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Gynecological and obstetric outcome in the French cohort of women with factor XIII deficiency

      Highlights

      • Owing to its role in pregnancy achievement, factor XIII deficiency increases the risk of miscarriages.
      • Without prophylaxis, the rate of miscarriages is high in women with FXIII deficiency
      • Full term-pregnancies were observed in women with prophylactic regimen
      • Early infusion at least once a month leads to successful pregnancy outcome

      Abstract

      Introduction

      Congenital factor XIII deficiency is a very rare bleeding disorder affecting 33 patients in France. Besides its role in fibrin clot stabilization, factor XIII is involved in placental attachment. Fetal miscarriages represent a frequent and concerning issue for these patients. The aim of the present study was to describe clinical characteristics of women presenting severe congenital FXIII deficiency in France, to focus on gynecological and obstetrical events, and to report the management of these rare situations.

      Methods

      We conducted a retrospective study in the French Hemophilia Comprehensive Care and Clinical Hemostasis Centers. Women between 15 and 65 years with factor XIII activity <10 IU dL−1 were included. Biological, clinical and therapeutic events that occurred to these patients during their gynecological and obstetrical period were recorded.

      Results

      Among 31 centers, eleven patients were included. The median age at diagnosis was 1.5 years (range: 0–35), and at inclusion it was 30 years (range: 15–63). Fetal miscarriage was the primary manifestations in 2 (18%) patients, the remaining were diagnosed during hemorrhage. Menorrhagias were reported by 2 women (27%), 13 pregnancies were reported by 9 women including one abortion. Every pregnancy was conducted under factor XIII substitution, no hemorrhagic episode was reported. Four patients (36%) experienced at least one fetal miscarriage with a total amount of 30 miscarriages with 6 occurring during substitution.

      Conclusion

      Altogether, our data confirmed the high incidence of miscarriage in women with factor XIII deficiency. Good outcome of pregnancies required prophylaxis in accordance with international guidelines.

      Keywords

      1. Introduction

      Congenital factor XIII (FXIII) deficiency is a very rare life-threatening autosomal recessive bleeding disorder. FXIII is a plasmatic protein circulating as a tetramer comprising two A-chains and two B-chains. After activation, FXIII increases the resistance of clots and possibly plays many other roles, notably in angiogenesis, placental attachment and it is essential for maintaining pregnancy [
      • Muszbek L.
      • Bereczky Z.
      • Bagoly Z.
      • Komáromi I.
      • Katona É.
      Factor XIII: a coagulation factor with multiple plasmatic and cellular functions.
      ,
      • Tahlan A.
      • Ahluwalia J.
      Factor XIII: congenital deficiency factor XIII, acquired deficiency, factor XIII A-subunit, and factor XIII B-subunit.
      ]. Two separate genes (F13A1 and F13B) located on 2 different chromosomes are responsible of the production of FXIII [
      • Kohler H.P.
      • Ichinose A.
      • Seitz R.
      • Ariens R.a.S.
      • Muszbek L.
      • Factor XIII And Fibrinogen SSC Subcommittee Of The ISTH
      Diagnosis and classification of factor XIII deficiencies.
      ].
      The prevalence of FXIII deficiency varies around the world. One in every 1–2 million live births is affected, with higher prevalence in consanguineous families [
      • Hsieh L.
      • Nugent D.
      Factor XIII deficiency.
      ,
      • Odame J.E.
      • Chan A.K.
      • Wu J.K.
      • Breakey V.R.
      Factor XIII deficiency management: a review of the literature.
      ]. In Europe, a register based on 13 centers identified 42 patients, corresponding to 7% of rare bleeding disorders (sRBD) [
      • Peyvandi F.
      • Palla R.
      • Menegatti M.
      • Siboni S.M.
      • Halimeh S.
      • Faeser B.
      • et al.
      Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders.
      ]. In France, among the 476 patients with rare bleeding disorders registered in the FranceCoag Network, 33 patients (6%) present a severe FXIII deficiency (<10 IU dL−1) [
      • FranceCoag R.
      Données démographiques: autres Déficits Héréditaires en Protéines Coagulantes.
      ]. FXIII-A deficiency is the most severe form which leads to neonatal umbilical hemorrhage in 80% of cases, and spontaneous intracranial hemorrhage in 30% of cases [
      • Hsieh L.
      • Nugent D.
      Factor XIII deficiency.
      ,
      • Schroeder V.
      • Kohler H.P.
      New developments in the area of factor XIII.
      ]. Factor XIII deficiencies can also be revealed by induced bleeding, delayed wound healing, and repeated miscarriages [
      • Sharief L.a.T.
      • Kadir R.A.
      Congenital factor XIII deficiency in women: a systematic review of literature.
      ]. The minimum FXIII activity level required to prevent major bleeding remains controversial in the absence of controlled prospective data [
      • Menegatti M.
      • Palla R.
      • Boscarino M.
      • Bucciarelli P.
      • Muszbek L.
      • Katona E.
      • et al.
      Minimal factor XIII activity level to prevent major spontaneous bleeds.
      ,
      • Dorgalaleh A.
      • Tabibian S.H.
      • Safa M.
      • Shams M.
      • Naderi M.
      Minimal factor XIII activity level to prevent major spontaneous bleeds: comment.
      ,
      • Mumford A.D.
      • Ackroyd S.
      • Alikhan R.
      • Bowles L.
      • Chowdary P.
      • Grainger J.
      • et al.
      Guideline for the diagnosis and management of the rare coagulation disorders: a United Kingdom Haemophilia Centre Doctors’ Organization guideline on behalf of the British Committee for Standards in Haematology.
      ].
      During the reproductive period of life, menstruation and pregnancy are 2 circumstances in which women with severe FXIII deficiency may experience an increased risk of bleeding. Yet little data in the literature are available as to how to manage these situations in women affected by FXIII deficiency due to the rarity of the disease. Because FXIII deficiency leads to frequent abortion in pregnant women, the knowledge of the gynecological issues and/or obstetric complications in affected women could be helpful to propose prophylactic treatment during pregnancy. A recent review of the literature highlighted the high frequency of pregnancy loss in these women and that treatment by FXIII concentrates is required for pregnancy success [
      • Sharief L.a.T.
      • Kadir R.A.
      Congenital factor XIII deficiency in women: a systematic review of literature.
      ]. In addition, Naderi et al. reported data from 17 cases in Iran [
      • Naderi M.
      • Eshghi P.
      • Cohan N.
      • Haghpanah S.
      • Karimi M.
      Evaluation of the FXIII deficiency prophylaxis intervals in large number of FXIII deficiency patients from Iran.
      ], but these authors revealed the lack of consistent data in Western countries.
      The aim of the present study was to describe clinical characteristics of women presenting severe congenital FXIII deficiency in France, to focus on gynecological and obstetrical events, and to report the management of these rare situations.

      2. Materials

      A retrospective study based on medical files of patients followed in one of the French Hemophilia Comprehensive Care and Clinical Hemostasis Centers was conducted. Inclusion criteria were: follow-up in one of these centers, age between 15 and 65 years, and to have provided informed consent. Laboratory assessment of FXIII deficiency was performed using the Berichrom® FXIII activity assay (Siemens Healthcare Diagnostics, Tarrytown, NY, US). Because the diagnostic accuracy of FXIII measurements remains uncertain, in the present study the limit of quantification of the method to assess the FXIII activity level varied from <1 IU dL−1 or <10 IU dL−1 according to the analyzer and the laboratory. Data on medical history including demographic characteristics, age, and circumstance of diagnosis, and prophylactic treatment were recorded. Gynecological and obstetrical events including abortions, pregnancies, and modalities of treatment during pregnancy and delivery were particularly investigated. The study was approved by the medical ethics committee of the National Reference Center in Lyon.

      3. Results

      Eleven women from 31 centers were included. The median age at diagnosis was 1.5 years (range: 0–35), and at inclusion it was 30 years (range: 15–63). Consanguinity was reported in 2 patients. Nine patients presented a FXIII-A deficiency, while genotype was unavailable in 2 patients. Eight patients had FXIII levels <1%, and 3 had <10% of FXIII. In 7 patients, umbilical cord or cerebral hemorrhage was the primary clinical manifestation. The 2 remaining patients were diagnosed following fetal miscarriage with massive bleedings (Table 1).
      Table 1Demographic, clinical, and prophylaxis regimen in 11 women with FXIII deficiency.
      PatientAge at inclusion, yearsAge at diagnosis, yearsFXIII level, IU dL−1First bleeding symptomProphylactic regimen (pdFXIII), IU/weeks
      1151<10Central nervous system1250/4
      2220<10Umbilical cord500/3
      3280<1Umbilical cord2500/4
      4333<1Hematoma1500/4
      5471<1Central nervous system1250/4
      6252<1Umbilical cord1250/4
      7260<1Umbilical cord2500/4
      84231<10Fetal miscarriagesnone
      9403<1Hemarthrosis1750/4
      104118<1Fetal miscarriages1250/8
      116335<1Umbilical cordnone
      At inclusion, prophylactic regimen was reported in 9 women, it was based on plasma-derived FXIII concentrates (pdFXIII; Fibrogammin, CSL Behring, Germany) administered at a variable dose per infusion (range: 500–2500 IU) and frequency of infusion outside pregnancy (range: every 3–8 weeks).
      Menorrhagia was reported in 2 patients receiving prophylaxis with pdFXIII (Table 2). These patients were also treated with tranexamic acid, and one received combined oral contraceptives, and iron supplementation. Three patients did not report menorrhagia in the absence of prophylaxis.
      Table 2Gynecological and obstetrical events in 11 women with severe FXIII deficiency.
      PatientMenorrhagiaPregnancies

      (n = 43)
      Fetal miscarriages

      (n = 30)
      Deliveries

      (n = 12)
      1No000
      2Yes000
      3No101
      4Yes101
      5No101
      6No10Abortion
      7No202
      8No743
      9No761
      10No1183
      11No12120
      Nine women experienced pregnancies. One patient had an abortion and 1 patient presented 12 miscarriages but no full-term pregnancy. Twelve deliveries were reported in 7 women: 4 patients experienced pregnancies without miscarriages, 3 had both pregnancies and miscarriages. Two preterm deliveries occurred, at 26 and 33 gestational weeks, respectively due to incompetent cervix or to premature rupture of membrane (Table 2). In the particular case of patient 8, a premature delivery occurred in a context of incompetent cervix and disseminated intra-vascular coagulation with a fetal death due to prematurity. In this woman, the diagnosis of inherited FXIII deficiency was made after this first bleeding complication.
      Among the 30 miscarriages reported in 4 patients: 97% occurred during the first trimester. Six miscarriages occurred despite prophylactic regimen; for 3 of these very early miscarriages occurred under pre-gestational prophylaxis (1 infusion every 2 months) (Table 3).
      Table 3Fetal miscarriages (n = 30) in the 4 patients concerned.
      PatientNumber of fetal miscarriageFM without prophylactic treatment, n (%)FM under prophylactic treatment, n (%)Curettage, n (%)Hemorrhagic complications
      843 (75)1 (25)2 (50)Yes
      962 (33)4 (77)6 (100)No
      1087 (87)1 (23)6 (75)Yes
      111212 (100)0 (0)8 (66)No
      All full term-pregnancies (n = 11) were observed in women with prophylactic regimen. The doses and the frequency of infusion varied among included patients. One infusion at least per month was administered; the frequency of infusion ranged from 1 every 2 weeks to 1 every 4 weeks. There was no intensification of treatment during 8 pregnancies in 5 women. In 2 pregnancies the same dose was infused more frequently (1/3 weeks to 1/2 weeks, then 1/10 days) and patient 5 received a higher frequency of infusion only during the second trimester (Table 4). FXIII measurements were not systematically performed, leading to a systematic prescription at the same regimen. Only 2 centers were able to collect these data: the median of FXIIII levels before an infusion was 17 IU dL−1 (range: 7–30).
      Table 4Data of prophylactic regimen during pregnancies and mode of deliveries (n = 11) in 7 women.
      PatientpdFXIII (IU)/infusionFrequency (infusion/weeks or days)Mode of delivery
      First trimesterSecond trimesterThird trimester
      325001/3 w1/2 wVaginal
      417501/4 wCesarean section
      512501/2 w1/3 w1/2 wCesarean section
      725001/4 wVaginal
      25001/4 wVaginal
      812501/3 wCesarean section
      12501/3 w1/2 w1/10 dCesarean section
      12501/3 wCesarean section
      917501/2 wCesarean section
      1012501/3 wVaginal
      12501/3 wVaginal
      w: weeks, d: days.
      There were 5 vaginal deliveries and 6 cesarean sections. A bolus of a least 1250 IU of pdFXIII was administered just before the delivery in all patients and was sufficient to prevent hemorrhagic complications during delivery and post-partum. No epidural analgesia was performed. All newborns were healthy and no neonatal haemorrhagic complication associated with the birth process was reported. No bleeding complication was observed in the patient who had an abortion under infusion pdFXIII prior to the procedure.

      4. Discussion

      The present report also found that the main feature of pregnancies in women with FXIII deficiency is the high risk of miscarriage; 30 miscarriages were reported in 4 patients, including 12 in one patient who did not receive FXIII substitution before or during pregnancies. Six miscarriages occurred despite a substitution: one patient experienced 3 miscarriages due to incompetent cervix but one patient experienced 3 miscarriages probably due to a too low dose of pdFXIII. In a recent review Sharief et al. estimated that in women with severe FXIII deficiency the risk of miscarriages occurs in 2 out of 3 pregnancies. Without FXIII substitution, the achievement of pregnancy with birth of a healthy infant was estimated to be 10%, the miscarriages occurring mainly during the 1st trimester [
      • Sharief L.a.T.
      • Kadir R.A.
      Congenital factor XIII deficiency in women: a systematic review of literature.
      ]. The role of FXIII is well-known in coagulation but also in the pregnancy achievement. But the role of FXIII in maintaining of pregnancy is not completely understood. Although, FXIII is not essential to become pregnant, it has been reported that FXIII knockout mice can initiate pregnancies but died prematurely due to vaginal bleedings concomitant with massive placental hemorrhage. Embryos exhibit no abnormalities, suggesting a maternal origin to these miscarriages [
      • Koseki-Kuno S.
      • Yamakawa M.
      • Dickneite G.
      • Ichinose A.
      Factor XIII A subunit-deficient mice developed severe uterine bleeding events and subsequent spontaneous miscarriages.
      ]. Fibrin and fibronectin are 2 substrates of FXIII and are major components of the layer between zona compacta and zona spongiosa, also known as Nitabuch's layer, which constitutes the separating line at the time of delivery. Co-localization of FXIII, fibrin and fibronectin has been described in this layer: its activity would participate in the maintenance of the integrity of this layer. Moreover, Nitabuch's layer would be involved in immune tolerance and FXIII deficiency could disrupt this function and participate in fetal losses [
      • Muszbek L.
      • Bereczky Z.
      • Bagoly Z.
      • Komáromi I.
      • Katona É.
      Factor XIII: a coagulation factor with multiple plasmatic and cellular functions.
      ].
      Eleven pregnancies conducted under prophylaxis had a good outcome. During the study period, there were no guidelines available with regard to substitution regimen during pregnancy and a large variation of doses and frequency were reported by each center. Herein, 9 pregnancies were conducted and the pdFXIII doses ranged from 400 to 800 IU/week throughout the pregnancy. Increased doses were reported in only 3 pregnancies. These results suggest that at least one infusion of 400 IU/week could lead up to healthy child birth. The level of substitution remains debated but a target between 10 and 20 IU dL−1 of FXII activity is recognized [
      • Dorgalaleh A.
      • Tabibian S.H.
      • Safa M.
      • Shams M.
      • Naderi M.
      Minimal factor XIII activity level to prevent major spontaneous bleeds: comment.
      ]. The United Kingdom Doctor's Hemophilia Organisation, recommend a monthly injection from the diagnosis of pregnancy, with a FXIII level above 3 IU dL−1 [
      • Bolton-Maggs P.H.B.
      • Perry D.J.
      • Chalmers E.A.
      • Parapia L.A.
      • Wilde J.T.
      • Williams M.D.
      • et al.
      The rare coagulation disorders—review with guidelines for management from the United Kingdom Haemophilia Centre Doctors’ Organisation.
      ]. Some authors advocate for the use of 250 FXIII IU/week from the beginning of the pregnancy until the 6th month, followed by 500 IU/week and an additional dose of 1000 IU at the time of the delivery [
      • Asahina T.
      • Kobayashi T.
      • Takeuchi K.
      • Kanayama N.
      Congenital blood coagulation factor XIII deficiency and successful deliveries: a review of the literature.
      ,
      • Inbal A.
      • Muszbek L.
      Coagulation factor deficiencies and pregnancy loss.
      ]. Furthermore, herein the administration of an additional dose before delivery prevented post-partum hemorrhage that has been described in previous studies; these series reported >25% of post-partum hemorrhage in this population, which represents a 5-fold increased risk as compared to healthy population in France [
      • Deneux-Tharaux C.
      • Bonnet M.-P.
      • Tort J.
      Epidemiology of post-partum haemorrhage.
      ].
      In addition, a quarter of women with FXIII deficiency (n = 3) did not experience menorrhagia before introduction of prophylaxis and among women receiving prophylaxis, 2 patients reported menorrhagia; no life-threatening peritoneal bleeding was observed. In the literature, however, a high rate of peritoneal bleeding by ruptured ovarian cyst and of menorrhagia (26 to 64%) were described in women without prophylaxis [
      • Sharief L.a.T.
      • Kadir R.A.
      Congenital factor XIII deficiency in women: a systematic review of literature.
      ,
      • Lak M.
      • Peyvandi F.
      • Ali Sharifian A.
      • Karimi K.
      • Mannucci P.M.
      Pattern of symptoms in 93 Iranian patients with severe factor XIII deficiency.
      ,
      • Burrows R.F.
      • Ray J.G.
      • Burrows E.A.
      Bleeding risk and reproductive capacity among patients with factor XIII deficiency: a case presentation and review of the literature.
      ], The low rate of gynecological bleeding in the series reported herein could be explained by prophylaxis treatment received by the patients.
      One of the limitations of this study is the lack of measurement of FXIII levels to guide the frequency of infusions. The observational nature and the absence of control group represent other potential limitations of the study. But this is the biggest series reporting obstetrical outcome in pregnant women with severe FXIII deficiency in Western countries.
      Taken together, despite the small number of patients due to the rarity of this bleeding disorder, the results confirm the high prevalence of miscarriages and the effectiveness of FXIII prophylaxis to achievement of pregnancy. An injection per month of at least 400 IU of FXIII as soon as possible, personalized individual care through collaboration between obstetricians, hematologists should allow successful outcome of each pregnancy.

      Author contributions

      Lucia Rugeri, Christophe Martinaud and Sandrine Meunier performed the research, designed the research study, analysed the data and wrote the paper. Philippe Beurrier, Yvonne Borg, Hervé Chambost, Vanessa Milien, Mirela Chirila, Dominique Desprez, Annie Harroche, Brigitte Pan-Petesch performed the research and reviewed the manuscript. All authors read and approved the final manuscript. The authors have indicated that they have no other conflicts of interest regarding the content of this article.

      Declaration of competing interest

      All authors declare no conflicts of interest.

      Acknowledgments

      We thank Philip Robinson (DRCI, Hospices Civils de Lyon) for their advice.

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