The Role Of Subclinical Infection And Cytokines In Preterm Parturition

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

I. A new taxonomy of obstetrical disease based on clinical symptoms and the results of placental pathology The current taxonomy of obstetrical disease refers to preeclampsia, preterm labor, preterm premature rupture of the membranes, small-for-gestational-age fetus, fetal death, etc. Each complication of pregnancy is named based on symptoms and signs, and does not provide etiological information. We propose that a new taxonomy of obstetrical syndromes, which incorporates information derived from placental pathology, would facilitate the discovery of biomarkers, which are tools to predict, diagnose, and monitor response to therapy. This study was conducted to examine whether subclassification of obstetrical syndromes, according to the presence or absence of placental lesions, would improve the performance of biomarkers. We reported the results of a retrospective case cohort study based on 4,006 pregnant women. The case cohort included 1,499 patients from the parent cohort. Pregnant patients were classified into a control group of patients who delivered at term without pregnancy complications (n=540) and a series of cases including patients with: 1) preterm labor with intact membranes (n=203); 2) preterm PROM (n=112); 3) preeclampsia (n=230); and 4) small for gestational age (n=334). Serial samples of maternal plasma were assayed for placental growth factor and soluble Flt-1 (7,560 samples). Placentas were examined by pathologists masked to the clinical outcome to assess the presence or absence of lesions reflecting maternal vascular malperfusion. We compared the profile of PlGF and sFlt-1, and its ratio between controls and each obstetrical syndrome with and without subclassification of cases according to the presence or absence of maternal vascular lesions of malperfusion. We found that: 1) when obstetrical syndromes are classified based on the presence or absence of placental lesions of maternal vascular malperfusion, significant differences in the mean plasma concentrations of PlGF, sFlt-1, and the PlGF/sFlt-1 ratio between cases and controls emerge earlier in gestation; 2) the strength of association between an abnormal PlGF/sFlt-1 ratio and the occurrence of obstetrical syndromes increases when placental lesions of maternal vascular malperfusion are present; and 3) the PlGF/sFlt-1 ratio at 28 to 32 weeks of gestation is abnormal in patients who subsequently delivered due to preterm labor with intact membranes and in those with preterm premature rupture of the membranes if both groups have placental lesions of maternal vascular malperfusion. Such association is not significant in patients with these obstetrical syndromes who do not have placental lesions. We propose that a new taxonomy of obstetrical disorders informed by placental pathology will facilitate the discovery and implementation of biomarkers as well as the prediction and prevention of such disorders. II. Preeclampsia at term: the identification of two clusters based on angiogenic and anti-angiogenic markers with different clinical characteristics and pregnancy outcomes Preeclampsia is a major cause of maternal and neonatal death. Most cases of preeclampsia occur at term. An anti-angiogenic state is a mechanism of disease in this syndrome and maternal plasma concentrations of angiogenic and anti-angiogenic factors such as PlGF and sFlt-1, respectively, have been used for risk assessment (now approved by the FDA). The role of the PlGF/sFLT-1 ratio is mainly in early onset disease. This study was conducted to determine the prevalence and clinical significance of abnormal angiogenic and anti-angiogenic factors in preeclampsia at term. We found that while 90% of cases of early preeclampsia had an abnormal angiogenic profile, only 50% of women with preeclampsia at term had such abnormal profile. Patients with preeclampsia at term with an abnormal PlGF/sFLT-1 ratio were more likely to be nulliparous, had a higher rate of maternal and neonatal complications, and were more likely to have placental lesions of malperfusion than those without an abnormal profile. Patients with a normal angiogenic profile have a higher frequency of chronic hypertension and obesity than those with an abnormal profile. These observations have implications for the understanding of preeclampsia at term, prediction of late onset preeclampsia, and its clinical management. III. The vaginal microbiota of pregnant women varies with gestational age, maternal age, and parity Intra-amniotic infection is a major cause of spontaneous premature labor and delivery, and is present in 25% of spontaneous preterm births. These infections are largely subclinical in nature and thought to result from microorganisms ascending from the vagina. Changes in the microbial ecosystem or microbiota are believed to predispose to ascending infection. This study was undertaken to characterize the vaginal microbiota of pregnant women who delivered at term without complications using sequence-based microbiologic techniques (16s). We performed a longitudinal study which included 474 women and 1,862 samples of vaginal fluid from a predominantly African American cohort. Each patient had 3-4 samples collected between 8-38 weeks of gestation. The general pattern was that the composition of the vaginal microbiota remains or transitions to a state of Lactobacillus dominance. We found that the vaginal microbiota changed as a function of gestational age, maternal age, and parity. Network analyses revealed dynamic associations among specific bacterial taxa within the vaginal ecosystem, which shifts through the course of pregnancy. This study provides a robust foundational understanding of the vaginal microbiota in pregnancy and lays the groundwork for further investigation of the microbiota prior to spontaneous premature labor.