Hypercoagulable State Will I Ever Be Able to Have a Baby
N Engl J Med. Author manuscript; bachelor in PMC 2014 October iii.
Published in final edited form equally:
PMCID: PMC4035479
NIHMSID: NIHMS584313
Take chances of a Thrombotic Event after the 6-Week Postpartum Period
Hooman Kamel, M.D., Babak B. Navi, M.D., Nandita Sriram, B.Due south., Dominic A. Hovsepian, B.S., Richard B. Devereux, M.D., and Mitchell Due south.V. Elkind, Thousand.D.
Abstract
Background
The postpartum country is associated with a substantially increased hazard of thrombosis. It is uncertain to what extent this heightened risk persists across the conventionally divers 6-week postpartum menses.
Methods
Using claims information on all discharges from nonfederal emergency departments and acute care hospitals in California, nosotros identified women who were hospitalized for labor and commitment between January i, 2005, and June 30, 2010. Nosotros used validated diagnosis codes to identify a blended primary outcome of ischemic stroke, astute myocardial infarction, or venous thromboembolism. We and then used provisional logistic regression to assess each patient's likelihood of a first thrombotic event during sequential 6-calendar week periods after delivery, equally compared with the respective 6-week period ane year later.
Results
Among the 1,687,930 women with a first recorded delivery, 1015 had a thrombotic effect (248 cases of stroke, 47 cases of myocardial infarction, and 720 cases of venous thromboembolism) in the period of 1 year plus upwardly to 24 weeks later delivery. The run a risk of chief thrombotic events was markedly higher within 6 weeks after delivery than in the same period 1 year later, with 411 events versus 38 events, for an accented take chances difference of 22.1 events (95% conviction interval [CI], 19.six to 24.half-dozen) per 100,000 deliveries and an odds ratio of 10.eight (95% CI, seven.8 to 15.1). At that place was also a pocket-sized but meaning increase in hazard during the menstruum of 7 to 12 weeks afterwards commitment as compared with the same period 1 yr later, with 95 versus 44 events, for an absolute risk departure of 3.0 events (95% CI, 1.6 to four.v) per 100,000 deliveries and an odds ratio of 2.2 (95% CI, 1.v to 3.i). Risks of thrombotic events were not significantly increased beyond the first 12 weeks later on delivery.
Conclusions
Amongst patients in our study, an elevated hazard of thrombosis persisted until at to the lowest degree 12 weeks later delivery. However, the absolute increment in risk beyond 6 weeks after delivery was low. (Funded by the National Constitute of Neurological Disorders and Stroke.)
Pregnancy significantly increases the run a risk of thrombosis. This heightened thrombotic risk rises further during the postpartum period, which is conventionally defined as the 6 weeks after commitment.1 As compared with the nonpregnant state, the 6-calendar week postpartum menstruation is associated with increases past a gene of 3 to 9 in the take a chance of stroke, by a factor of 3 to vi in the risk of myocardial infarction, and by a cistron of 9 to 22 in the risk of venous thromboembolism.2-viii It is unknown whether these risks remain increased after the conventionally defined 6-week postpartum period. Guidelines for the treatment of thrombotic disorders during pregnancy advise the discontinuation of safe therapy at half dozen weeks later commitment in women at high risk for venous thromboembolism.1 Even so, previous studies and isolated case reports have suggested that an increased thrombotic hazard may persist across 6 weeks after delivery.5,viii-ten Therefore, more than information are needed to rigorously assess the risk after the 6-calendar week postpartum menstruum. We designed this study to assess the duration of an increased postpartum thrombotic risk in a large population-based cohort of women.
Methods
Study Design
We performed a retrospective crossover-accomplice study (a study blueprint in which each patient serves every bit his or her own control), using administrative claims information on all discharges from nonfederal emergency departments and acute care hospitals in California. We compared each patient's likelihood of a first thrombotic event during sequential 6-calendar week periods after commitment with the likelihood of an event during the corresponding half dozen-week menstruum 1 twelvemonth later. Since exposure to pregnancy varies discretely over time, this design allowed each patient to serve as her own command, thereby minimizing unmeasured confounding.eleven,12 California was chosen because information technology is a big and demographically heterogeneous land13 with administrative data that permit tracking of individual patients across visits over numerous years,14 thereby providing sufficient statistical ability to detect associations amidst atmospheric condition with low accented issue rates. Analysts at each facility used detailed reporting and formatting specifications and automated online-reporting software to provide uniform data on all discharges to the California Office of Statewide Health Planning and Develop ment.15 Afterward a multistep quality-assurance procedure to flag invalid or inconsistent entries, these data were provided in a deidentified format to the Healthcare Price and Utilization Project.14 The institutional review boards at Weill Cornell Medical College and Columbia University Medical Heart certified that this analysis of publicly bachelor, deidentified data was exempt from review and from the need for informed consent. All authors take responsibility for the integrity of the information and analyses.
Study Patients
We identified all women who had been hospitalized for labor and delivery, using standard codes from the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) for vaginal delivery (72, 73, 75, V27, or 650–659) and cesarean delivery (74).16 To maximize longitudinal follow-up, nosotros excluded non-California residents. We included patients 12 years of age or older, given the infrequency of births among patients younger than 12 years of age (<0.1% of all births17). Post hoc sensitivity analyses that included patients regardless of age or included only patients 18 years of age or older did non substantially alter our findings.
For women with multiple labor-related hospitalizations during a single 40-week menstruum, we excluded cases of false labor by identifying delivery as the latest hospitalization during that time. Since women who have had a thrombotic consequence may be less likely to subsequently go meaning, we included only the first pregnancy captured in our database for each patient. To focus on incident outcomes, nosotros excluded patients who had had whatsoever thrombosis diagnoses before their first recorded delivery (meet the Methods section in the Supplementary Appendix, available with the full text of this article at NEJM.org, for definitions).
To compare thrombotic gamble during the post-partum menstruation with the risk during nonpregnant periods, we excluded patients with a 2nd delivery during the follow-up period. Nosotros included hospitalizations for labor starting on Jan one, 2005, when patient-specific longitudinal tracking identifiers were introduced in these databases.fourteen Information were available through December 31, 2011,fourteen so to accommodate analyses of the 24 weeks afterwards delivery and the aforementioned 24-week menses 1 year afterward, we included patients with a hospitalization for a beginning labor through June 30, 2010.
Study Outcomes and Measurements
The primary outcome was a composite of ischemic stroke, astute myocardial infarction, or venous thromboembolism. We identified these outcomes using validated diagnosis-code algorithms that were previously shown to accept a positive predictive value of 90% or more (see the Supplementary Appendix).18-20 To maximize accuracy, we limited our case ascertainment to stroke and myocardial infarction resulting in hospitalization but included discharges from the emergency department every bit well as hospitalizations for venous thromboembolism, since this condition is now often managed in the outpatient setting.21 To focus on incident outcomes and avoid bias from the furnishings of antithrombotic therapy prescribed after the initial thrombotic event, nosotros included a maximum of one thrombosis diagnosis for each patient; however, in a sensitivity analysis, we also included thrombosis diagnoses subsequent to the alphabetize event.
In add-on to the primary composite outcome, we separately assessed arterial events (stroke or myocardial infarction) as compared with venous thromboembolism. The definition of venous thromboembolism in our chief analysis did not include cerebral venous thrombosis because that status lacks rigorously validated ICD-9-CM diagnosis codes, merely it was included among secondary outcomes, which consisted of the primary outcome plus a broader set of other thrombosis diagnoses (come across the Supplementary Appendix for definitions).
We performed subgroup analyses stratified according to thrombotic gamble, using ICD-ix-CM codes to identify consistently reported risk factors for postpartum thrombosis: maternal age of more than 35 years, chief hypercoagulable country, eclampsia or preeclampsia, smoking, and cesarean delivery (run into the Supplementary Appendix for definitions).1,iii,22,23
Statistical Analysis
For each patient, we compared the likelihood of a get-go-ever recorded thrombosis during postpartum days 0 through 41 versus the aforementioned menses exactly 1 year afterwards. We repeated this crossover-cohort assay for postpartum days 42 through 83, 84 through 125, and 126 through 167. We used conditional logistic regression to calculate odds ratios for each interval because each patient was matched to her own crossover period 1 yr later.11 Our a priori hypothesis was that the take chances would progressively decrease beyond sequential half-dozen-calendar week periods only remain significantly elevated at least through the period of 7 to 12 weeks afterwards delivery. To assist ensure that visits that were related to venous thromboembolism did not correspond the sequelae of previous outpatient diagnoses, we performed a sensitivity assay that excluded diagnoses of venous thromboembolism with a concomitant bleeding-related diagnosis,24 since the event may have represented a complexity of preexisting anticoagulant therapy.
To assess the sensitivity of our results to our baseline model structure, nosotros inverted the model and performed a case-crossover analysis. We identified all women who were 12 years of age or older in whom the primary outcome had been diagnosed from July i, 2006, to December 31, 2011. We compared the likelihood of a first recorded labor and delivery during days 0 through 41 earlier the thrombotic event versus the aforementioned 6-week period exactly 1 year earlier. We repeated this instance-crossover analysis for postpartum days 42 to 83, 84 to 125, and 126 to 167 before the thrombotic outcome. In a sensitivity assay, nosotros included just cases that occurred across 1 year 24 weeks after a commencement documented commitment. This nested design ensured that all patients were alive and under ascertainment throughout the unabridged written report period, while also allowing united states of america to assess the furnishings of the inclusion of pregnancies subsequent to the start.
We performed a carve up post hoc case–control analysis to confirm whether whatsoever heightened risk of postpartum thrombosis was associated with labor and commitment specifically, rather than with hospitalization in full general. We divers cases and controls on the basis of the presence or absence of the master effect. The exposure variable was a preceding hospitalization for delivery versus for any other diagnosis. To business relationship for potential confounders, these analyses were adjusted for age, race, insurance type, the presence or absenteeism of a primary hypercoagulable state, smoking, and the Elixhauser comorbidity index.25
Results
Study Population
We identified 1,687,930 California residents with a first recorded hospitalization for labor and delivery between January i, 2005, and June xxx, 2010. This number was within 6% of the expected number on the basis of nascence certificates issued during that time.17 In the 1 year 24 weeks later on delivery, 1015 women had a thrombotic consequence (248 cases of stroke, 47 cases of myocardial infarction, and 720 cases of venous thromboembolism). Every bit compared with patients without post-partum thrombosis, those with postpartum thrombotic events were older, were more probable to exist white or blackness than Hispanic or Asian, were less often privately insured, and were more likely to have risk factors for thrombosis (Table 1).
Tabular array ane
Baseline Characteristics of the Patients, According to the Presence or Absence of a Postpartum Thrombotic Effect.*
| Feature | Thrombotic Issue (Northward = 1015) | No Thrombotic Outcome (N = one,686,915) |
|---|---|---|
| Historic period — yr | 29.5±7.2 | 28.0±vi.seven |
| Race or ethnic group — no. (%)† | ||
| White | 430 (42.4) | 635,852 (37.vii) |
| Black | 135 (thirteen.iii) | 99,486 (v.9) |
| Hispanic | 293 (28.9) | 593,790 (35.2) |
| Asian or Pacific Islander | 66 (6.v) | 188,125 (11.ii) |
| Native American | 2 (0.2) | 2,208 (0.1) |
| Other | 24 (two.4) | 49,024 (two.9) |
| Missing information | 65 (vi.iv) | 118,430 (vii.0) |
| Payment source — no. (%) | ||
| Medicare | 9 (0.9) | 6,764 (0.4) |
| Medicaid | 344 (33.ix) | 500,534 (29.7) |
| Private insurance | 516 (50.8) | 1,021,579 (60.6) |
| Self-pay | 93 (nine.2) | 104,111 (6.2) |
| Other | 53 (v.ii) | 53,526 (three.2) |
| Missing data | 0 | 401 (<0.1) |
| Thrombotic take a chance factors — no. (%) | ||
| Historic period >35 yr | 264 (26.0) | 271,729 (16.1) |
| Eclampsia or preeclampsia | 240 (23.6) | 131,527 (vii.8) |
| Primary hypercoagulable state‡ | 8 (0.8) | 1,495 (0.1) |
| Smoking | 45 (4.four) | 29,853 (1.viii) |
| Cesarean commitment | 490 (48.3) | 548,217 (32.5) |
Take a chance of Thrombotic Events
Significantly more thrombotic events occurred inside 6 weeks after delivery than during the aforementioned period one year later (411 events, or 24.4 events per 100,000 deliveries, vs. 38 events, or 2.iii events per 100,000 deliveries), corresponding to an absolute adventure difference of 22.1 (95% confidence interval [CI], 19.6 to 24.6) per 100,000 deliveries and an odds ratio of 10.eight (95% CI, 7.8 to 15.1). In the period of vii to 12 weeks after delivery, in that location was a pocket-sized only still significant increment in the number of thrombotic events, equally compared with the same period one year afterwards (95 events, or v.6 events per 100,000 deliveries, vs. 44 events, or two.vi events per 100,000 deliveries), corresponding to an absolute risk difference of 3.0 (95% CI, 1.6 to 4.five) per 100,000 deliveries and an odds ratio of 2.two (95% CI, i.five to 3.1).
The risk was no longer significantly elevated later on 12 weeks, with an odds ratio of 1.4 (95% CI, 0.9 to 2.ane) for the flow of 13 to xviii weeks later delivery and an odds ratio of 1.0 (95% CI, 0.7 to one.4) for the menses of xix to 24 weeks afterwards delivery (Table 2). In post hoc exploratory analyses, the thrombotic take chances was increased during the period of 13 to 15 weeks afterward delivery (odds ratio, ii.0; 95% CI, 1.1 to 3.half dozen) but was no longer elevated in the period of 16 to 18 weeks (odds ratio, 1.0; 95% CI, 0.6 to ane.viii) (Fig. 1, and Table S1 in the Supplementary Appendix).
Risk of a Thrombotic Issue, According to the Interval after Delivery.
Shown are the results of a post hoc exploratory assay of the chance of a composite primary outcome of ischemic stroke, astute myocardial infarction, or venous thromboembolism across sequential three-week periods later labor and delivery, as compared with each patient'due south gamble during the same menstruation 1 yr afterward. The thrombotic adventure was still increased during the menstruation of 13 to 15 weeks after delivery (odds ratio, 2.0; 95% CI, 1.i to 3.vi) just was no longer elevated in the period of 16 to 18 weeks after delivery (odds ratio, i.0; 95% CI, 0.six to 1.8). The vertical lines indicate 95% confidence intervals.
Table ii
Number and Charge per unit of Postpartum Thrombotic Events during Sequential half-dozen-Calendar week Intervals after Labor and Commitment.*
| Time Interval after Labor and Delivery and Outcome | Case Period | Crossover Period | Absolute Take chances Deviation (95% CI)† | Odds Ratio (95% CI)‡ |
|---|---|---|---|---|
| no. of events (rate per 100,000 deliveries) | ||||
| Weeks 0–half-dozen | ||||
| Stroke, myocardial infarction, or venous thromboembolism§ | 411 (24.four) | 38 (two.3) | 22.1 (19.6 to 24.6) | 10.8 (7.8 to 15.1) |
| Stroke | 119 (vii.ane) | 14 (0.8) | 6.two (4.8 to 7.half-dozen) | 8.5 (4.ix to 14.viii) |
| Myocardial infarction | xiii (0.8) | 1 (01) | 0.seven (0.ii to i.ii) | thirteen.0 (1.7 to 99.4) |
| Venous thromboembolism | 279 (xvi.5) | 23 (one.4) | 15.2 (thirteen.ane to 17.two) | 12.1 (7.9 to xviii.6) |
| Stroke, myocardial infarction, venous thromboembolism, or other¶ | 2253 (133.5) | 99 (5.nine) | 127.6 (121.9 to 133.3) | 22.eight (18.half dozen to 27.8) |
| Weeks seven–12 | ||||
| Stroke, myocardial infarction, or venous thromboembolism | 95 (5.6) | 44 (2.6) | iii.0 (i.half dozen to 4.v) | 2.2 (one.5 to 3.1) |
| Stroke | 15 (0.9) | 9 (0.five) | 0.4 (–0.iii to one.0) | 1.7 (0.7 to iii.8) |
| Myocardial infarction | eight (0.five) | ii (0.i) | 0.4 (–0.one to 0.8) | 4.0 (0.viii to 18.8) |
| Venous thromboembolism | 72 (four.3) | 33 (two.0) | ii.iii (1.1 to 3.half-dozen) | 2.2 (ane.four to 3.3) |
| Stroke, myocardial infarction, venous thromboembolism, or other | 197 (11.seven) | 94 (five.6) | 6.1 (4.i to 8.1) | 2.1 (1.6 to ii.seven) |
| Weeks 13–18 | ||||
| Stroke, myocardial infarction, or venous thromboembolism | 55 (3.3) | 39 (2.3) | 0.ix (–0.2 to 2.1) | 1.4 (0.9 to 2.1) |
| Stroke | 9 (0.5) | 9 (0.v) | 0 (–0.half dozen to 0.6) | 1.0 (0.4 to 2.five) |
| Myocardial infarction | 2 (0.one) | ii (0.1) | 0 (–0.3 to 0.3) | 1.0 (0.ane to 7.1) |
| Venous thromboembolism | 44 (2.6) | 28 (1.vii) | 0.9 (–0.ane to 2.0) | 1.six (1.0 to 2.5) |
| Stroke, myocardial infarction, venous thromboembolism, or other | 99 (5.9) | 95 (5.6) | 0.2 (–one.4 to 1.9) | 1.0 (0.8 to 1.4) |
| Weeks 19–24 | ||||
| Stroke, myocardial infarction, or venous thromboembolism | 52 (3.1) | 53 (3.1) | –0.i (–i.three to 1.2) | 1.0 (0.7 to 1.4) |
| Stroke | 16 (0.ix) | 15 (0.9) | 0.i (–0.6 to 0.8) | 1.1 (0.5 to 2.2) |
| Myocardial infarction | 5 (0.three) | ii (0.one) | 0.2 (–0.ii to 0.5) | two.v (0.5 to 12.9) |
| Venous thromboembolism | 31 (1.viii) | 36 (2.1) | –0.3 (–1.3 to 0.vii) | 0.9 (0.v to ane.4) |
| Stroke, myocardial infarction, venous thromboembolism, or other | 98 (5.viii) | 113 (six.seven) | –0.nine (–2.6 to 0.9) | 0.9 (0.7 to 1.1) |
The risk of thrombosis during the menstruum of 7 to 12 weeks afterwards commitment appeared to be similarly elevated for arterial events (odds ratio, 2.1; 95% CI, 1.0 to 4.iii) and venous events (odds ratio, 2.2; 95% CI, 1.iv to three.3), although the absolute risk difference was especially low for arterial events. We found a similar temporal blueprint of thrombotic hazard in the secondary analysis, which included a broader set of thrombosis diagnoses, including cerebral venous thrombosis (Tabular array two).
The menstruation during which thrombotic hazard was significantly increased was also materially unchanged in sensitivity analyses that excluded diagnoses of venous thromboembolism with accompanying bleeding codes or that included thrombosis diagnoses subsequent to the beginning recorded result. Except for a significantly college gamble within 6 weeks after delivery amidst women who had undergone cesarean section than among those who had undergone vaginal delivery, we institute no pregnant variation in thrombotic risk over the different time periods beyond subgroups with or without thrombotic gamble factors (Tables S2 and S3 in the Supplementary Appendix).
Case-Crossover and Case–Control Analyses
In a example-crossover analysis of the likelihood of labor and delivery before a first thrombotic issue versus the same periods 1 year earlier, we institute that the odds of a showtime commitment were markedly elevated in the catamenia of 0 to 6 weeks earlier a thrombotic event (odds ratio, 9.8; 95% CI, seven.0 to thirteen.nine), significantly elevated in the menses of 7 to 12 weeks before a thrombotic event (odds ratio, two.ii; 95% CI, 1.5 to 3.2), and non significantly dissimilar in the periods of thirteen to 18 weeks or 19 to 24 weeks earlier a thrombotic upshot (Table 3). This pattern was essentially unchanged in a nested analysis that included only patients who were known to be alive and under observation for the entire 1 year 24 weeks before the thrombotic event. In a split case–command analysis, women with a thrombotic consequence were more likely to accept been hospitalized for labor and delivery within the previous 7 to 12 weeks than to take been hospitalized for another diagnosis (odds ratio, one.ix; 95% CI, 1.iv to ii.5) (data non shown).
Tabular array 3
Number and Charge per unit of Deliveries during Sequential 6-Week Intervals Preceding a Thrombotic Event (Instance-Crossover Analysis). *
| Fourth dimension Interval after Labor and Delivery and Consequence | Case Flow | Crossover Period | Accented Take chances Difference (95% CI) | Odds Ratio (95% CI) |
|---|---|---|---|---|
| no. of events (rate per 100,000 deliveries) | ||||
| Weeks 0–6 | ||||
| Stroke, myocardial infarction, or venous thromboembolism | 354 (22.8) | 36 (2.3) | 20.4 (17.9 to 23.0) | 9.eight (7.0 to 13.ix) |
| Stroke | 96 (vi.two) | thirteen (0.8) | 5.3 (4.0 to 6.vii) | 7.4 (4.1 to thirteen.2) |
| Myocardial infarction | 19 (1.ii) | ane (0.1) | ane.2 (0.5 to 1.8) | nineteen.0 (two.5 to 141.9) |
| Venous thromboembolism | 239 (xv.iv) | 22 (ane.4) | fourteen.0 (11.9 to 16.1) | x.9 (7.0 to sixteen.8) |
| Stroke, myocardial infarction, venous thromboembolism, or other | 2013 (129.4) | 92 (5.9) | 123.5 (117.half dozen to 129.3) | 21.ix (17.eight to 27.0) |
| Weeks 7–12 | ||||
| Stroke, myocardial infarction, or venous thromboembolism | 76 (4.9) | 35 (2.two) | 2.6 (1.2 to 4.0) | two.ii (1.5 to 3.2) |
| Stroke | 12 (0.eight) | viii (0.5) | 0.iii (–0.4 to 0.ix) | 1.5 (0.6 to three.7) |
| Myocardial infarction | seven (0.5) | ii (0.i) | 0.3 (–0.1 to 0.eight) | 3.five (0.7 to 16.8) |
| Venous thromboembolism | 57 (3.vii) | 25 (one.half dozen) | 2.1 (0.9 to 3.3) | two.iii (1.4 to three.half dozen) |
| Stroke, myocardial infarction, venous thromboembolism, or other | 182 (11.7) | 74 (4.viii) | 6.nine (4.9 to nine.0) | two.5 (1.9 to 3.2) |
| Weeks thirteen–xviii | ||||
| Stroke, myocardial infarction, or venous thromboembolism | 48 (3.1) | 36 (ii.3) | 0.eight (–0.iv to ii.0) | ane.3 (0.9 to two.1) |
| Stroke | 11 (0.7) | ix (0.6) | 0.1 (–0.5 to 0.8) | i.two (0.v to ii.nine) |
| Myocardial infarction | 2 (0.1) | 2 (0.one) | 0 (–0.3 to 0.iii) | 1.0 (0.1 to vii.1) |
| Venous thromboembolism | 35 (2.3) | 25 (1.half dozen) | 0.half-dozen (–0.four to 1.7) | 1.4 (0.8 to two.3) |
| Stroke, myocardial infarction, venous thromboembolism, or other | 94 (six.0) | 81 (5.2) | 0.viii (–0.9 to 2.6) | 1.2 (0.9 to 1.vi) |
| Weeks 19–24 | ||||
| Stroke, myocardial infarction, or venous thromboembolism | 46 (3.0) | 53 (three.iv) | –0.4 (–ane.8 to 0.9) | 0.nine (0.6 to one.iii) |
| Stroke | 15 (ane.0) | xv (ane.0) | 0 (–0.viii to 0.8) | 1.0 (0.five to ii.0) |
| Myocardial infarction | 4 (0.3) | 2 (0.one) | 0.1 (–0.2 to 0.v) | 2.0 (0.4 to 10.9) |
| Venous thromboembolism | 27 (one.seven) | 36 (2.three) | –0.6 (–i.half-dozen to 0.5) | 0.8 (0.5 to one.2) |
| Stroke, myocardial infarction, venous thromboembolism, or other | 86 (5.5) | 105 (half dozen.7) | –i.2 (–3.0 to 0.6) | 0.8 (0.vi to ane.1) |
Discussion
Using administrative claims data from a large land population, we constitute that the risk of a thrombotic upshot remained elevated across the 6-week postpartum menstruation, as compared with a similar fourth dimension period ane yr subsequently, although absolute hazard increases were pocket-sized later six weeks. As compared with the absolute increase in take chances during the menses within 6 weeks afterwards commitment (22.1 cases per 100,000 deliveries), the accented increase during the postpartum menses of seven to 12 weeks was much smaller (3.0 cases per 100,000 deliveries). During the latter period, odds ratios for thrombosis were similar for women with recognized adventure factors for thrombosis and those without those take chances factors, then the increased relative risk would be expected to exist especially important amid high-risk patients (e.one thousand., those with an inherited primary hypercoagulable country or previous thrombosis).
To our knowledge, previous studies take not reliably adamant the relative risk of thrombosis beyond 6 weeks after delivery. A population-based analysis of pregnancy-related venous thromboembolism over several decades included events up to three months afterwards commitment, but merely two cases were captured beyond vi weeks, and relative risks for this period were non reported.five In a population-based written report of venous thromboembolism after in vitro fertilization, thrombosis rates between 7 weeks and 1 yr after delivery were reported, but the report lacked suitable nonpregnant command patients or intervals.26 In some other population-based written report, there was no significantly elevated run a risk of thrombosis between 7 weeks and 1 year afterwards delivery, only investigators did not assess risks across discrete intervals during that time.iv Two other studies suggested a possibly heightened risk of venous thromboembolism between vii and 12 weeks later on delivery but lacked sufficient statistical ability8 or had imbalances between cases and controls, which probably resulted in an overestimation of post-partum risks.9
Despite this limited prior evidence, our finding that increased risk for thrombosis persists beyond half dozen weeks after delivery has face validity. The magnitude of increased take chances is high throughout the half-dozen weeks later delivery,2,5 and information technology is unlikely that this prothrombotic state would resolve suddenly. Our findings are consistent with a more biologically plausible tapering of take chances through at least 12 weeks after delivery (Fig. 1). This pattern is concordant with data on laboratory coagulation markers afterward delivery; most of these markers normalize by 6 weeks after delivery, but some remain aberrant through at least 8 to 12 weeks after delivery.27-29
The validity of our study is buttressed by its crossover-accomplice design, which allowed each patient to serve as her ain command and thus reduced the unmeasured confounding that can occur with traditional example–command or accomplice studies.12 The validity of our study is further supported by the consistency of our findings in a confirmatory instance-crossover analysis. Our study fully meets the assumptions of these crossover designs, in that we modeled a transient, discrete exposure with stable prevalence over time and an outcome that was defined by an astute event.30
Limitations of our report require consideration, yet. First, in the absence of prospective case observation and detailed clinical information, some outcome events may accept represented delayed sequelae of previous thrombotic events. For case, an outpatient in whom venous thromboembolism is diagnosed at 2 weeks after delivery who is then hospitalized with symptoms of venous thromboembolism 8 weeks later would have incorrectly appeared to have had a kickoff thrombotic issue at 10 weeks after delivery. This scenario would have artificially increased the credible length of time betwixt delivery and result, thereby upwardly biasing our estimates for afterwards postpartum periods. However, we recall that this possibility is unlikely to have substantially affected our results. Although we may not have captured some cases of venous thromboembolism that were diagnosed entirely in the outpatient setting, almost all diagnoses of ischemic stroke and acute myocardial infarction are made in the emergency department and result in hospitalization,31,32 and our assay of these arterial events alone was consistent with our overall analysis. Furthermore, our estimates of the magnitude of thrombotic risk inside half dozen weeks after delivery closely overlap with those of previous studies that incorporated detailed clinical information,2,5 suggesting that we did not ofttimes miss thrombotic events and incorrectly ascribe them to subsequently periods. 2nd, patients may have been progressively lost to follow-upward during the 1 year 24 weeks after delivery owing to unre-corded out-of-hospital deaths or emigration from California, and this would also have upwardly biased our estimates. Yet, we recollect that this is unlikely because we institute the same results in a nested instance-crossover analysis that was express to patients who were known to be alive and under observation throughout the entire report period. Tertiary, the sensitivities of the diagnosis codes that we used to decide take chances factors for thrombosis have non been validated, and therefore our subgroup analyses may not take detected true interactions betwixt specific hazard factors — especially between the presence of a primary hypercoagulable state and smoking — and the elapsing of thrombotic risk afterwards commitment. Quaternary, nosotros lacked data from federal wellness care facilities, which comprise 3.1% of the facilities in California.33
Current guidelines advise that loftier-take a chance patients receive prophylactic anticoagulant therapy until six weeks later on delivery, but these recommendations are based largely on skillful opinion.1 The duration of therapy that all-time balances the risk of thrombosis with the adventure of bleeding34,35 remains uncertain.36 Our findings propose that the risks and benefits of continuing handling for high-run a risk women beyond vi weeks later delivery should be investigated. In addition, clinicians who are evaluating possible symptoms of thrombosis in postpartum women should recognize that risk remains increased for at to the lowest degree 12 weeks afterward commitment, although the accented take chances of thrombotic events beyond half dozen weeks afterward commitment is low.
Supplementary Material
Supplement1
Acknowledgments
The views expressed in this article are those of the authors and do not necessarily correspond the official views of the National Institutes of Health (NIH).
Supported by a grant from the National Institute of Neurological Disorders and Stroke of the NIH (K23NS082367, to Dr. Kamel).
Dr. Kamel reports receiving advisory board and lecture fees from Genentech; Dr. Devereux, receiving consulting fees from Merck; and Dr. Elkind, receiving consulting fees from Daiichi Sankyo, Janssen, Biogen Idec, and Bristol-Myers Squibb/Pfizer, grant support from diaDexus and Bristol-Myers Squibb/Sanofi, and fees for providing expert testimony related to prescription treatments from Merck/Organon, Novartis, and GlaxoSmithKline. No other potential conflict of interest relevant to this article was reported.
Footnotes
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
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