Three successful deliveries involving a woman with congenital afibrinogenaemia – conventional fibrinogen concentrate infusion vs. ‘as required’ fibrinogen concentrate infusion based on changes in fibrinogen clearance –

Congenital afibrinogenaemia is an autosomal recessive disorder that induces a critical bleeding tendency with a prevalence of 1–2 per million in the general population, although it is more common in populations with a high rate of consanguinity [1]. Pregnancies involving patients with afibrinogenaemia are extremely rare. We previously reported the first case in the world in which a pregnancy involving a patient with congenital afibrinogenaemia was successfully managed [2]. In addition, we subsequently demonstrated that insufficient fibrinogen replacement in pregnant patients with congenital afibrinogenaemia results in abortion during the early gestational period [2,3], placental abruption or considerable genital bleeding during the second or third trimester of pregnancy, and massive bleeding during delivery or the puerperium [3,4]. Therefore, we proposed that appropriate fibrinogen replacement is essential for maintaining pregnancies that are complicated with afibrinogenaemia [3,4]. As far as we know, 13 successful deliveries involving patients with congenital afibrinogenaemia have been reported in the English literature (Table S1), including five deliveries that occurred at our institution before this case [2–5]. Factor VIII is usually infused into patients with haemophilia in accordance with their factor VIII clearance, the site and severity of any bleeding, and the intensity of any surgical stress [6]. In contrast, the use of fibrinogen clearance data to guide the administration of fibrinogen replacement therapy during pregnancy has not been reported previously. Indeed, fibrinogen concentrate was administered via the conventional empirical method in all five of the deliveries involving patients with afibrinogenaemia that we reported previously [2–5]. Considering the extreme rarity of deliveries involving patients with congenital afibrinogenaemia, the establishment of a standard fibrinogen replacement method for use during pregnancy based on continuous assessments of fibrinogen clearance would be beneficial to clinicians who have no experience of caring for pregnant women with congenital afibrinogenaemia. However, it would be difficult to conduct large-scale clinical studies to establish a standard management strategy for pregnancies involving patients with congenital afibrinogenaemia because such cases are extremely rare. Here, we report our experience of the use of two different fibrinogen replacement therapy methods; i.e. the conventional infusion of fibrinogen concentrate and a trial of the ‘as required’ infusion of fibrinogen based on continuous assessments of the patient’s fibrinogen clearance. All three pregnancies involved the same woman; therefore, we consider that the findings reported in this study are extremely valuable for comparing the efficacy of these strategies considering the limited amount of clinical data available. As a more objective fibrinogen replacement method, we considered administering fibrinogen based on the patient’s fibrinogen clearance. As afibrinogenaemic patients do not produce fibrinogen, any infused fibrinogen concentrate is consumed by their bodies and so their fibrinogen levels gradually decrease. Fibrinogen clearance (in g kg 1 day ) was determined as the total fibrinogen replacement dose administered divided by the number of days and the patient’s body weight, and the amount consumed was calculated as the difference in the fibrinogen level between consecutive two time points multiplied by the plasma volume (Table S2). It is known that maternal blood plasma volume increases as pregnancy advances [7]. We calculated the maternal plasma volume as 1/20th of the subject’s body weight multiplied by the rate of increase in that week of gestation. The subsequent fibrinogen infusion doses were calculated based on the total fibrinogen deficit compared with the target value for that time point plus the amount of fibrinogen that Correspondence: Tomoaki Oda, MD, Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan. Tel.: +81 53 435 2309; fax: +81 53 435 2308; e-mail: tomoakingdom@outlook.jp