Uneventful delivery of two pregnancies in a woman with severe factor XII deficiency: case report and systematic review

Introduction

Coagulation factor XII (FXII) is a plasma protein with a significant role in the blood coagulation cascade [1]. Potential deficiency, either congenital or inherited, increases significantly the risk for arterial and vein thrombotic episodes [2], [3], [4]. The frequency of this deficiency is reported to be 1.5–3.0% in the general population. However, as most of these patients are asymptomatic, diagnosis may be delayed [5].

FXII deficiency has been shown to have a detrimental effect on pregnancy outcome [6], [7], [8]. Several authors reported an increased associated risk for antenatal complications such as miscarriage or neonatal morbidity, with only a few published case reports of uncomplicated deliveries [9], [10]. Furthermore, even in published case series with pregnancies leading to live neonates, thrombotic episodes or coexisting morbidity were also present [11]. As a result, FXII deficiency poses a therapeutic challenge with a high risk of endometrial demise. However, close follow-up with appropriate medical interventions may alter the prognosis and increase the chance of an uneventful delivery.

We present here one amongst a very few published cases of a woman with severe FXII deficiency that, following her first pregnancy that led to a neonatal death 2 days after delivery due to extreme prematurity, she eventually managed to deliver two uncomplicated pregnancies following appropriate treatment in our high risk pregnancy unit. Furthermore, we also performed a systematic review of published cases of pregnancies with severe FXII deficiency that had also ended in uneventful deliveries.

Materials and methods

Medical records of patients followed in the high risk pregnancy unit of the 3^rd Department of Obstetrics and Gynaecology, Hippokrateion Hospital, Aristotle University of Thessaloniki, Greece were reviewed in terms of signs and symptoms, laboratory and imaging examinations and neonatal outcomes. Furthermore, a systematic review was performed in the Pubmed database by using the following combination of keywords: FXII deficiency[tiab] or XII deficiency[tiab] or FXII[tiab] and pregnancy[tiab] or delivery[tiab] or miscarriage[tiab] or pregnancy loss[tiab]. Inclusion criteria were considered to be case reports and case series reporting the delivery of uncomplicated pregnancies in women with severe FXII deficiency written in the English language. PRISMA guidelines were followed in order to perform a systematic review. Non-English studies, studies written before 1990, studies with other primary outcomes, narrative or systematic reviews were excluded from the present analysis.

Results

Case presentation

A 33-year-old woman, gravida 1, para 0, was admitted to the high-risk pregnancy unit of our department at 24 weeks + 4 days. The woman presented with signs of possible deep vein thrombosis of the right calf (pain, swelling, redness). The patient had a history of a diagnosed FXII deficiency and she was therefore treated with vemiparine natriate 3.5 mg/kg and acetylsalicylic acid 100 mg/day. Until the time of admission in our department, she was followed-up by a private physician and her pregnancy had already been complicated by early intrauterine growth restriction (IUGR). The relevant blood test confirmed FXII deficiency, as factor levels were as low as 12%, with normal laboratory values ranging between 70 and 150%. A Doppler ultrasound examination was negative for a thrombotic episode. However, a fetal ultrasound examination showed the absence of end diastolic flow (EDF) in the umbilical artery, redistribution of the fetal blood flow and signs of fetal heart failure with reversed α-wave in the ductus venosus. These findings and further cardiotocographic signs of imminent intrauterine death led to an urgent cesarean delivery at 25 weeks + 2 days, despite the initial decision for expectant management because of the extreme prematurity. A live male infant weighing 850 g was born and was immediately transported to the neonatal intensive care unit (NICU). Unfortunately, the neonate died 2 days later because of severe respiratory insufficiency.

Following the adverse outcome of her first pregnancy, the woman was set on a regular follow-up by a specialized hematologist and was encouraged to continue efforts of child bearing. As a result, she had three subsequent pregnancies which resulted in the delivery of two healthy live newborns. The patient’s medication was the same as in her first complicated pregnancy, that is vemiparine natriate 3.5 mg/kg and acetylsalicylic acid 100 mg/day, however, the treatment was initiated from the first trimester of pregnancy and the patient was set on a strict follow-up with blood testing and biweekly obstetrical examination in the first two trimesters of pregnancy and on a weekly basis in the third trimester of pregnancy, with no complications identified. The patient also tested negative for antiphospholipid antibodies. As a result, her second pregnancy was delivered by a scheduled cesarean section (CS) at 38 weeks + 3 days, her third pregnancy ended up as a miscarriage at 9 weeks + 2 days and her fourth pregnancy was also delivered by CS at 37 weeks + 4 days. No signs or symptoms of thrombotic disease presented in any of the three subsequent pregnancies or during the puerperium.

Systematic review

Overall, our search based on the aforementioned keywords identified 62 abstracts and, after excluding irrelevant studies according to title/abstract and duplicates, 44 studies were assessed for eligibility. Of these, there were three case reports of women with FXII deficiency delivering live newborns and one case series of 12 women with a final outcome of 19 deliveries. Apart from these four studies, there was one case report of a woman with antiphospholipic syndrome and transient lupus coagulant who had multiple pregnancy losses without reporting any uneventful pregnancy and this was excluded, 24 other studies were excluded as they had a different primary outcome (either FXII levels or other factors during pregnancy and delivery or the potential correlation of FXII levels or other coagulation factors with recurrent pregnancy loss), four studies were performed in animals, while one study was written before 1990 (Figure 1).

Figure 1:

Flowchart of studies included in our systematic review.

Discussion

We report the rare case of a woman that, despite a medical history of congenital FXII deficiency, finally managed to deliver two healthy neonates at term. The patient’s follow-up during these pregnancies revealed no signs or symptoms of thrombotic episodes while the puerperium was also uneventful.

A systematic review of the relevant literature revealed only four case reports/series of women with a history of congenital severe FXII deficiency that delivered live newborns. Specifically, Matsura et al. [10] reported on the case of a 26-year-old female with congenital FXII deficiency (levels <5%) who experienced four pregnancies and three deliveries of term neonates, her second pregnancy being terminated because of an early missed miscarriage. Lao et al. [9] reported on the case of a 19-year-old primigravida with congenital FXII deficiency (pre-pregnancy FXII values of 21%) that presented at 26 weeks with placental abruption but finally managed to deliver vaginally a healthy female neonate weighing 925 g. Banga et al. also reported the case of a woman with a history of severe FXII deficiency that finally delivered an uncomplicated pregnancy after receiving systematic medication with oral ketanserin, while she previously had four pregnancies complicated with IUGR, deep vein thrombosis and placental abruption [11]. Apart from case reports, Banga et al. [12] have published a case series of 12 women who delivered 19 neonates in a 16-year period. However, the authors reported that three of 19 pregnancies were complicated by deep vein thrombosis while five of 19 cases had bleeding complications. Finally, as all previous studies referred to congenital deficiency, there is also the publication of D’Uva et al. that reported the case of a 34-year-old woman with antiphospholipic syndrome and transient lupus coagulant that had multiple pregnancy losses, without reporting any uneventful pregnancy and this was the reason that this publication was not included in the case reports/series of the present systematic review [13].

Considering the aforementioned studies as well as our case report, it becomes obvious that pregnancies with even mild FXII deficiency pose a therapeutic challenge to the physician. Our systematic review indicated that there is no report of a woman with congenital FXII deficiency that delivered only uncomplicated pregnancies. Apart from the apparent danger for thrombotic episodes, it is now globally accepted that FXII deficiency is significantly associated with recurrent pregnancy losses. In a recent systematic review and meta-analysis of all studies dealing with fibrinolytic defects and the risk for miscarriage, it was shown that FXII deficiency is significantly associated with increased risk of miscarriage (odds ratio of 18.11) [14]. Similarly, in a more recent study performed by Dendrinos et al. [15], 100 women with a history of at least two recurrent spontaneous abortions (RSA) were compared with an age-matched population of 100 healthy controls. The authors concluded that the mean values of FXII activity were significantly lower in the RSA group. Similar results were found in cases with recurrent in vitro fertilization-frozen embryo transfer (IVF-FET) failure [16]. Thus, Matsubayashi et al. compared 110 patients that had at least three IVF-FET failures with 87 healthy controls and also 191 patients with recurrent miscarriages and found a significantly lower FXII activity levels in the recurrent IVF-failure group than in both the control and the recurrent miscarriage group. Therefore, FXII activity is not only significantly associated with a higher risk of miscarriage but also potentially with an increased risk for IVF failure, when there is severe FXII deficiency.

Despite the fact that the enzymology of the FXII-driven contact system in vitro is well understood, in vivo contribution has not been clear. Despite the predominant role of FXII in fibrin formation in vitro, FXII-initiated coagulation in vivo was not considered to be of significance. This was potentially based on the fact that persons with partial or severe FXII deficiency do not bleed excessively from sites of injury despite a marked prolongation of the aPTT [17], [18], [19]. This apparent discrepancy between the essential role of FXII for contact-driven fibrin formation in test tubes and actual contribution in vivo puzzled investigators for decades. Furthermore, the issue may be even more complicated during pregnancy as not much have been known about normal ranges of values, potential complications of deficiency to fetus and mother as well as dignosis and optimal therapeutic approach.

The optimal therapeutic approach is upraised as the principal concern in cases of FXII deficiency but there is no consensus to date. Banga et al. [12] proposed the use of prophylactic oral ketanserin as a measure to prevent antenatal complications in FXII deficiency cases, reporting a single uneventful in a total of six pregnancies in a patient with congenital FXII deficiency. In our case, however, prophylactic administration of veripamine natriate and acetylsalicylic acid were also effective in terms of preventing complications.

In conclusion, we presented the case of a 33-year-old woman that delivered two uncomplicated pregnancies following appropriate treatment in our high risk unit along with a relevant systematic review. FXII deficiency still poses a great therapeutic challenge with a high risk of complications. Therefore, despite the methodological difficulties in detecting an appropriate study population, multi-center prospective trials are needed in order to examine the comparative effectiveness of various antithrombotic agents and achieve a consensus regarding the optimal medication and follow-up of pregnant women with FXII deficiency.