The detrimental role of angiotensin receptor agonistic autoantibodies in intrauterine growth restriction seen in preeclampsia.

Growth-restricted fetuses are at risk for a variety of lifelong medical conditions. Preeclampsia, a life-threatening hypertensive disorder of pregnancy, is associated with fetuses who suffer from intrauterine growth restriction (IUGR). Recently, emerging evidence indicates that preeclamptic women harbor AT(1) receptor agonistic autoantibodies (AT(1)-AAs) that contribute to the disease features. However, the exact role of AT(1)-AAs in IUGR and the underlying mechanisms have not been identified. We report that these autoantibodies are present in the cord blood of women with preeclampsia and retain the ability to activate AT(1) receptors. Using an autoantibody-induced animal model of preeclampsia, we show that AT(1)-AAs cross the mouse placenta, enter fetal circulation, and lead to small fetuses with organ growth retardation. AT(1)-AAs also induce apoptosis in the placentas of pregnant mice, human villous explants, and human trophoblast cells. Finally, autoantibody-induced IUGR and placental apoptosis are diminished by either losartan or an autoantibody-neutralizing peptide. Thus, these studies identify AT(1)-AA as a novel causative factor of preeclampsia-associated IUGR and offer two possible underlying mechanisms: a direct detrimental effect on fetal development by crossing the placenta and entering fetal circulation, and indirectly through AT(1)-AA-induced placental damage. Our findings highlight AT(1)-AAs as important therapeutic targets.

Neural tube defects in Mexican-Americans living on the US-Mexico border: The effects of folic acid and dietary folate

Neural tube defects (NTDs) are malformations of the developing brain and spinal cord; the most common are anencephaly and spina bifida. Evidence from many populations suggests that 50% of NTDs can be prevented through daily consumption of folic acid. A recent study has reported that folic acid may not protect populations of Mexican descent. This finding has serious implications for women living along the US-Mexico border. Not only is risk high in these Mexican American women compared with other US women; they also differ markedly in supplemental folic acid and dietary folate consumption, and in NTD-related risks (e.g., obesity, diabetes). This case-control study investigated whether folic acid supplements and dietary folate reduces NTDs in Mexican Americans. Cases included liveborn, stillborn, electively and spontaneously aborted NTD-affected fetuses and infants occurring in the 14-county Texas-Mexico border. Controls were randomly selected from unaffected live births, frequency matched to cases by hospital and year. An in-person interview of 110 case and 113 control mothers solicited data on folic acid supplements, dietary folate, and other covariates. Consumption of folic acid-containing vitamins before conception was only 5% for both case and control women. Taking vitamins the trimester before conception had no apparent effect, after adjusting for covariates [odds ratio (OR) = 1.0, 95% confidence interval (CI) = 0.3–3.4]. Combining folate from vitamins and diet showed a 20% risk reduction for women consuming at least 400 μg of folate daily [OR = 0.8, 95% CI = 0.5–1.5]; however, this estimate is statistically indistinguishable from the null. Although consistent with an inherent ineffectiveness of supplemental folic acid, that so few women consumed multivitamins during the critical time severely limited the assessment of folic acid in this population. A reduced folate response in Mexican descent women may be due to a genetic heterogeneity for metabolizing folate. Alternatively, folate intakes may be insufficient to overcome other underlying risk factors. In conclusion, determining whether folic acid reduces NTD risk in Mexican American women requires further study in populations with higher folic acid exposures. Meanwhile, we should pursue all recommended prevention strategies to reduce risk, including motivating Mexican American women of childbearing age to take folic acid routinely. ^

Birth prevalence of isolated congenital limb reduction defects in Texas 1999--2001

Objective. Congenital limb defects are common birth defects occurring in approximately 2-7/10,000 live births. Because congenital limb defects are pervasive throughout all populations, and the conditions profoundly affect quality of life, they represent a significant public health concern. Currently there is a paucity of etiologic information in the literature regarding congenital limb reduction defects which represents a major limitation in developing treatment strategies as well as identifying high risk pregnancies. ^ Additionally, despite the fact that the majority of congenital limb reduction defects are isolated, most previous studies have not separated them from those occurring as part of a known syndrome or with multiple additional congenital anomalies of unknown etiology. It stands to reason that factors responsible for multiple congenital anomalies that happen to include congenital limb reduction defects may be quite different from those factors leading to an isolated congenital limb reduction defect. ^ As a first step toward gaining etiologic understanding, this cross-sectional study was undertaken to determine the birth prevalence and obtain demographic information about non-syndromic (isolated) congenital limb reduction defects that occurred in Texas from 1999-2001. ^ Methods. The study population included all infants/fetuses with isolated congenital limb reduction defects born in Texas during 1999-2001; the comparison population was all infants who were born to mothers who were residents of Texas during the same period of time. The overall birth prevalence of limb reduction defects was determined and adjusted for ethnicity, gender, site of defect (upper limb versus lower limb), county of residence, maternal age and maternal education. ^ Results. In Texas, the overall birth prevalence of isolated CLRDs was 2.1/10,000 live births (1.5 and 0.6/10,000 live births for upper limb and lower limb, respectively). ^ The risk of isolated lower limb CLRDs in Texas was significantly lower in females when gender was examined individually (crude prevalence odds ratio of 0.57, 95% CI of 0.36-0.91) as well as in relation to all other variables used in the analysis (adjusted prevalence odds ratio of 0.58, 95% CI of 0.36-0.93). ^ Harris County (which includes the Houston metropolitan area) had significantly lower risks of all (upper limb and lower limb combined) isolated CLRDs when examined in relation to other counties in Texas, with a crude prevalence odds ratio of 0.4 (95% CI: 0.29-0.72) and an adjusted prevalence odds ratio of 0.50 (95% CI: 0.31-0.80). The risk of isolated upper limb CLRDs was significantly lower in Harris County (crude prevalence odds ratio of 0.45, CI of 0.26-0.76 and adjusted prevalence odds ratio of 0.49, CI of 0.28-0.84). This trend toward decreased risk in Harris County was not observed for isolated lower limb reduction defects (adjusted prevalence odds ratio of 0.50, 95% confidence interval: 0.22-1.12). ^ Conclusions. The birth prevalence of isolated congenital limb reduction defects in Texas is in the lower limits of the range of rates that have been reported by other authors for other states (Alabama, Arkansas, California, Georgia, Hawaii, Iowa, Maryland, Massachusetts, North Carolina, Oklahoma, Utah, Washington) and other countries (Argentina, Australia, Austria, Bolivia, Brazil, Canada, Chile, China, Colombia, Costa Rica, Croatia, Denmark, Ecuador, England, Finland, France, Germany, Hungary, Ireland, Israel, Italy, Lithuania, Mexico, Norway, Paraguay, Peru, Spain, Scotland, Sweden, Switzerland, Uruguay, and Venezuela). In Texas, the birth prevalence of isolated congenital lower limb reduction defects was greater for males than females, while the birth prevalence of isolated congenital upper limb reduction defects was not significantly different between males and females. The reduced rates of limb reduction defects in Harris County warrant further investigation. This study has provided an important first step toward gaining etiologic understanding in the study of isolated congenital limb reduction defects. ^

Obstetrical Forceps: History, Mystery, and Morality

The history of obstetrical forceps has almost always been one cloaked in controversy after a long history of being shrouded in mystery. Forceps have a long history and have evolved from facilitating the delivery of dead fetuses to aiding in the delivery and survival of live babies. In the middle of all of this arises the story of the Chamberlain family whose contribution was enormous but whose behaviors pushed at the envelope of (at least) our present-day concepts of medical ethics. This lecture traces an interesting story that spans a millennium.