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Discussion
Main Findings
Using nationally linked primary and secondary care data, we have provided population level absolute and relative rates of antepartum venous thromboembolism by admission to hospital (including after discharge) while taking into account other risk factors for venous thromboembolism. We found that 18% of pregnant women were admitted to hospital at least once during pregnancy (before the delivery admission). Most admissions were of short duration and occurred during the third trimester. While 85% of antepartum venous thromboembolism events occurred in outpatients, the risk was 17-fold higher during admission to hospital compared with time "outside hospital." We also found a higher rate of venous thromboembolism during the first 28 days after discharge, corresponding to a six fold risk compared with baseline. While the rate of venous thromboembolism during admission and after discharge was particularly high for women with stays of three or more days, there was also a fourfold increase in the risk of venous thromboembolism for those admitted to hospital for less than three days. The rate for admission/after discharge was also high in all three trimesters and in women aged ≥35 years. The association between admission and venous thromboembolism remained when we restricted our analysis to women without medical comorbidities including obesity, cardiac disease, and varicose veins.
Strengths and Limitations
Our study used an open cohort approach, with prospectively collected data and information from linked primary and secondary care data sources from all over England, covering 3% of the total UK population with a similar age and sex distribution to the population as a whole. Our finding should be generalisable to the UK and other developed nations with similar healthcare systems. The use of linked data enabled us not only to obtain comprehensive information on risk factors documented in either level of care (primary and secondary) but gave us the opportunity to follow pregnant women in and outside hospital with accurate dates of admission and discharge. This permitted us to calculate the absolute and relative rates of antepartum venous thromboembolism with respect to admission while taking into account other potential risk factors, which has not been assessed previously in the literature. The completeness of HES data and recording of diagnoses in different centres is always a concern. The Department of Health, however, has undertaken studies to assess the completeness of HES coverage, which is reported to be high. Moreover, a systematic review of discharge coding in HES found that the median coding accuracy rate for diagnostic codes is 91%. As we used data from both primary and secondary care, our prevalence of risk factors such as diabetes in pregnancy, gestational hypertension, and antepartum haemorrhage is similar to the expected prevalence in the UK.
A limitation of this study is the relatively small number of venous thromboembolism events either during or immediately after admission. This not only gave us estimates with wide confidence intervals but restricted our ability to stratify our analysis by reason for admission. We also acknowledge that the increased risk of venous thromboembolism during admission could be caused by other well understood risk factors (such as unmeasured comorbidities), leading to an overestimate in the independent effect of admission. Our calculated estimates for admission and after discharge, however, remained unchanged when we excluded pregnant women with other known risk factors. We also found that the increased rate of venous thromboembolism decreased in the weeks after discharge, which should not have been the case if the effect was solely because of other risk factors. Despite the fact that the risk of venous thromboembolism was high in the later period after discharge (five to 10 weeks), the decrease in the risk from around 1,800 (during admission) to 387 per 100,000 person years shows some longer term effect of admission on the incidence of venous thromboembolism. While the cause of the association between admission and venous thromboembolism is not clear, immobility is often considered the main culprit. Regardless of the reasons for admission, pregnant women admitted to hospital for reasons other than delivery represent a group at high risk as evident by a fourfold increased risk in those with stays in hospital of less than three days.
Our conclusions, in part, depend on two investigators agreeing on whether the venous thromboembolism was a cause or consequence of the hospital admission. To determine this, two of the investigators carefully and independently reviewed 30 days of electronic primary and secondary data before and after all venous thromboembolisms during the antepartum period. Overall, agreement between investigators was high. When we repeated analyses firstly accepting only cases when investigator 1 judged antepartum venous thromboembolism to be the consequence of the admission (n=24 events) and secondly accepting only cases judged by investigator 2 to be a consequence (n=27 events), the impact on our effect estimates was modest and our conclusions were unaltered on both occasions. Subsequently we also involved a third investigator, who independently agreed with the consensus assessment of the other investigators for all cases.
We acknowledge that the diagnosis of venous thromboembolism in pregnancy can be difficult and that leg swelling and calf pain are common in the third trimester in women without deep vein thrombosis. This could lead to a misclassification. Additionally, D-dimer levels also increase with gestation, with gestational hypertension, and in preterm labour, leading to false positive results if normal ranges for non-pregnant women are use, which could add to this misclassification. In pregnancy, however, venous thromboembolism is diagnosed only when there is confirmatory imaging, and for our analysis we accepted only a diagnosis made by a clinician if it was complemented by use of anticoagulant therapy. One current drawback of UK secondary care data is the lack of information on heparin and warfarin prescribed in hospital, which might have led to underascertainment of cases using our definition of venous thromboembolism. We believe, however, that the impact of this limitation should be minimal as pregnant women with a diagnosis of venous thromboembolism are expected to be given anticoagulation therapy throughout the remainder of their pregnancy. Therefore these prescriptions are likely to be captured in the primary care data. Furthermore, the algorithm used to define venous thromboembolism in our study has been previously validated in primary care data with a positive predicted value of 85%, and our estimates of the incidence of venous thromboembolism during the antepartum period are in concordance with most recent studies published on this topic.
There could have been under ascertainment of deep vein thrombosis during the time outside hospital compared with during admission, when women would be closely monitored for venous thromboembolism thus inflating our rate ratios for that period. We believe venous thromboembolism events occurring outside hospital, however, will be captured in primary care data with a similar degree of ascertainment as pregnancy is a known and established risk factor. It also is worth stating that we were not able to consider certain risk factors such as thrombophilia and anti-phospholipid syndrome, which are often associated with increased risk. We believe that pragmatically those risk factors cannot be used to predict venous thromboembolism as routine screening for thrombophilia/anti-phospholipid syndrome is not recommended for pregnant women. Additionally the impact of those variables on our estimates might be small as we considered only the first venous thromboembolism whereas most cases of thrombophilia may be diagnosed after a venous thromboembolism event has occurred.
Our increased absolute risk observed during admission and after discharge to a certain extent advocates the use of thromboprophylaxis measures during that period. Though it could be argued that more liberal use of heparin might be associated with a higher risk of osteoporosis, it should be noted that low molecular weight heparin is now commonly used for thromboprophylaxis during pregnancy and is considered to be safe and effective. For instance, a systematic review of 2,777 pregnancies reported no increased risk of heparin induced thrombocytopenia or osteoporosis associated with use of low molecular weight heparin.
Our estimates for risk of venous thromboembolism during admission and after discharge do not take into account that some pregnant women might already be receiving thromboprophylaxis during those periods. We believe, however, that since the first RCOG guidelines for antenatal thromboprophylaxis were published only in 2004 (updated 2009), the use of antenatal thromboprophylaxis with low molecular weight heparin was unusual before 2004 except for those women with previous venous thromboembolism. We found that both absolute and relative rates of venous thromboembolism have increased since 2004, which should not be the case if those women were given adequate pharmacological thromboprophylaxis. This does not take into account the increasing ascertainment of less severe venous thromboembolisms. Additionally, 67% of all pregnant women diagnosed with antepartum pulmonary embolism (between 2005 and 2006) in the UK did not receive pharmacological thromboprophylaxis according to national guidelines even though they qualified for thromboprophylaxis. Despite these limitations, we believe a bespoke cohort study of a similar size and scale to our study (using routine data) in which women are followed up prospectively throughout pregnancy would not be practically possible.
Finally in this study we have provided absolute risk expressed as per 100,000 person years, which helps standardisation and comparison. Another way of expressing those estimates might be as risk per admission. For instance, 26 venous thromboembolism events out of 59,537 hospital admissions gives an overall rate of one per 2,000 hospital admissions and one per 1,000 for those admitted for longer duration (three days and more). Though this might be of potential clinical use, it should be noted that these calculations are crude and do not take into account the element of time associated with each hospital episode.
Comparison With Previous Studies
To our knowledge this is the first study to assess the impact of antepartum admission to hospital on the incidence of venous thromboembolism during pregnancy. Therefore we cannot directly compare our findings with those from other research. A previous study carried out in Rochester, Minnesota, however, showed an age adjusted 135-fold increased risk of venous thromboembolism among patients in hospital compared with people outside hospital in the general population (including men); in the present study to observed increase outside pregnancy was 67-fold. While our confidence interval for this estimate (36.3 to 120) does not include the value observed in the Rochester study, this might not be surprising given that the Rochester study was carried out in a much older population (mean age 65), who would therefore be more likely to have longer inpatient spells complicated by comorbidity.
Clinical Implications
We believe that this study has important implications in the way pharmacological thromboprophylaxis is delivered to pregnant women and hope that it will help targeting prophylaxis in three ways. Firstly, we found a six fold increased risk of venous thromboembolism in the 28 days after hospital discharge. This suggests prudent consideration of all pregnant women during that period in terms of assessment of risk of venous thromboembolism. Secondly, at present RCOG guidelines advise that prophylaxis should be considered for women at the time of hospital admission provided that she has two or more risk factors including obesity (BMI >30) and significant medical comorbidity and is expected to be immobile for three or more days. Our study showed that the risk of venous thromboembolism during admission and after discharge remained around 22-fold and eightfold, respectively, even in women without such risk factors. Therefore pregnant women might be at high risk of venous thromboembolism during admission and for 28 days after discharge, particularly those with longer stay in hospital. Our post hoc analysis found a higher risk of venous thromboembolism among pregnant women aged ≥35 years admitted to hospital. This should be investigated further in future research. Finally, the risk of venous thromboembolism remained increased fourfold (during admission and 28 days after discharge) even in women who stay in hospital for less than three days (rate equivalent to 0.4% per year), which might also require careful consideration. It is important to take into account the effectiveness of low molecular weight heparin in term of costs involved in prophylaxis both financial and also the tolerability surrounding a daily heparin prescription as well as the well recognised side effects of allergy and bleeding. For instance, the benefits would need to be weighed against a risk of major haemorrhage, which is believed to occur in 1% of pregnant women. Such a risk:benefit analysis clearly goes beyond the scope of the present work; however, we believe our presentation of population based risks of venous thromboembolism in pregnant women admitted to hospital goes some way to help clinicians involved in making decisions in this area. In conclusion, we found that admission substantially increases the risk of venous thromboembolism in pregnant women as has been found in other non-pregnant populations. These findings support the National Institute of Clinical Excellence guidelines on thromboprophylaxis among admitted patients. In light of this, careful consideration of which women should receive prophylaxis during an antepartum admission and for how long is needed.
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