Michael F. Greene

Live attenuated, multiply deleted simian immunodeficiency virus causes AIDS in infant and adult macaques.

A substantial risk in using live attenuated, multiply deleted viruses as vaccines against AIDS is their potential to induce AIDS. A mutant of the simian immunodeficiency virus (SIV) with large deletions in nef and vpr and in the negative regulatory element induced AIDS in six of eight infant macaques vaccinated orally or intravenously. Early signs of immune dysfunction were seen in the remaining two offspring. Prolonged follow–up of sixteen vaccinated adult macaques also showed resurgence of chronic viremia in four animals: two of these developed early signs of disease and one died of AIDS. We conclude that this multiply deleted SIV is pathogenic and that human AIDS vaccines built on similar prototypes may cause AIDS.

Delay in the Fetal Globin Switch in Infants of Diabetic Mothers

In the normal fetus, a switch from production of hemoglobin F (alpha 2 gamma 2) to hemoglobin A (alpha 2 beta 2) occurs at 28 to 34 weeks of gestation. In the fetus with beta-hemoglobinopathy or beta-thalassemia, this switch proceeds despite the morbidity that results when production of beta-globin is abnormal or reduced. Since insulin has recently been shown to induce renewed expression of some inactive genes, we studied globin biosynthesis during the natural evolution of the fetal globin switch under conditions of hyperinsulinemia, which occurs in infants of diabetic mothers. Such infants develop in a hyperglycemic environment, which produces reactive hyperinsulinemia. The normal increase in beta-globin production from pre-switch levels did not occur in 9 of 10 such infants at term, as compared with 11 normal infants, in whom the switch occurred by 36 to 39 weeks of gestation (P less than 0.0001). The delay in the switch from gamma-globin to beta-globin in this unique clinical setting may allow identification of physiologic factors that can modulate developmental gene suppression.

Glucose intolerance as a predictor of hypertension in pregnancy.

Insulin resistance is associated with and may be causal in essential hypertension, but the relation between insulin resistance and hypertension arising de novo in pregnancy is unclear. Transient hypertension of pregnancy (new-onset nonproteinuric hypertension of late pregnancy) is associated with a high risk of later essential hypertension and thus may have similar pathophysiology. To assess the association between glucose intolerance and subsequent development of proteinuric and nonproteinuric hypertension in pregnancy in women without underlying essential hypertension or overt glucose intolerance, we performed a retrospective case-control study comparing glucose levels on routine screening for gestational diabetes mellitus among women subsequently developing hypertension. Women who developed hypertension in pregnancy (n = 97) had significantly higher glucose levels on 50-g oral glucose loading test (P < .01) and a significantly higher frequency of abnormal glucose loading tests (> or = 7.8 mmol/L) (P < .01) than women who remained normotensive (n = 77). Relative glucose intolerance was particularly common in women who developed nonproteinuric hypertension. Women who developed hypertension also had greater prepregnancy body mass index (P < or = .0001) and baseline systolic and diastolic blood pressures (P < or = .0001 for both), although all subjects were normotensive at baseline by study design. However, after adjustment for these and other potential confounders, an abnormal glucose loading test remained a significant predictor of development of hypertension (P < .05) and, specifically, nonproteinuric hypertension in pregnancy (P < .01). Among a subgroup of women in whom insulin levels were also measured (n = 80), there was a nonsignificant trend toward higher insulin levels in women developing hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Collection and preservation of cord blood for personal use.

Unrelated-donor umbilical cord blood (CB) is a useful alternative hematopoietic stem cell source for patients without suitably matched and readily available related or unrelated stem cell donors. Expectant parents today may have the option of either donating the CB to a public CB bank or keeping and storing the CB in a private bank for potential use in the future. The alternatives are often referred to as public banking and private banking. On behalf of the American Society of Blood and Marrow Transplantation (ASBMT), we have reviewed the currently available data and opinions and offer the following recommendations: The committee acknowledges the expanding potential of indications for CB in the future, and suggests review of these recommendations at regular intervals.

Anesthesia and Developing Brains — Implications of the FDA Warning

The FDA has issued a warning regarding use of general anesthetic and sedation drugs in children under 3 years of age and in pregnant women in their third trimester — a warning that will change practice and raise questions that currently have no clear answers.

A New Era in Noninvasive Prenatal Testing

Cell-free fetal DNA testing permits earlier detection of common trisomies and generally provides earlier information about a fetuss sex. But with its clinical utility in the general population uncertain, such testing is drifting into routine practice ahead of the evidence.

Massive chronic intervillositis associated with recurrent abortions

Massive chronic intervillositis (MCI) is an unusual placental lesion associated with poor fetal growth and adverse pregnancy outcome; it has not previously been associated with spontaneous abortion or recurrent pregnancy loss. This article reports a patient who had 10 spontaneous abortions with repetitious massive chronic intervillositis documented in four of five gestations spanning all three trimesters. Characteristic placental histology induced massive infiltration of the maternal intervillous space by chronic inflammatory cells and fibrin, without associated chronic villitis; the cellular infiltrate was composed predominantly of LCA and CD68 immunoreactive cells with scattered CD45RO positivity, consistent with a monocyte/macrophage population with occasional T lymphocytes. Elevated maternal serum alpha-fetoprotein was documented in two pregnancies. These findings support the concept that this unusual placental lesion may have an immunologic basis, and suggest that MCI may be a histopathologically recognizable cause of recurrent spontaneous abortion.

Prematurity among insulin-requiring diabetic gravid women.

From Jan. 1, 1983, through Dec. 31, 1987, 420 gravidas with insulin-requiring diabetes antedating pregnancy delivered on the Joslin Clinic service. Among them, 110 pregnancies (26.2% of the total) delivered before 37 completed weeks of gestation compared with a 9.7% incidence (906/9368) for the general population at the Brigham and Womens Hospital during calendar year 1985. Thirty-three percent of all premature deliveries were the result of the development of preeclampsia. The relative risk of prematurity for diabetic patients with any hypertensive complication was 2.0 (95% confidence interval, 1.40 to 2.87) compared with normotensive diabetic subjects. Compared with the general population, most of the excess risk of prematurity was confined to hypertensive diabetics and normotensive patients of more advanced White class. A history of having had a previous premature delivery, increasing duration of diabetes antedating pregnancy, and carrying a male fetus in the index pregnancy were significantly associated with premature delivery. Future efforts to reduce the incidence of prematurity among diabetic gravidas should be directed toward reducing the incidence of preeclampsia.

The Ribavirin Pregnancy Registry: Findings after 5 years of enrollment, 2003–2009†‡

INTRODUCTION Ribavirin, with interferons or pegylated interferons, is used to treat chronic hepatitis C. Ribavirin is contraindicated in pregnancy (FDA Pregnancy Category X) and in men whose partners may become pregnant. In 2003, the Ribavirin Pregnancy Registry was established to monitor pregnancy exposures to ribavirin and to evaluate the potential human teratogenicity of prenatal exposure. METHODS This voluntary registry enrolls pregnant women who have been exposed to ribavirin during pregnancy or during the six months prior to conception either directly, by taking ribavirin, or indirectly through sexual contact with a man taking ribavirin. Women are followed until delivery; live born infants are followed for one year. The Registry aims to enroll 131 live births following direct (maternal) exposure to ribavirin and 131 live births following indirect (male) exposures. RESULTS After more than five years of operation, the Registry has enrolled 49 live births with direct exposure and 69 live births following indirect exposure. Six outcomes with birth defects have been reported. All were among live born infants: torticollis (2), hypospadias (1), polydactyly and a neonatal tooth (1), glucose-6-phosphate dehydrogenase deficiency (1), ventricular septal defect and cyst of 4th ventricle of the brain (1). Three received direct exposures ([6.1% (95% CI: 1.2, 16.9)], three were exposed indirectly [4.3% (95% CI: 0.9, 12.2)]. CONCLUSIONS Although current enrollment is far short of the required sample size, preliminary findings have not detected a signal indicating human teratogenicity for ribavirin. However, findings must be interpreted with caution concerning direct or indirect prenatal ribavirin exposures.

The Long-Term Effects of In Utero Exposures — The DES Story

In 1971, Herbst et al. reported an association between in utero exposure to diethylstilbestrol (DES) and development of clear-cell adenocarcinoma of the vagina — changing medical thinking about embryologic development of the genital tract and mechanisms of carcinogenesis.