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Hindawi Case Reports in Immunology Volume 2018, Article ID 2706751, 4 pages https://doi.org/10.1155/2018/2706751 Case Report In Vitro Fertilization Using Luteinizing Hormone-Releasing Hormone Injections Resulted in Healthy Triplets without Increased Attack Rates in a Hereditary Angioedema Case Ceyda Tunakan DalgJç ,FatmaDüGünür Günsen, Gökten Bulut, Emine Nihal Mete Gökmen, and Aytül Zerrin Sin Department of Internal Medicine, Division of Allergy and Clinical Immunology, Ege University Medical Faculty, Izmir, Turkey Correspondence should be addressed to Ceyda Tunakan Dalgıc¸; dr email@example.com Received 20 October 2017; Revised 5 January 2018; Accepted 22 January 2018; Published 13 February 2018 Academic Editor: Jiri Litzman Copyright © 2018 Ceyda Tunakan Dalgıc¸ et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) is a rare, autosomal dominant disorder. The management of pregnant patients with C1-INH-HAE is a challenge for the physician. Intravenous plasma-derived nanofiltered C1-INH (pdC1INH) is the only recommended option throughout pregnancy, postpartum, and breastfeeding period. In order to increase pregnancy rates, physicians use fertilization therapies increasing endogen levels of estrogens. Therefore, these techniques can provoke an increase in the number and severity of edema attacks in C1-INH-HAE. Our patient is a 32-year-old female, diagnosed with C1-INH-HAE type 1 since 2004. She had been taking danazol 50–200 mg/day for 9 years. Due to her pregnancy plans in 2013, danazol was discontinued. PdC1INH was prescribed regularly for prophylactic purpose. Triplet pregnancy occurred by in vitro fertilization using luteinizing hormone-releasing hormone (LHRH) injections. In our patient, LHRH injections were done four times without causing any severe attack during in vitro fertilization. Angioedema did not worsen during pregnancy and delivery due to the prophylactic use of intravenous pdC1INH in our patient. According to the attack frequency and severity, there was no difference between the three pregnancy trimesters. To our knowledge, this is the first published case of C1-INH-HAE receiving in vitro fertilization therapies without any angioedema attacks during pregnancy and delivery and eventually having healthy triplets with the prophylactic use of intravenous pdC1INH. 1. Introduction breastfeeding [2–5]. Nanofiltered plasma-derived C1-INH concentrate (pdC1INH) is the only therapeutic option recom- C1-INH-HAE is characterized by recurrent attacks of edema mended throughout pregnancy, the postpartum period, and formation in the skin, upper airways, and the gastrointestinal breastfeeding . tract . Three types of hereditary angioedema (HAE) have been described: two of them are due to C1 inhibitor (C1- 2. Case Presentation INH) deficiency (C1-INH-HAE types I and II) and one is characterized by normal C1-INH (nC1-INH-HAE). The A 32-year-old female was diagnosed with hereditary angio- management of pregnant patients with C1-INH-HAE is oen ft edema type 1 (C1-INH-HAE) in 2004. Her major symp- a challenge, because their symptoms can become more toms were abdominal and peripheral edema attacks. She prevalent because of elevated estrogen levels. Attenuated had been taking danazol (dosage: 50–200 mg/day) for 9 androgens, such as danazol, are contraindicated in pregnancy years due to the frequency and severity of the attacks. and breastfeeding . Surgical procedures (such as cesarean She had abdominal attacks every month before her men- section) areassociatedwithanincreased risk ofattacks,and strual cycle; breakthrough attacks had been effectively con- continuing postpartum attacks can prevent mothers from trolled with pdC1INH (Cetor, 500 IU, Sanquin, Amsterdam, 2 Case Reports in Immunology Table 1: eTh schema of therapies. Period eTh rapy Dosage and reasons of dosage changes Attack frequency Abdominal attacks (every 50–200 mg/day (according to the patient’s Diagnosis (2004), 2013 Danazol peroral month before her menstrual symptoms) cycle) 1000 U/twice a week (LHRH injections were repeated four times. 2013-2014 (in vitro fertilization Each time LHRH was injected, and an extra No attack IV (intravenous) pdC1INH therapies) dosage of 1000 U pdC1INH was administered) 2014-2015 IV pdC1INH 1000 U every 2 days No attack (pregnancy< 20th week) 1500 U every 2 days 2014-2015 (>20th week (She gained extra 20 kg weight) IV pdC1-INH No attack pregnancy-cesarean section) (Before and 12 hours aer ft cesarean section, extra 1000 U pdC1INH was administered) Postpartum period and 1000 U/twice a week (each abdominal attack IV pdC1INH 2 abdominal attacks breastfeeding (4 months) was treated with extra 1000 U pdC1INH) Netherlands). Due to her pregnancy plans in 2013, danazol and breastfeeding, hepatitis A, B, C viruses (HAV, HBV, and was stopped 1 year before the conception attempts. Aeft r HCV), human immune deficiency virus (HIV), Epstein-Barr changing therapy, angioedema attacks started again; so pro- virus (EBV), cytomegalovirus (CMV), and parvovirus B19 phylactic intravenous pdC1-INH was administered (dosage: were tested and the tests resulted negative. Viral transmission 1000 U) twice a week. Between 2013 and 2014, in vitro fertil- did not occur as a result of pdC1INH therapy. No antibodies ization therapies started. Intravenous pdC1INH 1000 U twice against pdC1INH were either detected. Repeated administra- a week was continued and during that period she received tion did not reduce the efficacy of pdC1INH. LHRH injection four times. Prior to every LHRH injec- tion, an extra dosage of 1000 U intravenous pdC1INH was 3. Discussion administered. Although plasma estrogenic status increased during in vitro fertilization therapies, no attacks were Women with C1-INH-HAE suer ff from more frequent and observed during LHRH injections by means of extra dosages more severe attacks than men . eTh disease is oeft n affected of pdC1INH. Triplet pregnancy was achieved by in vitro by estrogenic status due to increased kininogenase activities fertilization methods in 2014. Prophylaxis with pdC1INH [5, 6]. An awareness of the disease is critical for clinicians 1000Uevery 2dayswasprescribed during herpregnan- involved in the care of women because of potential compli- cy until the 20th week. After cerclage operation at the 20th cations related to pregnancy, labor, and delivery and other week,prophylacticintravenouspdC1INHwasincreasedupto women’s health issues . Pregnancy aggravates symptoms 1500 U every 2 days because of weight gain. Although she had in 40% of cases, and exogenous estrogen oeft n aggravates the gained extra 20 kg weight, she did not have any angioedema disease . Some women report that their symptoms coincide attacks probably due to the prophylactic procedure. Before with their periods . Estroprogestin contraception increases and 12 hours after cesarean section, extra 1000 U of intra- the frequency of attacks in 63% to 80% of women, and venous pdC1INH was administered. Cesarean section was hormone replacement treatment can trigger the appearance performed under epidural anesthesia at the 32nd week of the of the rfi st symptoms . Deliveries seem to be safe but it is gestation with uneventful delivery. Three healthy babies (1 advisedtohavepdC1INH availableinthe delivery room;in female and 2 males) were born without any complications. case of worsening during the pregnancy, it is recommended The patient received 188 vials (94.000 units) of pdC1INH in to use short term prophylaxis with intravenous pdC1INH total during her whole pregnancy, which successfully pre- . As shown in the literature, our patient had the risk of vented the recurrence of attacks. Aeft r the delivery, because of increased attack frequency, especially because of estrogenic breastfeeding, intravenous pdC1INH was continued 1000 U therapies (like LHRH injections) . er Th e are many treat- twice a week regularly (Table 1). The patient suffered 2 ment schedules in which LHRH agonists are used in assisted abdominal attacks during the 4 months of breastfeeding, reproductive technology. eir Th duration and initiation par- which were treated with extra dosages of 1000 U pdC1INH ticularly in ovarian hyperstimulation in vitro fertilization for each attack. Those attacks were thought to be related to (IVF) injection treatments vary. Pulsatile administration of uterine contractions because of hormonal changes during LHRH in physiologic amounts at a frequency that is similar lactation. Shereceivedintotal 64 vials(32.000units) of to the endogenous release stimulates the ovaries which intravenous pdC1INH during breastfeeding. No side effects will induce ovulation . Also, significantly higher serum were observed. Prior to and after completion of pregnancy estradiol concentration and increased number of oocytes are Case Reports in Immunology 3 observed in IVF treatments due to the cyclic supplementation Consent of LHRH . However, due to long term prophylaxis and The authors have gained written consent from the patient short term prophylaxis with pdC1INH, our patient did not regarding the use of her clinical details in this case report. suffer from angioedema attacks. For the treatment of our patient, we had to administer very high therapeutic dosages of pdC1INH: in total 126000 units during pregnancy, delivery, Conflicts of Interest and breastfeeding. Due to the triplet pregnancy, gaining extra eTh authors declare that they have no conflicts of interest 20 kg weight, distention of abdominal cavity, and increased regarding publication of this paper. intra-abdominal pressure, the patient was under the risk of worsening of angioedema. In literature, recommended dosage for prophylactic use of pdC1INH varies [Cinryze References Shire, FiercePharma, 1000 U intravenously (IV)] ; that is  A. Agostoni,E.Aygor ¨ en-Pur ¨ sun, ¨ K. E. Binkley et al., “Hered- why pdC1INH dosages were increased up to 1,500 U every 2 itary and acquired angioedema: problems and progress: pro- days in our patient . Moreover, there is a non-indication ceedings of the third C1 esterase inhibitor deficiency workshop approval notice for prophylactic use in pregnancy which had and beyond,” eTh Journal of Allergy and Clinical Immunology , been taken from the ministry of health in our country. This vol. 114, no. 3, pp. S51–S131, 2004. case has proven the safety and efficacy of pdC1INH despite  T. Caballero, H. Farkas, L. Bouillet et al., “International consen- the high dosages used, different from conventional treatment sus and practical guidelines on the gynecologic and obstetric protocols.AccordingtothestudybyMartinez-Sagueretal.,in management of female patients with hereditary angioedema 83% of pregnancies, attack rates increased during pregnancy; caused by C1 inhibitor deficiency,” The Journal of Allergy and highestmeanrates wereobservedinthesecondandthird Clinical Immunology, vol. 129, no. 2, pp. 308–320, 2012. trimesters . The published review by Bouillet noted a  L.Bouillet,H.Longhurst,I.Boccon-Gibod et al., “Disease close relationship between female hormones and angioedema expression in women with hereditary angioedema,” American . In the context of bradykinin mediated angioedema, Journal of Obstetrics & Gynecology,vol.199,no. 5, pp.484–e4, female sex hormones act on the kallikrein-kinin system by increasing synthesis of bradykinin. 17𝛽-estradiol increases  I.Czaller,B.Visy, D.Csuka, G. Fust, ¨ F. To´th, and H. Farkas, Hageman factor levels by stimulation of gene transcription “eTh natural history of hereditary angioedema and the impact of treatment with human C1-inhibitor concentrate during preg- and this hormone also increases kininogen and kallikrein nancy: A long-term survey,” European Journal of Obstetrics & levels . os Th e results suggest that increased estrogenic Gynecology and Reproductive Biology,vol.152,no. 1,pp.44–49, status and kininogenase activities would have increased the frequency of abdominal attacks in our patient and this could  I.Martinez-Saguer,E.Rusicke,E.Aygor ¨ en-Pur ¨ sun, ¨ C. Heller, T. have been prevented by the use of long term prophylaxis Klingebiel, and W. Kreuz, “Characterization of acute hereditary with pdC1INH. In another study, Gonzale ´ z-Quevedo et al. angioedema attacks during pregnancy and breast-feeding and made a retrospective review of 61 C1-INH-HAE patients their treatment with C1 inhibitor concentrate,” American Jour- with 125 full-term pregnancies . According to that study, nal of Obstetrics & Gynecology,vol.203,no. 2,pp.131–e7, 2010. pregnancy had a variable influence on the clinical expression  T.Caballero,J.Canabal,D.Rivero-Paparoni,andR.Cabanas, ˜ of C1-INH-HAE. Although some of the patients reported “Management of hereditary angioedema in pregnant women: A an increased frequency of attacks, the others reported the review,” International Journal of Women’s Health,vol.6,pp.839– presence of the same symptoms throughout pregnancy 848, 2014. .  A. Banerji and M. Riedl, “Managing the female patient with In summary, pdC1INH was effective as acute treatment, hereditary angioedema,” Women’s Health Journal (WHJ),vol.12, no.3,pp. 351–361,2016. as well as for the long and short term prophylaxis of C1- INH-HAE during pregnancy and lactation. An important  L. Bouillet and A. Gompel, “Hereditary angioedema in women: specific challenges,” Immunology and Allergy Clinics of North pointinourcase studyisthatthepatientreceivedestrogen America, vol. 33, no. 4, pp. 505–511, 2013. raising therapies, especially in vitro fertilization methods like  P. Kumar and A. Sharma, “Gonadotropin-releasing hormone LHRH injections, without developing angioedema attacks. A analogs: Understanding advantages and limitations,” Journal of triplet pregnancy was achieved safely without any increased Human Reproductive Sciences,vol.7,no.3, p.170, 2014. attack rates by means of long term pdC1INH prophylaxis  R. Depalo, K. Jayakrishnan, G. Garruti et al., “GnRH agonist with the appropriate dosage according to her weight gain. versus GnRH antagonist in in vitro fertilization and embryo el Th argecumulativedoseofpdC1INH issafe forboththe transfer (IVF/ET),” Reproductive Biology and Endocrinology, mother and the babies. Apparently, individualized treatment vol. 10, article 26, 2012. with administrations of different dosages of intravenous  B. L. Zuraw, P. J. Busse, M. White et al., “Nanofiltered C1 inhi- pdC1INH at different times can help physicians to manage C1- bitor concentrate for treatment of hereditary angioedema,” The INH-HAE patients without complications despite increased New England Journal of Medicine,vol.363,no.6,pp.513–522, estrogenic status. In conclusion, early discontinuation of attenuated androgens, regular monitoring of the patient, and  J. A. Bernstein, M. E. Manning, H. Li et al., “Escalating doses the administration of intravenous pdC1INH in appropriate of C1 esterase inhibitor (CINRYZE) for prophylaxis in patients doses may be necessary during pregnancy and breastfeed- with hereditary angioedema,” Journal of Allergy and Clinical ing. Immunology: In Practice,vol.2,no. 1,pp.77–84,2014. 4 Case Reports in Immunology  L. Bouillet, “Hereditary angioedema in women,” Allergy, Asth- ma & Clinical Immunology, vol. 6, no. 1, p. 17, 2010.  T. Gonza´lez-Quevedo,J.I.Larco,C.Marcosetal.,“Management of pregnancy and delivery in patients with hereditary angio- edema due to C1 inhibitor deficiency,” JournalofInvestigational Allergology and Clinical Immunology,vol.26, no.3,pp. 161–167, 2016. 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Published: Feb 13, 2018
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