Maternal-Fetal Medicine

Microarray Renewal

The objective of this study, a renewal of a previous investigation into the use of molecular cytogenetic testing by array copy number analysis (aCNA) in prenatal diagnostic testing, is to improve our understanding of the natural history, penetrance, and expressivity of copy number variants when discovered in-utero. Our work to date demonstrates that aCNA identifies all pathologic findings seen by karyotyping and provides significant incremental information in 2% of all patients tested—making it highly likely that aCNA will become an important part of prenatal diagnosis. However, important additional information is still required to assure a smooth transition to this new method. Over 650 mothers with a prenatal diagnosis of a copy number variant in their fetus will be identified and recruited, and detailed developmental evaluations will be conducted at age 3 on over 400 of those recruited during the first two years of the project. For the more common copy number variants associated with neurocognitive abnormalities, sibling controls will undergo similar evaluations to allow quantitative comparisons. The data from all participants will be included in a national registry of copy number variants, and will be available for clinical and research use.

NICHD National Standard for Normal Fetal Growth

Normal fetal growth is a critical component of a healthy pregnancy and the long-term health of the offspring. Pivotal to understanding the dynamics of human fetal growth and to defining normal and abnormal fetal growth is the development of standards for fetal anthropometric parameters measured longitudinally throughout gestation, which, in turn, can be used to develop interval velocity curves and customized for genetic and physiological factors. This study will recruit 2,400 healthy, non-obese, low- risk pregnant women from five clinical centers, as well as 600 obese women. Approximately 600 women will come from each of the following four self-identified race/ethnicity backgrounds: African American, Asian, Caucasian, and Hispanic. Women will be recruited in the first trimester and followed up through pregnancy. The aims of this study are (1) to establish a standard for normal fetal growth (velocity) and size for gestational age in the U.S. population; (2) to create an individualized standard for fetal growth potential; and (3) to improve accuracy of fetal weight estimation. The study will have important implications in clinical practice and research.

NICHD Fetal Growth – Twin Gestations

Twins represent 3.2% of all births in the U.S. These pregnancies are at increased risk for fetal growth disorders, preterm and, most importantly, very preterm delivery. This is a prospective cohort study with longitudinal measurement of fetal growth which will recruit 350 pregnant women with a twin gestation from nine clinical centers. Women will be recruited during the first trimester and followed until delivery. There are four main research objectives: 1) to describe fetal growth trajectories in twins using two- and selected three-dimensional ultrasound measures; 2) to compare and contrast fetal growth trajectories for twins with the newly established fetal growth standard developed for singletons to determine its applicability for monitoring the growth of twin fetuses and discordant growth of the pair; 3) to estimate the incidence of growth restriction (with SGA as a proxy) in singleton and twin gestations (by zygosity); however, growth restriction may be defined by the new growth standard; and 4) to compare singleton and twin gestations with respect to maternal biomarkers of fetal growth, well-being and maternal nutritional status using two banked biospecimens to determine if the biomarkers ranges established for singletons are applicable to twin gestations.

Maternal-Fetal Medicine Units Network

The National Institute of Child Health and Human Development (NICHD) created the Maternal Fetal Medicine Units (MFMU) Network in 1986 to focus on clinical questions in maternal fetal medicine and obstetrics, particularly with respect to the continuing problem of preterm birth. Operating under cooperative agreements, the current Network is comprised of fourteen university-based clinical centers and a data coordinating center. More than 36 randomized clinical trials, cohort studies and registries have been completed or are in progress. The following protocols are active at our Center at the current time:

  • STAN: “A Randomized Trial of Fetal ECG ST Segment and T Wave Analysis as an Adjunct to Electronic Fetal Heart Rate Monitoring” Fetal ECG analysis of the ST segment (STAN) is now FDA-approved and clinically available in the United States as an adjunct for the interpretation of electronic fetal heart rate patterns. There have been a number of randomized controlled trials, as well as observational studies in Europe, documenting the utility of STAN in terms of reducing fetal acidosis at birth, and decreasing the need for operative vaginal delivery. However, despite these endorsements, there remain concerns with the application of the technology to the United States. None of the randomized trials were performed in the U.S., where patient case-mix and obstetrical practice, such as the use of fetal scalp pH, differ from Europe, which may affect the impact of this technology on perinatal outcomes. Moreover, the results of the European studies are not uniformly positive. There is a critical window of opportunity to evaluate the technology. This study is a randomized controlled trial of the STAN technology as an adjunct to electronic fetal heart rate monitoring versus fetal heart rate monitoring alone, which, if it yields positive results, will encourage clinicians to introduce the methodology into practice. From the viewpoint of obstetricians, fetal STAN offers the promise of providing a practical and relatively objective method for evaluating intrapartum fetal status.
  • ALPS: “Antenatal Late Preterm: Randomized Placebo-Controlled Trial” The rate of preterm birth has steadily increased in the United States over the past 10 years. This increase is driven in part by the rising rate of late preterm birth, defined as those births occurring between 34 and 36 weeks, which has increased at a faster rate than overall preterm birth. Late preterm infants experience a higher rate of readmission than their term counterparts, and these infants are more likely to suffer complications such as respiratory distress, kernicterus, feeding difficulties, and hypoglycemia. Late preterm infants also have a higher mortality for all causes when compared to term infants. The use of antenatal corticosteroids has been shown to be beneficial in women at risk for preterm delivery prior to 34 weeks, but has not been evaluated in those likely to deliver in the late preterm period. This study is a randomized placebo-controlled trial to evaluate whether antenatal corticosteroids can decrease the rate of neonatal respiratory support, thus decreasing the rate of NICU admissions and improving short-term outcomes in the late preterm infant.
  • GDM Follow-Up: “Mild GDM Management and Long Term Maternal and Child Health: Follow-Up of the Mild GDM Trial” In a recently completed trial, A Randomized Clinical Trial of Treatment for Mild Gestational Diabetes Mellitus, conducted between 2002-2007 by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network, treatment of pregnant women with mild gestational diabetes mellitus (GDM) was found to significantly decrease their infants’ birth weight and fat mass, as well as frequency of macrosomia and large for gestational age. However, whether there is a long-term health benefit in metabolic status to the children of treated women is unknown, and it is also not known whether lesser degrees of maternal glucose intolerance than conventional GDM are related to an increased risk of obesity in children. This follow-up study is proposed of the women and their children who participated in the MFMU mild GDM randomized trial. It provides the opportunity to examine factors associated with the development of obesity, and differences in metabolic parameters in a large group of ethnically diverse children whose mothers participated in the trial. This seminal investigation will yield scientific information that will examine the importance of the intrauterine environment, its role in the intergenerational transmission of obesity and differences in metabolic parameters, and the impact of prenatal interventions in reducing these risks.
  • CMV: “A Randomized Trial to Prevent Congenital Cytomegalovirus Infection (CMV)” Cytomegalovirus (CMV) is the most common congenital infection, affecting approximately 1% of babies in the U.S., or 44,000 congenitally infected infants per year—a substantial proportion of which will die or suffer permanent injury as a result of their infection. The severity of congenital infection is greatest with primary maternal CMV infection. Currently, there is no proven method of preventing congenital CMV infection and the approach to primary maternal CMV infection in the U.S. is haphazard and ineffective. One small, non-randomized study suggests that maternal administration of CMV hyperimmune globulin may reduce the rate of congenital CMV infection following maternal primary infection. This randomized clinical trial will address the primary research question: does maternal administration of CMV hyperimmune globulin lower the rate of congenital CMV infection among the offspring of women who have been diagnosed with primary CMV infection during early pregnancy?
  • Thyroxine Therapy: “A Randomized Trial of Thyroxine Therapy for Subclinical Hypothyroidism or Hypothyroxinemia Diagnosed During Pregnancy” The value of maternal thyroxine therapy given to improve neurodevelopment of the fetus in women with variously defined hypothyroidism is a controversial topic. Conflicting reports published in the last decade have led to conflicting and confusing recommendations as to whether or not all pregnant women in the U. S. should be screened for subclinical hypothyroidism or hypothyroxinemia. As a result, American medical organizations and conferences have called for randomized trials to examine the risks and benefits of diagnosing and treating these conditions in pregnant women. This study is a randomized placebo-controlled trial of thyroxine therapy in pregnant women with 1) subclinical hypothyroidism defined as elevated thyroid stimulating hormone (TSH) and normal free-Thyroxine (free-T4), or 2) hypothyroxinemia defined as a normal TSH and a low free-T4 (free-T4), from eight weeks of gestation to delivery. The objective is to determine whether therapy is effective in improving intellectual ability at five years of age in subjects’ offspring.
nuMoM2b

The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) established the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b) to study women for whom the current pregnancy will lead to their first delivery (nulliparas). Nulliparas comprise about 40% of pregnant women in the United States. Because no information is available from previous pregnancy outcomes to guide assignment of risk or mitigating interventions, adverse outcomes in nulliparas are especially unpredictable. The underlying mechanisms of adverse pregnancy outcomes such as preterm birth, preeclampsia, and fetal growth restriction are interrelated, and therefore will be evaluated as part of this study. The goals of this study are to 1) determine maternal characteristics, including genetics, epigenetics, and physiological response to pregnancy as well as environmental factors that influence and /or predict adverse pregnancy outcome; 2) identify specific aspects of placental development and function that lead to adverse pregnancy outcome; and 3) characterize genetic, growth, and developmental parameters of the fetus that are associated with adverse pregnancy outcome. The information gained will benefit women who are pregnant or who are considering pregnancy, and their health care providers. In addition, the knowledge will support future research aimed at improving outcomes for this critical group of at-risk, currently understudied women. The nuMoM2b project is a prospective cohort study of a racially/ethnically/geographically diverse population of 10,000 nulliparous women with singleton gestations. Ancillary Studies to nuMoM2b:

  • Fetal Adrenal Gland: Preterm birth remains the paramount clinical challenge in obstetrics, as it affects 12.7% of U.S. pregnancies and is the primary contributor to perinatal mortality. Recently two investigations have suggested that sonographic measurement of the fetal adrenal gland in the early third trimester may accurately predict spontaneous preterm birth. To fully evaluate the validity of measurement of the fetal adrenal gland to predict preterm birth, this study will measure the fetal adrenal gland in 2,000 nulliparous women. The primary objectives are to establish the predictive accuracy of sonographic measurement of the fetal adrenal gland size with regard to spontaneous preterm birth, and to evaluate the association of the fetal adrenal gland measurements with other biomarkers, to further define the phenotype of premature birth due to activation of the Maternal-Fetal Hypothalamic-Pituitary Adrenal (HPA) axis.
  • Sleep Breathing: The association between cardiovascular (CV) risk and untreated adult sleep disordered breathing (SDB) is well established, with a 2-3 fold increased risk of incident hypertension, coronary artery disease, diabetes, arrhythmia, stroke, and all-cause mortality. Accumulating data indicate that SDB symptoms are reported by nearly 30% of women during pregnancy, and that self-reported SDB symptoms are associated with an increased frequency of gestational high blood pressure, preeclampsia, gestational diabetes, and other adverse pregnancy outcomes. In addition, the pathophysiological profile of SDB resembles that of maternal cardiovascular and metabolic disease indicators, including elevated sympathetic tone, oxidative stress, systemic inflammation, insulin resistance, and hyperlipidemia. Together, these findings indicate that SDB may be a potentially unrecognized health risk in women during pregnancy. This study is designed to determine the prevalence of SDB in pregnancy, and the relationship between SDB phenotype with maternal cardiovascular and metabolic disease; and specifically, to evaluate the relationship between SDB and the development of preeclampsia.
  • Sleep Quality: Women are a population at increased risk for poor sleep quality (insufficient sleep and fragmented sleep), and emerging studies demonstrate that pregnant women are at increased risk for sleep disturbances. Yet systematic, population-based prospective studies to determine the type and prevalence of sleep problems during pregnancy are lacking. Furthermore, few studies have addressed the potentially important link between sleep and maternal/fetal outcomes, particularly metabolic and cardiovascular complications of pregnancy. Specifically, data are limited on how short sleep duration may contribute to the development of gestational diabetes, gestational hypertension, and preeclampsia. This study aims to comprehensively assess sleep patterns in a large cohort of pregnant women to determine the relationships between abnormal sleep patterns and cardiovascular and metabolic disorders of pregnancy, specifically gestational hypertension, preeclampsia, gestational diabetes.
  • Loss of Imprinting: Approximately two thirds of preterm births arise from spontaneous rupture of the membranes, while the remaining third are associated with preeclampsia (PE) or intrauterine growth restriction (IUGR). Several studies have shown an association of PE and IUGR with aberrant imprinted gene expression, and it has been proposed that defects in genomic imprinting may be involved in the pathogenesis of these disorders at the molecular level. Contrary to the prevailing theory that genomic imprinting patterns are permanently fixed throughout one’s lifespan, we hypothesize that loss of imprinting (LOI) patterns in the human placenta are subject to developmental and environmental influences over the course of pregnancy, which predispose to adverse pregnancy outcome. The goals of this study are to 1) monitor LOI in placenta samples from first trimester chorionic villus sampling (CVS) to birth and 2) determine which LOI patterns in the first trimester lead to normal pregnancy outcomes, and which patterns are predictive of pregnancy complications. The overall objective is to determine whether an LOI profile can be used as an indicator of normal placenta development over the course of pregnancy, and whether it could be used as the basis to develop a panel of epigenetic biomarkers to predict which pregnancies might develop complications.
  • Leukocyte Telomere Length: Studies of inter-individual differences in LTL have focused largely on middle age and elderly persons, and have provided compelling evidence that shortened LTL is related to CVD, principally atherosclerosis, and reduced longevity. Yet empirical observations and simulations suggest that LTL at birth is a major determinant of LTL throughout the human lifespan, such that individuals endowed with short (or long) LTL at birth are likely to have short (or long) LTL later in life. Therefore, we posit that determinants of LTL at birth impact the evolution of health and disease throughout the life course. In this study, by identifying these determinants, we will provide a foundation for linking experience from conception to birth with health and longevity in later life. Accordingly, the present study has the potential to transform our understanding of population health by opening novel investigations of the pathways through which intra-uterine experiences are biologically embedded in an individual’s constitution, and might be reflected in risk factors for disease which emerge in childhood and evolve thereafter. The study will also provide impetus for a nascent transformation in public health practice toward population prevention over the life course, providing empirical data to help assess the potential benefits of initiating prevention of adult disease as early as pregnancy.
PreNATUS

The current standard first-trimester screening programs involve minimally invasive methods, such as measuring blood hormone levels and certain physical dimensions by ultrasound. Women with a high screening risk for trisomy then have invasive testing, which carries a risk of miscarriage, to definitively determine if the fetus has trisomy. Because of the high false-negative rate of the first trimester screening, an unacceptable number of trisomic fetuses are not detected. Moreover, because of the high false positive-rate, an unacceptable number of women undergo invasive follow-up testing. Natera (also known as Gene Security Network) has developed a novel technology called Parental SupportTM, which is used for genetic diagnosis based on very small amounts of genetic material (DNA). This technology may allow doctors to identify, in a minimally invasive manner, pregnant women who have a high risk of carrying a fetus with an aneuploidy. This is a prospective observational study to assess the diagnostic capability of Parental SupportTM.

NEXT

For years, it has been hoped that the use of fetal cells in maternal blood might be used to assessthe genetic status of a developing fetus. Fetal cells, however, are rarely found in maternal blood,and their rarity limits the clinical utility of such an approach. Circulating fetal cell-free deoxyribonucleic acid (cfDNA) is present in maternal blood at significantly higher amounts than fetal cells, and therefore has the potential to be utilized for detection of fetal chromosomal abnormalities. Various targeted approaches to analysis of cfDNA from maternal blood have shown promise for fetal aneuploidy detection. This study supports the development of an assay from Aria Diagnostics for fetal aneuploidy detection (Aria Test). The Aria Test is a proprietary prenatal blood test for detection of fetal chromosomal abnormalities that is simpler and more cost-effective than massively parallel shotgun sequencing (MPSS) approaches, while maintaining the same level of performance. The Aria Test selectively analyzes cfDNA fragments from specific chromosomes of interest. This test has the potential for broad clinical use, and could reduce or eliminate the need for unnecessary invasive testing via CVS or amniocentesis if it is confirmed to result in lower false-positive test results.