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.

Pathogenicity of live, attenuated SIV after mucosal infection of neonatal macaques.

Adult macaques do not develop disease after infection with a nef deletion mutant of the simian immunodeficiency virus (SIV) and are protected against challenge with pathogenic virus. This finding led to the proposal to use nef-deleted viruses as live, attenuated vaccines to prevent human acquired immunodeficiency syndrome (AIDS). In contrast, neonatal macaques developed persistently high levels of viremia after oral exposure to and SIV nef, vpr, and negative regulatory element (NRE) deletion mutant. Severe hemolytic anemia, thrombocytopenia, and CD4+ T cell depletion were observed, indicating that neither nef nor vpr determine pathogenicity in neonates. Because such constructs have retained their pathogenic potential, they should not be used as candidate live, attenuated virus vaccines against human AIDS.

Maternal metabolic control and risk of microcephaly among infants of diabetic mothers.

OBJECTIVE: To measure the incidence of microcephaly among infants of diabetic mothers (IDM) and assess its relationship to metabolic control during pregnancy. RESEARCH DESIGN AND METHODS: Head circumference data for 556 consecutive live-born singleton infants of women with insulin-requiring diabetes antedating pregnancy delivered between 28 and 40 weeks of gestation and the results of 3,242 HbA1 determinations collected during their pregnancies were examined. RESULTS: There were fewer head circumferences at or below the 3rd percentile and more at or above the 97th percentile than expected. Head circumference was not related to maternal metabolic control as documented by the HbA1 values. CONCLUSIONS: The less-than-expected incidence of microcephaly observed in this patient population probably reflects the well-known tendency of IDM toward macrosomia.

Low risk of post-cesarean section infection in insulin-requiring diabetic women.

OBJECTIVE: The purpose of this study was to determine if insulin-requiring diabetic women undergoing nonelective cesarean section are at higher risk for postoperative infection than nondiabetic women. RESEARCH DESIGN AND METHODS: Medical records of a cohort of insulin-requiring diabetic women who underwent cesarean section after labor or rupture of membranes and nondiabetic control subjects matched for age and insurance status were retrospectively reviewed. Data abstracted included maternal characteristics, antepartum, intrapartum, and postpartum events. RESULTS: Post-cesarean section infection including endometritis, wound infection, and septic pelvic thrombophlebitis occurred in 10.2% of 205 diabetic women and 12.1% of control subjects, in whom antibiotic prophylaxis was used in 79% of diabetic women and 84% of control subjects. Duration of rupture of membranes was a significant risk factor for post-cesarean section infection in both groups. CONCLUSIONS: Insulin-requiring diabetic women undergoing nonelective cesarean section with antimicrobial prophylaxis have a rate of postoperative infection similar to that for nondiabetic women.

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)

A physiological delay in human fetal hemoglobin switching is associated with specific globin DNA hypomethylation.

The human fetal-to-adult globin switch normally occurs on a fixed schedule, beginning at 32-34 weeks gestation, and recent studies have suggested an association between this developmental inactivation of the fetal (gamma) globin genes and the appearance of methylation within and around these genes. We have studied a population of infants in whom this switch does not occur before birth (infants of diabetic mothers, IDM) and examined the patterns of methylation surrounding their active gamma-globin genes, in comparison to the gamma-globin genes of age-matched controls who have switched their pattern of globin gene expression on schedule. All genomic DNA samples from infants with delays in the globin switch demonstrated extensive hypomethylation in the region of the gamma-globin genes, comparable to that found in the genomes of fetuses of less than 21 weeks gestation. DNA from the erythroid cells of infants of 32-40 weeks gestation had no detectable hypomethylation in the gamma-globin region. These findings support the concept that hypomethylation is an accurate developmental marker of globin gene switching, and suggest that globin gene expression in IDM may be arrested at an early preswitch stage.

Simian immunodeficiency virus infection via amniotic fluid: a model to study fetal immunopathogenesis and prophylaxis.

The rising prevalence of infection with the human immunodeficiency virus type 1 (HIV-1) in young women will increase the number of infected children worldwide. Because HIV-1 seems to be transmitted mostly intrapartum, fetal infection probably occurs mainly via skin or mucous membrane exposure. A model for this route of fetal infection has been established in primates. After injecting the simian immunodeficiency virus (SIV) into amniotic fluid during late gestation, six of seven rhesus monkeys were born infected. All infected neonates were viable and showed signs of disease, such as low birth weights, lymphadenopathy, and rashes. Cytotoxic T-cell responses to SIV were absent in neonates, but present in mothers. The high fetal infection rate allows studies of lentiviral immunopathogenesis during ontogeny and the development of strategies to prevent maternal HIV-1 transmission.

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.

A predictive model for fetal lung maturity employing gestational age and test results.

Most laboratory tests for fetal lung maturity (FLM) are optimized to exclude false-negative predictions of absence of respiratory distress syndrome (RDS), with a reciprocal low predictive value for maturity. The authors employed FLM Surfactant/Albumin Ratio (FLM S/A) test results to construct a predictive model for FLM that included the obstetric estimates of gestational age. The charts of 388 newborns were abstracted and reviewed. The clinical outcome was the gold standard of the multivariate logistic analysis. Both the obstetric estimates of gestational age and the test result were significant predictors of the clinical outcome (P values of < .0002 and .001, respectively). The prediction rule for RDS as a function of both of these variables allows for adjustment of the test cutoffs, so that there is a consistent probability of RDS at the cutoff FLM S/A result for different gestational ages. Fetal lung maturity probability reporting may facilitate clinical decision-making.

Comparison of disaturated phosphatidylcholine and fetal lung maturity surfactant/albumin ratio in diabetic and nondiabetic pregnancies.

We studied fetal lung maturity (FLM) by the amniotic fluid surfactant/albumin (FLM S/A) ratio and the disaturated phosphatidylcholine (DSPC) amniotic fluid levels at different gestational ages in diabetic (179 women with type 1 diabetes mellitus antedating pregnancy; infants delivered within 72 hours after amniotic fluid testing for DSPC level and FLM S/A ratio) and nondiabetic pregnancies (2 independent nondiabetic groups, 300 for FLM S/A ratio and 1,231 for DSPC level). The degree of maternal glycemia during gestation was estimated by serial measurements of hemoglobin A1. Multiple regression analyses, including gestational age (GAs) and diabetic status as independent variables and FLM S/A ratio and DSPC level as dependent variables, revealed significant effect from diabetic status and GA for FLM S/A ratio and a significant effect from GA but not from diabetic status for DSPC level. Glucose levels were controlled adequately throughout gestation as reflected by mean total glycated hemoglobin levels. Amniotic fluid levels of DSPC, the major surface tension-lowering component of pulmonary surfactant, are not significantly different between diabetic and nondiabetic pregnancies at different GAs.

Prediction of fetal lung maturity in infants of diabetic mothers using the FLM S/A and disaturated phosphatidylcholine tests.

The authors evaluated the performance of the amniotic fluid surfactant to albumin ratio (FLM S/A), and disaturated phosphatidylcholine (DSPC) tests in assessing fetal lung maturity in infants of mothers with insulin-dependent diabetes mellitus antedating pregnancy. The distribution of the study population (n = 180) by class of diabetes was class B (27%); class C (28%); class D (29%); class F, FR and T (8%); and class R patients (8%). The diagnosis of respiratory distress syndrome (RDS) was the standard for evaluating the performance of FLM S/A and DSPC. The mean estimated gestational age was 37.4 weeks. Three infants (1.7%) were diagnosed with RDS. All three were delivered before 36 weeks. FLM S/A at the cut-off for "maturity" of > or = 70 mg/g, had a sensitivity of 66.6%, specificity of 94.9%, positive predictive value (PPV) of 18.2%, and negative predictive value (NPV) of 99.4%. DSPC at the cut-off for "maturity" of 1,000 micrograms/dL, had identical sensitivity and NPV, but lower specificity (89.2%) and PPV (9.5%) than FLM S/A. Both tests mispredicted maturity in the same case of RDS. The false "mature" rate of FLM S/A was 0.6% (95% confidence interval 0.0%-3.2%). The FLM S/A result of > or = 70 mg/g, obtained at or near-term, is a reliable predictor of the absence of RDS in infants of mothers with diabetes mellitus antedating pregnancy.

Animal models for perinatal transmission of pathogenic viruses.

In earlier work, mouse models have been used to demonstrate the efficacy and lack of toxicity of transplacental and perinatal AZT therapy. These practical small animal models can be useful for evaluating antiviral drugs aimed at common retroviral functions only, since Type C MuLVs are used. A primate model for fetal infection with an immunosuppressive lentivirus, SIV, has been established using ultrasound-guided inoculation of the amniotic fluid. The infection rate was 86% overall and 100% if the fetal SIV exposure occurred at least 19 days before delivery. The suspected major route of vertical HIV-1 transmission, that is, virus entry through fetal mucous membranes or skin, is replicated by our approach. The high fetal infection rate will allow studies of SIV pathogenesis during various stages of fetal development. This model should be well suited to development and evaluation of therapeutic strategies for preventing fetal infection.

Prenatal diagnosis in diabetic gravidas: utility of ultrasound and maternal serum alpha-fetoprotein screening.

The differences in both the biology of pregnancy and the content of routine care between gravidas with and without diabetes mellitus lead to important differences in the potential utility of both ultrasound examination and maternal serum alpha-fetoprotein (MSAFP) screening. However, both diagnostic methods have become standards of care for these patients, without critical evaluation. This study examines the utility of both ultrasound and MSAFP in diabetic women. Four hundred thirty-two women with diabetes mellitus antedating pregnancy were examined sonographically between 12-23 weeks' gestation. Of these, 393 were also screened with MSAFP determinations. At delivery, 32 of these fetuses were found to have 38 major congenital malformations. All fatal or potentially life-threatening defects had been diagnosed in utero by sonography before 24 weeks' gestation. Ultrasound had a positive predictive value of 90% and a negative predictive value of 97% for identification of major birth defects before 24 weeks' gestation. There were 14 MSAFP values greater than 2.0 multiples of the median, and nine of these patients elected to undergo amniocentesis. Maternal serum alpha-fetoprotein screening had a positive predictive value of 17% and a negative predictive value of 94%. No malformations were detected through MSAFP screening that had not been diagnosed by sonography. No malformations missed sonographically were detected by MSAFP screening, and none of the amniocenteses were helpful diagnostically. We conclude that MSAFP screening is of minimal utility for diagnosing major congenital malformations in a high-risk population examined universally by an experienced sonographer.

Is there a sea change ahead for obstetrics and gynecology?

A number of beneficial sociocultural reforms have occurred throughout our society, including a new work/family balance. This change, and a number of others, are challenging the dynamic balance within our specialty. We must advocate for appropriate social, political, and economic interventions that will realistically mesh with the health care needs of our nation, while preserving that which is best about the culture of American medicine.

Estimating the time of death in stillborn fetuses: I. Histologic evaluation of fetal organs; an autopsy study of 150 stillborns.

OBJECTIVE: To determine whether the autopsy histology of fetal tissues can determine the time of death of stillborn fetuses. METHODS: Hematoxylin and eosin slides from autopsies of 150 stillborn fetuses with well-timed deaths were evaluated retrospectively. Fetuses were divided into a learning set (100 fetuses) and a test set (50 fetuses). RESULTS: From assessment of the 100 fetuses in the learning set, 23 histologic features were identified with possible temporal associations with fetal death. When those histologic features were randomly and blindly assessed in the 50 test fetuses, ten features performed well as diagnostic tests (sensitivity, specificity, and positive predictive values at or above 0.875), correctly classifying 43 of 50 fetuses (86%) with respect to the time of death. The ten histologic features and their predicted death-to-delivery intervals were: loss of nuclear basophilia in individual cells in renal cortical tubules (4 hours), liver (24 hours), inner half of the myocardium (24 hours), outer half of the myocardium (48 hours), bronchial epithelium (96 hours), and tracheal cartilage (1 week); and loss of nuclear basophilia of all cells in the liver (96 hours), gastrointestinal tract (1 week), adrenal (1 week), and kidney (4 weeks). The development of these histologic changes appeared to be accelerated by fetal hydrops and a delivery-to-autopsy interval exceeding 24 hours and decelerated by fetal gestational age under 25 weeks. CONCLUSION: Histologic changes identifiable in hematoxylin and eosin-stained fetal tissue may be useful for estimating the time of death in many stillborn fetuses.

Pregnancy complicated by homozygous hypercholesterolemia.

The course of pregnancy in a woman with homozygous type IIa hypercholesterolemia is described. Despite prepartum cholesterol levels as high as 700 mg/dL, her cholesterol level increased further during gestation. Pathological examination of the placenta did not reveal insufficiency or vasculopathy.

Pregnancy outcome after premature rupture of the membranes at or before 26 weeks' gestation.

Pregnancy outcome was examined in 59 clinically stable patients with rupture of the membranes at or before 26 weeks' gestation. The mean gestational age at rupture of the membranes was 23.2 weeks, and the mean latent period was 21.5 days. Delivery occurred within 7 days in 29 patients (49.2%), chorioamnionitis developed in 27 patients (45.8%), and operative delivery was required in 24 patients (40.7%). Sixty-three infants were delivered, with a perinatal mortality rate of 49.1%. Among survivors, 84% required newborn intensive care during the initial hospitalization, 77% were discharged with minor to moderate reversible sequelae, and 16% were discharged with sequelae that were likely to be of long-term duration. Obstetric factors present at rupture of the membranes were evaluated for their ability to predict maternal and neonatal morbid outcomes; obstetric interventions were evaluated for their ability to modify outcomes. These data suggest that outcomes in this subset of patients may not be uniformly dismal, and support clinical decision-making on an individualized basis.

Prevention and diagnosis of congenital anomalies in diabetic pregnancies.

The high rate of major congenital malformations among infants of diabetic women represents the largest and most refractory problem in the perinatal care of these women. The prenatal diagnosis of these malformations will always be easier than their prevention. They are clearly not, however, entirely "beyond our therapeutic control."

Sonographic detection of fetal hydrops. A report of two cases.

Ultrasound can be useful for fetal assessment in Kell-isoimmunized pregnancies. Because severe hydrops may develop within six days, ultrasound should be repeated more frequently than once per week even if the delta OD450 values are low.

Use of the subcutaneous heparin pump during pregnancy.

Six patients requiring anticoagulation during pregnancy were managed with a continuous-infusion subcutaneous heparin pump. There were no cases of recurrent thrombosis; however, five of the six patients had major or minor bleeding complications despite therapeutic partial thromboplastin time levels.