Early-onset vs late-onset preeclampsia and risk of coronary atherosclerosis later in life: a clinical follow-up study.

BACKGROUND: Younger women with previous preeclampsia have an increased risk of coronary atherosclerosis. It is unknown if this risk is associated with the time of onset of preeclampsia. OBJECTIVE: This study aimed to investigate if women with early-onset preeclampsia have a higher risk of coronary atherosclerosis compared with women with late-onset preeclampsia, independent of other perinatal risk factors. STUDY DESIGN: A total of 911 women with previous preeclampsia aged 35 to 55 years participated in a clinical follow-up study, including clinical examination, comprehensive questionnaires, and cardiac computed tomography scan 13 years (range, 0-28) after index pregnancy. Early- and late-onset preeclampsia were defined as gestational age at delivery of <34+0 and ≥34+0 gestational weeks, respectively. The primary outcome of the study was the presence of coronary atherosclerosis on the cardiac computed tomography. A logistic regression analysis was performed to investigate the association between time of onset of preeclampsia, perinatal risk factors, and the primary outcome. RESULTS: Women with early-onset preeclampsia (N=139) were older (46.2±5.7 vs 44.4±5.5 years; P<.001), more likely to have hypertension (51.1% vs 35.1%; P≤.001), and had a higher body mass index (27.9±6.3 vs 26.9±5.5 kg/m2; P=.051) compared with women with late-onset preeclampsia (N=772) at follow-up. The prevalence of the primary outcome (coronary atherosclerosis) on the cardiac computed tomography among women with early- and late-onset preeclampsia was 28.8% vs 22.2%, respectively (P=.088; adjusted odds ratio, 1.74; 95% confidence interval, 1.01-3.01; P=.045 after adjustment for maternal age at index pregnancy, prepregnancy body mass index, parity, diabetes in pregnancy, smoking in pregnancy, offspring birthweight and sex, and follow-up length). CONCLUSION: Women with early-onset preeclampsia had a slightly higher risk of coronary atherosclerosis compared with women with late-onset preeclampsia. However, according to the current evidence, it does not seem indicated to limit screening, diagnostic, and preventive measures for cardiovascular disease only to women with early-onset preeclampsia.

Does fetal sex influence the risk of venous thrombosis in pregnancy? A cohort study.

BACKGROUND: Venous thromboembolism is a prominent cause of maternal death. OBJECTIVE: As inflammation is a well-known risk factor for venous thromboembolism and several studies have found a higher grade of inflammation in pregnancies bearing a male compared with female fetuses, we investigated the risk of pregnancy-related venous thromboembolism associated with sex of the fetus. METHODS: This cohort study linked data from national registries and compared event rates and hazard ratios of venous thrombosis for pregnancies bearing a male fetus with those bearing a female fetus during pregnancy and in the first 3 months postpartum. National data from 1995 to 2017 were used. All Danish women aged 15 to 49 years with a live or stillbirth were eligible for inclusion; 1 370 583 pregnancies were included. Women with venous thrombosis, ischemic heart disease, cerebrovascular disease, thrombophilia, or cancer before conception were excluded. RESULTS: The event rate for a venous thrombosis was 8.0 per 10.000 pregnancy years with a male fetus compared with 6.8 for a female fetus. The adjusted hazard ratio for venous thrombosis during pregnancies bearing a male was 1.2 (95% CI, 1.1-1.4), whereas in the postpartum period, it was 0.9 (95% CI, 0.7-1.0). The risk was elevated until week 30. CONCLUSION: These findings indicate a slightly greater risk of venous thrombosis during pregnancies bearing a male fetus than during pregnancies bearing a female fetus. There was no increased risk associated with fetal male sex in the postpartum period.

Long-Term Morbidity and Mortality in Children After In Utero Exposure to Maternal Cancer.

PURPOSE: In utero exposure to maternal cancer and cancer treatment might influence the child's short- and long-term health and development. The objective of the study was to investigate short- and long-term somatic and psychiatric outcomes in children exposed to maternal cancer in utero. METHODS: This nationwide cohort study identified all liveborn children in Denmark between January 1978 and December 2018. Exposure was defined as maternal cancer diagnosis during pregnancy, and in a subgroup analysis, exposure to chemotherapy in utero. The main outcomes of interest were overall mortality, somatic diagnoses, and psychiatric diagnoses identified in the National Health Registers. Follow-up started at birth and ended at an event, death, emigration, or end of 2018. Hazard ratios of end points adjusted for potential confounders were estimated using Cox regression analysis. RESULTS: Of 2,526,163 included liveborn children, 690 (0.03%) were exposed to maternal cancer in utero. Compared with unexposed fetuses, children exposed in utero had no higher overall mortality, adjusted hazard ratio 0.8 (95% CI, 0.4 to 1.5), nor increased risk of congenital malformations, overall somatic or psychiatric disease. During the period 2002-2018, of 378 (0.03%) children exposed to cancer in utero, 42 (12.5%) were exposed to chemotherapy. Among these 42 children, in utero exposure to chemotherapy was not associated with selected somatic diseases nor to congenital malformations when compared with in utero exposure to maternal cancer without chemotherapy. CONCLUSION: Overall, findings did not indicate excess risk of mortality or severe morbidity among children exposed to cancer in utero. Fetal exposure to chemotherapy was not associated with adverse health outcomes in childhood.

Pregnancy loss is associated with type 2 diabetes: a nationwide case-control study.

AIMS/HYPOTHESIS: Type 2 diabetes is killing more people than ever, and early-life predictors remain critical for the development of effective preventive strategies. Pregnancy loss is a common event associated with later atherosclerotic disease and ischaemic heart failure and might constitute a predictor for type 2 diabetes. The objective of this study was to investigate whether pregnancy loss is associated with later development of type 2 diabetes. METHODS: Using a Danish nationwide cohort, we identified all women born from 1957 through to 1997 and who had a diagnosis of type 2 diabetes during the period 1977 to 2017. The women were matched 1:10 on year of birth and educational level to women without diabetes in the general Danish population. Conditional logistic regression models provided odds ratios for type 2 diabetes with different numbers of pregnancy losses. RESULTS: We identified 24,774 women with type 2 diabetes and selected 247,740 controls without diabetes. Women who had ever been pregnant (ever-pregnant women) with 1, 2 and ≥ 3 pregnancy losses had ORs of type 2 diabetes of 1.18 (95% CI 1.13, 1.23), 1.38 (95% CI 1.27, 1.49) and 1.71 (95% CI 1.53, 1.92) compared with ever-pregnant women with no pregnancy losses, respectively. Women who never achieved a pregnancy had an OR of type 2 diabetes of 1.56 (95% CI 1.51, 1.61) compared with ever-pregnant women with any number of losses. Similar results were found after adjustment for obesity and gestational diabetes. CONCLUSIONS/INTERPRETATION: We found a significant and consistent association between pregnancy loss and later type 2 diabetes that increased with increasing number of losses. Thus, pregnancy loss and recurrent pregnancy loss are significant risk factors for later type 2 diabetes. Future studies should explore whether this association is due to common background factors or whether prediabetic metabolic conditions are responsible for this association. Graphical abstract.

Pregnancy loss: A 40-year nationwide assessment.

INTRODUCTION: Pregnancy loss is frequent. We aimed to assess the frequency and trends in pregnancy losses according to female age and mode of conception over a 40-year follow-up period. MATERIAL AND METHODS: In a national historical prospective cohort study, we followed all Danish women 10-49 years over the 40-year study period 1978-2017. Data on pregnancies and their outcomes were obtained from the National Health Registry, the Medical Birth Registry and the National Fertility Registry. Incidence rates per 100 pregnancies and per 1,000 women-years as well as lifetime risks per 100 women were calculated. Women included in the lifetime analysis were followed from age 12 to age 49. Pregnancy loss included spontaneous abortion, missed abortion and anembryonic pregnancy. RESULTS: In 3 519 455 recorded pregnancies, 337 008, or 9.6%, were diagnosed with a pregnancy loss. The proportion increased from 7.5% in 1978-1979, peaked at 10.7% in 2000 and thereafter decreased to 9.1% in 2015-2017. Pregnancy loss rate in women 10-14 years was 3.9%, increasing gradually with age to 26.9% in pregnant women 45-49 years, a 6.9-fold increase. Loss rates were slightly lower in naturally conceived pregnancies than in assisted pregnancies except for women above 45 years, where the risk of loss was higher in the spontaneously conceived group. Lifetime risk of specific numbers of losses were: 0: 76.9%, 1: 17.9%, 2: 3.9%, 3: 0.87%, and 4+: 0.35%. CONCLUSIONS: The proportion of women experiencing pregnancy loss has changed little throughout four decades and is still primarily influenced by female age. More than 75% of pregnant women are never recorded with a pregnancy loss, and <1.5% will experience three or more losses.

Pregnancy Loss and Cancer Risk: A Nationwide Observational Study.

BACKGROUND: Cancer is the second leading cause of death worldwide. Few studies have investigated if recurrent pregnancy loss is associated with an increased risk of cancer. We aimed to assess whether pregnancy loss is associated with later cancer development. METHODS: We identified all invasive cancers after age 40, among all Danish women born between January 1957 and December 1972, ensuring a full reproductive history. Cases were matched by birth year 1:10 to cancer-free controls. Women were followed until the end of 2017. The number of pregnancy losses (miscarriages or still births) was correlated to long-term cancer risk using conditional logistic regression, providing odds ratios for specific cancers with different numbers of pregnancy losses, all adjusted for age, education, and other potential confounders. FINDINGS: The study included 28,785 women with cancer (mean age 48.7 [SD 5.0]) and 283,294 matched controls (mean age 48.6 [SD 5.0]). We found no overall association between pregnancy loss and later development of 11 site-specific types of cancer or cancer overall. Taking the sequence of pregnancy losses into account, primary recurrent pregnancy loss (three consecutive pregnancy losses without prior live birth) was associated with later overall cancer by an odds ratio of 1.27 (1.04-1.56). Secondary recurrent pregnancy loss showed no association to cancer. INTERPRETATION: Pregnancy loss was not associated with later cancer development. Women with primary recurrent pregnancy loss had a borderline significant association to later cancer overall, this may be a chance finding. FUNDING: Ole Kirk's Foundation and Copenhagen University Hospital Rigshospitalet's Research Grant.

Non-vitamin K antagonist oral anticoagulation agents in anticoagulant naïve atrial fibrillation patients: Danish nationwide descriptive data 2011-2013.

AIMS: Non-vitamin K antagonist oral anticoagulation (NOAC) agents have been approved for stroke prophylaxis in atrial fibrillation (AF). We investigated 'real-world' information on how these drugs are being adopted. METHODS AND RESULTS: Using Danish nationwide administrative registers, we identified all oral anticoagulation-naïve AF patients initiating oral anticoagulation from 22 August 2011 through 31 October 2013. Using logistic regression analysis, baseline characteristics and temporal utilization trends were compared between initiators of warfarin vs. one of the N OACs: dabigatran, rivaroxaban, or apixaban. We identified 18 611 oral anticoagulation-naïve AF patients of which 9902 (53%) initiated warfarin treatment, 7128 (38%) dabigatran, 1303 (7%) rivaroxaban, and 278 (1%) apixaban. Overall, 40% of newly initiated patients were started on dabigatran within the first 4 months of when the drug came on market. By October, 2013, 40% were being started on warfarin and dabigatran, respectively, and another 20% were started on either rivaroxaban or apixaban. Rivaroxaban and apixaban users generally had a higher predicted risk of stroke and bleeding compared with warfarin and dabigatran users. Older age, female gender, and prior stroke were some of the factors associated with NOAC use vs. warfarin, whereas chronic kidney disease, myocardial infarction, and heart failure showed the opposite association. CONCLUSION: Among oral anticoagulation-naïve AF patients initiated on oral anticoagulation in Denmark, warfarin initiation has declined since the introduction of dabigatran in August 2011. Dabigatran is the most frequently used alternative option to warfarin; however, use of rivaroxaban and apixaban is increasing. Patients initiated with rivaroxaban or apixaban in general have a higher predicted stroke and bleeding risks compared with warfarin or dabigatran initiators.

Antiplatelet therapy for stable coronary artery disease in atrial fibrillation patients taking an oral anticoagulant: a nationwide cohort study.

BACKGROUND: The optimal long-term antithrombotic treatment of patients with coexisting atrial fibrillation and stable coronary artery disease is unresolved, and commonly, a single antiplatelet agent is added to oral anticoagulation. We investigated the effectiveness and safety of adding antiplatelet therapy to vitamin K antagonist (VKA) in atrial fibrillation patents with stable coronary artery disease. METHODS AND RESULTS: Atrial fibrillation patients with stable coronary artery disease (defined as 12 months from an acute coronary event) between 2002 and 2011 were identified. The subsequent risk of cardiovascular events and serious bleeding events (those that required hospitalization) was examined with adjusted Cox regression models according to ongoing antithrombotic therapy. A total of 8700 patients were included (mean age, 74.2 years; 38% women). During a mean follow-up of 3.3 years, crude incidence rates were 7.2, 3.8, and 4.0 events per 100 person-years for myocardial infarction/coronary death, thromboembolism, and serious bleeding, respectively. Relative to VKA monotherapy, the risk of myocardial infarction/coronary death was similar for VKA plus aspirin (hazard ratio, 1.12 [95% confidence interval, 0.94-1.34]) and VKA plus clopidogrel (hazard ratio, 1.53 [95% confidence interval, 0.93-2.52]). The risk of thromboembolism was comparable in all regimens that included VKA, whereas the risk of bleeding increased when aspirin (hazard ratio, 1.50 [95% confidence interval, 1.23-1.82]) or clopidogrel (hazard ratio, 1.84 [95% confidence interval, 1.11-3.06]) was added to VKA. CONCLUSIONS: In atrial fibrillation patients with stable coronary artery disease, the addition of antiplatelet therapy to VKA therapy is not associated with a reduction in risk of recurrent coronary events or thromboembolism, whereas risk of bleeding is increased significantly. The common practice of adding antiplatelet therapy to oral VKA anticoagulation in patients with atrial fibrillation and stable coronary artery disease warrants reassessment.