Clinical risk factors for pre-eclampsia determined in early pregnancy: systematic review and meta-analysis of large cohort studies.

OBJECTIVE: To develop a practical evidence based list of clinical risk factors that can be assessed by a clinician at ≤ 16 weeks' gestation to estimate a woman's risk of pre-eclampsia. DESIGN: Systematic review and meta-analysis of cohort studies. DATA SOURCES: PubMed and Embase databases, 2000-15. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Cohort studies with ≥ 1000 participants that evaluated the risk of pre-eclampsia in relation to a common and generally accepted clinical risk factor assessed at ≤ 16 weeks' gestation. DATA EXTRACTION: Two independent reviewers extracted data from included studies. A pooled event rate and pooled relative risk for pre-eclampsia were calculated for each of 14 risk factors. RESULTS: There were 25,356,688 pregnancies among 92 studies. The pooled relative risk for each risk factor significantly exceeded 1.0, except for prior intrauterine growth restriction. Women with antiphospholipid antibody syndrome had the highest pooled rate of pre-eclampsia (17.3%, 95% confidence interval 6.8% to 31.4%). Those with prior pre-eclampsia had the greatest pooled relative risk (8.4, 7.1 to 9.9). Chronic hypertension ranked second, both in terms of its pooled rate (16.0%, 12.6% to 19.7%) and pooled relative risk (5.1, 4.0 to 6.5) of pre-eclampsia. Pregestational diabetes (pooled rate 11.0%, 8.4% to 13.8%; pooled relative risk 3.7, 3.1 to 4.3), prepregnancy body mass index (BMI) >30 (7.1%, 6.1% to 8.2%; 2.8, 2.6 to 3.1), and use of assisted reproductive technology (6.2%, 4.7% to 7.9%; 1.8, 1.6 to 2.1) were other prominent risk factors. CONCLUSIONS: There are several practical clinical risk factors that, either alone or in combination, might identify women in early pregnancy who are at "high risk" of pre-eclampsia. These data can inform the generation of a clinical prediction model for pre-eclampsia and the use of aspirin prophylaxis in pregnancy.

Maternal Origin and Risk of Neonatal and Maternal ICU Admission.

OBJECTIVES: To evaluate maternal world region of birth, as well as maternal country of origin, and the associated risk of admission of 1) a mother to a maternal ICU, 2) her infant to a neonatal ICU, or 3) both concurrently to an ICU. DESIGN: Retrospective population-based cohort study. SETTING: Entire province of Ontario, Canada, from 2003 to 2012. PATIENTS: All singleton maternal-child pairs who delivered in any Ontario hospital. MEASUREMENTS AND MAIN RESULTS: We explored how maternal world region of birth, and specifically, maternal country of birth for the top 25 countries, was associated with the outcome of 1) neonatal ICU, 2) maternal ICU, and 3) both mother and newborn concurrently admitted to ICU. Relative risks were adjusted for maternal age, parity, income quintile, chronic hypertension, diabetes mellitus, obesity, dyslipidemia, drug dependence or tobacco use, and renal disease. Compared with infants of Canadian-born mothers (110.7/1,000), the rate of neonatal ICU admission was higher in immigrants from South Asia (155.2/1,000), Africa (140.4/1,000), and the Caribbean (167.3/1,000; adjusted relative risk, 1.41; 95% CI, 1.36-1.46). For maternal ICU, the adjusted relative risk was 1.79 (95% CI, 1.43-2.24) for women from Africa and 2.21 (95% CI, 1.78-2.75) for women from the Caribbean. Specifically, mothers from Ghana (adjusted relative risk, 2.71; 95% CI, 1.75-4.21) and Jamaica (adjusted relative risk, 2.74; 95% CI, 2.12-3.53) were at highest risk of maternal ICU admission. The risk of both mother and newborn concurrently admitted to ICU was even more pronounced for Ghana and Jamaica. CONCLUSIONS: Women from Africa and the Caribbean and, in particular, Ghana and Jamaica, are at higher risk of admission to ICU around the time of delivery, as are their newborns.

Soluble T cell immunoglobulin mucin domain 3 is shed from CD8+ T cells by the sheddase ADAM10, is increased in plasma during untreated HIV infection, and correlates with HIV disease progression.

UNLABELLED: Chronic HIV infection results in a loss of HIV-specific CD8(+) T cell effector function, termed "exhaustion," which is mediated, in part, by the membrane coinhibitory receptor T cell immunoglobulin mucin domain-3 (Tim-3). Like many other receptors, a soluble form of this protein has been described in human blood plasma. However, soluble Tim-3 (sTim-3) is poorly characterized, and its role in HIV disease is unknown. Here, we show that Tim-3 is shed from the surface of responding CD8(+) T cells by the matrix metalloproteinase ADAM10, producing a soluble form of the coinhibitory receptor. Despite previous reports in the mouse model, no alternatively spliced, soluble form of Tim-3 was observed in humans. Shed sTim-3 was found in human plasma and was significantly elevated during early and chronic untreated HIV infection, but it was not found differentially modulated in highly active antiretroviral therapy (HAART)-treated HIV-infected subjects or in elite controllers compared to HIV-uninfected subjects. Plasma sTim-3 levels were positively correlated with HIV load and negatively correlated with CD4 counts. Thus, plasma sTim-3 shedding correlated with HIV disease progression. Despite these correlations, we found that shedding Tim-3 did not improve the function of CD8(+) T cells in terms of gamma interferon production or prevent their apoptosis through galectin-9. Further characterization studies of sTim-3 function are needed to understand the contribution of sTim-3 in HIV disease pathogenesis, with implications for novel therapeutic interventions. IMPORTANCE: Despite the overall success of HAART in slowing the progression to AIDS in HIV-infected subjects, chronic immune activation and T cell exhaustion contribute to the eventual deterioration of the immune system. Understanding these processes will aid in the development of interventions and therapeutics to be used in combination with HAART to slow or reverse this deterioration. Here, we show that a soluble form of T cell exhaustion associated coinhibitory molecule 3, sTim-3, is shed from the surface of T cells. Furthermore, sTim-3 is elevated in the plasma of treatment-naive subjects with acute or chronic HIV infection and is associated with markers of disease progression. This is the first study to characterize sTim-3 in human plasma, its source, and mechanism of production. While it is still unclear whether sTim-3 contributes to HIV pathogenesis, sTim-3 may represent a new correlate of HIV disease progression.