Third-Trimester Cardiovascular Function and Risk of Hypertensive Disorders of Pregnancy.

BACKGROUND: Whether cardiovascular dysfunction is associated with preeclampsia in women without fetal growth restriction (FGR) is unclear. Our objective was to investigate associations between third-trimester cardiac output (CO) and systemic vascular resistance and risk of hypertensive disorders of pregnancy in women with and without FGR. METHODS AND RESULTS: A case-cohort study in 906 pregnant women in Denmark with repeated third-trimester cardiac function assessments was performed using the Ultrasound Cardiac Output Monitor 1A. Using Cox regression, we compared rates of hypertensive disorders of pregnancy in women with low, normal, and high CO and normal and high systemic vascular resistance, by FGR status and gestational age, and evaluated associations between a third-trimester drop in CO or increase in systemic vascular resistance and preeclampsia risk in women without FGR. The analysis included 249 women with preeclampsia (42 with FGR) and 119 women with gestational hypertension. Low CO was strongly associated with preeclampsia at <37 weeks (women with FGR: hazard ratio [HR], 5.25 [95% CI, 1.26-21.9]; women without FGR: HR, 2.19 [95% CI, 1.07-4.48]). Our results also suggested an association between low CO and preeclampsia at ≥37 weeks among women without FGR (HR, 1.31 [95% CI, 0.84-2.03]), and between a third-trimester drop in CO >75th percentile and preeclampsia in women without FGR (odds ratio, 1.91 [95% CI, 0.84-4.36]). High systemic vascular resistance was strongly associated with increased rates of all forms of hypertensive disorders of pregnancy. CONCLUSIONS: Low CO is associated with preeclampsia risk in women with and without FGR, particularly before 37 weeks. Repeated measurements of third-trimester cardiovascular function might identify women without FGR for monitoring for preeclampsia, but this result needs to be confirmed in other studies.

Reference ranges for third-trimester maternal cardiovascular function parameters measured in normotensive pregnant women using a non-invasive cardiac output monitor: A study based on data from the prospective PEACH cohort study.

OBJECTIVE: We defined reference ranges for maternal cardiac output, systemic vascular resistance, and stroke volume measured in the third trimester of pregnancy using the Ultrasound Cardiac Output Monitor 1A. DESIGN: Based on data from the prospective PEACH (PreEclampsia, Angiogenesis, Cardiac dysfunction and Hypertension) cohort study. SETTING: Rigshospitalet and Hvidovre Hospital, Denmark. SAMPLE: Normotensive pregnant women aged 18-45 years with singleton pregnancies, enrolled in the PEACH study in 2016-2018. METHODS: We modelled cardiac output, systemic vascular resistance and stroke volume as a function of gestational age using multilevel linear models with fractional polynomials. MAIN OUTCOME MEASURES: Unconditional and conditional reference ranges for cardiovascular parameters measured in gestational weeks 28-40. RESULTS: Our study cohort included 405 healthy pregnant women who contributed 1210 cardiovascular function measurements for analysis. Maximum cardiac output and stroke volume values were measured in gestational weeks 30-32 and decreased over the third trimester, whereas systemic vascular resistance increased during the same period. We created reference ranges for eight combinations of maternal height, age and parity. We also created a simple calculator to allow for implementation of the reference ranges in clinical practice. CONCLUSIONS: Our reference ranges allow the use of a bedside ultrasound device to non-invasively assess cardiac function in pregnancy and identify women at risk of complications. The unconditional ranges allow clinicians to evaluate isolated measurements and identify women needing follow-up. The conditional ranges incorporate information from previous measurements and improve monitoring over time.

Hypertensive disorders of pregnancy and peripartum cardiomyopathy: A nationwide cohort study.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is a serious cardiac disorder occurring late in pregnancy or early in the postpartum period. We examined associations between hypertensive disorders of pregnancy (HDP: preeclampsia and gestational hypertension) and PPCM, accounting for other pregnancy-related risk factors for PPCM. METHODS: Using nationwide Danish register data, we constructed a cohort of all women with ≥1 live birth or stillbirth in Denmark between 1978 and 2012. Using log-linear binomial regression and generalized estimating equations, we estimated risk ratios (RRs) for PPCM associated with HDP of varying severity. RESULTS: In a cohort of 1,088,063 women with 2,078,822 eligible pregnancies, 126 women developed PPCM (39 in connection with an HDP-complicated pregnancy). The risks of PPCM were significantly higher in women with HDP-complicated pregnancies than in women with normotensive pregnancies (severe preeclampsia, RR 21.2, 95% confidence interval [CI] 12.0-37.4; moderate preeclampsia, RR 10.2, 95% CI 6.18-16.9; gestational hypertension, RR 5.16, 95% CI 2.11-12.6). The RRs for moderate preeclampsia and gestational hypertension were not significantly different from one another (p = 0.18); the RR for severe preeclampsia was significantly different from the RR for moderate preeclampsia and gestational hypertension combined (p = 0.02). CONCLUSIONS: Although 70% of PPCM occurred in women with normotensive pregnancies, HDPs were associated with substantial increases in PPCM risk that depended on HDP severity. The heart's capacity to adapt to a normal pregnancy may be exceeded in some women already susceptible to cardiac insult, contributing to PPCM. HDPs, severe preeclampsia in particular, probably represent an additional cardiac stressor during pregnancy.

Risk of post-pregnancy hypertension in women with a history of hypertensive disorders of pregnancy: nationwide cohort study.

Objectives To determine how soon after delivery the risk of post-pregnancy hypertension increases in women with hypertensive disorders of pregnancy and how the risk evolves over time.Design Nationwide register based cohort study.Setting Denmark.Populations 482 972 primiparous women with a first live birth or stillbirth between 1995 and 2012 (cumulative incidence analyses), and 1 025 118 women with at least one live birth or stillbirth between 1978 and 2012 (Cox regression analyses).Main outcome measures 10 year cumulative incidences of post-pregnancy hypertension requiring treatment with prescription drugs, and hazard ratios estimated using Cox regression.Results Of women with a hypertensive disorder of pregnancy in a first pregnancy in their 20s, 14% developed hypertension in the first decade post partum, compared with 4% of women with normotensive first pregnancies in their 20s. The corresponding percentages for women with a first pregnancy in their 40s were 32% and 11%, respectively. In the year after delivery, women with a hypertensive disorder of pregnancy had 12-fold to 25-fold higher rates of hypertension than did women with a normotensive pregnancy. Rates in women with a hypertensive disorder of pregnancy were threefold to 10-fold higher 1-10 years post partum and remained twice as high even 20 or more years later.Conclusions The risk of hypertension associated with hypertensive disorders of pregnancy is high immediately after an affected pregnancy and persists for more than 20 years. Up to one third of women with a hypertensive disorder of pregnancy may develop hypertension within a decade of an affected pregnancy, indicating that cardiovascular disease prevention in these women should include blood pressure monitoring initiated soon after pregnancy.

Self-monitoring of blood pressure during pregnancy: an observational study in the obstetrical waiting room.

OBJECTIVE: The aim of this study was to assess the feasibility of self-monitoring of blood pressure with a semiautomatic device in pregnant women. PARTICIPANTS AND METHODS: Women attending routine obstetrical ultrasound scanning were invited to participate. The hospital staff initially demonstrated and instructed each participant in correct measurement and then took three measurements on both arms. The participant then repeated the measurements and filled an evaluation questionnaire. We used a validated semiautomatic device for all measurements. Mean values were calculated for systolic, diastolic and mean arterial blood pressure (MAP) and were compared using the paired sample t-test. Mean values and differences of systolic and diastolic pressure were plotted in Bland-Altman plots to test the agreement of the measurements. Finally, a mean evaluation score was calculated. RESULTS: One hundred pregnant women were included in the study. Mean values of systolic, diastolic and MAP were 110.6, 69.7 and 83.3 mmHg, respectively, as assessed by the hospital staff. The corresponding self-measurements were 111.4, 70.2 and 83.9 mmHg, respectively. Mean differences between hospital and self-measurements were 0.79 mmHg for systolic [P=0.052, 95% confidence interval (CI)=-0.008 to 1.58], 0.49 mmHg for diastolic (P=0.056, 95% CI=-0.01 to 0.99) and 0.59 mmHg for MAP (P=0.019, 95% CI=0.099-1.08). The mean evaluation score was 9.2 of 10. CONCLUSION: Differences between hospital staff and self-measurements in systolic, diastolic and MAP are within acceptable international standards. The semiautomatic device Microlife-VSA is well suited for self-measurement; however, safety studies on the use of home measurements in hypertensive pregnancies are still warranted.

Time from pre-eclampsia diagnosis to delivery affects future health prospects of children.

Background and objectives: Pre-eclampsia often has detrimental health effects for pregnant women and their fetuses, but whether exposure in the womb has long-term health-consequences for children as they grow up remains poorly understood. We assessed overall morbidity of children following exposure to either mild or severe pre-eclampsia up to 30 years after birth and related disease risks to duration of exposure, i.e. the time from diagnosis to delivery. Methodology: We did a registry-based retrospective cohort study in Denmark covering the years 1979-2009, using the separate diagnoses of mild and severe pre-eclampsia and the duration of exposure as predictor variables for specific and overall risks of later disease. We analysed 3 537 525 diagnoses for 14 disease groups, accumulated by 758 524 singleton children, after subdividing deliveries in six gestational age categories, partialing out effects of eight potentially confounding factors. Results: Exposure to mild pre-eclampsia appeared to have consistent negative effects on health later in life, although only a few specific disease cases remained significant after corrections for multiple testing. Morbidity risks associated with mild pre-eclampsia were of similar magnitude as those associated with severe pre-eclampsia. Apart from this overall trend in number of diagnoses incurred across disease groups, hazard ratios for several disorders also increased with the duration of exposure, including disorders related to the metabolic syndrome. Conclusions and implications: Maternal pre-eclampsia has lasting effects on offspring health and differences between exposure to severe and mild pre-eclampsia appear to be less than previously assumed. Our results suggest that it would be prudent to include the long-term health prospects of children in the complex clinical management of mild pre-eclampsia.

Angiogenic biomarkers in pregnancy: defining maternal and fetal health.

We review diagnostic and predictive roles of the angiogenic proteins placental growth factor, soluble fms-like tyrosine kinase 1, and soluble endoglin in preeclampsia, and their association with future cardiovascular disease, diabetes, and breast cancer. Specific patterns of these proteins represent preeclamptic prediction markers and combined with maternal and clinical characteristics, the predictive values increase. Women experiencing preeclampsia have increased risks of developing cardiovascular diseases and diabetes, and a decreased risk of breast cancer. High placental growth factor concentrations have, in elderly patients, been shown to predict cardiovascular events. Diabetes is also a risk factor for future cardiovascular disease. Diabetic vascular complications are associated with increased soluble endoglin concentrations, and vascular endothelial growth factor concentrations are correlated to HbA1c and fasting glucose. Hence dysregulation in angiogenic proteins may link preeclampsia and cardiovascular diseases, targeting women who could in future benefit from prophylactic programs to possibly prevent, delay or reduce cardiovascular disease.

Recurrence of hypertensive disorders of pregnancy: an individual patient data metaanalysis.

OBJECTIVE: We performed an individual participant data (IPD) metaanalysis to calculate the recurrence risk of hypertensive disorders of pregnancy (HDP) and recurrence of individual hypertensive syndromes. STUDY DESIGN: We performed an electronic literature search for cohort studies that reported on women experiencing HDP and who had a subsequent pregnancy. The principal investigators were contacted and informed of our study; we requested their original study data. The data were merged to form one combined database. The results will be presented as percentages with 95% confidence interval (CI) and odds ratios with 95% CI. RESULTS: Of 94 eligible cohort studies, we obtained IPD of 22 studies, including a total of 99,415 women. Pooled data of 64 studies that used published data (IPD where available) showed a recurrence rate of 18.1% (n=152,213; 95% CI, 17.9-18.3%). In the 22 studies that are included in our IPD, the recurrence rate of a HDP was 20.7% (95% CI, 20.4-20.9%). Recurrence manifested as preeclampsia in 13.8% of the studies (95% CI,13.6-14.1%), gestational hypertension in 8.6% of the studies (95% CI, 8.4-8.8%) and hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome in 0.2% of the studies (95% CI, 0.16-0.25%). The delivery of a small-for-gestational-age child accompanied the recurrent HDP in 3.4% of the studies (95% CI, 3.2-3.6%). Concomitant HELLP syndrome or delivery of a small-for-gestational-age child increased the risk of recurrence of HDP. Recurrence increased with decreasing gestational age at delivery in the index pregnancy. If the HDP recurred, in general it was milder, regarding maximum diastolic blood pressure, proteinuria, the use of oral antihypertensive and anticonvulsive medication, the delivery of a small-for-gestational-age child, premature delivery, and perinatal death. Normotensive women experienced chronic hypertension after pregnancy more often after experiencing recurrence (odds ratio, 3.7; 95% CI, 2.3-6.1). CONCLUSION: Among women that experience hypertension in pregnancy, the recurrence rate in a next pregnancy is relatively low, and the course of disease is milder for most women with recurrent disease. These reassuring data should be used for shared decision-making in women who consider a new pregnancy after a pregnancy that was complicated by hypertension.

[Caesarean section may have long-term consequences for both mother and child].

The rate of caesarean section is increasing worldwide. There is scientific evidence that caesarean sections have long-term consequences in consecutive pregnancies and for mother and child. This article reviews these consequences. When consulting women before decision on mode of delivery it is encouraged that all these issues are taken into account and balanced to the benefits of having a caesarean section.

First trimester bleeding and maternal cardiovascular morbidity.

OBJECTIVES: First trimester bleeding without miscarriage is a risk factor for complications later in the pregnancy, such as preterm delivery. Also, first trimester miscarriage has been linked to subsequent maternal ischemic heart disease. We investigated the link between maternal cardiovascular disease prior to and subsequent to first trimester bleeding without miscarriage. STUDY DESIGN: We performed a registry-based retrospective cohort study of 796,915 women who gave birth to a singleton infant after 20 completed weeks in Denmark in 1978-2007. The exposures and endpoints were registry diagnoses of cardiovascular diseases preceding pregnancy, first trimester vaginal bleeding without miscarriage, and subsequent maternal cardiovascular disease. In the adjusted models, we considered preterm delivery, prelabor rupture of membranes, hypertensive pregnancy disorders, fetal growth restriction, placental abruption and stillbirth as possible confounders. We used logistic regression and Cox proportional hazard models to assess the associations. RESULTS: Women with pre-pregnancy cardiovascular disease had a 2.2-fold (95% CI 1.3-4.1) increased risk of first trimester bleeding without miscarriage, and first trimester bleeding without miscarriage was associated with a 1.6-fold (1.4-1.8) increase in risk of subsequent maternal ischemic hearth disease after adjusting for other adverse pregnancy outcomes. CONCLUSION: First trimester bleeding without miscarriage is associated with pre-pregnancy as well as subsequent maternal cardiovascular morbidity.

Vascular associated gene variants in patients with preeclampsia: results from the Danish National Birth Cohort.

OBJECTIVE: Preeclampsia has been linked to subsequent vascular disease with many shared predisposing factors. We investigated the association between severe preeclampsia, and its subtypes, and specific vascular-related polymorphisms. DESIGN: The study was a retrospective nested case-cohort design. SETTING: Pregnant Danish women participating in the Danish National Birth Cohort. Population. 263 cases of severe preeclampsia and 1851 random controls were selected from the Danish National Birth Cohort. METHODS: We validated all cases of severe preeclampsia and genotyped for 108 single nucleotide polymorphisms (SNPs) that were selected based on previous publications on the association with vascular disease. Logistic models were used for statistical analyses. MAIN OUTCOME MEASURES: Maternal polymorphisms in genomic models. RESULTS: We found 17 of 108 SNPs associated with severe preeclampsia (p < 0.05). Women homozygous for the rs1799983 in NOS3 were 1.6-fold [95% confidence interval (CI) 1.0-2.4] more likely to develop severe preeclampsia. Women homozygous for the rs1010 SNP in VAMP8 were twofold (95%CI 1.1-3.5) more likely to deliver preterm when preeclampsia was present. Women homozygous for the rs10811661 SNP were 2.1-fold (95%CI 1.1-3.9) more likely to develop severe preeclampsia and 3.7-fold (95%CI 1.1-12.4) more likely to deliver a small-for-gestational age child when preeclampsia was present. All associations are available as Supporting Information. CONCLUSION: We found several vascular-associated SNPs linked to severe preeclampsia; however, most of these associations are probably by pure chance, which warrants replication and further translational research. To date, no specific SNP has yet proven valuable in a clinical setting in predicting preeclampsia.

Fetal growth and later maternal death, cardiovascular disease and diabetes.

OBJECTIVES: Low birthweight of the offspring has been associated with increased risk of early death and ischemic heart disease in the mother. However, other measurements of fetal growth than the basic birthweight are more accurate. We investigated the relation between the standardized birthweight by gestational age and gender and the ponderal index and the mother's subsequent mortality and cardiovascular morbidity. DESIGN: Registry-based retrospective cohort study. SETTING: Women with a first singleton delivery in Denmark from 1978 to 2007. POPULATION: 782 287 women followed for 14.6 years yielding 11 600 945 person-years. METHODS: Cox proportional hazard models. MAIN OUTCOME MEASURES: The primary exposures were variation in the standardized birthweight and ponderal index. The endpoints were subsequent maternal death, hypertension, ischemic heart disease, stroke, thrombosis, and diabetes mellitus. RESULTS: The risk-profile for the standardized birthweight and subsequent maternal death had a nadir between -0.5 and -1 SD (HR 0.91; 95%CI 0.83-1.00) and increased with decreasing fetal growth peaking at <-3 SD (HR 2.75; 95%CI 2.37-3.19) compared to the median. The risk-profile for subsequent diabetes mellitus by standardized ponderal index had a nadir between +0.5 to +1 SD (HR 0.82; 95%CI 0.76-0.89) rising with increasing fetal growth and peaking at >+3 SD (HR 17.8; 95%CI 15.0-21.0). The risk-profiles for standardized ponderal index paralleled those for birthweight, but with smaller risk estimates. Adjusting for other pregnancy complications diminished the estimates. CONCLUSION: The fetal growth is a marker of subsequent risk for premature death, cardiovascular disease, and diabetes mellitus in the mother.

Mortality of mothers from cardiovascular and non-cardiovascular causes following pregnancy complications in first delivery.

The combined effects of preterm delivery, small-for-gestational-age offspring, hypertensive disorders of pregnancy, placental abruption and stillbirth on early maternal death from cardiovascular causes have not previously been described in a large cohort. We investigated the effects of pregnancy complications on early maternal death in a registry-based retrospective cohort study of 782 287 women with a first singleton delivery in Denmark 1978-2007, followed for a median of 14.8 years (range 0.25-30.2) accruing 11.6 million person-years. We employed Cox proportional hazard models of early death from cardiovascular and non-cardiovascular causes following preterm delivery, small-for-gestational-age offspring and hypertensive disorders of pregnancy. We found that preterm delivery and small-for-gestational-age were both associated with subsequent death of mothers from cardiovascular and non-cardiovascular causes. Severe pre-eclampsia was associated with death from cardiovascular causes only. There was a less than additive effect on cardiovascular mortality hazard ratios with increasing number of pregnancy complications: preterm delivery 1.90 [95% confidence intervals 1.49, 2.43]; preterm delivery and small-for-gestational-age offspring 3.30 [2.25, 4.84]; preterm delivery, small-for-gestational-age offspring and pre-eclampsia 3.85 [2.07, 7.19]. Thus, we conclude that, separately and combined, preterm delivery and small-for-gestational-age are strong markers of early maternal death from both cardiovascular and non-cardiovascular causes, while hypertensive disorders of pregnancy are markers of early death of mothers from cardiovascular causes.

Hypertensive pregnancy disorders and subsequent cardiovascular morbidity and type 2 diabetes mellitus in the mother.

Minimal data exist concerning the relationship between hypertensive pregnancy disorders and various subsequent cardiovascular events and the effect of type 2 diabetes mellitus on these. In a registry-based cohort study, we identified women delivering in Denmark from 1978 to 2007 with a first singleton (n=782 287) and 2 first consecutive singleton deliveries (n=536 419). The exposures were gestational hypertension and mild and severe preeclampsia. We adjusted for preterm delivery, small for gestational age, placental abruption, and stillbirth and, in a second model, we also adjusted for the development of type 2 diabetes mellitus. The end points were subsequent hypertension, ischemic heart disease, congestive heart failure, thromboembolic event, stroke, and type 2 diabetes mellitus. The risk of subsequent hypertension was increased 5.31-fold (range: 4.90 to 5.75) after gestational hypertension, 3.61-fold (range: 3.43 to 3.80) after mild preeclampsia, and 6.07-fold (range: 5.45 to 6.77) after severe preeclampsia. The risk of subsequent type 2 diabetes mellitus was increased 3.12-fold (range: 2.63 to 3.70) after gestational hypertension and 3.68-fold (range: 3.04 to 4.46) after severe preeclampsia. Women having 2 pregnancies both complicated by preeclampsia had a 6.00-fold (range: 5.40 to 6.67) increased risk of subsequent hypertension compared with 2.70-fold (range: 2.51 to 2.90) for women having preeclampsia in their first pregnancy only and 4.34-fold (range: 3.98 to 4.74) for women having preeclampsia in their second pregnancy only. The risk of subsequent thromboembolism was 1.03-fold (range: 0.73 to 1.45), 1.53-fold (range: 1.32 to 1.77), and 1.91-fold (range: 1.35 to 2.70) increased after gestational hypertension and mild and severe preeclampsia, respectively. Thus, hypertensive pregnancy disorders are strongly associated with subsequent type 2 diabetes mellitus and hypertension, the latter independent of subsequent type 2 diabetes mellitus. The severity, parity, and recurrence of these hypertensive pregnancy disorders increase the risk of subsequent cardiovascular events.

Treatment of deep venous thrombosis in pregnant women.

The recommended dosage of tinzaparin in the treatment of thromboembolism during pregnancy is 175 IU/kg/day, as for non-pregnant subjects. In clinical practice, we have experienced a need for a higher dosage, especially in the initial phase of the treatment of deep vein thrombosis, based on four-hour post-dose measurements of anti-Xa activity. Twenty-two pregnant patients with a confirmed deep venous thrombosis were treated with tinzaparin either in a once- or twice-daily regimen. Four-hour post-dosage plasma anti-Xa activity was measured in 357 sequential blood samples during treatment. An higher dosage than recommended, was required to maintain anti-Xa activity in the target range. We suggest that the starting dosage should be 250 IU/kg/day in a twice-daily regimen, and that the dose in the initial phase be adjusted by daily monitoring of anti-Xa.