Effects of Low-Molecular-Weight Heparin on Pregnancy Outcomes in Protein S Deficiency: A Prospective, Randomized Controlled Phase II Clinical

Introduction:

Venous thromboembolism (VTE) is one of the leading causes of maternal mortality, occurring in 1–2 out of every 1,000 pregnancies. Hereditary thrombophilia (e.g., antithrombin, protein C and protein S(PS) deficiency) is associated with a 5–7% risk of VTE during pregnancy. However, there remains limited general consensus on the association with poor pregnancy outcomes, and the need for thromboprophylaxis. Therefore, there is an urgent need to clarify whether and how PS deficiency requires intervention to improve pregnancy outcomes. This study is a prospective, randomized controlled phase II clinical trial to assess whether low-molecular-weight heparin could improve pregnancy outcomes in pregnant patients with PS deficiency. This study is registered at clinicaltrials.gov. NCT06531525.

Methods:

Eligible pregnant women with PS deficiency (PS activity less than 60–70% in nonpregnant women, 30% and 24% in the 2nd and 3rd trimesters, respectively, or with a genetic diagnosis) were randomized 1:1:1 into three groups, each receiving 0.4 ml of enoxaparin daily plus 75 mg of aspirin, 75 mg of aspirin alone, or no intervention until delivery, and 0.4 ml of enoxaparin daily for up to 6 weeks postpartum. The drug dosage was adjusted according to events, including bleeding and thrombosis. The primary endpoints was live birth. The secondary endpoints were D-dimer levels, PS activity, safety outcomes (maternal thrombocytopenia, bleeding episodes, and skin reactions), pregnancy-associated thrombosis/thromboembolism, placental insufficiency complications such as preeclampsia, intrauterine growth retardation, placental abruption, and intrauterine fetal death, other pregnancy outcomes (early miscarriage (pre-12 weeks of gestation), late miscarriage(13-pre-28 weeks of gestation)), and preterm live birth (28-37 weeks of gestation)), and neonatal outcomes (body weight, height, Apgar scores and complications).

Results:

All enrolled patients with PS deficiency were randomized 1:1:1 into a combination group (n=16), monotherapy group (n=16) or no intervention group (n=16). All patients were followed up until 6 weeks postpartum. In the three groups, the ages at delivery were 34 years (range 27–41), 35 years (range 29–43), and 32 years (range 26–41), respectively, and the durations of initiation of medication in the combination group and the monotherapy group were 8.66 weeks and 12.36 weeks, respectively. There were 2 patients in the combination group with antepartum VTE. In the three groups, 0, 2 and 1 cases of preeclampsia occurred, respectively. There were two cases of immediate postpartum hemorrhage in the combination group and 3 cases each in the monotherapy and no intervention groups. The volume of intraoperative hemorrhage in each of the three groups were 340.63±264.71 ml, 221.88±135.36 ml, and 284.38±179.55 ml, none of which were significantly different (P>0.05), and the volume of 24-hour postoperative hemorrhage were 544.29±313.29 ml, 521.15±315.73 ml, and 444.17± 183.67 ml, respectively, which were also not significantly different (P>0.05). No placental abruption was observed in any of the three groups. Both the combination and monotherapy groups had 3 cases of hemorrhage in the stool, vaginal hemorrhage, epistaxis and gingival bleeding during pregnancy, with no bleeding events occurring in the no-intervention group. All neonates were born alive in the combination and monotherapy groups, but 2 and 1 preterm births occurred, respectively. Except for 1 neonate in the combination group whose Apgar score was 8 at 1 min, the remaining neonates in this group and in the monotherapy group had Apgar scores of 10 at 1 min, 5 min and 10 min. In the no intervention group, 1 neonate suffered severe asphyxia (3, 7 and 9 Apgar scores at 1 min, 5 min and 10 min, respectively), 1 was induced due to chromosomal abnormality, and 1 was stillborn (Apgar scores were 0 in all). Two neonates in the monotherapy group suffered neonatal anemia (HB 117 g/L) and fetal growth restriction, and no neonatal complications were observed in the combination group. There were no significant differences in pregnancy or neonatal outcomes among the three groups (P>0.05).

Conclusion:

Neither the combination group nor the monotherapy group improved pregnancy outcomes in pregnancies with PS deficiency. We do not recommend the use of low-molecular-weight heparin and aspirin in these patients.