Prophylactic Low Molecular Weight Heparin (LMWH) during Pregnancy Is Not Associated with a Decrease in Bone Mineral Density (BMD). The TIPPS (Thrombophilia in Pregnancy Prophylaxis Study) BMD Substudy.
Authors: Rodger Marc A. , Lazo-Langner Alejandro , Kahn Susan , Kovacs Michael , Robinson Sue , Blostein Mark , Smith Graeme , Kingdom John , Demers Christine , Solymoss Susan , Khurana Rshmi , Rey Evelyn , Clement Anne Marie , Wells Philip S. 
Published: April 2020

Background: Decreased BMD is a relatively common serious complication of long-term heparin use, however there have not been adequately powered randomized controlled trials addressing its risk in association with long-term use of LMWH. The TIPPS study is an ongoing multi-center randomized trial designed to compare the effect of LMWH prophylaxis vs. no prophylaxis on pregnancy outcomes in thrombophilic pregnant women. A separate sub-study was planned a priori to assess the effect of LMWH on BMD.

Methods: Pregnant women (&lt;20 weeks) were included if they had history of: pregnancy complications or were at moderate risk of venous thrombosis, and had a confirmed thrombophilia. They were excluded if they had history of underlying bone or thyroid disease, long-term use of corticosteroids, metabolic bone agents or anticonvulsants, or &gt;100 kg wt. Patients (pts) were randomized to either LMWH (dalteparin [dalt] 5,000 U qd until 20 wks and then 10,000 qd until term) or control (ctrl) group. All participants received post-partum dalt 5,000 U qd from postpartum d1 to d42. BMD (hip and lumbar spine) was performed 6 wk post-partum. A sample size of 26 pts per group was calculated to detect a 10% difference in absolute BMD (α=0.05, β=0.10). Primary outcome was absolute spine BMD compared using an unpaired t-test. Results were analyzed as-treated; 31 pts received dalt and 22 did not (4 pts randomized to ctrl group crossed over).

BMD and T-score results in treatement groups Dalteparin1 No dalteparin1 p Value 1Mean (SD) BMD (spine) 1.12 (0.26) 1.21 (0.14) 0.115 T-score (spine) −0.32 (1.25) 0.13 (1.15) 0.196 BMD (hip) 0.97 (0.21) 1.02 (0.12) 0.319 T-score (hip) 0.17 (0.96) 0.36 (1.01) 0.479

Duration of dalt treatment was 214.5±41.9d for dalt group and 47±38.6d for ctrl (p&lt;0.001). Two cases of osteoporosis (Opo) and 7 cases of osteopenia (Ope) were documented in the dalt group vs 0 of Opo and 3 of Ope in the ctrl group respectively. Results of post-hoc logistic regression analysis examining the odds of obtaining an abnormal (Opo or Ope) spine or hip BMD result in both treatment groups were non significant (Crude OR 2.59; 95%CI 0.61, 10.97; p=0.20; Adjusted OR 6.83; 95%CI 0.17, 272.33; p=0.307) as well as results of post-hoc multiple linear regression to predict changes in BMD and T-scores.

Multiple linear regression analysis predicting BMD and T-score in patients receiving dalteparin Unadjusted Adjusted Beta (SE) p Beta (SE) p BMD (spine) −0.099(0.06) 0.12 −0.226(0.16) 0.16 BMD (hip) −0.051(0.05) 0.32 −0.190(0.13) 0.15 T-score (spine) −0.444(0.34) 0.66 −0.641(0.87) 0.47 T-score (hip) −0.195(0.27) 0.48 −0.661(0.68) 0.34

Conclusion: Our results suggest that the use of long term prophylactic dalteparin in pregnancy is not associated with a significant decrease in BMD.