National Institutes of Health

Eunice Kennedy Shriver National Institute of Child Health and Human Development

2015 Annual Report of the Division of Intramural Research

Program in Perinatal Research and Obstetrics

Director: Roberto Romero, MD

The Program in Perinatal Research and Obstetrics (PPRO) conducts clinical and laboratory research on maternal and fetal diseases responsible for excessive infant mortality in the United States. The Program focuses on the mechanisms of disease responsible for premature labor and delivery, with particular emphasis on the role of subclinical intrauterine infection and inflammation. The prenatal diagnosis of congenital anomalies is also a major area of interest.

The Perinatology Research Branch was created by Public Law (1993) to address the causes of the excessive infant mortality in the United States. The Branch, now called the Program in Perinatal Research and Obstetrics, uses a multidisciplinary approach to study complications of pregnancy, which include the disciplines of Maternal-Fetal Medicine, Neonatology, Placental Pathology, Perinatal Epidemiology, and High-Dimensional Biology (genomics, proteomics, metabolomics, and computational biology), as well as Immunology, Microbiology, and Nanomedicine. The Program is housed in Detroit, Michigan, on the campus of Wayne State University and at the Detroit Medical Center. The location is appropriate given the high perinatal and infant mortality in the city, as well as the contribution of ethnic social disparities to adverse pregnancy outcome. The PPRO provides state-of-the-art prenatal care to women enrolled in NICHD protocols and has made major contributions to the diagnosis of congenital anomalies and the understanding of mechanisms of disease in premature labor/delivery and preeclampsia.

Preterm birth is the leading cause of perinatal mortality and morbidity worldwide. The cost of prematurity in the U.S. alone is $26 billion per year. The Perinatology Research Branch proposed that preterm parturition is a syndrome caused by multiple pathologic processes (Preterm Labor: One Syndrome, Many Causes; Science, 2014). The PPRO established that a sonographic short cervix is a risk factor for preterm delivery and that the administration of vaginal progesterone can reduce the rate of preterm birth in these patients by 45%. This year, the PPRO reported the public health implications of universal cervical assessment in the midtrimester and treatment with vaginal progesterone. The approach is at least as cost-effective as, if not more than, other screening strategies during pregnancy (e.g., screening for group B streptococcus, asymptomatic bacteriuria, etc.). The PPRO calculated that the number of patients needed to be screened to prevent one preterm delivery (with cervical length and vaginal progesterone) is 125, which compares favorably with other interventions in obstetrics (magnesium sulfate to prevent eclampsia, aspirin to prevent recurrent preeclampsia, magnesium sulfate to prevent cerebral palsy, etc.).

One of the areas of emphasis has been the study of intra-amniotic infection and inflammation in spontaneous preterm birth, the only proven cause of spontaneous preterm labor. This year, the PPRO reported that a rapid point-of-care test for the cytokine interleukin-6 (IL-6) can be employed for the rapid diagnosis of intra-amniotic inflammation (within 20 minutes), which brings discoveries made by the PPRO a step closer to clinical application. Moreover, the PPRO reported that a new combination of antimicrobial agents can reduce the risk of adverse pregnancy outcome and histologic inflammation in the context of preterm premature rupture of membranes (PROM). Given that one third of all preterm deliveries are related to physician-initiated birth due to preeclampsia or intrauterine growth restriction, the PPRO also identified biomarkers for the prediction of indicated preterm delivery in mothers carrying small-for-gestational age fetuses.

The second cause of infant mortality in the U.S. is congenital anomalies. Therefore, the prenatal diagnosis of congenital anomalies is a major area of interest of the PPRO. Among anomalies, congenital heart disease is the leading organ-specific birth defect, as well as the leading cause of infant mortality from congenital malformations. The detection of these disorders in the U.S. is suboptimal, and nearly half of newborns affected by congenital heart disease are not diagnosed before birth. Screening for fetal congenital heart disease requires technological developments to improve examination of the fetal heart. The PPRO developed fetal intelligent navigation echocardiography (FINE) as a method to extract and display diagnostic planes recommended by professional societies for the screening of congenital heart disease. This year, members of the PPRO reported that the collection of STIC volumes (datasets of the heart) is possible in 75% of cases and can therefore improve the screening for congenital heart disease.

Clinical chorioamnionitis is the most frequent infection diagnosed in labor and delivery units around the world and affects 5–12% of all pregnant women. The condition is a major risk factor for maternal death, post-operative wound infections, neonatal sepsis, and meconium aspiration syndrome. Last year, the PPRO reported, for the first time, the use of cultivation and molecular microbiologic techniques to identify the most frequent organisms involved in these infections (Gardnerella vaginalis, Ureaplasma spp.). This year, the PPRO characterized the nature of the intra-amniotic inflammatory response, the maternal and fetal cytokine profile, placental pathology, and the accuracy of the diagnostic criteria for this disorder. It is now clear that the clinical criteria routinely used for diagnosis have limited accuracy (about 50%). Importantly, a subset of patients diagnosed as having clinical chorioamnionitis do not have any evidence of infection or inflammation, which results in overdiagnosis and unnecessary administration of antibiotics in the perinatal period, which can alter the microbiota and have long-term consequences (increased risk of obesity, diabetes, etc.). An important line of investigation of the PPRO is to improve the accuracy of the diagnosis of clinical chorioamnionitis to optimize the outcome of mothers and newborns.

The Human Placenta Project is a major initiative of NICHD. One of the stated goals of the Project has been to identify new experimental systems to study placental function, and specifically, the development of a "placenta-on-a-chip". The most important function of the placenta is the exchange of exogenous and endogenous substances, which permit an adequate supply of oxygen and nutrients, excretion of fetal metabolic waste, and protection against potentially harmful agents (xenobiotics, bacteria, viruses, parasites). Studies of placental transport are difficult to perform in humans, are time-consuming, and always carry the risk of fetal exposure. This year, the PPRO reported a new approach to model placental transport that combines microfluidics and microfabrication technologies with the culture of placental-derived human cells to recapitulate the organ-specific architecture and physiologic microenvironment of the placental barrier. The PPRO developed a "placenta-on-a-chip" microdevice that permits perfusion of co-cultured human trophoblast and human umbilical endothelial veins on a thin extracellular matrix membrane. Members of the PPRO also tested the physiologic function of the microengineered placental barrier by measuring glucose transport across the trophoblast endothelial interface over time. The "placenta-on-a-chip" model has the potential to serve as a low-cost experimental platform with a broad range of applications. Such a biomimetic model may also enable the quantitative analysis of placental transport of small molecules and biologics for the development and screening of new therapeutic modalities.

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