Placental-mediated complications cause considerable neonatal morbidity and mortality, in addition to being emotionally devastating for parents. These complications include pre-eclampsia, birth of small-for-gestational-age neonates, placental abruption, and pregnancy loss. Microvascular and macrovascular thrombosis of the placenta are considered contributing causes of these complications,1 and hence, potentially modifiable with anticoagulant therapy.
Dr. Marc Rodger and colleagues reported the results of their meta-analysis of randomized controlled trials comparing low-molecular-weight heparin (LMWH) with nothing or with aspirin alone in pregnant women with a prior history of one or more placenta-mediated complications. Eight randomized clinical trials (occurring between 2000 and 2013) enrolling a total of 963 pregnant women were included in the analysis. The dose, type, and timing of LMWH varied, as did the use of aspirin. The primary outcome measure was a composite of early-onset (<34 weeks) or severe pre-eclampsia, birth of a small-for-gestational-age neonate (<5th percentile), late pregnancy loss (≥20 weeks), or placental abruption leading to delivery. The majority of the study population were Caucasian with a mean age 30.9 years, and 42 percent had documented thrombophilia (not all participants were tested).
LMWH did not produce a statistically significant reduction in the primary composite outcome, with 14 percent (62 of 444) of participants who received LMWH experiencing placenta-related complications compared with 22 percent (95 of 443) who did not receive LMWH (difference, –8%; 95% CI, –17.3 to 1.4; p=0.09). The only subgroup that showed a statistically significant reduction with LMWH were women with a previous history of placental abruption (8% vs. 25% incidence of recurrent abruption; difference, –16.7%; 95% CI, –23.0 to 10.4; p<0.0001).
The key message from this meta-analysis is that LMWH is not the answer for placenta-mediated complications we had hoped it would be. Given the multifactorial nature of these complications, this finding is not surprising. Furthermore, while some may point out that this meta-analysis is underpowered to exclude any benefit of LMWH, it is important to consider the magnitude of that potential benefit. For the majority of subgroups, the highest estimated absolute risk reduction is 10 percent. Although the rate of complications due to LMWH was very low, having a pregnant woman inject daily for nine months and require planned induction for delivery is not a small “ask” for what appears to be a small benefit. It is possible that specific high-risk groups, such as women with previous placental abruption, might benefit from LMWH during future pregnancies; however, this needs to be decided on a case-by-case basis. Studies in pregnant women are very challenging to conduct, so more definitive answers in this subgroup may be a long time coming.
In Brief
In conclusion, it is worthy to note that the findings of Dr. Rodgers and colleagues support the movement away from conducting thrombophilic work-ups in pregnant women who experience placenta-mediated complications (with the exception of screening for antiphospholipid antibodies in women with three or more pregnancy losses before 10 weeks gestation).2 Nearly half of the women included in their meta-analysis had documented inherited or acquired thrombophilia, yet there was no difference in the effect of LMWH within these subgroups. Thrombophilia testing causes anxiety; has insurance implications; and, based on evidence provided by this meta-analysis, falsely reassures patients that a modifiable cause for their recurrent pregnancy complications has been found.
References
Competing Interests
Dr. Linkins indicated no relevant conflicts of interest.
