et al. 2009). The latter approach involves early treatment upon the identification of prodromal symptoms. In our patient, erythema marginatum, or a sensation of skin tightness, often preceded acute oedema formation (Farkas et al. 2001). Full-blown attacks did not occur following treatment with a 500 IU dose at the onset of prodromal symptoms (156 injections). This dose was effective also in episodes of mild oedema formation (96 injections). Higher doses were seldom needed; 1,000 or 1,500 IU was given in three instances for oedema. The efficacy of the drug did not decline with repeated administration; the symptoms always resolved quickly following acute treatment. The patient received IRT in the home setting from the 2nd to the 3rd trimester and tolerated intravenous dosing without problems. The majority of the acute episodes were abdominal attacks (Table II). Caesarean section, followed by tubal ligation, was performed under epidural anaesthesia on Week 38. A 1,000-IU dose of pnfC1INH was administered as short-term prophylaxis 1 h before surgery. Oedema formation did not occur during the subsequent 48 h. The patient delivered a healthy baby, who – similar to the first one – did not inherit C1-INH deficiency. During the subsequent 3 weeks of
90
Obstetrics Case Reports Table I. Historical information on the patient. Historical information
Event
Initial onset of symptoms HAE type I diagnosed Affected family members with confirmed HAE type I
At 2 years of age At 3 years of age Mother Aunt Uncle Cousin At 21 years of age At 22 years of age At 32 years of age At 32 years of age At 33 years of age At 35 years of age At 36 years of age
J Obstet Gynaecol Downloaded from informahealthcare.com by Kainan University on 04/04/15 For personal use only.
History of pregnancies
Subcutaneous and abdominal attacks Complement testing Died due to laryngeal oedema Oedema in all locations Subcutaneous oedema Oedema in all locations Spontaneous abortion at week 9 Spontaneous abortion at week 11 Spontaneous abortion at week 20 Spontaneous abortion at week 9 Successful delivery at week 37 Spontaneous abortion at week 9 Successful delivery at week 38
Table II. Oedematous episodes and treatment during the two successful pregnancies. Attack types (n) All episodes
1st trimester 2nd trimester 3rd trimester
Subcutaneous
Abdominal
500-IU vials of pnfC1-INH (n) Upper airway
Mixed
Routine prevention
IRT
On-demand
1st
2nd
1st
2nd
1st
2nd
1st
2nd
1st
2nd
1st
2nd
1st
2nd
1st
2nd
48 1 1
38 22 7
24 1 1
5 5 2
16 0 0
29 15 4
1 0 0
0 1 0
7 0 0
4 1 1
18 48 48
17 0 0
0 0 0
0 62 77
15 0 0
50 34 12
IRT, Individual replacement therapy; 1st, episodes that occurred during the first successful pregnancy; 2nd, episodes that occurred during the second successful pregnancy.
breast-feeding, repeated administration of a 500-IU dose (11 injections) was necessary for mild oedema. LTP with 100 mg/day danazol, introduced at the end of breast-feeding, proved effective. During the past 6 months, the patient has had only four subcutaneous and two abdominal attacks, which all responded to the 500-IU dose. Our case illustrates that, notwithstanding the long-term use of attenuated androgens introduced as early as childhood, successful pregnancies are possible following appropriate planning and preparation. Irregular menstruation associated with danazol therapy could delay the recognition of pregnancy. Further, danazol taken during early pregnancy might contribute to spontaneous abortion. Pregnancy may have a different influence on disease symptoms (Bouillet et al. 2008). During this second, successful pregnancy, symptoms occurred more often than during the previous one. The 1st trimester was most demanding, and all three trimesters were dominated by abdominal attacks. These observations are in agreement with our previous findings from an analysis of 88 cases (Czaller et al. 2010). Treatment with pnfC1-INH, either on demand or as a prophylaxis, proved effective during pregnancy, labour and breastfeeding. Martinez-Saguer et al. (2010) have also shown the benefit of treating oedematous attacks with pnfC1-INH in 29 pregnancies. IRT prevented severe attacks and this supports the consensus recommendation to start treatment as early as possible (Farkas et al. 2007; Caballero et al. 2012; Craig et al. 2012; Martinez-Saguer et al. 2010). The large cumulative (131,500 IU) dose proved safe. No side-effects or virus transmission resulted, and antibodies against C1-INH did not occur. The combination of pnfC1-INH and concomitant, uninterrupted dosing with TXA were not associated with thrombotic adverse events. Attenuated androgens are inexpensive and straightforward to administer orally. Therefore, these drugs offer the only option for LTP in many countries. As shown by this case, the chance of a successful pregnancy still exists after LTP with attenuated androgens. However, family planning, individualised management and close patient surveillance are indispensable to this end. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Henriette Farkas has received consultancy/speaker fees and honoraria from Shire Human Genetic Therapies Inc., Pharming, Viropharma and CSL Behring. Dorottya Csuka has received a travel grant from Viropharma and Lilian Varga has received travel grants from CSL Behring and Shire Human Genetic Therapies Inc.
References Bouillet L, Longhurst H, Boccon-Gibod I et al. 2008. Disease expression in women with hereditary angioedema. American Journal of Obstetrics and Gynecology 199:484.e1–e4. Caballero T, Farkas H, Bouillet L et al. 2012. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. Journal of Allergy and Clinical Immunology 129:308–320. Craig T, Aygoren-Pursun E, Bork K et al. 2012. WAO Guideline for the management of hereditary angioedema. World Allergy Organization Journal 5:182–199. Czaller I, Visy B, Csuka D et al. 2010. The natural history of hereditary angioedema and the impact of treatment with human C1-inhibitor concentrate during pregnancy: a long-term survey. European Journal of Obstetrics, Gynecology, and Reproductive Biology 152:44–49. Farkas H, Csuka D, Toth F et al. 2012. Successful pregnancy outcome after treatment with C1-inhibitor concentrate in a patient with hereditary angioedema and a history of four miscarriages. European Journal of Obstetrics, Gynecology, and Reproductive Biology 165:366–367. Farkas H, Harmat G, Fay A et al. 2001. Erythema marginatum preceding an acute oedematous attack of hereditary angioneurotic oedema. Acta DermatoVenereologica 81:376–377. Farkas H, Jakab L, Temesszentandrasi G et al. 2007. Hereditary angioedema: a decade of human C1-inhibitor concentrate therapy. Journal of Allergy and Clinical Immunology 120:941–947. Kreuz W, Martinez-Saguer I, Aygoren-Pursun E et al. 2009. C1-inhibitor concentrate for individual replacement therapy in patients with severe hereditary angioedema refractory to danazol prophylaxis. Transfusion 49: 1987–1995. Longhurst H, Cicardi M. 2012. Hereditary angio-oedema. Lancet 379:474–481. Martinez-Saguer I, Rusicke E, Aygoren-Pursun E et al. 2010. Characterization of acute hereditary angioedema attacks during pregnancy and breast-feeding and their treatment with C1 inhibitor concentrate. American Journal of Obstetrics and Gynecology 203:131 e1–e7.
J Obstet Gynaecol Downloaded from informahealthcare.com by Kainan University on 04/04/15 For personal use only.
but did not find nerves associated with spiral arterioles in eight abnormal placental beds in the 3rd trimester of pregnancy (Khong et al. 1997). Uterine nerves are sparse in the second half of pregnancy, owing to marked increases in uterine size associated with hyperplasia and hypertrophy; muscle cells proliferate and enlarge, whereas the nerves are relatively fixed (Wikland et al. 1984). It may not be possible to identify abnormal nerves near uterine spiral arterioles in the 3rd trimester of pregnancy, owing to the enlargement of the uterus and lengthening of injured blood vessels. The level of the section in the placental bed and the original source of the neural injury may also be significant in this context. In contrast to recent theories of pre-eclampsia, the ‘uterine reinnervation’ view imputes a pre-pregnancy injury to the uterus (Quinn 2014). Neural signals from the uterus to the kidneys result in vasoconstriction in the renal cortex, hypertension and proteinuria, and varying phenotypes of the hypertensive disorders of pregnancy. Further studies to identify neural cytokines in thickened, uterine spiral arterioles in the first half of pregnancy may be helpful. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References Atwal GSS, Du Plessis D, Armstrong G et al. 2005. Uterine innervation after hysterectomy for chronic pelvic pain with, or without, endometriosis. American Journal of Obstetrics and Gynecology 193:1650–1655. Brosens I, Pijnenborg R, Vercryusse L et al. 2011. The “Great Obstetrical Syndromes” are associated with disorders of deep placentation. American Journal of Obstetrics and Gynecology 204:193–201. Brosens JJ, de Souza NM, Barker FG. 1995. Uterine junctional zone: function and disease. Lancet 346:558–560. Dixon HG, Robertson WB. 1958. A study of the vessels of the placental bed in normotensive and hypertensive women. Journal of Obstetrics and Gynaecology of the British Empire 65:803–809. Heaton KW, Cripps HA. 1993. Straining at stool and laxative taking in an English population. Digestive Diseases and Sciences 38:1004–1008. Khong TY, Tee JH, Kelly AJ. 1997. Absence of innervation of the uteroplacental arteries in normal and abnormal human pregnancies. Gynecologic and Obstetric Investigation 43:89–93. Page NM, Woods RJ, Gardiner SM et al. 2000. Excessive placental secretion of neurokinin B during the third trimester causes pre-eclampsia. Nature 405:797–800. Pijnenborg R, Dixon HG, Robertson WB et al. 1980. Trophoblastic invasion of human decidua from 8 to 18 weeks of pregnancy. Placenta 1:3–19. Quinn M. 2007a. Perivascular nerve fibre proliferation; the consequence of prolonged straining. Journal of Obstetrics and Gynaecology 27:185–188. Quinn M. 2007b. Uterine innervation in adenomyosis. Journal of Obstetrics and Gynaecology 27:287–291. Quinn MJ. 2014. Preeclampsia: 2 placental phenotypes, 1 etiology? American Journal of Obstetrics and Gynecology [Epub ahead of print]. Savitskii GA, Morozov VV, Svechnikova FA et al. 1981. Pathogenesis of uterine myoma development. Akusherstvo I Ginekologiia (Moskva) 4:13–15. Stephansson O, Kieler H, Granath F et al. 2009. Endometriosis, assisted reproduction technology, and risk of adverse pregnancy outcome. Human Reproduction 24:2341–2347. Wikland M, Lindblom B, Dahlström A et al. 1984. Structural and functional evidence for the denervation of human myometrium during pregnancy. Obstetrics and Gynecology 64:503–509. Wu XQ, Chen HY, Li W et al. 2014. Abnormal innervation of narrowed uterine vessels in cornual ectopic pregnancy. Journal of Obstetrics and Gynaecology (in press).
Management of pregnancies in a hereditary angioedema patient after treatment with attenuated androgens since childhood H. Farkas1, N. Veszeli1, D. Csuka1, G. Temesszentandrási1, F. Tóth2, L. Kőszegi3 & L. Varga1
13rd Department of Internal Medicine, 2Department of Obstetrics
and Gynecology, Semmelweis University, Budapest and 3Department of Obstetrics and Gynecology, ‘Balassa János’ Hospital, Szekszárd, Hungary DOI: 10.3109/01443615.2014.925860 Correspondence: H. Farkas, 3rd Department of Internal Medicine, Faculty of Medicine, Semmelweis University, H-1125 Budapest, Kútvölgyi út 4, Hungary. E-mail: [email protected]
Introduction We wish to describe the course of pregnancies in a patient with severe hereditary angioedema due to C1 inhibitor deficiency (HAEC1-INH). This autosomal dominant disorder belongs to the group of bradykinin-mediated angioedemas, characterised by episodic oedema-formation involving the skin and the mucous membranes (Longhurst and Cicardi 2012).
Case report A 34-year-old woman with type I HAE-C1-INH had severe and frequent oedematous episodes and danazol prophylaxis (100 mg/day) had started at 9 years of age. This attenuated androgen reduced the number and severity of oedematous episodes, but caused irregular menstruation. No other adverse effects were observed, and the patient was satisfied with this therapy. While taking the danazol, she experienced four unplanned pregnancies. All were recognised during the danazol treatment and resulted in miscarriages. The role of the danazol treatment in the miscarriages could not be ruled out. The patient planned a fifth pregnancy and therefore, her treatment had to be modified. Danazol was substituted by tranexamic acid. After conception, the patient received long-term prophylaxis (LTP) with plasma-derived, nanofiltrated C1-INH concentrate (pnfC1-INH, Berinert, Marburg, Germany) every 2 days (500 IU per occasion); it prevented the recurrence of attacks. Pre-procedural prophylaxis with pnfC1-INH concentrate (1,000 IU) was administered before caesarean section, which was uneventful, and a healthy baby was delivered. The patient received pnfC1-INH concentrate, administered on demand during breast-feeding (Farkas et al. 2012). She was switched to LTP after breast-feeding of the first child had ended. Tranexamic acid (TXA) 1,500 mg/day was chosen, because the patient wished to have one more child. She conceived again, but miscarried on Week 9. However, spontaneous pregnancy occurred 3.5 months after the miscarriage (Table I). Because the frequency of oedematous episodes had increased, we administered pnfC1INH concentrate twice a week for LTP during the 1st trimester. The patient continued on TXA, because minor vaginal bleeding kept recurring. Ultrasound confirmed a twin pregnancy with one viable and one ‘vanishing’ fetus. Oedematous episodes recurred despite treatment with 1,000–1,500 IU ⫻ 2/week. Therefore, we recommended switching to an on-demand treatment regimen and individualised replacement therapy (IRT) (Kreuz et al. 2009). The latter approach involves early treatment upon the identification of prodromal symptoms. In our patient, erythema marginatum, or a sensation of skin tightness, often preceded acute oedema formation (Farkas et al. 2001). Full-blown attacks did not occur following treatment with a 500 IU dose at the onset of prodromal symptoms (156 injections). This dose was effective also in episodes of mild oedema formation (96 injections). Higher doses were seldom needed; 1,000 or 1,500 IU was given in three instances for oedema. The efficacy of the drug did not decline with repeated administration; the symptoms always resolved quickly following acute treatment. The patient received IRT in the home setting from the 2nd to the 3rd trimester and tolerated intravenous dosing without problems. The majority of the acute episodes were abdominal attacks (Table II). Caesarean section, followed by tubal ligation, was performed under epidural anaesthesia on Week 38. A 1,000-IU dose of pnfC1INH was administered as short-term prophylaxis 1 h before surgery. Oedema formation did not occur during the subsequent 48 h. The patient delivered a healthy baby, who – similar to the first one – did not inherit C1-INH deficiency. During the subsequent 3 weeks of
90
Obstetrics Case Reports Table I. Historical information on the patient. Historical information
Event
Initial onset of symptoms HAE type I diagnosed Affected family members with confirmed HAE type I
At 2 years of age At 3 years of age Mother Aunt Uncle Cousin At 21 years of age At 22 years of age At 32 years of age At 32 years of age At 33 years of age At 35 years of age At 36 years of age
J Obstet Gynaecol Downloaded from informahealthcare.com by Kainan University on 04/04/15 For personal use only.
History of pregnancies
Subcutaneous and abdominal attacks Complement testing Died due to laryngeal oedema Oedema in all locations Subcutaneous oedema Oedema in all locations Spontaneous abortion at week 9 Spontaneous abortion at week 11 Spontaneous abortion at week 20 Spontaneous abortion at week 9 Successful delivery at week 37 Spontaneous abortion at week 9 Successful delivery at week 38
Table II. Oedematous episodes and treatment during the two successful pregnancies. Attack types (n) All episodes
1st trimester 2nd trimester 3rd trimester
Subcutaneous
Abdominal
500-IU vials of pnfC1-INH (n) Upper airway
Mixed
Routine prevention
IRT
On-demand
1st
2nd
1st
2nd
1st
2nd
1st
2nd
1st
2nd
1st
2nd
1st
2nd
1st
2nd
48 1 1
38 22 7
24 1 1
5 5 2
16 0 0
29 15 4
1 0 0
0 1 0
7 0 0
4 1 1
18 48 48
17 0 0
0 0 0
0 62 77
15 0 0
50 34 12
IRT, Individual replacement therapy; 1st, episodes that occurred during the first successful pregnancy; 2nd, episodes that occurred during the second successful pregnancy.
breast-feeding, repeated administration of a 500-IU dose (11 injections) was necessary for mild oedema. LTP with 100 mg/day danazol, introduced at the end of breast-feeding, proved effective. During the past 6 months, the patient has had only four subcutaneous and two abdominal attacks, which all responded to the 500-IU dose. Our case illustrates that, notwithstanding the long-term use of attenuated androgens introduced as early as childhood, successful pregnancies are possible following appropriate planning and preparation. Irregular menstruation associated with danazol therapy could delay the recognition of pregnancy. Further, danazol taken during early pregnancy might contribute to spontaneous abortion. Pregnancy may have a different influence on disease symptoms (Bouillet et al. 2008). During this second, successful pregnancy, symptoms occurred more often than during the previous one. The 1st trimester was most demanding, and all three trimesters were dominated by abdominal attacks. These observations are in agreement with our previous findings from an analysis of 88 cases (Czaller et al. 2010). Treatment with pnfC1-INH, either on demand or as a prophylaxis, proved effective during pregnancy, labour and breastfeeding. Martinez-Saguer et al. (2010) have also shown the benefit of treating oedematous attacks with pnfC1-INH in 29 pregnancies. IRT prevented severe attacks and this supports the consensus recommendation to start treatment as early as possible (Farkas et al. 2007; Caballero et al. 2012; Craig et al. 2012; Martinez-Saguer et al. 2010). The large cumulative (131,500 IU) dose proved safe. No side-effects or virus transmission resulted, and antibodies against C1-INH did not occur. The combination of pnfC1-INH and concomitant, uninterrupted dosing with TXA were not associated with thrombotic adverse events. Attenuated androgens are inexpensive and straightforward to administer orally. Therefore, these drugs offer the only option for LTP in many countries. As shown by this case, the chance of a successful pregnancy still exists after LTP with attenuated androgens. However, family planning, individualised management and close patient surveillance are indispensable to this end. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Henriette Farkas has received consultancy/speaker fees and honoraria from Shire Human Genetic Therapies Inc., Pharming, Viropharma and CSL Behring. Dorottya Csuka has received a travel grant from Viropharma and Lilian Varga has received travel grants from CSL Behring and Shire Human Genetic Therapies Inc.
References Bouillet L, Longhurst H, Boccon-Gibod I et al. 2008. Disease expression in women with hereditary angioedema. American Journal of Obstetrics and Gynecology 199:484.e1–e4. Caballero T, Farkas H, Bouillet L et al. 2012. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. Journal of Allergy and Clinical Immunology 129:308–320. Craig T, Aygoren-Pursun E, Bork K et al. 2012. WAO Guideline for the management of hereditary angioedema. World Allergy Organization Journal 5:182–199. Czaller I, Visy B, Csuka D et al. 2010. The natural history of hereditary angioedema and the impact of treatment with human C1-inhibitor concentrate during pregnancy: a long-term survey. European Journal of Obstetrics, Gynecology, and Reproductive Biology 152:44–49. Farkas H, Csuka D, Toth F et al. 2012. Successful pregnancy outcome after treatment with C1-inhibitor concentrate in a patient with hereditary angioedema and a history of four miscarriages. European Journal of Obstetrics, Gynecology, and Reproductive Biology 165:366–367. Farkas H, Harmat G, Fay A et al. 2001. Erythema marginatum preceding an acute oedematous attack of hereditary angioneurotic oedema. Acta DermatoVenereologica 81:376–377. Farkas H, Jakab L, Temesszentandrasi G et al. 2007. Hereditary angioedema: a decade of human C1-inhibitor concentrate therapy. Journal of Allergy and Clinical Immunology 120:941–947. Kreuz W, Martinez-Saguer I, Aygoren-Pursun E et al. 2009. C1-inhibitor concentrate for individual replacement therapy in patients with severe hereditary angioedema refractory to danazol prophylaxis. Transfusion 49: 1987–1995. Longhurst H, Cicardi M. 2012. Hereditary angio-oedema. Lancet 379:474–481. Martinez-Saguer I, Rusicke E, Aygoren-Pursun E et al. 2010. Characterization of acute hereditary angioedema attacks during pregnancy and breast-feeding and their treatment with C1 inhibitor concentrate. American Journal of Obstetrics and Gynecology 203:131 e1–e7.
