Maternal risk of hypertension 7-15 years after pregnancy: clues from the placenta.

OBJECTIVE: To assess whether pre-eclampsia (PE)-related placental/extraplacental membrane findings are linked to moderately elevated blood pressure (BP) in pregnancy and later-life hypertension. DESIGN: Prospective cohort. SETTING: 52 prenatal clinics, 5 Michigan communities. SAMPLE: The POUCH Study recruited women at 16-27 weeks' gestation (1998-2004) and studied a sub-cohort in depth. This sample (n = 490) includes sub-cohort women with detailed placental assessments and cardiovascular health evaluations 7-15 years later in the POUCHmoms follow-up study. METHODS: PE-related placental/extraplacental membrane findings (i.e. mural hyperplasia, unaltered/abnormal vessels or atherosis in decidua; infarcts) were evaluated in relation to pregnancy BP and odds of Stage 2 hypertension at follow up using weighted polytomous regression. Follow-up hypertension odds also were compared in three pregnancy BP groups: normotensives (referent) and moderately elevated BP with or without PE-related placental/extraplacental membrane findings. MAIN OUTCOME MEASURES: Stage 2 hypertension (SBP ≥140 mmHg and/or DBP ≥90 mmHg, or using antihypertensive medications) at follow up. RESULTS: After excluding women with pregnancy hypertension (i.e. chronic, PE, gestational), mural hyperplasia and unaltered/abnormal decidual vessels were each associated with Stage 2 hypertension at follow up: adjusted odds ratio (aOR) = 2.7, 95% CI 1.1-6.6, and aOR = 1.7 (95% CI 0.8-3.4), respectively. Women with moderately elevated BP in pregnancy and evidence of mural hyperplasia or unaltered/abnormal decidual vessels had greater odds of Stage 2 hypertension at follow up: aOR = 4.5 (95% CI 1.6-12.5 and aOR = 2.6, 95% CI 1.1-5.9, respectively. CONCLUSIONS: PE-related placental/extraplacental membrane findings help risk-stratify women with moderately elevated BP in pregnancy for later development of hypertension. TWEETABLE ABSTRACT: Placental findings associated with mother's risk of later-life hypertension.

Moderately elevated blood pressure during pregnancy and odds of hypertension later in life: the POUCHmoms longitudinal study.

OBJECTIVE: Hypertensive disorders in pregnancy signal an increased risk of cardiovascular disease for women. However, future hypertension risk among pregnant women with moderately elevated blood pressure (BP) is unknown. We examined associations among moderately elevated BP or hypertensive disorders during pregnancy and later prehypertension or hypertension. DESIGN: Longitudinal cohort study. SETTING: Five communities in Michigan, USA. SAMPLE: Data are from pregnant women enrolled in the Pregnancy Outcomes and Community Health Study. We included 667 women with gestational BP measurements who participated in the POUCHmoms Study follow-up 7-15 years later. METHODS: Moderately elevated BP was defined as two measures of systolic BP ≥ 120 mmHg or diastolic BP ≥80 mmHg among women without a hypertensive disorder. Weighted multinomial logistic regression models estimated odds of prehypertension or hypertension at follow-up, adjusted for maternal confounders and time to follow-up. MAIN OUTCOME MEASURES: Prehypertension or hypertension. RESULTS: Women meeting the moderately elevated BP criteria (64%) had significantly higher odds of hypertension at follow-up (adjusted odds ratio 2.6; 95% confidence interval 1.2-5.5). These increased odds were observed for moderately elevated BP first identified before or after 20 weeks of gestation, and for elevated systolic BP alone or combined with elevated diastolic BP. CONCLUSIONS: Moderately elevated BP in pregnancy may be a risk factor for future hypertension. Pregnancy offers an opportunity to identify women at risk for hypertension who may not have been identified otherwise. TWEETABLE ABSTRACT: Moderately elevated blood pressure in pregnancy may be associated with hypertension later in life.

Evidence of placental haemorrhage and preterm delivery.

OBJECTIVE: To evaluate evidence of placental haemorrhage (PH) obtained through maternal interviews, patient charts and placental pathology examinations as potential indicators of a 'bleeding pathway' to preterm delivery (PTD). DESIGN: Prospective cohort. SETTING: Fifty-two clinics in five communities in Michigan, USA (1998-2004). POPULATION: A subset (n = 996) of cohort participants with complete placental pathology data. METHODS: First-trimester bleeding and placental abruption were ascertained by mid-trimester interviews and chart review, respectively. Disc-impacting blood clot was defined as a gross placental examination finding of a blood clot impacting adjacent tissue. Microscopic haemorrhage was defined as 'high' (top quintile) scores on an aggregate measure of placental pathology findings suggestive of atypical maternal vessel haemorrhage. These four PH indicators were compared with one another and with risk of PTD assessed by logistic regression analyses. MAIN OUTCOME MEASURES: Preterm delivery and PTD subtypes (i.e. <35 weeks, 35-36 weeks; spontaneous, medically indicated) compared with term deliveries. RESULTS: Placental abruption cases had 2.3-fold to 5.5-fold increased odds of the other three PH indicators. Disc-impacting blood clots and microscopic haemorrhage were associated with one another (odds ratio [OR] = 4.6), but not with first-trimester bleeding. In a multivariable model that included all four PH indicators and confounders, risk of PTD < 35 weeks was elevated with first-trimester bleeding (OR = 1.9 [1.0, 3.4]), placental abruption (OR = 5.2 [1.7, 16.2]), disc-impacting blood clots (OR = 2.3 [1.0, 5.0]) and microscopic haemorrhage (OR = 2.4 [1.4, 4.2]). CONCLUSIONS: Multiple clinical and subclinical PH indicators are associated with PTD, particularly early PTD.

Placental vascular pathology findings and pathways to preterm delivery.

The authors examined the associations between placental vascular findings and preterm delivery in 1,053 subcohort women (239 preterm, 814 term) from a Michigan pregnancy cohort study (1998-2004). Twenty-nine placental vascular variables from microscopic examinations were grouped into 5 constructs: 3 maternal constructs-obstructive lesions (MV-O), bleeding/vessel integrity (MV-I), and lack of physiologic conversion of maternal spiral arteries (MV-D)--and 2 fetal constructs--obstructive lesions (FV-O) and bleeding/vessel integrity (FV-I). Construct-specific scores were created by adding the number of positive findings and deriving a dichotomous variable to approximate the top quintile ("high") and bottom 4 quintiles ("not high") within each construct. In multivariate polytomous logistic regression models, medically indicated preterm delivery at <35 weeks was significantly associated with high scores for each of the vascular constructs; adjusted odds ratios ranged from 2.4 to 5.4. Spontaneous preterm delivery at 35-36 weeks was significantly associated with a high score on any 1 of 3 constructs: MV-I, MV-D, and FV-I. Spontaneous preterm delivery at <35 weeks was significantly associated with a high score on 2 or more of 3 constructs: MV-I, MV-D, and FV-I; adjusted odds ratios ranged from 4.1 to 7.4. These results support a role for various placental vascular lesions in medically indicated and spontaneous preterm delivery.

Depressive symptoms in mid-pregnancy, lifetime stressors and the 5-HTTLPR genotype.

Few studies of gene-environment interactions for the serotonin transporter promoter polymorphism (5-HTTLPR), life stressors and depression have considered women separately or examined specific types of stressful life events. None have looked at depression during pregnancy. In the Pregnancy Outcomes and Community Health (POUCH) Study, women were queried about history of stressful life events and depressive symptoms at the time of enrollment (15-27 weeks gestation). Stressful life events were grouped a priori into "subconstructs" (e.g. economic, legal, abuse, loss) and evaluated by subconstruct, total subconstruct score and total stressful life event score. The effect of genotype on the association between stressful life events and elevated depressive symptoms was assessed in 568 white non-Hispanic participants. The relationship between exposure to abuse and elevated depressive symptoms was more pronounced in the s/s group (OR = 24.5) than in the s/l group (OR = 3.0) and the l/l group (OR = 7.7), but this significant interaction was detected only after excluding 73 (13%) women with recent use of psychotropic medications. There was no evidence of gene-environment interaction in analytic models with other stressful life events subconstructs, total subconstruct score or total stressful life events score. These data offer modest support to other reports of gene-environment interaction and highlight the importance of considering specific stressful life events.

Perinatal brain injury in premature infants born to mothers using alcohol in pregnancy. Neonatal Brain Hemorrhage Study Team.

OBJECTIVE: Alcohol has been shown to have teratogenic effects on the fetal central nervous system. However, little research has been done to assess the impact of prenatal alcohol exposure on premature infants, a group particularly vulnerable to perinatal brain injury. METHODS: We examined the relation between maternal alcohol use and the most common forms of brain injury in premature infants--germinal matrix/intraventricular hemorrhage (GM/IVH) and white-matter damage--in a large population-based cohort of infants weighing 2000 g or less. The analyses included 349 infants younger than 31 weeks' gestation who received at least one cranial ultrasound scan and whose mothers were queried about prenatal alcohol use in a postpartum interview. RESULTS: Infants of mothers who reported "moderate" alcohol use (fewer than seven drinks per week and fewer than three drinks per occasion) to "high" use (seven or more drinks per week and/or three or more drinks per occasion) before recognized pregnancy, and moderate alcohol use during pregnancy, were not at increased risk for brain injury. However, after controlling for potentially confounding factors, infants of women reporting high alcohol use during pregnancy were at increased risk of developing isolated brain hemorrhage (odds ratio [OR] = 5.5, 95% confidence interval [CI] = 1.2, 24.7), any brain hemorrhage (OR = 6.7, 95% CI = 1.8, 26.4), and white-matter damage (OR = 9.5, 95% CI = 1.9, 46.4). CONCLUSION: Premature infants of women who report consuming seven or more drinks per week and/or three or more drinks per occasion during pregnancy have substantially elevated risks of both of the most common forms of brain injury in premature infants.

Cranial ultrasound prediction of disabling and nondisabling cerebral palsy at age two in a low birth weight population.

OBJECTIVE: To employ multivariate analytic techniques to assess the association between neonatal cranial ultrasound (US) abnormalities and subsequent cerebral palsy (CP), defined as disabling CP (DCP) or nondisabling CP (NDCP) depending on the level of motor dysfunction. DESIGN: Prospective cohort study. SUBJECTS AND METHODS: The Neonatal Brain Hemorrhage Study enrolled a geographically representative sample of 1105 newborns 501 to 2000 g and obtained follow-up data on 777 (86%) of the 901 survivors at age two. One hundred thirteen children (14.6%) had motor findings severe enough to classify them as having CP. The 61 (7.9%) of these children who were disabled by their motor impairment we classified as having DCP. The remaining 52 (6.7%) who had definite neurologic findings (usually mild spastic diplegia) but without evidence of interference with daily living, we classified as having NDCP. RESULTS: In a multivariate logistic regression model of perinatal and postnatal variables, the following factors were found to be significant risk factors for DCP: parenchymal echodensities/lucencies or ventricular enlargement (PEL/VE) on cranial US (OR = 15.4; 7.6, 31.1), germinal matrix/intraventricular hemorrhage (GM/IVH) (OR = 3.5; 1.7, 6.9) and mechanical ventilation (OR = 2.9; 1.2, 7.1). Fully 93.4% of infants were correctly classified as to presence or absence of DCP on the basis of this model. Birth weight, gestational age, length of hospital stay, gender, race, plurality, presence of labor and Apgar score were not significant independent predictors of DCP. For NDCP, the only risk factor significant in the multivariate model was PEL/VE (OR = 5.3; 2.2, 12.6). CONCLUSIONS: Among perinatal and postnatal factors, cranial US abnormalities are by far the most powerful predictors of disabling CP in low birth weight infants. Although PEL/VE was the strongest predictor, GM/IVH also appeared to independently contribute to the risk of DCP. NDCP in low birth weight infants appears to have a different risk profile than DCP. In particular, it is less closely related to US evidence of perinatal brain injury.

Second trimester corticotropin-releasing hormone levels in relation to preterm delivery and ethnicity.

OBJECTIVE: To assess the relationship between maternal corticotropin-releasing hormone (CRH) levels in second trimester sera, and the risk of preterm delivery in an ethnically heterogeneous sample of pregnant women. METHODS: This nested case-control study included two case groups (97 women who delivered before 35 weeks' gestation, 144 who delivered at 35--36 weeks' gestation), and a control group (244 women who delivered at or after 37 weeks' gestation) frequency matched by ethnicity (black, white) and by alpha-fetoprotein levels (normal, unexplained high). Corticotropin-releasing hormone was evaluated in stored maternal sera collected at 15--19 weeks' gestation from cases and controls. RESULTS: Delivery before 35 weeks' gestation was associated positively with a second trimester, ethnic-specific CRH above 1.5 multiples of the median in white women [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.1, 5.1] and black women (OR 5.0, 95% CI 1.8, 13.3). Sensitivity was 29% in whites and 41% in blacks; specificity was 84% in whites and 80% in blacks. We estimated the positive and negative predictive values to be 6% and 97%, respectively, in white women, and 16% and 93%, respectively, in black women. It was also noted that, within case and control groups, black women had consistently lower CRH levels than white women. CONCLUSION: Factors that lead to a premature increase in placental CRH production and are associated with an increased risk of preterm birth are evident as early as 15--19 weeks' pregnancy. When considering potential links between stressors, placental changes, CRH levels, and preterm birth, it might be important to stratify or adjust for ethnicity.

Training medical students in evidence-based medicine: a community campus approach.

BACKGROUND AND OBJECTIVES: Clinicians need skills in critical appraisal of medical literature to improve quality of care. This report on evidence-based medicine (EBM) curricula describes 1) the role of family medicine educators, 2) timing, 3) value of a standard format across multiple communities, and 4) outcomes in attitudes and skills. METHODS: In 1992, a nine-session curriculum delivered across six community campuses was introduced during the third year of medical school in the College of Human Medicine at Michigan State University. Evaluation compared 1) responses on the Association of American Medical Colleges graduation questionnaires from classes who received the curriculum with the 1994 class who did not (424 students), 2) responses to questions on group process performance, and 3) focused surveys of two classes. RESULTS: Trained classes reported higher levels of confidence in critical appraisal and research skills than the 1994 class and other schools. Respondents reported the small-group process as effective, greater appreciation of the training after 1 year of residency than at graduation, and no change in research activity. CONCLUSIONS: Family medicine educators can lead a new curriculum in EBM and maintain consistent standards across multiple communities. Many questions remain concerning the ideal curricular design to help clinicians apply the best research to patient care.

Maternal circulating PlGF concentrations and placenta-related pregnancy complications: First results from the CoLab AngF Study.

INTRODUCTION: Circulating angiogenic factors are potential markers for preeclampsia, but heterogeneous studies have failed to identify precise predictive/diagnostic properties. The Global CoLaboratory is investigating how to merge published data of angiogenic factors for meta-analysis on an individual sample basis. OBJECTIVE: To amalgamate pregnancy angiogenic factor studies, investigate diagnostic and predictive properties of these markers in preeclampsia and placenta-related pregnancy complications, and to test if measures from disparate platforms can be standardised. This is the first report using PlGF measures to diagnose preeclampsia. METHODS: Data were derived from 15 cohorts, within and outside the CoLaboratory network. Women were classified as either case (confirmed diagnosis of preeclampsia at sampling) or non-case (no preeclampsia at sampling). Individual PlGF measurements from four different analytical platforms were used, along with transformations of the data (e.g. log-transformations, transformations to a baseline platform). Transformed measurements were standardised both for specific platforms and globally, stratifying on gestational age. Different statistical techniques were compared. RESULTS: The database currently contains 1442 cases and 11,512 non-cases, which were used to define an algorithm to merge PlGF measurements from different platforms. Non-case distributions were used to standardise case results. Diagnostic PlGF measurements in relation to preeclampsia will be presented and confirm feasibility. CONCLUSIONS: Future studies can extend this approach to other angiogenic factors, prediction as well as diagnosis and to other placenta-related disorders.

Biological indicators of the in-utero environment and their association with birth weight for gestational age.

Birth weight for gestational age (BW/GA) has been associated with a risk of adverse health outcomes. Biological indices of pregnancy complications, maternal mid-pregnancy serum biomarkers and placental pathology may shed light on these associations, but at present, they are most often examined as single entities and offer little insight about overlap. In addition, these indices are typically assessed in relation to the extremes of the BW/GA distribution, leaving open the question of how they relate to the entire BW/GA distribution. Addressing issues such as these may help elucidate why postnatal health outcomes vary across the BW/GA continuum. In this study, we focused on a subset of women who participated in the Pregnancy Outcomes and Community Health Study (n = 1371). We examined BW/GA (i.e. gestational age and sex-referenced z-scores) in relation to obstetric complications, second trimester maternal serum screening results and histologic evidence of placental pathology along with maternal demographics, anthropometrics and substance use. In adjusted models, mean reductions in BW/GA z-scores were associated with preeclampsia (ß = -0.70, 95% CI -1.04, -0.36), high maternal serum alpha fetoprotein (ß = -0.28, 95% CI -0.43, -0.13), unconjugated estriol (ß = -0.31/0.5 multiples of the median decrease, 95% CI -0.41, -0.21) and high levels of maternal obstructive vascular pathology in the placenta (ß = -0.46, 95% CI -0.67, -0.25). The findings were similar when preterm infants, small-for-gestational age or large-for-gestational age infants were excluded. More research is needed to examine how the factors studied here might directly mediate or mark risk when evaluating the associations between BW/GA and postnatal health outcomes.

Pregnancy outcomes and community health: the POUCH study of preterm delivery.

In light of the social/ethnic disparity in preterm delivery (PTD) rates, the Pregnancy Outcomes and Community Health (POUCH) Study takes a broad view of the determinants of PTD by attempting to link underlying biological and psychosocial factors. The relationships between placental pathology, maternal biomarkers, and antecedent psychosocial factors are evaluated in three hypothesised pathways of PTD - one characterised primarily by infection, one by maternal vascular disease, and one by premature elevations in corticotropin releasing hormone in the absence of histological evidence of placental pathology. Within each pathway, an emphasis is placed on understanding the roles of stress and of maternal serum alpha-fetoprotein, an early biomarker associated with PTD. The POUCH Study enrolls pregnant women from five Michigan communities. Information about these women and their environments is gathered through detailed interviews and collection of biological samples including hair, urine, saliva, blood, vaginal fluid, and vaginal smear at 15-26 weeks of gestation. We have chosen to focus on the second trimester--a time when pathological processes may have evolved to a detectable stage, but generally before the onset of biological changes that accompany labour. This focus is consistent with the long-range goal of early detection/intervention and prevention of PTD.

Factors linked to bacterial vaginosis in nonpregnant women.

OBJECTIVES: The purposes of this study were to test the hypothesis that vaginal douching is linked to bacterial vaginosis in both symptomatic and asymptomatic women and to identify other demographic, reproductive, and lifestyle factors associated with bacterial vaginosis. METHODS: In this cross-sectional study involving 3 clinic sites, 496 nonpregnant women completed a self-administered questionnaire. Their vaginal smears were assessed and cross-validated for bacterial vaginosis. RESULTS: The prevalence of bacterial vaginosis across clinics ranged from 15% to 30%. In analyses restricted to site 1, adjusted odds ratios (ORs) for bacterial vaginosis remained significant for African American women with 13 or fewer years of education (OR = 5.5, 95% confidence interval [CI] = 2.1, 14.5), hormone use within the past 6 months (OR = 0.5, 95% CI = 0.2, 0.8), and vaginal douching within the past 2 months (OR = 2.9, 95% CI = 1.5, 5.6). CONCLUSIONS: Two lifestyle factors emerge as strongly associated with bacterial vaginosis: systemic contraceptives appear protective, whereas douching is linked to an increase in prevalence. The temporal relationship between douching and bacterial vaginosis needs further clarification.

Association of maternal IgM concentrations above the median at 15-19 weeks of gestation and early preterm delivery.

IgM concentrations greater than the median in maternal serum collected at 15-19 weeks of pregnancy were strongly associated (odds ratio 15.6) with delivery before 29 weeks. Our results suggest that the postulated inflammatory component in the aetiology of very preterm delivery may elicit a measurable maternal humoral response as early as mid-trimester.

Fish consumption and other characteristics of reproductive-aged Michigan anglers--a potential population for studying the effects of consumption of Great Lakes fish on reproductive health.

There has been considerable interest in the benefits and risks of eating Great Lakes fish, particularly with regard to reproductive health. We report the results of a survey conducted from 1993-1995 among Michigan anglers. The survey was designed to identify a reproductive-aged cohort of persons who consume high or low levels of Great Lakes fish in order to study the impact of polyhalogenated biphenyl (PHB) compounds and other toxins on human reproduction outcomes. Using fishing license data obtained from the Michigan Department of Natural Resources, we identified anglers of early reproductive age (18-34 years) in ten Michigan counties. The screening survey ascertained demographic, behavioral, fish consumption, and reproductive history information on anglers and their partners. Over 4,000 angler households were contacted. One thousand nine hundred fifty questionnaires were returned from 1,168 households. The median age of respondents was 30 years; 58% were male and 64% reported being married. Slightly more than one-half the respondents had attended or graduated from college, and less than 10% had not completed high school. In the past year, most respondents (46%) reported having eaten sport-caught fish 1-12 times, while 20% reported having eaten no sport-caught fish; 20% had consumed 13-24 meals. More sport-caught fish was consumed in the spring and summer than in the fall and winter, and males reported eating more fish than females. About 43% of our respondents reported that they intend to have one or more children in the next five years. Of these respondents, 287 couples had no identified impairments to reproduction and therefore would be eligible to participate in the future reproductive study.