Maternal Research
This portfolio includes basic, translational, and clinical research studies that address a myriad of issues in pregnancy to understand normal and abnormal physiological events and the effects of maternal, acute, or chronic diseases on pregnancy and fetal development.
Birth Weight and Cardiovascular Disease
Gestational Diabetes Mellitus (GDM)
Preeclampsia
Other Maternal Research Topics
Birth Weight and Cardiovascular Disease
It is well recognized that the causes of adult diseases involve a combination of a "lifestyle" (environmental) component and a genetic component. Accumulating research over the last decade has provided evidence of a third component: in utero environment. Barker and colleagues reported on the role of the in utero environment by demonstrating an inverse relationship between birth weight and death from cardiovascular disease in adulthood. Subsequently, a number of epidemiological studies have suggested that maternal malnutrition impacts the fetus and results in the onset of other major adult diseases, such as diabetes, obesity, hypertension, and cardiovascular disease, a theory known as the "fetal origins of adult disease" or the Barker hypothesis. Although this hypothesis remains controversial, accumulating research has provided increasingly strong support for this theory. This research indicates that factors in the perinatal environment, probably related to maternal nutrition, can program the fetus for increased disease risk in later life.
The precise physiologic and molecular mechanisms by which this programming occurs are unknown. One PPB-supported researcher has demonstrated that moderate protein restriction to pregnant rats results in pups born with reduced weight and decreased renal development that persist into adulthood. The resulting decrease in renal function and increased arterial pressure leads to hypertension and an increased risk of cardiovascular disease. This investigator also demonstrated the mechanism by which this occurs: suppression of the intrarenal renin-angiotensin system (RAS) during fetal life. This hormonal system is known to be important in regulating blood pressure and volume in adults. Based on these findings, it is likely that the RAS plays other critical roles during fetal development, such as setting the total nephron endowment of the kidney and programming the set point for adult blood pressure. These findings support a possible mechanism by which the fetal environment could "program" an individual for hypertension, and for increased cardiovascular risk in adulthood (Pediatr Res 2001; 49:1-8).
Gestational Diabetes Mellitus (GDM)
The adverse maternal and fetal effects of GDM have long been an important research area for the PPB. The maternal hormonal and metabolic alterations associated with GDM profoundly modify the in utero environment, which can lead to an abnormal pattern of fetal growth. Impaired fetal development has severe metabolic consequences, including increased risk of developing glucose intolerance and obesity in adolescence and adulthood. The molecular basis for the imbalance that leads to fetal, neonatal, and adult metabolic compromises has not been well understood. An NICHD grantee's study has provided the first explanation of the molecular basis of this imbalance. This work linked GDM to changes in expression of specific placental genes, including interleukin 1 (IL-1), leptin, and tumor necrosis-alpha (TNF-α). These changes result in adverse fetal programming, which leads to an increased risk of glucose intolerance and obesity in adolescence and adulthood (Diabetes 2003; 52:2951-58).
Preeclampsia
Preeclampsia is a major and potentially serious disorder of pregnancy. This hypertensive disease affects approximately 7 percent of first pregnancies and 3 percent of all pregnancies. Preeclampsia contributes significantly to premature deliveries in the United States and, in its severest form, eclampsia, is a leading cause of maternal morbidity and mortality.
Although its exact mechanism is unknown, preeclampsia is widely believed to result from poor vascular development between the placenta and the uterus. In a normal pregnancy, trophoblastic cells, the main cell type of the placenta, invade deep within the uterus and remodel the small uterine arteries into large diameter vessels. In preeclampsia, the trophoblastic cells fail to invade the uterus adequately, which prevents the normal remodeling process of the uterine vessels. In turn, the poorly perfused placenta releases factors into the maternal circulation that result in the systemic symptoms of the disease.
In pursuit of one of these placental factors, one PPB-supported grantee compared plasma from women with severe preeclampsia to plasma of normal women, specifically looking at interleukin-6 (IL-6). This research demonstrated that severe preeclampsia results in the production of endothelial cell IL-6. The administration of vitamin E inhibits the production of IL-6. These findings provide a potential cellular mechanism for preeclampsia and suggest beneficial effects of antioxidant therapy for the condition (Am J Obstet Gynecol 2003; 188:740-4).
Other pathophysiologic mechanisms involved in preeclampsia and potential targets for prevention and therapy are under active pursuit by PPB-funded investigators. Earlier work indicated that a majority of preeclamptic women experience an abnormal immune response, called autoimmunity, in which they produce antibodies against one of their own proteins; these antibodies are called autoantibodies. Autoantibodies target a receptor, designated AT-1, which is involved in mediating the effects of angiotensin II, a potent protein hormone involved in the contraction of blood vessels. In contrast to most antibodies that neutralize their target, autoantibodies actually activate the AT-1 receptor. Researchers speculate that these autoantibodies are responsible for the hypertension associated with preeclampsia because of their ability to contract blood vessels.
Because trophoblastic cells also express AT-1 receptors, efforts are under way to understand how these cells are affected by the presence of autoantibodies. One PPB-funded investigator has shown that the autoantibodies can inhibit the invasiveness of trophoblastic cells through increased production of PAI-1, a regulatory protein that inhibits the conversion of plasminogen to plasmin, a key enzyme important in cellular invasion and involved in blood clot degradation. These results are consistent with those of other investigators that show elevated blood levels of PAI-1 and increased clot formation in preeclamptic women. Autoantibodies to the AT-1 receptor appear to be linked to many of the symptoms associated with preeclampsia, suggesting that they may be the cause of the disease. If causality can be substantiated, it may be possible to develop effective therapeutic interventions for preeclampsia (J Soc Gynecol Investig 2003; 10:82-83).
Other Maternal Research Topics
Regular physical activity during pregnancy and its potential to reduce the redistribution of blood flow away from the viscera is another area of study for PPB-funded investigators. One research group compared the infants of women who were randomly assigned to a high volume of physical activity (defined as moderate-intensity, weight-bearing exercise in mid- and late pregnancy) with infants of women who were randomly assigned to reduce their exercise volume after the 20th week. They found that infants in the first group were significantly lighter and thinner than their counterparts (3.39 kg versus 3.81 kg, and 8.3 percent fat versus 12.1 percent fat, respectively). These data suggest that a high volume of moderate-intensity, weight-bearing exercise during mid- and late pregnancy symmetrically reduces fetoplacental growth, whereas reduction in exercise enhances fetoplacental growth with a proportionally greater increase in fat mass than in lean body mass (Am J Obstet Gynecol 2002; 186:142-7). This group of investigators also demonstrated that portal vein flow rises significantly during pregnancy, and that exercise training reduces the normal flow redistribution away from the splanchnic and uterine circulations in response to severe hemodynamic stress in mid- and late pregnancy. Regular exercise during pregnancy confers maternal and fetal protective effects by allowing maintenance of adequate uterine blood flow during times of severe hemodynamic stress (Am J Obstet Gynecol 2000; 183:167-72).
During pregnancy, a decrease in the motility of the gastrointestinal tract (GIT) can result in significant discomfort because of esophageal reflux, bloating, and constipation. Release of nitric oxide (NO) by neuronal NO synthase (nNOS) found in nonadrenerergic, noncholinergic (NANC) neurons in the GIT has been shown to be responsible for reducing GIT mobility. Little is known, however, about the factors responsible for regulating NO release by NANC neurons during pregnancy. A PPB-supported researcher investigated the role of the prominent sex steroids, estradiol and progesterone, produced during pregnancy, as likely candidates involved in this regulation. Using a rat model, the researcher demonstrated that estradiol, but not progesterone, was involved in decreasing GIT mobility. Estradiol enhanced NO levels via an increase in nNOS that was mediated by an increase of nNOS mRNA. This finding has broader implications in that it suggests that sex steroids may be involved in the regulation of the NO component of NANC nerves in other systems, including the central nervous system, urogenital system, and other organs innervated by the NANC (Am J Physiol Regul Integr Comp Physiol 2001; 280:R1546-54).
Medication use during pregnancy is another understudied research area. A team of researchers jointly funded by the NICHD, NIMH, and the National Center for Research Resources is studying birth outcomes after maternal use of antidepressant medication during pregnancy. They found that prenatal use of selective serotonin reuptake inhibitor medications was not associated with an increase in neonatal complications or in congenital anomalies above that for the general population. However, maternal use of high doses of fluoxetine throughout pregnancy was associated with an increase rate of low birth weight (LBW) infants (Am J Obstet Gynecol 2003; 188:812-5).
Recurrent miscarriage affects one out of 100 couples who attempt to have children. Numerous reasons for this malady have been identified, including anatomic, immunologic, infectious, endocrine, and genetic causes; however, approximately half of all recurrent miscarriages are unexplained. A team of researchers supported by the PPB has identified a novel genetic cause that accounts for 25 percent of previously unexplained cases of recurrent miscarriages (Am J Obstet Gynecol 2001; 185:563-68). This research showed that the genetic flaw resides in one of the mother's two X chromosomes, only affects male fetuses, and results in miscarriage. Because male fetuses receive only one copy of the mothers' X chromosome, the chances of receiving the abnormal chromosome are 50 percent. Female fetuses, who receive an additional normal X chromosome from their fathers, preferentially use the paternal chromosome over the flawed maternal X chromosome (normal female fetuses randomly use one or the other of the parental X chromosomes). However, females with one flawed X chromosome are at high risk for future recurrent miscarriages, with a probability of 25 percent of all their conceptions resulting in miscarriage. The identification of this genetic defect may allow researchers to develop a blood test to assess the risk of miscarriage due to this defect in future pregnancies, as well as to provide an explanation and hope to the women who are carriers of this malady.
first | previous | next | last
