Prepregnancy physiology and subsequent preterm preeclampsia.

BACKGROUND: Preeclampsia is a common pregnancy complication with debated etiology. OBJECTIVE: To evaluate the contribution of prepregnancy physiology, biochemistry, and anthropometrics to the subsequent development of preterm preeclampsia. STUDY DESIGN: One hundred twenty-four participants were recruited through open recruitment and targeted mailings. Participants included 81 nulliparous women and 43 with a history of preterm preeclampsia. We characterized cardiovascular function, metabolic profile, and body composition in 100 nonpregnant women who went on to subsequent pregnancy. Measures included plasma volume, baseline cardiovascular function and cardiovascular response to volume challenge, body composition, and circulating biochemical measures. Pregnancy outcome was obtained through chart review. Prepregnancy metrics for women who developed preterm preeclampsia were compared with measurements for those who did not, with adjustment for a history of prior preterm preeclampsia. Logistic regression modeling was used to identify the strongest prepregnancy factors associated with preterm preeclampsia. RESULTS: Pregnancy outcomes included 11 women with preterm preeclampsia, 7 women with term preeclampsia, 20 women with other hypertension affecting their pregnancy, and 62 with uncomplicated pregnancies. We observed no difference in maternal age, study cycle day, lean body mass, uterine hemodynamics, or flow-mediated dilation across groups. Women with preterm preeclampsia had greater android fat content 3215±1143 vs 1918±1510 g (P=.002), faster supine pulse, 77±7 vs 67±10 beats per minute (P=.001), higher supine diastolic blood pressure 82±6 vs 68±6 mmHg (P<.001), increased cardiac output 5.6±1.1 vs 4.6±1 L/min (P=.002), faster aortic-popliteal pulse wave velocity 4.5±0.7 vs 3.8±0.5 m/sec (P<.001), and exaggerated cardiac output response to volume challenge 20±9 vs 9±12 L/min (P=.002) compared to those with other pregnancy outcomes. Women who developed preterm preeclampsia also had reduced renal vascular resistance index 0.86±0.08 vs 0.97±0.12 (P=.005) compared with other pregnancy outcomes when assessed prior to pregnancy. Women with subsequent preterm preeclampsia had higher serum c-reactive protein 10.7±12.5 vs 4.1±5.8 mg/mL (P=.003) and greater insulin resistance, as assessed by Homeostatic Model Assessment for Insulin Resistance calculation 2.2±1.1 vs 1.2±0.9 (P<.001). CONCLUSION: Prepregnancy physiology is linked to subsequent preterm preeclampsia. The same factors associated with metabolic syndrome are more prominent in patients who develop preterm preeclampsia than those who do not, including increased vessel stiffness, low vascular compliance, high cardiac output, reduced renal vascular resistance index, insulin resistance, and increased android fat, all consistent with subclinical features of the metabolic syndrome.

Subclinical Metabolic and Cardiovascular Factors and Brain White Matter Microstructural Integrity in Young Women.

Women who have experienced pregnancy complications, specifically preeclampsia and gestational diabetes, have well documented increased risks of cardiovascular, metabolic, and neurological disease later in life. This study examined how specific cardiovascular and metabolic risk factors for preeclampsia assessed in a non-pregnant state were associated with brain white matter microstructural integrity. This study examined sixty-two healthy women (mean age 31 ± 5 years) who received metabolic and cardiovascular assessments as well as multiple modality MRI imaging. Participants were either nulliparous (n = 31) or had a history of preterm preeclampsia (n = 31). Imaging included acquisition Diffusion Tensor Imaging (DTI) to assess white matter integrity within the brain. We hypothesized that healthy, young, non-pregnant women with cardiovascular and metabolic profiles suggesting elevated risk would have decreased white matter integrity, represented by lower Fractional Anisotropy (FA) and increased Mean Diffusivity (MD) estimates in the posterior cortical areas of the brain. We observed increased white matter degradation (lower FA and increased MD) in posterior and occipital tracts, commissural fibers, and subcortical structures in women with increased adiposity, worse measures of cardiovascular and metabolic function, including greater insulin resistance (HOMA-IR), hyperlipidemia, elevated blood pressure, and increased arterial stiffness. The relationships detected between subclinical cardiovascular and metabolic phenotypes and increased white matter disruption at a young age, outside of pregnancy, are indicative that adverse changes are detectable long before cognitive clinical presentation. This may suggest that many of the long-term cardiovascular and metabolic risks of aging are influenced by physiologic aging trajectories rather than damage caused by pregnancy complications.

Preterm Preeclampsia Risk Modelling: Examining Hemodynamic, Biochemical, and Biophysical Markers Prior to Pregnancy.

Preeclampsia (PE) is a leading cause of maternal and perinatal death globally and can lead to unplanned preterm birth. Predicting risk for preterm or early-onset PE, has been investigated primarily after conception, and particularly in the early and mid-gestational periods. However, there is a distinct clinical advantage in identifying individuals at risk for PE prior to conception, when a wider array of preventive interventions are available. In this work, we leverage machine learning techniques to identify potential pre-pregnancy biomarkers of PE in a sample of 80 women, 10 of whom were diagnosed with preterm preeclampsia during their subsequent pregnancy. We explore prospective biomarkers derived from hemodynamic, biophysical, and biochemical measurements and several modeling approaches. A support vector machine (SVM) optimized with stochastic gradient descent yields the highest overall performance with ROC AUC and detection rates up to .88 and .70, respectively on subject-wise cross validation. The best performing models leverage biophysical and hemodynamic biomarkers. While preliminary, these results indicate the promise of a machine learning based approach for detecting individuals who are at risk for developing preterm PE before they become pregnant. These efforts may inform gestational planning and care, reducing risk for adverse PE-related outcomes.Clinical Relevance- This work considers the development and optimization of pre-pregnancy biomarkers for improving the identification of preterm (early-onset) preeclampsia risk prior to conception.

Preterm Preeclampsia Risk Modelling: Examining Hemodynamic, Biochemical, and Biophysical Markers Prior to Pregnancy.

Preeclampsia (PE) is a leading cause of maternal and perinatal death globally and can lead to unplanned preterm birth. Predicting risk for preterm or early-onset PE, has been investigated primarily after conception, and particularly in the early and mid-gestational periods. However, there is a distinct clinical advantage in identifying individuals at risk for PE prior to conception, when a wider array of preventive interventions are available. In this work, we leverage machine learning techniques to identify potential pre-pregnancy biomarkers of PE in a sample of 80 women, 10 of whom were diagnosed with preterm preeclampsia during their subsequent pregnancy. We explore biomarkers derived from hemodynamic, biophysical, and biochemical measurements and several modeling approaches. A support vector machine (SVM) optimized with stochastic gradient descent yields the highest overall performance with ROC AUC and detection rates up to .88 and .70, respectively on subject-wise cross validation. The best performing models leverage biophysical and hemodynamic biomarkers. While preliminary, these results indicate the promise of a machine learning based approach for detecting individuals who are at risk for developing preterm PE before they become pregnant. These efforts may inform gestational planning and care, reducing risk for adverse PE-related outcomes.

Quality Initiative to Reduce Failed Trial of Labor after Cesarean Using Calculated VBAC Success Likelihood.

OBJECTIVE: Vaginal birth after cesarean can reduce morbidity associated with multiple cesarean deliveries. Failed vaginal birth after cesarean is associated with increased maternal and neonatal morbidity. The Maternal-Fetal Medicine Units Vaginal Birth After Cesarean calculator is a validated tool to predict the likelihood of successful trial of labor after cesarean. Predicted likelihood < 60% has been associated with increased maternal and neonatal morbidity. We sought to determine if formal incorporation of calculated vaginal birth after cesarean likelihood into patient-centered counseling would reduce failed vaginal birth after cesarean. STUDY DESIGN: This is a quality improvement intervention at a single tertiary-care academic medical center, in which standardized patient counseling was implemented, facilitated by an electronic medical record template featuring patient-specific likelihood of vaginal birth after cesarean success. Term singleton pregnancies with history of one to two cesareans were included; those with contraindication to labor were excluded. Historical controls (January 2016-December 2018, n = 693) were compared with a postimplementation cohort (January 2019-April 2020, n = 328). Primary outcome was failed vaginal birth after cesarean. RESULTS: Fewer patients in the postintervention cohort had a history of an arrest disorder (PRE: 48%, 330/693 vs. POST: 40%, 130/326, p = 0.03); demographics were otherwise similar, including the proportion of patients with <60% likelihood of success (PRE: 39%, 267/693, vs. POST: 38%, 125/326). Following implementation, induction of labor in patients with a <60% likelihood of successful vaginal birth after cesarean decreased from 17% (45/267) to 5% (6/125, p < 0.01). The proportion of failed vaginal birth after cesarean decreased from 33% (107/329) to 22% (32/143, p = 0.04). Overall vaginal birth after cesarean rate did not change (PRE: 32%, 222/693, vs. POST: 34%, 111/326, p = 0.52). CONCLUSION: An intervention targeting provider counseling that included a validated vaginal birth after cesarean success likelihood was associated with decreased risk of failed trial of labor after cesarean without affecting overall vaginal birth after cesarean rate. KEY POINTS: · Labored cesarean increases maternal morbidity.. · Application of the Maternal-Fetal Medicine Units (MFMU) calculator to antenatal counseling decreased labored cesarean.. · Application of the MFMU calculator to antenatal counseling did not decrease overall vaginal birth after cesarean rate..

Corrigendum: Preeclampsia and its relationship to pathological brain aging.

[This corrects the article DOI: 10.3389/fphys.2022.979547.].

Preeclampsia and its relationship to pathological brain aging.

The development of preeclampsia during pregnancy may have long-term effects on brain aging in women. Associations between preeclampsia and vascular dementia have been established, however the connection between preeclampsia and Alzheimer's disease has not been as thoroughly explored. Both preeclampsia and Alzheimer's disease have been associated with misfolded amyloid beta proteins and inflammation; due to these similarities, in this minireview, we examined the potential links between a history of preeclampsia and the development of dementia. We also discussed how hypertensive disorders of pregnancy may relate to both normal brain aging and dementia to highlight the need for additional research regarding the long-term cognitive effects of preeclampsia on the brain.

Medication for Addiction Treatment and Postpartum Health Care Utilization Among Pregnant Persons With Opioid Use Disorder.

OBJECTIVE: To estimate treatment and postpartum health care utilization among pregnant persons with opioid use disorder (OUD) in Vermont and Maine. METHODS: Vermont's and Maine's All Payer Claims Databases were used to identify deliveries 2010 to 2018 that were paid for, in part, by Medicaid. OUD was identified among pregnant persons if they had any claim with an OUD-diagnosis code (ICD-9/10) or medication for addiction treatment (MAT) code during the 5 months before delivery event. Consistent and inconsistent MAT were compared to no MAT on the rate of hospitalizations and emergency department (ED) visits in the first 12 months' postpartum using negative binomial regression. RESULTS: From 2010 through 2018, 27,652 deliveries in Vermont and 43,480 deliveries in Maine were among persons insured by Medicaid. The prevalence of OUD among pregnant persons increased from 6.7% to 11.6% in Vermont and from 7.4% to 11.0% in Maine. Among pregnant persons with OUD in 2018, 57% had consistent MAT in Vermont and 50% had consistent MAT in Maine; approximately 32% and 27% were not in treatment in Vermont and Maine, respectively. In Maine, consistent MAT was associated with a 47% lower rate of hospitalization and 37% to 46% lower rates of ED visits when compared to those without MAT; in Vermont, those with consistent buprenorphine treatment had a 30% lower rate of ED visits. CONCLUSIONS: Medicaid data from Vermont and Maine suggests that medication for addiction treatment for opioid use disorder during pregnancy reduces emergency health care utilization in the first year postpartum.

Placental Maternal Vascular Malperfusion is Associated with Prepregnancy and Early Pregnancy Maternal Cardiovascular and Thrombotic Profiles.

Characteristics of maternal vascular malperfusion (MVM) are frequently observed in placentas from pregnancies impacted by preeclampsia, intrauterine growth restriction, preterm labor, and intrauterine fetal demise. We sought to evaluate the associations of features of MVM with subclinical measures of cardiovascular health and coagulation potential in healthy young women. Sixty-three healthy young women were recruited and assessed prior to pregnancy on cycle day 9 ± 4, at gestational age 90 ± 6 of early pregnancy, and gestational age 216 ± 5 of late pregnancy. Women were assessed for plasma volume, blood pressure, response to volume loading, cardiac output, and uterine hemodynamics. Platelet-poor plasma was collected to assess thrombin generation on a subset of 33 women at all time points. Following delivery, placentas were collected and analyzed for evidence of MVM. Thrombin generation (TG) was evaluated in the presence of tissue factor (TF) with and without recombinant soluble thrombomodulin (TM). For each, we compared TG lagtime, peak level, and endogenous thrombin potential (ETP). Comparisons were made between dichotomized presence and absence of each individual feature of MVM and cardiovascular and coagulation features. Mean ± standard deviation are presented. Women were 31 ± 4 years of age, body mass index of 24 ± 5 kg/m2, 86% white race, and 80% nulliparous. MVM occurred in 70% of placentas, with infarcts and agglutination (44%), decidual arteriopathy (40%), accelerated villous maturation (32%), placental hypoplasia (29%), and distal villous hypoplasia (17%) documented. Decidual arteriopathy and distal villous hypoplasia were associated with prepregnancy maternal physiology, including decreased plasma volume and subclinical cardiovascular variations. All assessed MVM characteristics had identifiable early pregnancy physiologic characteristics consistent with altered cardiovascular function and decreased uterine response to pregnancy when compared with women who did and did not develop MVM. Accelerated villous maturation was the only MVM feature to differ by thrombin generation parameters in early pregnancy. Thrombin generation potential and blood pressure were elevated in late pregnancy in women who developed decidual arteriopathy. Prepregnancy health status and adaptation to pregnancy play important roles in pregnancy outcomes. Both cardiovascular health and thrombin generation potential may influence early placentation. Longitudinal assessment of subclinical maternal factors may allow for better understanding of the etiologies of MVM lesions, as well as allow for identification of a timeline of the origins of placental pathologies.

Cardiovascular profiles associated with white matter hyperintensities in healthy young women.

Women who experience hypertension in pregnancy have increased risk of both chronic hypertension and dementia. High blood pressure is associated with increased evidence of white matter hyperintensities (WMH) in brain imaging. WMH are disruptions of the white matter of the brain that occur with demyelination and axonal degeneration, are associated with vascular disease, occur more frequently in people with hypertension, and are associated with cognitive impairment. We evaluated the relationship between WMH and subclinical cardiovascular function in healthy young nulliparous women and women with a history of early-onset preeclampsia. Sixty-two reproductive-aged women were assessed during the follicular phase of the menstrual cycle after a 3-day sodium/potassium-controlled diet. Half of participants had a history of early-onset preeclampsia, and half were nulliparous. Blood was drawn to assess inflammatory markers. Cardiovascular assessments included tonometric blood pressure monitoring, volume loading to assess vascular compliance, echocardiography to assess cardiac ejection time, brachial pulse wave velocity of the brachial artery, assessing cardiovascular stiffness, and brachial artery flow mediated vasodilation to assess endothelial mediated dilatory response. T2 fluid-attenuated inversion recovery (FLAIR) MRI imaging was obtained. Two raters, blinded to cardiovascular assessments and pregnancy history, reviewed MRI scans for evidence of WMH using the Fazekas rating scale. WMHs were detected in 17 women; 45 had normal white matter structure. Participants with Fazekas score>0 had exaggerated response to volume loading compared to women with a Fazekas score of 0 and longer cardiac ejection times. Fazekas scores >0 had lower brachial flow-mediated vasodilation and increased white blood count compared to those with no evidence of WMH. Women with WMH had reduced cardiovascular compliance, and a trend towards decreased endothelial responsiveness compared to those without WMH. These data demonstrated that the relationship between cardiovascular and brain health was detectable in young, healthy, reproductive-aged women, and may play a role in later development of clinical disease. These findings may help identify women who are at risk for cognitive decline and pathological aging.

Association of pre-pregnancy subclinical insulin resistance with cardiac dysfunction in healthy nulliparous women.

OBJECTIVES: To investigate the association between pre-pregnancy subclinical insulin resistance and cardiovascular dysfunction in healthy nulliparous women, and with hypertension in subsequent pregnancy. STUDY DESIGN: Secondary analysis of a single center prospective observational study conducted November 2011-June 2014. Healthy nulliparous women underwent detailed cardiovascular and metabolic assessment. Insulin resistance was determined by homeostasis model assessment (HOMA-IR). Associations of HOMA-IR with metabolic and cardiovascular measurements were assessed with Spearman correlations. Charts were reviewed in women who conceived singleton pregnancies. MAIN OUTCOME MEASURES: Metabolic measurements included serum glucose, insulin, creatinine, CRP, and lipids. HOMA-IR was calculated using fasting serum insulin and glucose. Indices of cardiovascular stiffness were determined from pulse wave velocity and response to volume challenge. Pregnancy outcomes included delivery mode and gestational age, birthweight, and hypertension. RESULTS: HOMA-IR was positively associated with BMI (r = 0.462, p < 0.001), body fat percentile (r = 0.463, p < 0.001), CRP (r = 0.364, p = 0.003), and negatively associated with serum HDL (r = -0.38, p = 0.002) and creatinine (r = -0.242, p = 0.049). HOMA-IR was positively associated with blood pressure (r = 0.347, p = 0.004), resting heart rate (r = 0.433, p = <0.001), response to volume challenge (r = 0.325, p < 0.01). Increased HOMA-IR was associated with a faster cardiac ejection time in response to volume challenge (r = -0.415, p < 0.001), which is a marker of decreased cardiac compliance to volume increase, or cardiac stiffness. CONCLUSION: HOMA-IR is associated with pre-pregnancy cardiac stiffness. Cholesterol was not associated with cardiovascular dysfunction. A non-significant trend was observed between HOMA-IR and hypertension in subsequent pregnancy.

Measures of adiposity correlate with renal filtration in young nulliparous women: An observational cohort study.

OBJECTIVE: Renal hyperfiltration, which has been documented in severe obesity and obesity-associated hypertension, can occur with hypertensive disorders of pregnancy. Identification of prepregnancy risk factors for unrecognized renal hyperfiltration could inform screening and intervention strategies to protect against pregnancy complications. In young, healthy, nulliparous women, associations between associations between measures of adiposity, insulin resistance, and renal vascular resistance were thus evaluated. METHODS: This is a secondary analysis of a prospective observational trial characterizing associations of prepregnancy and late-pregnancy maternal physiology. Seventy-nine nulligravid women aged 18-42 years without major medical conditions were assessed for percent android body fat using dual-energy X-ray absorption. Renal cortical vessel blood flow resistance index (CVRI) was determined using Doppler ultrasonography. Creatinine clearance was calculated from 24-hour urine collection. RESULTS: Renal CVRI inversely correlates with body mass index (r = -0.23, p = 0.047), percent android fat (r = -0.30, p = 0.008), and supine pulse (r = -0.44, p < 0.001). Creatinine clearance is positively associated with BMI and HOMA-IR.In regression modeling, supine pulse (r2 = 0.22, p < 0.001) and cardiac index (r2 = 0.05, p = 0.045) predict renal CVRI, whereas HOMA-IR (r2 = 0.11, p = 0.008) and cardiac output (r2 = 0.06, p = 0.039) predict creatinine clearance. Measures of adiposity are not independently predictive of either measure. CONCLUSIONS: In healthy young women, measures of adiposity and insulin resistance correlate positively with renal filtration. Preclinical manifestations of renal hyperfiltration may have implications for pregnancy outcomes.

Subclinical cardiac stiffness is associated with arterial stiffness in healthy young nulligravid women: Potential links to preeclampsia.

OBJECTIVES: Preeclampsia is an independent risk factor for subsequent cardiovascular disease and diastolic dysfunction and has been linked to arterial stiffness. We hypothesized that arterial stiffness would be associated with echocardiographic markers of diastolic dysfunction in healthy nulligravid women. STUDY DESIGN: 31 healthy nulligravid women underwent assessment of peripheral arterial stiffness via aorto-femoral pulse wave velocity, popliteal distensibility and ß stiffness measures as well as hemodynamic response to volume challenge. 22 underwent cardiac assessment via conventional and stress echocardiography with a focus on diastolic function utilizing tissue/pulse wave Doppler imaging and 3D speckle tracking. Bivariate associations between variables were evaluated using correlation coefficients (Pearson r) and Student's t-tests. RESULTS: No participants had echocardiographic values meeting criteria for overt diastolic dysfunction. Baseline global circumferential strain was significantly correlated with distensibility and ß stiffness (n = 18, r = -0.61, p = 0.007, n = 18, r = 0.56, p = 0.01). Peak deceleration time was correlated with ßstiffness (n = 9; r = 0.80, p = 0.01). Pulse wave velocity was not significantly correlated with cardiac measures (p > 0.05). Family history of a first or second degree relative with myocardial infarction or hypertension was associated with decreased popliteal artery distensibility (p = 0.02 and p = 0.03, respectively). CONCLUSIONS: In healthy nulligravid women there is evidence that markers of decreased left ventricular relaxation are associated with increased peripheral vascular stiffness as is a family history of myocardial infarction or hypertension. These findings raise the possibility that the diastolic dysfunction and arterial stiffness observed in the setting of preeclampsia are driven by underlying properties present prior to pregnancy and contribute to lifetime cardiovascular risk.

Adiposity, but not Obesity, Is Associated With Arterial Stiffness in Young Nulliparous Women.

Subclinical vascular dysfunction is increasingly recognized as an independent risk factor for cardiovascular events and adverse pregnancy outcomes. The evidence linking indices of obesity and vascular dysfunction is mixed. As an example, some data suggest that adiposity may be a better predictor of endothelial dysfunction than body mass index (BMI). The aim of the current study is to compare the association of obesity, as evaluated by BMI, and a direct measure of body fat to biophysical parameters of vascular function including flow-mediated vasodilation and pulse wave velocity (PWV) in healthy nulliparous reproductive-age women. This is a secondary analysis of data collected as a prospective study of prepregnancy physiology in healthy, nulliparous women. Body mass index was calculated as weight (kg)/height (m2). Total and android body fat were calculated by dual-energy X-ray absorptiometry. Brachial PWV and flow-mediated vasodilation were assessed ultrasonographically. Seventy-nine women were evaluated. Mean BMI was 24.4 (5.4) kg/m2, and 15% of women were obese (BMI ≥ 30 kg/m2). In contrast, 39% were considered to have excess adiposity, with ≥39% android body fat. Brachial PWV was associated with increased adiposity, but not obesity. We found no differences in flow-mediated dilation associated with either BMI or body fat. Adiposity may be superior to BMI in identifying women with vascular dysfunction at increased risk of adverse pregnancy outcome and cardiovascular disease. Proper identification may allow implementation of prevention strategies to improve perinatal outcomes and maternal health.

Maternal Hypertension and Mortality in Small for Gestational Age 22- to 29-Week Infants.

Infants born before 30 weeks gestational age (GA) to mothers with hypertension (HTN) experience lower rates of mortality and serious morbidities when corrected for maternal and infant characteristics. Growth restriction and maternal HTN are often associated. We sought to determine if small for gestational age (SGA) infants have similarly decreased mortality risk when born to mothers with HTN. We identified 6897 singleton SGA, 22 + 0 to 29 + 6 weeks GA infants born between 2008 and 2011, cared for at 578 North American centers in the Vermont Oxford Network. Chromosomal abnormalities and birth defects were excluded. Mortality rates prior to discharge were compared between 4317 HTN and 2580 comparison infants. Logistic regression was used to adjust for birth weight, infant sex, maternal race, inborn/outborn, antenatal steroid exposure, prenatal care, and GA. Small for gestational age HTN infants were older (mean: 26.9 [1.9] vs 26.6 [2.2] weeks; P < .001) and larger (HTN = 584 [159] g vs 562 [156] g; P < .001) than comparison infants. Death prior to discharge occurred in 29% of HTN and 43% of comparison infants. Univariate analyses revealed lower mortality for HTN infants (odds ratio [OR] = 0.54, 95% confidence interval [CI]: 0.48-0.60). After adjustment, mortality remained lower when compared to non-HTN infants (OR = 0.60, 95% CI: 0.52-0.69). Extremely preterm SGA infants face high rates of mortality. Although maternal HTN is associated with SGA, SGA infants born to mothers with HTN have decreased risk of mortality compared to non-HTN SGA infants, prior to and after adjustment for antenatal and maternal characteristics. This may reflect detrimental physiologic effects associated with alternative mechanisms for fetal growth restriction and is important for parental counseling.

Examination of Prepregnancy and Pregnancy Urinary Protein Levels in Healthy Nulliparous Women.

During pregnancy, abnormal proteinuria is defined as urine protein excretion greater than 300 mg/24 h. Although widely accepted, this definition is not based on clinical outcomes. Our study aimed to longitudinally examine proteinuria in healthy women prior to, and in late pregnancy and to compare inpatient and outpatient 24-hour urine collections. Nulliparous women planning to conceive were recruited and completed a 24-hour urinary collection. Those who subsequently conceived completed a second 24-hour urinary collection in late pregnancy. In the first 5 years of the study, urinary collections were completed during an inpatient admission; all collections during the latter part of the study were performed as outpatients. Urine protein was measured using the VITROS UPRO Slide kit. Wilcoxon signed rank tests were used for paired comparisons of prepregnancy and late pregnancy proteinuria and Wilcoxon rank sum tests were used to compare inpatient and outpatient collections. Among 134 women completing a prepregnancy collection, median urinary protein excretion was 188 mg/24 h (IQR 103-280). Sixty-five women subsequently conceived and completed a late pregnancy collection. In healthy women, urinary protein increased to 254 mg/24 h during pregnancy (IQR 166-396). Forty-five percent of women exceeded the defined normal threshold of proteinuria in 24 hours in the absence of disease. Inpatient collections resulted in higher levels of urinary protein than outpatient at both time points. Our data suggest that significant proteinuria is present in healthy nonpregnant women. Even in the absence of disease, proteinuria increases during pregnancy. Outpatient collections may underestimate proteinuria, especially in late pregnancy.

Differences in cardiovascular function comparing prior preeclamptics with nulliparous controls.

OBJECTIVE: The objective of the current study was to evaluate cardiovascular function; including blood pressure, cardiac output, pulse wave velocity and vascular compliance in nonpregnant nulliparous women compared to women with a history of preterm preeclampsia. STUDY DESIGN: This was a case control study. Blood pressure was measured using the Finapres Pro. Baseline cardiac output was determined by echocardiography. Pulse wave velocity was estimated using simultaneous electrocardiographic tracings and ultrasound determined arterial flow waveforms and calculated as estimated distance divided by the time interval between EKG r-wave peak and ultrasound derived peak popliteal artery flow. During volume challenge, 500mL of lactated Ringers solution was infused through an indwelling antecubital catheter over 10min. Cardiac output and blood pressure during and 15min after the infusion were estimated using the Finapres Pro. MAIN OUTCOME MEASURES: Indices of arterial stiffness and vascular compliance. RESULTS: Previous preeclamptics exhibited a significant increase in pulse pressure and cardiac output in response to volume challenge when compared with nulliparous controls. Prior preeclamptics had a strong positive correlation between blood pressure indices (r=0.50-0.68, p⩽0.01) and pulse pressure (r=0.58, P=0.008) with pulse wave velocity that was not evident in control women. CONCLUSIONS: In women with prior preterm preeclampsia a relationship between blood pressure, intravascular volume and arterial stiffness, is evident in the nonpregnant state and in the absence of hypertension or overt cardiovascular disease. This supports an overarching hypothesis that nonpregnant physiology is an important contributor to pregnancy adaptations.

The effect of maternal hypertension on mortality in infants 22, 29weeks gestation.

OBJECTIVE: To evaluate the effect of maternal hypertension on mortality risk prior to discharge, in infants 22+0 to 29+6weeks gestational age. STUDY DESIGN: We evaluated 88,275 North American infants whose births were recorded in Vermont Oxford Network centers between 2008 and 2011 Infants born between 22+0 and 29+6weeks gestational age were evaluated in 2-week gestational age cohorts and followed until death or discharge. Logistic regression was used to adjust for birth weight, antenatal steroid exposure, infant sex, maternal race, inborn/outborn, prenatal care and birth year. RESULTS: 21,896 infants were born to hypertensive mothers; 13% died prior to Neonatal Intensive Care Unit discharge compared to 20% of the 66,379 infants born to mothers without hypertension. After adjustment, infants had significantly lower mortality compared to preterm infants not born to hypertensive mothers, at all gestational ages examined (22/23: odds ratio (OR)=0.65 (95% Confidence Interval (CI): 0.55, 0.77; 24/25); OR=0.77 (95% CI: 0.71, 0.84); 26/27: OR=0.66 (95% CI: 0.59, 0.74); 28/29: OR=0.58 (95% CI: 0.51, 0.67). Additionally, births associated with maternal hypertension increase dramatically by gestational age, resulting in a larger proportion of births associated with maternal hypertension at later gestational ages. CONCLUSIONS: Preterm birth due to any cause carries significant risk of mortality, especially at the earliest of viable gestational ages. Maternal hypertension independently influences mortality, with lower odds of mortality seen in infants born to hypertensive mothers, after adjustment, and should be taken into consideration as an element in counseling parents.

The relationship of a family history for hypertension, myocardial infarction, or stroke with cardiovascular physiology in young women.

Cardiovascular disease (CVD) and preeclampsia share several pathophysiologic risk factors. We examined family history (FH) and physiologic status in 60 healthy, nulliparous women to determine the relationship between FH and known risk factors for CVD. Data are presented as mean ± standard error (SE). Decreased uterine blood flow was observed in women with FH of hypertension (+FH: 21.5 ± 1.7, no FH: 33.3 ± 9.0 mL/min; P = .04). Women reporting an FH of stroke showed increased alpha- and beta-adrenergic response, as measured by Valsalva maneuver (α: FH: 24.7 ± 1.9, -FH: 18.9 ± 1.1 mm Hg, P = .02; ß: FH: 22.0 ± 2.1, -FH: 16.9 ± 1.4 mm Hg; P = .04), and increased cardiac output (4.83 ± 0.22 vs 4.31 ± 0.12 L/min; P = .01). We identified no significant physiologic associations linked to an FH of myocardial infarction. Our observations show significant differences in physiologic characteristics in women with specific CVD family histories. These data, coupled with known heritable contributions to CVD and preeclampsia, suggest a distinct physiologic phenotype that may link preeclampsia risk with FH of CVD, independent of pregnancy.

Prepregnancy Vascular Dysfunction in Women who Subsequently Develop Hypertension During Pregnancy.

OBJECTIVE: To evaluate vascular dysfunction using both physiologic measures and biochemical markers, longitudinally, prior to and during pregnancy, in nulliparous women who had uncomplicated pregnancies compared to those who developed complicated hypertension during pregnancy. METHODS: Twenty healthy nulliparous women were studied during the follicular phase and in early (EP) and late (LP) pregnancy. All had singleton conceptions and delivered at term, seventeen with uncomplicated pregnancies (NP) and three who developed complicated hypertension (HP) after the LP evaluation. We compared prepregnancy, EP and LP pulse wave velocity (PWV) and soluble vascular cell adhesion molecule (sVCAM-1) between the NP and HP groups. PWV was measured using ultrasound and simultaneous echocardiogram tracing then calculated as the estimated distance divided by interval between EKG r-wave peak and peak brachial artery flow. SVCAM-1 was measured using a commercially available kit. Data are means ± SE, significance accepted as p < 0.05. RESULTS: The NP group had significantly lower prepregnant PWV (NP: 2.66 ± 0.06 m/s, HP: 3.00 ± 0.04, p=.02), but PWV was not different at the EP or LP time points. SVCAM-1 was significantly lower prior to pregnancy and during EP and LP in the NP group (Prepregnancy: NP: 712 ± 32 ng/mL, HP: 1058 ± 107, p < .001; EP: NP: 695 ± 31 ng/mL, HP: 924 ± 52, p = .004; LP: NP: 663 ± 25 ng/mL, HP: 946 ± 36, p < .001). CONCLUSIONS: PWV and sVCAM-1 may be important prepregnancy discriminators useful in assessing risk for preeclampsia prior to pregnancy.