Management Of Pregnancy In Patients With Antithrombin Deficiency
Authors: von Depka Mario , Döpke Stefanie , Henkel-Klene Anja , Wermes Cornelia , Ekhlasi-Hundrieser Mahnaz , Detering Carsten 
Published: October 2019

Abstract

Introduction
During pregnancy women have a four- to five-fold increased risk of thromboembolism (TE) compared to women who are not pregnant. Among the most important risk factors for TE in pregnancy is the presence of thrombophilia. Multiple reports have described an association between antithrombin (AT) deficiency and an increased rate of thromboembolic events especially during pregnancy. As the placental development depends on well-balanced pro- and anticoagulant mechanisms, thrombophilia, e.g. AT deficiency may be associated with poor pregnancy outcome. Despite anticoagulation with low molecular weight heparin (LMH) during pregnancy and the postpartum period alone, women with AT deficiency are still at a high risk to develop TE, especially perinatal and during puerperium because of withheld anticoagulation to prevent bleeding complications. Therefore, several guidelines recommend the administration of antithrombin concentrates during high risk situations as pregnancy. Here, we present the results of our study on the usage of AT concentrates in pregnant women with AT deficiency who either suffered from fetal loss or thromboembolism prior inclusion.

Methods
In total, 22 pregnancies in 19 patients (age: 31.9±4.7; 22-41) with AT deficiency were included in this open-label, single-center study. Ten patients (53%) had a history of fetal loss, 9/19 (47%) patients hat a history of thromboembolism. During all pregnancies AT concentrate (AT-C) was administered, in 18/22 (81.8%) pregnancies LMH was given in addition. Prior pregnancy losses (21/30, 70%) occurred in all trimester (t1: n=11, t2: n=5, and in t3: n=5). Historical live birth rate (LBR) was 30%. Blood samples were collected in all trimesters and postpartum to analyze AT activity and antigen, endogenous thrombin potential (ETP), thrombin-antithrombin-complex (TAT), Fragment 1+2 (F1+2) and c-reactive protein test (CRP). A total of 114 uneventful pregnancies of 113 healthy women served as controls. Furthermore, the mean doses of AT concentrates/kg BW and the mean total number of infusions were calculated.

Results
In total, 21 pregnancies (95.5%) were successful. Mean total requirement of AT concentrate per pregnancy was 79.454 IU (range: 3.000-272.000 IU) during 27.8 treatment days per pregnancy (range: 1-88). Our data show an increase of F1+2 in the course of pregnancy. Mean levels of F1+2 at t1, t2 and t3 (t1= 255.9 ± 107.6, t2= 360.9 ± 117.4, t3= 545.3 ± 220.3 pmol/L) were significantly higher than in controls (t1= 82.2 ± 43, t2= 140 ± 100.2, t3= 183.5 ± 103.1, p<.001). Mean level of TAT was higher (3.1 ± 1.4 ng/mL) than in controls (1.7 ± 1.6 ng/mL, p=.001) in t1, whereas mean TAT in t2 and t3 was lower than in controls (3.8 ± 1.3 vs. 4.8 ± 1.9, p=.03; 5.0 ± 1.4 vs. 6.1 ± 3.0 ng/mL, n.s., resp.). No thromboembolic events occurred. In patients receiving AT-C, LBR increased from 30% to 95.5% (p<0.001) with a relative risk of 49.0 to develop pregnancy loss without anticoagulant treatment (5.7 – 421.8; 95% CI).

Conclusion
In patients with AT deficiency receiving AT concentrate and LMH we could demonstrate a significant increase of LBR from 30% to 95.5%. Furthermore, no thromboembolic events occurred, though almost half of the patients had a history of thromboembolism. There was no clear evidence of increased hypercoagulability. We conclude that combined AT concentrate and LMH are safe and efficacious for mother and child in preventing thromboembolism and pregnancy loss. Further studies to evaluate the exact mode of anticoagulation and benefit of combining AT concentrate and LMH are warranted.

Disclosures:
No relevant conflicts of interest to declare.