Phyllis August

Hypertensive disorders of pregnancy (HDP) remain one of the major causes of pregnancy-related maternal and fetal morbidity and mortality worldwide. Affected women are also at increased risk for cardiovascular disease later in life, independently of traditional cardiovascular disease risks. Despite the immediate and long-term cardiovascular disease risks, recommendations for diagnosis and treatment of HDP in the United States have changed little, if at all, over past decades, unlike hypertension guidelines for the general population. The reasons for this approach include the question of benefit from normalization of blood pressure treatment for pregnant women, coupled with theoretical concerns for fetal well-being from a reduction in utero-placental perfusion and in utero exposure to antihypertensive medication. This report is based on a review of current literature and includes normal physiological changes in pregnancy that may affect clinical presentation of HDP; HDP epidemiology and the immediate and long-term sequelae of HDP; the pathophysiology of preeclampsia, an HDP commonly associated with proteinuria and increasingly recognized as a heterogeneous disease with different clinical phenotypes and likely distinct pathological mechanisms; a critical overview of current national and international HDP guidelines; emerging evidence that reducing blood pressure treatment goals in pregnancy may reduce maternal severe hypertension without increasing the risk of pregnancy loss, high-level neonatal care, or overall maternal complications; and the increasingly recognized morbidity associated with postpartum hypertension/preeclampsia. Finally, we discuss the future of research in the field and the pressing need to study socioeconomic and biological factors that may contribute to racial and ethnic maternal health care disparities.

BACKGROUND: The benefits and safety of the treatment of mild chronic hypertension (blood pressure, <160/100 mm Hg) during pregnancy are uncertain. Data are needed on whether a strategy of targeting a blood pressure of less than 140/90 mm Hg reduces the incidence of adverse pregnancy outcomes without compromising fetal growth. METHODS: In this open-label, multicenter, randomized trial, we assigned pregnant women with mild chronic hypertension and singleton fetuses at a gestational age of less than 23 weeks to receive antihypertensive medications recommended for use in pregnancy (active-treatment group) or to receive no such treatment unless severe hypertension (systolic pressure, ≥160 mm Hg; or diastolic pressure, ≥105 mm Hg) developed (control group). The primary outcome was a composite of preeclampsia with severe features, medically indicated preterm birth at less than 35 weeks' gestation, placental abruption, or fetal or neonatal death. The safety outcome was small-for-gestational-age birth weight below the 10th percentile for gestational age. Secondary outcomes included composites of serious neonatal or maternal complications, preeclampsia, and preterm birth. RESULTS: A total of 2408 women were enrolled in the trial. The incidence of a primary-outcome event was lower in the active-treatment group than in the control group (30.2% vs. 37.0%), for an adjusted risk ratio of 0.82 (95% confidence interval [CI], 0.74 to 0.92; P<0.001). The percentage of small-for-gestational-age birth weights below the 10th percentile was 11.2% in the active-treatment group and 10.4% in the control group (adjusted risk ratio, 1.04; 95% CI, 0.82 to 1.31; P = 0.76). The incidence of serious maternal complications was 2.1% and 2.8%, respectively (risk ratio, 0.75; 95% CI, 0.45 to 1.26), and the incidence of severe neonatal complications was 2.0% and 2.6% (risk ratio, 0.77; 95% CI, 0.45 to 1.30). The incidence of any preeclampsia in the two groups was 24.4% and 31.1%, respectively (risk ratio, 0.79; 95% CI, 0.69 to 0.89), and the incidence of preterm birth was 27.5% and 31.4% (risk ratio, 0.87; 95% CI, 0.77 to 0.99). CONCLUSIONS: In pregnant women with mild chronic hypertension, a strategy of targeting a blood pressure of less than 140/90 mm Hg was associated with better pregnancy outcomes than a strategy of reserving treatment only for severe hypertension, with no increase in the risk of small-for-gestational-age birth weight. (Funded by the National Heart, Lung, and Blood Institute; CHAP ClinicalTrials.gov number, NCT02299414.).

BACKGROUND: The standard test for the diagnosis of acute rejection in kidney transplants is the renal biopsy. Noninvasive tests would be preferable. METHODS: We prospectively collected 4300 urine specimens from 485 kidney-graft recipients from day 3 through month 12 after transplantation. Messenger RNA (mRNA) levels were measured in urinary cells and correlated with allograft-rejection status with the use of logistic regression. RESULTS: A three-gene signature of 18S ribosomal (rRNA)-normalized measures of CD3ε mRNA and interferon-inducible protein 10 (IP-10) mRNA, and 18S rRNA discriminated between biopsy specimens showing acute cellular rejection and those not showing rejection (area under the curve [AUC], 0.85; 95% confidence interval [CI], 0.78 to 0.91; P<0.001 by receiver-operating-characteristic curve analysis). The cross-validation estimate of the AUC was 0.83 by bootstrap resampling, and the Hosmer-Lemeshow test indicated good fit (P=0.77). In an external-validation data set, the AUC was 0.74 (95% CI, 0.61 to 0.86; P<0.001) and did not differ significantly from the AUC in our primary data set (P=0.13). The signature distinguished acute cellular rejection from acute antibody-mediated rejection and borderline rejection (AUC, 0.78; 95% CI, 0.68 to 0.89; P<0.001). It also distinguished patients who received anti-interleukin-2 receptor antibodies from those who received T-cell-depleting antibodies (P<0.001) and was diagnostic of acute cellular rejection in both groups. Urinary tract infection did not affect the signature (P=0.69). The average trajectory of the signature in repeated urine samples remained below the diagnostic threshold for acute cellular rejection in the group of patients with no rejection, but in the group with rejection, there was a sharp rise during the weeks before the biopsy showing rejection (P<0.001). CONCLUSIONS: A molecular signature of CD3ε mRNA, IP-10 mRNA, and 18S rRNA levels in urinary cells appears to be diagnostic and prognostic of acute cellular rejection in kidney allografts. (Funded by the National Institutes of Health and others.).

OBJECTIVE: To assess the relationship between the factor V Leiden (1691 G-A) single nucleotide polymorphism (SNP), the methylene tetrahydrofolate reductase (MTHFR) 677 C-T SNP, and the prothrombin 20210 G-A SNP and the risk of preeclampsia, by conducting a meta-analysis of all case-control studies with data on these polymorphisms and the risk of preeclampsia. DATA SOURCES: MEDLINE (1966 to November 2002), EMBASE (1980 to November 2002). Search terms included "preeclampsia," "thrombophilia," "factor V Leiden," "protein C," "MTHFR," "methylenetetrahydrofolate reductase," "homocysteine," and "prothrombin gene 20210." METHODS OF STUDY SELECTION: Case-control studies of genetic thrombophilias and preeclampsia were included. TABULATION, INTEGRATION, AND RESULTS: We identified 349 titles and reviewed 47 articles for inclusion and exclusion criteria. Thirty-one studies with 7,522 patients were included in the meta-analysis. Data from patients characterized as having severe preeclampsia were extracted and analyzed separately. The pooled odds ratio (OR) for the association of factor V Leiden and all cases of preeclampsia was 1.81 (95% confidence interval [CI] 1.14-2.87) and 2.24 (95% CI 1.28-3.94) for cases of severe preeclampsia. The pooled OR for the MTHFR 677 TT genotype and all preeclampsia was 1.01 (95% CI 0.79-1.29) and 1.38 (95% CI 0.93-2.06) for severe preeclampsia. The OR for the prothrombin 20210 polymorphism and all preeclampsia was 1.37 (95% CI 0.72-2.57) and 1.98 (.94-4.17) for severe preeclampsia. CONCLUSION: This meta-analysis suggests that the factor V Leiden SNP is associated with an increased risk of preeclampsia. Further studies are warranted to determine whether subgroups of high-risk women should be screened for this mutation.