Feb. 2, 2000 Despite advances in prenatal care, about one in twenty babies in the United States are severely underweight at birth -- below the 10th percentile -- resulting in significantly higher rates of infant mortality and childhood disease in that group. Reductions in mental capacities and a vulnerability to heart disease and other difficulties in adult life have been linked to the low-birth weight condition, known as intrauterine growth retardation, or IUGR. While some risk factors have been identified -- most prominently, cigarette smoking, diabetes, and nutritional deprivation of the placenta due to high blood pressure -- the direct cause or causes of IUGR are not known. Prevention and treatment have lagged accordingly.
Now, researchers at the University of Pennsylvania Medical Center report development of a strain of mice in whom pregnancy leads to a condition that closely models IUGR, opening the way for scientists to better understand IUGR and develop interventions to effectively treat it. Indeed, working with the mice, the scientists found they were able to completely rescue underweight fetuses through administration of a drug called indomethacin during what would correspond roughly to the middle trimester of pregnancy. Indomethacin inhibits the action of cyclooxygenase, or COX, a kind of master enzyme involved in such vital processes as inflammation and blood clotting. Well-known members of the COX-inhibitor family of drugs include aspirin and ibuprofen. A report on the new study appears in the February issue of Nature Medicine.
"Intrauterine growth retardation is a relatively common and quite serious complication in pregnancy for which we have very few insights into mechanisms, although we know some of the risk factors," says Garret A. FitzGerald, MD, chairman of pharmacology and senior author on the report. "We now have a mouse that models the condition, including important aspects of what we believe to be the underlying biochemistry of the disorder, and we have identified a promising therapeutic approach based on that biochemistry."
At the outset, FitzGerald and his colleagues knew that cigarette smoking and diabetes are among the leading risk factors for IUGR. They knew that both of these conditions are characterized in part by overproduction of thromboxane, a hormone-like substance formed by COX that causes blood vessels to constrict. Pregnancy, too, is known to trigger increased production of thromboxane. They theorized that chronically reduced blood flow to the placenta, mediated by excessive levels of thromboxane, might be a key to IUGR.
A way to test the theory would be to develop a mouse in which the action of thromboxane was increased, see if IUGR or a similar condition emerged during pregnancy, and then administer a COX inhibitor like indomethacin with the aim of rescuing the affected fetuses.
By genetically engineering a strain of mice to overexpress the receptor for thromboxane, the researchers were able to exaggerate the responsiveness of the blood vessels to thromboxane. When these mice became pregnant, their fetuses did, in fact, develop a condition very similar to IUGR. And, when given indomethacin during the middle period of the pregnancy, the fetuses returned to patterns of normal growth and reached appropriate, healthy weights.
FitzGerald notes that other products of COX play critical roles in both the early and late periods of a pregnancy, so that administering indomethacin or any COX inhibitor during these times could be dangerous to fetal health. In early pregnancy, COX products help the fetus or fetuses to implant properly in the uterine wall. In late pregnancy, they mediate separation of the fetal and maternal blood supplies to set the stage for birth. Any future therapeutic strategy involving COX inhibitors to treat IUGR, therefore, would need to account for the necessary role of COX products in a normal pregnancy.
The lead author on the Nature Medicine report is Bianca Rocca, MD. Coauthors with Rocca and senior author FitzGerald are Alex L. Loeb, MD; Jerome R. Strauss III, MD, PhD, professor of obstetrics and gynecology; Roberta Vezza, PhD; Aida Habib, PhD; and Hongwei Li, PhD.
Funding for the study was provided by the National Institutes of Health and the American Heart Association. FitzGerald is also the Robinette Foundation Professor of Cardiovascular Medicine.
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