Emtonjeni-A Structural Intervention to Integrate Sexual and Reproductive Health into Public Sector HIV Care in Cape Town, South Africa: Results of a Phase II Study.

Integration of sexual and reproductive health within HIV care services is a promising strategy for increasing access to family planning and STI services and reducing unwanted pregnancies, perinatal HIV transmission and maternal and infant mortality among people living with HIV and their partners. We conducted a Phase II randomized futility trial of a multi-level intervention to increase adherence to safer sex guidelines among those wishing to avoid pregnancy and adherence to safer conception guidelines among those seeking conception in newly-diagnosed HIV-positive persons in four public-sector HIV clinics in Cape Town. Clinics were pair-matched and the two clinics within each pair were randomized to either a three-session provider-delivered enhanced intervention (EI) (onsite contraceptive services and brief milieu intervention for staff) or standard-of-care (SOC) provider-delivered intervention. The futility analysis showed that we cannot rule out the possibility that the EI intervention has a 10 % point or greater success rate in improving adherence to safer sex/safer conception guidelines than does SOC (p = 0.573), indicating that the intervention holds merit, and a larger-scale confirmatory study showing whether the EI is superior to SOC has merit.

Child spacing and birth order: effect on intellectual ability in two-child families.

The effect on intellectual ability of the spacing of the birth of siblings was studied in two series of young men from two-child families: (i) 535 pairs of brothers and (ii) 1511 unrelated firstborn and secondborn. Birth-order effect and level of ability were not influenced by length of interval between firstborn and secondborn.

Cognitive development and social policy.

The city of Warsaw was razed at the end of World War II and rebuilt under a socialist government whose policy was to allocate dwellings, schools, and health facilities without regard to social class. Of the 14,238 children born in 1963 and living in Warsaw, 96 percent were given the Raven's Progressive Matrices Test and an arithmetic and a vocabulary test in March to June of 1974. Information was collected on the families of the children, and on characteristics of schools and city districts. Parental occupation and education were used to form a family factor, and the district data were collapsed into two factors, one relating to social marginality, and the other to distance from city center. Analysis showed that the initial assumption of even distribution of family, school, and district attributes was reasonable. Mental performance was unrelated either to school or district factors; it was related to parental occupation and education in a strong and regular gradient. It is concluded that an egalitarian social policy executed over a generation failed to override the association of social and family factors with cognitive development that is characteristic of more traditional industrial societies.

Results of a tuberculosis-specific IFN-gamma assay in children at high risk for tuberculosis infection.

The specificity of the tuberculin skin test (TST) for the diagnosis of latent tuberculosis infection (LTBI) is adversely affected by bacille Calmette-Guérin (BCG) vaccination and infection with non-tuberculous mycobacteria. Interferon-gamma release assays (IGRAs) using TB-specific antigens promise higher specificity. We compared a new IGRA and TST in 184 schoolchildren at high risk for LTBI. The IGRA and TST were positive in 33.2% and 43.5% of the children, respectively (P < 0.001). If studies confirm that this difference is due to higher specificity of this IGRA, it may have an important role to play in the diagnosis of LTBI and identification of children at true risk for TB.

Family history as an independent risk factor for coronary artery disease.

The risk of family history of ischemic heart disease independent of other well described risk factors has remained difficult to quantitate. Significant coronary artery disease was determined by coronary arteriography to be present in 223 patients and absent in 57 control subjects. Age, sex, blood pressure, serum cholesterol, cigarette smoking and the presence of diabetes and left ventricular hypertrophy on the electrocardiogram were tabulated for each patient and the data used to assign a risk score based on the American Heart Association multivariate model. Subjects were stratified and matched according to risk score to estimate risk of family history independent of familial aggregation of these seven other risk factors. Angina, myocardial infarction, cardiac death and any ischemic heart disease were ascertained in 1,319 first degree relatives. Odds ratios for overall, stratified and matched comparisons of these end points in relatives of patients and control subjects ranged between 2.0 and 3.9 (p less than 0.01 for all comparisons), indicating a higher frequency of all ischemic heart disease end points in relatives of patients with documented coronary artery disease. Life table comparison of patients at lowest risk with those at higher risk showed significantly greater cumulative frequency and earlier age of onset of all ischemic heart disease end points in relatives of low risk patients. These observations indicate that some of the risk associated with family history is independent of familial aggregation of other known risk factors and suggest that the independent effects of family history may be most important in individuals who otherwise are at low risk.

A randomized trial of hierarchical counseling in a short, clinic-based intervention to reduce the risk of sexually transmitted diseases in women.

INTRODUCTION: Effective public health interventions to reduce the incidence of sexually transmitted disease (STD), including HIV, among women are urgently needed. METHODS: A randomized trial among STD clinic patients of two types of counseling regarding methods to reduce disease transmission: a 'hierarchical' message (HP), with counseling on male condoms, female condoms, diaphragms, cervical caps, and spermicides (three formulations) and a single method message (SM) covering male condoms only or female condoms only. For this analysis, 1591 subjects received one of three educational messages at the central public STD clinic in Philadelphia. Disease incidence data for up to 6 months following the index visit were extracted from the clinic's electronic database. The primary outcome was STD reinfection: laboratory-confirmed trichomonas infection and/or clinical diagnoses of at least one of four STD. Rates were based on the full sample of randomized women (full sample) and on the subset who spontaneously returned between 22 days and 183 days following their initial visit (returners). RESULTS: Rates of trichomonas infection (SM 2.5% full sample and 12.9% returners versus HP 2.4% full sample and 11.5% returners) and clinical diagnoses (SM 6.3% full sample and 39.7% returners versus HP 6.9% full sample and 41.2% returners) did not differ across the two arms of the randomized trial, both as a straight percentage and in survival analysis (P = .81). CONCLUSION: At least in this single-session intervention trial, increasing choices in protection for women did not produce a change in disease risk compared with single-method approaches.

Phase 1 trial of nonoxynol-9 film among sex workers in South Africa.

OBJECTIVES: To assess the acceptability and safety of a vaginal nonoxynol-9 film in a group of sex workers at a truck stop in South Africa. DESIGN: A randomized double-blinded crossover trial was conducted between April 1995 and July 1995. INTERVENTION: Seventy-two mg nonoxynol-9 film and an identical glycerine placebo film. METHODS: Following informed consent, each study participant was randomly assigned the designated pre-coded film for 1 month. The second month was a film-free washout period and the participants used the alternate film in the third month. Besides measuring behavioural and clinical outcomes, colposcopy examination for genital lesions, serology and microbiology investigations for sexually transmitted diseases and semi-quantitative PCR for vaginal HIV load estimates were performed. RESULTS: Twenty women participated in the study. The women reported, on average, 19 sexual encounters per week. Vaginal intercourse was protected 25% of the time by condoms. On average, 11 vaginal films, either nonoxynol-9 or placebos were inserted per week. There were no statistically significant differences between the two treatment groups for genital lesions (P = 0.29), reported side effects (P = 0.73), and viral load (P = 0.9). However, the proportions of clinically detected genital lesions (six out of eight versus two out of eight) and self-reported side-effects (five out of eight versus three out of eight) were higher in the nonoxynol-9 group when compared with the placebo group. Incident sexually transmitted diseases occurred more frequently in the placebo group. An increased viral load was associated with the development of a genital lesion (relative risk, 6.0; 95% confidence interval, 0.81-44.4). CONCLUSIONS: The 72 mg film formulation of nonoxynol-9 was an acceptable product for use in this population of sex workers. Although no statistically significant differences in adverse outcomes were detected, clinically there appeared to be an increase in minor lesions and self-reported side-effects with nonoxynol-9 and less protection against sexually transmitted diseases with the placebo. Furthermore, HIV shedding was correlated with the presence of incident vaginal or cervical lesions. This brings into question the potential narrow margin of safety for this product; additional Phase 2 studies are therefore required.

T-helper cell responses to HIV envelope peptides in cord blood: protection against intrapartum and breast-feeding transmission.

BACKGROUND: Acquired HIV-specific cell-mediated immune responses have been observed in exposed-uninfected individuals, and it has been inferred, but not demonstrated, that these responses constitute a part of natural protective immunity to HIV. This inference was tested prospectively in the natural exposure setting of maternal-infant HIV transmission in a predominantly breast-fed population. METHODS: Cord blood from infants of HIV-seropositive women in Durban, South Africa, were tested for in vitro reactivity to a cocktail of HIV envelope peptides (Env) using a bioassay measuring interleukin-2 production in a murine cell line. Infants were followed with repeat HIV RNA tests up to 18 months of age to establish which ones acquired HIV-infection. RESULTS: T-helper cell responses to Env were detected in 33 out of 86 (38%) cord blood samples from infants of HIV-seropositive women and in none of nine samples from seronegative women (P = 0.02). Among infants of HIV-seropositive mothers, three out of 33 with T-helper responses to Env were already infected before delivery (HIV RNA positive on the day of birth), two were lost to follow-up, and none of the others (out of 28) were found to be HIV infected on subsequent tests. In comparison, six out of 53 infants unresponsive to Env were infected before delivery, and eight out of 47 (17%) of the others were found to have acquired HIV infection intrapartum or post-partum through breast-feeding (P = 0.02). CONCLUSIONS: T-helper cell responses to HIV envelope peptides were detected in more than one-third of newborns of HIV-infected women; no new infections were acquired by these infants at the time of delivery or post-natally through breast-feeding if these T-helper cell responses were detected in cord blood.

Prenatal starvation and maternal blood pressure near delivery.

Maternities in cities exposed to the Dutch famine of 1944 to 1945 and in control cities were compared. Systolic blood pressure near the time of delivery was significantly reduced by exposure to famine late in the 2nd trimester and early in the 3rd trimester. Blood pressure correlated best with caloric rations in the 3rd month before delivery, and this relationship holds consistently below a ration level of 1900 cal. Above 1900 cal and up to 2200 cal (the upper limit of rations for the data analyzed) the relationship is inconsistent across cities. Edema, analyzed in one city, varied in a manner similar to blood pressure.

Effects of prenatal nutritional supplementation on the placenta: report of a randomized controlled trial.

Protein and nucleic acid content, and RNase levels were measured in placentas collected at birth in a randomized controlled trial of prenatal nutritional supplementation in New York City. These biochemical indices were explored to understand better the effects of nutritional supplementation. (With high-protein supplements, gross measures had shown no improvement in outcome at birth and adverse effects on fetal growth, prematurity, and newborn survival; with balanced protein-calorie supplements, there was a nonsignificant rise in birth weight and longer gestation.) The biochemical indices were in general somewhat weakly related to fetal growth measures. Significant effects of nutritional treatment on the indices were minimal, and added no information that could account for gross effects observed in the fetus.

Creutzfeldt-Jakob disease: familial clustering among Libyan-born Israelis.

Creutzfeldt-Jakob disease was studied among Libyan-born Israelis, in whom the disease appears with unusual frequency. Interviews with relatives of deceased victims revealed statistically significant clustering within families. The results suggest either a common source of exposure or a genetic influence on susceptibility to the virus.

Mortality risks in gay men with human immunodeficiency virus infection and cognitive impairment.

We obtained data from 111 gay men who entered a longitudinal study of the natural history of human immunodeficiency virus (HIV) without clinical evidence of acquired immunodeficiency syndrome (AIDS), and examined them regularly over a 36-month period. Using a Cox proportional-hazard regression model to compare cumulative risk of mortality in subjects with and without cognitive impairment and several putative risk factors present at baseline, we found that the mortality risk ratio (RR) associated with poor neuropsychologic test performance was significantly increased (RR = 2.9; 95% confidence interval [CI], 1.1 to 7.8), and increased further (RR = 4.1; 95% CI, 1.3 to 12.5) when adjusted for other factors associated with mortality (a history of a disturbance in movement or gait, CD4-lymphocyte and red blood-cell counts, and age). A significant increase in symptoms related to cognitive impairment and gait, a decline in neuropsychologic test performance, and declines in CD4-lymphocyte and red-cell counts occurred over the study period. A second model was constructed to adjust for changes in CD4-lymphocyte and red-cell counts, age, medical stage, and motor symptoms over the study period, but the mortality RR for poor neuropsychologic test performance at baseline changed very little (RR = 4.7; 95% CI, 1.5 to 14.9). We conclude that the presence of cognitive impairment, manifest by poor neuropsychologic test performance in both asymptomatic and symptomatic gay men with HIV infection, is associated with a significantly increased risk of death. This effect progresses in parallel with the immunologic and systemic effects of HIV.

A randomized controlled trial of prenatal nutritional supplementation in New York City.

This randomized controlled trial of nutritional supplementation in pregnancy, in a poor black urban population in the United States, aimed to increase the birth weight and influence the postnatal development of the offspring of mothers at high risk of having low birth weight infants. The execution of the research design and adherence to the treatment regimen among the experimental population appeared adequate for a reasonable test of the treatments. At birth, the only significant favorable effect of supplementation observed was the prevention of depressed birth weight among the offspring of mothers who smoked heavily. With balanced protein-calorie supplementation, length of gestation was increased, the proportion of low-birth-weight infants reduced, and mean birth weight raised by 41 gm (not statistically significant). With high protein supplementation, there was an excess of very early premature births and associated neonatal deaths, and there was significant growth retardation up to 37 weeks of gestation. At 1 year of age, significant effects of high protein supplement were found on three psychological measures: visual habituation, visual dishabituation, and mean length of free play episodes. These measures were unrelated to measures of growth at birth and at 1 year of age. There were no detectable residual adverse effects of high protein supplementation at 1 year of age.

Biological markers in reproductive epidemiology: prospects and precautions.

We begin by defining "biological markers" for the purposes of the present review, distinguishing markers from other types of information, such as subject reports or conventional clinical data. We find the distinctions to be hazy. Next, from the standpoint of epidemiologists, we set out circumstances in which exposure markers might be needed, suggesting requirements for useful markers. We give two instances (lead, PCB), drawn from studies of female reproduction, where the use of exposure markers is compared to environmental or anamnestic data. Effect markers are considered in turn. It is argued that their usefulness (if they are to be more informative than exposure markers) depends on their sensitivity and specificity in relation to the disease outcome. Also, their timeliness, and the use that can be made of the gain in time, for individuals and populations is discussed. In this context, we consider markers of events before and around fertilization; more specifically, we consider those events that precede the clinical marker of the first missed period. In returning to the potential uses of biological markers in discovering or interpreting female reproductive disorders that might be owed to environmental causes, we compare markers of the pre- and peri-implantation phases with markers of the postimplantation phase, drawing on experience with studies of chromosome anomaly in spontaneous abortion. Finally, we suggest other sensitive reproductive processes for which biological markers might usefully be developed.

Power considerations in studies of reproductive effects of vinyl chloride and some structural analogs.

We review the evidence examining the relation of reproductive function and exposure to vinyl chloride and selected structural analogs. Investigation of these compounds for possible reproductive effects has focused on paternal exposure, a much less well studied route than maternal exposure. Drawing on animal models, we discuss what is known about the possible reproductive consequences of exposure to the father as well as to the mother. In evaluating the studies of reproductive outcome in relation to vinyl chloride or analogs, we consider what biologic model may have been tested and whether there was statistical power to detect moderate increases in risk. Parameters influencing statistical power are reviewed, and recommended sample sizes are set out which would insure sufficient power, in future studies, to detect adverse effects.

Increased risk of proteinuria among a cohort of lead-exposed pregnant women.

Long-term exposure to high concentrations of lead results in renal dysfunction. During a prospective study of environmental lead and pregnancy outcomes in 1502 women residing in two towns in Yugoslavia, we explored whether moderate exposure to lead results in increased rates of proteinuria. The geometric mean blood lead concentrations (BPb) were 17.1 and 5.1 micrograms/dl in the smelter and nonexposed towns, respectively. Increases in BPb were associated with increased odds ratios for both trace and > or = 1+ proteinuria, measured using a urinary dipstick. Comparing the women in the upper 10th percentile of exposure to those in the lowest 10th percentile, the adjusted odds ratio for > or = 1+ proteinuria was 4.5 (95% CI 1.5, 13.6). Similarly, the adjusted odds ratio for trace proteinuria was 2.3 (95% CI 1.3, 4.1). Similar to other studies showing associations between chronic exposure to lead and renal dysfunction, our data suggest that long-term exposure to environmental lead may be associated with proteinuria.

Epidemiologic detection of low dose effects on the developing fetus.

Evaluations of the health effects of exposures in the workplace and environment have broadened to include effects on reproduction, as well as on the development of cancer. Models to assess risks associated with varying doses of exposure rest almost entirely on data about cancer. In this paper we discuss some distinctive features of reproduction which bear on the interpretation of such models, when applied to reproduction, rather than carcinogenesis. Dose-response curves describe the relationship between two exposures (smoking and alcohol drinking) and two outcomes (spontaneous abortion and birthweight) are used to illustrate some of the questions which arise in attempting to determine a "safe" level of exposure.

PIP: This paper examines the ways in which evaluation of risks of exposure to noxious substances differ in the field of reproduction from the risks of carcinogenesis, and presents models of the effects of varying doses of exposures to smoking and alcohol drinking on spontaneous abortion and birthweight. Models to assess risks associated with varying doses of exposure are almost all based on data about cancer, but the models for risk assessment in reproduction and in oncogenesis differ in at least 3 fundamental ways: 1) the range of relevant adverse reproductive outcomes is more varied and may involve different underlying mechanisms; 2) the relation of timing and duration of exposure to outcome may be different in reproductive endocrinology and in oncogenesis, with many morphological effects depending on exposure at a precise and relatively short period of development; and 3) in reproduction, the exposure can effect 2-3 individuals, although the outcome is usually described in terms of the fetus or infant only. 1 advantageous aspect of the biology of reproduction that has no parallel in carcinogenesis for the study of modest effects is that, for anomalies that are lethal in utero, the search for etiologic factors among aborted fetuses is considerably more parsimonious in terms of the numbers of pregnancies which need to be studied than a similar search among births would be. For example, the sample sizes for exposed and unexposed populations which would be needed to detect, with 80% statistical power, a doubling of the rate of trisomy 21 at conception would be 15,217 births or 1117 abortions. A study of dose-response relations of exposure to smoking and alcohol drinking on spontaneous abortion and birthweight was based on data drawn from an ongoing epidemiological study in 3 New York City hospitals which compares women admitted with spontaneous abortion to a comparison group matched for maternal age and payment status whose pregnancies continued longer than 28 weeks. The data indicate a dose-response relationship between the number of cigarettes smoked each day and both spontaneous abortion and lowered birthweight. In both instances, a logarithmic curve best described the data. A dose-response relationship was also found between alcohol drinking and spontaneous abortion; the odds of abortion increase linearly with increases in the number of days each month on which alcohol is consumed. No relation was found between smoking and alcohol drinking in their effects on spontaneous abortion. The relationship between the exposures of alcohol drinking and smoking and the outcomes of spontaneous abortion and birthweight are used to illustrate some of the problems in attempting to determine a safe level of exposure.

Cigarettes, alcohol and marijuana: varying associations with birthweight.

The relations of cigarette smoking, alcohol drinking and marijuana use during pregnancy to birthweight were examined in two prospectively studied pregnancy cohorts (Phases I and II). After analytic adjustment in ordinary least squares regressions for other factors that influence birthweight, cigarette smoking during at least half the pregnancy was associated with a significant decrease in mean birthweight (159 grams in Phase I, 202 grams in Phase II). In Phase II only, beer drinking was associated with a significant decrement of 8.4 grams in estimated birthweight per ounce of absolute alcohol per month. Neither wine nor liquor drinking in the Phase II data nor any of the three beverages in the Phase I data was associated with significant decrements in predicted birthweight. Furthermore, with one exception (drinking once a week in Phase II only), alcohol drinking, defined as the number of occasions per month on which any alcoholic beverage was consumed, was not associated with a change in birthweight. Regarding marijuana use, the data are not consistent between the two phases. In the Phase I data, no coherent trend in association with birthweight was observed. In the Phase II data, marijuana use 2-3 times per week, 4-6 times per week and daily was associated with increasing decrements in estimated birthweight: 127 g, 143 g and 230 g respectively. The inconsistent findings for alcohol drinking and marijuana use between phases stand in marked contrast to the consistent findings for cigarette smoking.

Timing in prenatal nutrition: a reprise of the Dutch Famine Study.

The array of results discussed in this paper is assembled by stage of gestation in the following table (Table 1). We must allow some uncertainty for some outcomes as to the precise stages of gestation in which they originate. For instance, with obesity, the effects of famine exposure may extend beyond the first trimester into the second. Yet, the table is perhaps sufficient in itself to support the point with which the paper opened, namely, that stage of development is crucial to the appreciation of the effects of prenatal nutrition.

Vitamin A and HIV infection: disease progression, mortality, and transmission.

Among HIV-infected individuals, many nutritional factors that influence disease progress, mortality, and transmission are not well understood. Of particular interest is the role of vitamin A. The benefits of vitamin A have been recognized since ancient times by Egyptian physicians who successfully treated night blindness with vitamin A. Contemporary scientists have since recognized the importance of vitamin A and have provided evidence that it may help in repairing damaged mucosal surfaces; what remains unclear, however, is its role during HIV infection. In this review, we examine the evidence provided in both observational studies and randomized controlled trials that assessed the effect of vitamin A during HIV infection.