Background
The postpartum period is associated with an elevated risk of a venous thromboembolic event (VTE). The American College of Chest Physicians recommends that patients at high risk of thromboembolism should receive prophylactic anticoagulation therapy for 6 weeks following delivery [
1]. In France, recommendations for prophylactic anticoagulation are similar [
2]. However, based on the results of four studies [
3‐
6], it is not clear whether the risk of VTE extends beyond 6 weeks postpartum. Studies by Ros et al. [
3] and Heit et al. [
4] (estimated by Jackson et al. [
7] from reported data) did not find an elevated risk of VTE after 6 weeks, whereas studies by Pomp et al. [
5] and Kamel et al. [
6] evidenced an elevated risk for at least 12 weeks after delivery. Indeed, the most detailed of these studies (with 3-week time intervals) concluded that an elevated risk could extend up to 15 weeks postpartum [
5].
In light of these findings, we decided to explore the relative risk of a postpartum VTE with a greater degree of precision. It is noteworthy that studies reporting incidence rates (without any assessment of the relative risk) give estimations for week-long intervals [
4,
5,
8,
9]. Hence, a large population-based study of how the risk of a postpartum VTE decreases over time after delivery was warranted.
Objective
The objective of the present study was to assess the risk of a postpartum VTE in 2-week time epochs extending from the date of delivery.
Discussion
Our present results showed that an elevated risk of a VTE was present for nearly 12 weeks after delivery. The shape of the risk curve suggests that this risk decreases exponentially over time. Beyond 12 weeks, the risk was no longer elevated.
The incidence of pulmonary embolism in our study is similar to that reported by Jacobsen et al. [
9] (22.0 per 100,000 deliveries) and by Lindqvist et al. [
21] (21 per 100,000 [estimated from reported data]), but is greater than the incidence reported by Gherman et al. [
22]: 8 per 100,000 (estimated from reported data).
It is also of value to compare the ORs for the occurrence of a VTE for weeks 1 to 6, weeks 7 to 12 and beyond 12 weeks. In Table
3, we report the ORs computed on our data, for the corresponding 6-week intervals (three control groups were used in this case). For the first 6 weeks, our results are close to those published by Kamel et al., but lower than those found by Heit et al. [
4] (estimated by Jackson et al. [
7] from reported data) or Pomp et al. [
5]. For weeks 7 to 12 after delivery, our results are close to those published by Kamel et al., but lower than those found by Heit et al. [
4], and higher than those found by Pomp et al. [
5]. Finally, we found that the risk was no longer elevated 12 weeks after delivery: This agrees with Kamel et al. [
6], who reported an OR [95%CI] of 1.4 [0.8–2.3] for weeks 13 to 18 and 0.8 [0.5–1.2] for weeks 19 to 24.
Table 3
Odds ratios reported by other studies, by 6-week intervals
Heit et al. [ 4] (Jackson et al. [ 7]) | 21.5 | 0.69 | - |
| 84.0 [31.7–222.6] | 8.9 [1.7–48.1] | - |
| 12.1 [7.9–18.6] | 2.3 [1.4–3.6] | 1.4 [0.8–2.3] |
Present study | 11.3 [9.7–13.2] | 2.6 [2.1–3.1] | 1.1 [0.9–1.5] |
Our use of a crossover design can be justified in two respects. Firstly, this design gave us more statistical power. Secondly, rigorous empirical evaluation by the OMOP has demonstrated that crossover design are superior in pharmaco-epidemiological studies [
9] - particularly when compared with “new user”-type cohorts [
23] and case-control studies [
24]. The OMOP also showed that crossover cohort and case-crossover designs had similar methodological quality; these two cross-over designs were applied to data initially collected in a retrospective cohort. The use of these designs requires short exposure periods and events that have short durations and brief effects; these conditions were met in the present study. Finally, the results obtained in the complementary analysis, showing a greater risk of thrombosis after caesarean delivery, are in line with the results of Morris et al. [
25], and in line with the most recent recommendations for thromboprophylaxis in United States (National Partnership for Maternal Safety) [
26] and United Kingdom (Royal College of Obstetrician and Gynaecologists) [
27]; However, the results of this additional analysis are not adjusted (in this case, the analysis compares groups of patients with each other -with or without cesarean section-, and no more the patient to herself) and no evaluation of the benefit-risk balance of thromboprophylaxis was conducted: For these reasons, these additional results do not assess the value of such thromboprophylaxis after cesarean.
The present study had several limitations. Firstly, it is also well known that survival bias can influence the findings from observational, pharmaco-epidemiological studies [
28‐
30], since the inclusion criteria can sometimes lead to the selection of low-risk patients. We cannot rule out the presence of survival bias because all patients with a VTE between January 1
st, 2007 and June 30
th, 2008 were excluded. Secondly, the use of a statistical test for each 2-week interval inevitably increases the type I error. This may have biased our estimates of the time point beyond which the risk of postpartum pulmonary embolism is no longer elevated, but not the temporal decrease in pulmonary embolism incidence. Thirdly, the use of hospital administrative databases always raises the question of data accuracy [
31,
32]. However, the codes we used for pulmonary embolism and delivery are both known to be associated with a good level of recall. In addition, it seems reasonable to consider that misclassification of VTE may occur in both case and control periods, which would not necessarily change the odds ratios and could thus be a non-differential bias. Fourthly, some dates of delivery could be inaccurate, since this date has only been mandatory since 2010. Before 2010, the database’s default delivery date is set to zero and so it is (sometimes wrongly) considered that delivery occurs on the first day of hospitalization. To some extent, this choice may have artificially lengthened the time period between delivery and the occurrence of a VTE. Furthermore, the analysis of events that only account for a proportion of the total events of interest constitutes another study limitation, and raises the question of whether our findings can be generalized to the entire set of events concerned. In the case of VTEs, it is unclear whether PE events are a good proxy for deep venous thromboses [
33]. In addition, it is possible that some massive pulmonary embolisms, leading to death without prior hospitalization, have not been detected. Finally, although our database is comprehensive for hospitalizations in France, some patients who gave birth in France could then have been lost to follow-up (e.g. emigration).
Lastly, we did not perform additional subgroup analyses as a function of the presence of anticoagulation therapy, since this information was not available in the database. It would be of value to evaluate the risk of bleeding associated with anticoagulation therapy. This could be performed by analyzing a drug prescription database. Measures of association, computed in our study, do not account for the use of mechanical or pharmacological VTE prophylaxis: It is likely that the measures of association computed for the first 6 weeks are modified by the use of prophylaxis in our population; Contrariwise, it seems reasonable to think that our estimation beyond 6 weeks is less modified. In addition, the presence of a prophylaxis beyond 6 weeks (for some patients in our analyzed sample) would be conservative regarding the results obtained for the intervals beyond 6 weeks, as it would decrease the risk of a pulmonary embolism.