The occurrence and risk factors for first venous thromboembolism in and around pregnancy: population based cohort studies using primary and secondary care data from the United Kingdom

Background: Venous thromboembolism (VTE) in one of the leading causes of maternal morbidity and mortality in high income countries. However there is a surprising shortage of evidence which allows us to accurately predict which women are at high risk which has hindered prevention to date. Therefore the aim of this thesis is to measure the occurrence of and risk factors for VTE during the antepartum and postpartum periods. Methods: Electronic health records from women of childbearing age (15-44 years) were identified from two separate databases; The Health Improvement Network (THIN) between 1995 and 2009 and the Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES) between 1997 and 2010. Five separate studies were then carried out to study the incidence and risk factors for VTE during antepartum and postpartum periods. In studies 1 and 2 I used the THIN database to assess the incidence of and risk factors for VTE during antepartum and postpartum periods separately. Studies 3, 4 and 5 incorporated the CPRD-HES linked data which enabled me to get better ascertainment of VTE and its potential risk factors. Using these data I externally validated my VTE definition which was followed by investigating the impact of non-delivery related hospitalisations on the incidence of antepartum VTE. I also examined the risk factors for postpartum VTE using a conceptual hierarchical analysis approach along with their impact on the timing of VTE during specific periods of postpartum. All results were presented in the form of absolute rates (AR) per 100,000 person-years and incidence rate ratios (IRR) were calculated using Poisson regression with adjustment for relevant covariates. Results: In THIN, there were a total of 1.7 million women of which 280,451 experienced 376,154 pregnancies resulting in live or stillbirths whereas the CPRD-HES linked data contained information on over 240,000 pregnancies among 204,929 women. Overall VTE rates were highest in the first few weeks postpartum. Women in their third trimester of antepartum were at a 5 fold increased risk of first VTE compared to their time outside pregnancy whereas in the first and second trimesters this rate was only marginally higher. However the use of CPRD-HES linked database gave me estimates of VTE risk with better precision in and around pregnancy that were comparable to the existing literature. For my risk factor analysis I found that the strongest risk factor for VTE during the antepartum period was hospitalisation corresponding to a 17-fold increase (IRR=17.7 95%CI=7.7-39.6) compared to time outside hospital. The rate of VTE was also high during the 28 days post-discharge (IRR=5.9; 95%CI=3.5-10.0; AR=646). These factors were not confounded by pregnancy related characteristics and complications, pre-existing medical co-morbidities or demographic or life style related characteristics. I also found that postpartum, women whose pregnancies resulted in stillbirth were at a 6- fold (IRR=6; 95%CI 3.17-14.6; AR=2570) increased risk of VTE. Those with caesarean delivery (elective or emergency), pre-term birth or postpartum haemorrhage had a 2-fold or higher risk of postpartum VTE compared to their respective baseline (AR>600/100,000 person-years). These findings were consistent across both the THIN and CPRD-HES linked data bases with respect women's risk factors for VTE. Finally the risk of VTE remains consistently high up to first six weeks postpartum (>700/100,000 person-years) for pregnancies of women complicated with BMI>30kg/m2 or caesarean delivery whereas risk of VTE was only high in the first three weeks postpartum (>1300/100,000 person-years) In those with pre-term birth or postpartum haemorrhage. Conclusion: I have provided some of the most precise estimates of absolute rates of VTE In and around pregnancy for better understanding of risks. The overall rate of antepartum VTE is substantially increased during non-delivery related hospitalisations and this increase is sustained in the 28 days post-discharge. Postpartum, delivery associated characteristics and complications including, stillbirth, caesarean delivery, BMI>30Kg/m2 postpartum haemorrhage are important risk factors for VTE particularly during the first three weeks postpartum. My analysis provides valuable information to clinicians for better decision making in terms of identifying high risk pregnant and postpartum women who may require some form of thromboprophylaxis

The occurrence and risk factors for first venous thromboembolism in and around pregnancy: population based cohort studies using primary and secondary care data from the United Kingdom

Background: Venous thromboembolism (VTE) in one of the leading causes of maternal morbidity and mortality in high income countries. However there is a surprising shortage of evidence which allows us to accurately predict which women are at high risk which has hindered prevention to date. Therefore the aim of this thesis is to measure the occurrence of and risk factors for VTE during the antepartum and postpartum periods. Methods: Electronic health records from women of childbearing age (15-44 years) were identified from two separate databases; The Health Improvement Network (THIN) between 1995 and 2009 and the Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES) between 1997 and 2010. Five separate studies were then carried out to study the incidence and risk factors for VTE during antepartum and postpartum periods. In studies 1 and 2 I used the THIN database to assess the incidence of and risk factors for VTE during antepartum and postpartum periods separately. Studies 3, 4 and 5 incorporated the CPRD-HES linked data which enabled me to get better ascertainment of VTE and its potential risk factors. Using these data I externally validated my VTE definition which was followed by investigating the impact of non-delivery related hospitalisations on the incidence of antepartum VTE. I also examined the risk factors for postpartum VTE using a conceptual hierarchical analysis approach along with their impact on the timing of VTE during specific periods of postpartum. All results were presented in the form of absolute rates (AR) per 100,000 person-years and incidence rate ratios (IRR) were calculated using Poisson regression with adjustment for relevant covariates. Results: In THIN, there were a total of 1.7 million women of which 280,451 experienced 376,154 pregnancies resulting in live or stillbirths whereas the CPRD-HES linked data contained information on over 240,000 pregnancies among 204,929 women. Overall VTE rates were highest in the first few weeks postpartum. Women in their third trimester of antepartum were at a 5 fold increased risk of first VTE compared to their time outside pregnancy whereas in the first and second trimesters this rate was only marginally higher. However the use of CPRD-HES linked database gave me estimates of VTE risk with better precision in and around pregnancy that were comparable to the existing literature. For my risk factor analysis I found that the strongest risk factor for VTE during the antepartum period was hospitalisation corresponding to a 17-fold increase (IRR=17.7 95%CI=7.7-39.6) compared to time outside hospital. The rate of VTE was also high during the 28 days post-discharge (IRR=5.9; 95%CI=3.5-10.0; AR=646). These factors were not confounded by pregnancy related characteristics and complications, pre-existing medical co-morbidities or demographic or life style related characteristics. I also found that postpartum, women whose pregnancies resulted in stillbirth were at a 6- fold (IRR=6; 95%CI 3.17-14.6; AR=2570) increased risk of VTE. Those with caesarean delivery (elective or emergency), pre-term birth or postpartum haemorrhage had a 2-fold or higher risk of postpartum VTE compared to their respective baseline (AR>600/100,000 person-years). These findings were consistent across both the THIN and CPRD-HES linked data bases with respect women's risk factors for VTE. Finally the risk of VTE remains consistently high up to first six weeks postpartum (>700/100,000 person-years) for pregnancies of women complicated with BMI>30kg/m2 or caesarean delivery whereas risk of VTE was only high in the first three weeks postpartum (>1300/100,000 person-years) In those with pre-term birth or postpartum haemorrhage. Conclusion: I have provided some of the most precise estimates of absolute rates of VTE In and around pregnancy for better understanding of risks. The overall rate of antepartum VTE is substantially increased during non-delivery related hospitalisations and this increase is sustained in the 28 days post-discharge. Postpartum, delivery associated characteristics and complications including, stillbirth, caesarean delivery, BMI>30Kg/m2 postpartum haemorrhage are important risk factors for VTE particularly during the first three weeks postpartum. My analysis provides valuable information to clinicians for better decision making in terms of identifying high risk pregnant and postpartum women who may require some form of thromboprophylaxis

Risk of acute appendicitis in and around pregnancy a population-based cohort study from England

Objective: To determine the absolute and relative risk of acute appendicitis during the antepartum and postpartum periods compared with the time outside pregnancy among women of childbearing age. Background: Acute appendicitis is the most common nonobstetric surgical emergency during pregnancy. Estimates of the incidence of acute appendicitis in pregnancy remain imprecise and inconsistent. Methods: All potential fertile women aged 15 to 44 years registered within Clinical Practice Research Datalink with linkages to the Hospital Episodes Statistics between 1997 and 2012 were identified. Absolute rates of acute appendicitis were calculated during the antepartum and postpartum periods and were compared with the time outside pregnancy in terms of incidence rate ratio (IRR) using a Poisson regression model. Results: Among 1,624,804 women, there were 362,219 pregnancies resulting in live or stillbirths. Compared with the time outside pregnancy, the rate of acute appendicitis was 35% lower during the antepartum period [IRR, 0.65; 95% confidence interval (CI), 0.55-0.76], with the lowest rate reported during the third trimester (IRR, 0.47; 95% CI, 0.35-0.64) for all ages; no increased risk of acute appendicitis was observed in the postpartum period compared with the time outside pregnancy amongwomen aged 15 to 34 years but an 84% increased risk for women older than 35 years (IRR, 1.84; 95% CI, 1.18-2.86). The highest and lowest rates of negative appendectomy were encountered in the second and the third trimesters, respectively. Conclusions: Pregnant women are less likely to be diagnosed with acute appendicitis than nonpregnant women, with the lowest risk reported during the third trimester

Recurrence risk of venous thromboembolism and hormone use in women from England: a cohort study using clinical practice research datalink

It is vital to identify people with low recurrence risk of venous thromboembolism (VTE) so as to protect them from dangers of prolonged anticoagulation therapy. Among women who develop VTE following hormone use, the evidence as to whether their risk of recurrence is low if they cease this therapy is conflicting. We investigated whether women whose initial VTE event was hormone-related have a lower risk of VTE recurrence than women whose initial event had no obvious cause (unprovoked). A cohort study utilising the Clinical Practice Research Datalink linked to Hospital Episode Statistics data from England was conducted. We selected 4170 women aged between 15 and 64 years who were diagnosed with a first VTE event between 1997 and 2011. Cox regression models were used to obtain hazard ratios (HR). Hormone users had 29% lower recurrence risk than non-users (adjusted HR = 0·71; 95% confidence interval 0·58–0·88), a relationship which existed both in women aged 15–44 years (predominantly oral contraceptive users) and those aged 45–64 years (predominantly hormone replacement therapy users). In conclusion, having a hormone-associated VTE is associated with a lower recurrence risk than one that is unprovoked after discontinuation of the hormone-containing preparation. Prolonged anticoagulation may therefore be unjustified in such women

The risk of community-acquired pneumonia among 9803 patients with coeliac disease compared to the general population: a cohort study

Background: Patients with coeliac disease are considered as individuals for whom pneumococcal vaccination is advocated. Aim: To quantify the risk of community-acquired pneumonia among patients with coeliac disease, assessing whether vaccination against streptococcal pneumonia modified this risk. Methods: We identified all patients with coeliac disease within the Clinical Practice Research Datalink linked with English Hospital Episodes Statistics between April 1997 and March 2011 and up to 10 controls per patient with coeliac disease frequency matched in 10-year age bands. Absolute rates of community-acquired pneumonia were calculated for patients with coeliac disease compared to controls stratified by vaccination status and time of diagnosis using Cox regression in terms of adjusted hazard ratios (HR). Results: Among 9803 patients with coeliac disease and 101 755 controls, respectively, there were 179 and 1864 first community-acquired pneumonia events. Overall absolute rate of pneumonia was similar in patients with coeliac disease and controls: 3.42 and 3.12 per 1000 person-years respectively (HR 1.07, 95% CI 0.91–1.24). However, we found a 28% increased risk of pneumonia in coeliac disease unvaccinated subjects compared to unvaccinated controls (HR 1.28, 95% CI 1.02–1.60). This increased risk was limited to those younger than 65, was highest around the time of diagnosis and was maintained for more than 5 years after diagnosis. Only 26.6% underwent vaccination after their coeliac disease diagnosis. Conclusions: Unvaccinated patients with coeliac disease under the age of 65 have an excess risk of community-acquired pneumonia that was not found in vaccinated patients with coeliac disease. As only a minority of patients with coeliac disease are being vaccinated there is a missed opportunity to intervene to protect these patients from pneumonia

Women with celiac disease present with fertility problems no more often than women in the general population

BACKGROUND & AIMS: Studies have associated infertility with celiac disease. However, these included small numbers of women attending infertility specialist services and subsequently screened for celiac disease, and therefore may not have been representative of the general population. We performed a large population-based study of infertility and celiac disease in women from the United Kingdom. METHODS: We identified 2,426,225 women with prospective UK primary care records between 1990 and 2013 during their child-bearing years from The Health Improvement Network database. We estimated age-specific rates of new clinically recorded fertility problems among women with and without diagnosed celiac disease. Rates were stratified by whether celiac disease was diagnosed before the fertility problem or afterward and compared with rates in women without celiac disease using Poisson regression, adjusting for sociodemographics, comorbidities, and calendar time.RESULTS: Age-specific rates of new clinically recorded fertility problems in 6506 women with celiac disease were similar to the rates in women without celiac disease (incidence rate ratio, 1.12; 95% confidence interval, 0.88-1.42 among women age 25-29 years). Rates of infertility among women without celiac disease were similar to those of women with celiac disease before and after diagnosis. However, rates were 41% higher among women diagnosed with celiac disease when they were 25-29 years old, compared with women in the same age group without celiac disease (incidence rate ratio, 1.41; 95% confidence interval, 1.03-1.92). CONCLUSIONS: Women with celiac disease do not have a greater likelihood of clinically recorded fertility problems than women without celiac disease, either before or after diagnosis, except for higher reports of fertility problems between 25-39 years if diagnosed with CD. These findings should assure most women with celiac disease that they do not have an increased risk for fertility problems

The incidence of first stroke in and around pregnancy: A population-based cohort study from Sweden

Introduction: Research has suggested that delivery is associated with an increased risk of stroke in women; however, there is a lack of contemporary estimates on the incidence of stroke in and after pregnancy compared with the baseline risk in women of childbearing age in Sweden. Patients and methods: All women aged 15–49 years with live births/stillbirths in 1992–2011 were identified from the Swedish Medical Birth Registry linked with the National Patient Registry. First stroke during the study period was identified. Incidence rates per 100,000 person-years and adjusted incidence rate ratios (IRRs) were calculated for antepartum, peripartum and early and late postpartum periods, compared with all other available follow-up time (time before pregnancy and after postpartum) using Poisson regression adjusted for maternal age, education attainment and calendar time. Results: Of 1,124,541 women, 3094 had a first incident stroke (331 occurred during pregnancy or first 12 weeks postpartum), about half having ischaemic stroke. The incidence was 15.0 per 100,000 person-years (95% confidence interval 14.5–15.6) in non-pregnant time. The incidence was lower antepartum (7.3/100,000 person-years, 6.0–8.9; adjusted IRR = 0.7, 0.5–0.8) but higher peripartum (314.4/100,000 person-years, 247.5–399.5; adjusted IRR = 27.3, 21.4–34.9) and early postpartum (64.0/100,000 person-years, 54.1–75.7; adjusted IRR = 5.5, 4.6–6.6). The increased risk in peripartum was more evident for intracerebral haemorrhage than other types of stroke. Conclusion: Overall risk of stroke was low in women of childbearing age, but stroke risk peaks in the peripartum and early postpartum periods. Future work should address factors that contribute to this increased risk in order to develop approaches to attenuate risk

Pregnancy complications and adverse birth outcomes among women with celiac disease: a population-based study from England

OBJECTIVES: Evidence-based information about adverse birth outcomes and pregnancy complications is crucial when counseling women with celiac disease (CD); however, limited population-based data on such risks exist. We estimated these for pregnant women with CD diagnosed before and after delivery. METHODS: We included all singleton pregnancies between 1997 and 2012 using linked primary care data from the Clinical Practice Research Datalink and secondary care Hospital Episode Statistics data. Risks of pregnancy complications (antepartum and postpartum hemorrhage, pre-eclampsia, and mode of delivery) and adverse birth outcomes (preterm birth, stillbirth, and low birth weight) were compared between pregnancies of women with and without CD using logistic/multinomial regression. Risks were stratified on the basis of whether women were diagnosed or yet undiagnosed before delivery. RESULTS: Of 363,930 pregnancies resulting in a live birth or stillbirth, 892 (0.25%) were among women with CD. Diagnosed CD was not associated with an increased risk of pregnancy complications or adverse birth outcomes compared with women without CD. However, the risk of postpartum hemorrhage and assisted delivery was slightly higher among pregnant women with diagnosed CD (adjusted odds ratio (aOR)=1.34). We found no increased risk of any pregnancy complication among those with undiagnosed CD. We only observed a 1% absolute excess risk of preterm birth and low birth weight among undiagnosed CD mothers corresponding to aOR=1.24 (95% confidence interval (CI)=0.82–1.87) and aOR=1.36 (95% CI=0.83–2.24), respectively. CONCLUSIONS: Whether diagnosed or undiagnosed during pregnancy, CD is not associated with a major increased risk of pregnancy complications and adverse birth outcomes. These findings are reassuring to both women and clinicians

Development and validation of risk prediction model for venous thromboembolism in postpartum women: multinational cohort study

Objective: To develop and validate a risk prediction model for venous thromboembolism in the first six weeks after delivery (early postpartum). Design: Cohort study. Setting: Records from England based Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES) and data from Sweden based registry. Participants: All pregnant women registered with CPRD-HES linked data between 1997 and 2014 and Swedish medical birth registry between 2005 and 2011 with postpartum follow-up. Main outcome measure: Multivariable logistic regression analysis was used to develop a risk prediction model for postpartum venous thromboembolism based on the English data, which was externally validated in the Swedish data. Results: 433 353 deliveries were identified in the English cohort and 662 387 in the Swedish cohort. The absolute rate of venous thromboembolism was 7.2 per 10 000 deliveries in the English cohort and 7.9 per 10 000 in the Swedish cohort. Emergency caesarean delivery, stillbirth, varicose veins, pre-eclampsia/eclampsia, postpartum infection, and comorbidities were the strongest predictors of venous thromboembolism in the final multivariable model. Discrimination of the model was similar in both cohorts, with a C statistic above 0.70, with excellent calibration of observed and predicted risks. The model identified more venous thromboembolism events than the existing national English (sensitivity 68% v 63%) and Swedish guidelines (30% v 21%) at similar thresholds. Conclusion: A new prediction model that quantifies absolute risk of postpartum venous thromboembolism has been developed and externally validated. It is based on clinical variables that are available in many developed countries at the point of delivery and could serve as the basis for real time decisions on obstetric thromboprophylaxis

External validation of a model to predict women most at risk of postpartum venous thromboembolism: Maternity clot risk

Introduction: Venous thromboembolism (VTE) is the leading cause of direct maternal mortality in high-income countries. We previously developed a risk prediction score for postpartum venous thromboembolism (VTE) in women without a previous VTE. In this paper, we provide further external validation and assess its performance across various groups of postpartum women from England.Materials and Methods: Cohort study using primary and secondary care data covering England. We used data from QResearch comprising women with pregnancies ending in live birth or stillbirth recoded in Hospital Episodes Statistics between 2004 and 2015. Outcome was VTE in the 6 weeks postpartum. Our predictor variables included sociodemographic and lifestyle characteristics, pre-existing comorbidities, and pregnancy and delivery characteristics.Results: Among 535,583 women with 700,185 deliveries, 549 VTE events were recorded (absolute risk of 7.8 VTE events per 10,000 deliveries). When we compared predicted probabilities of VTE for each woman from the original model with actual VTE events, we obtained a C-statistic of 0.67 (95% CI 0.65 to 0.70). However, our model slightly over-predicted VTE risk for the higher risk women (calibration slope=0.84; 95% CI 0.74 to 0.94). Performance was similar across groups defined by calendar time, socioeconomic status, age group and geographical area. The score performed comparably with the existing algorithm used by the UK Royal College of Obstetrician and Gynaecologists. Conclusions: Our model enables flexibility in setting new treatment thresholds. Adopting it in clinical practice may help optimise use of low-molecular-weight heparin postpartum to maximise health gain by better targeting of high-risk groups