Elevated frequencies of micronucleated erythrocytes in infants exposed to zidovudine in utero and postpartum to prevent mother-to-child transmission of HIV

Zidovudine-based antiretroviral therapies (ARTs) for treatment of HIV-infected pregnant women have markedly reduced mother-to-child transmission of the human immunodeficiency virus (HIV-1) from approximately 25% to <1%. However, zidovudine (ZDV; AZT), a nucleoside analogue, induces chromosomal damage, gene mutations, and cancer in animals following direct or transplacental exposure. To determine if chromosomal damage is induced by ZDV in infants exposed transplacentally, we evaluated micronucleated reticulocyte frequencies (%MN-RET) in 16 HIV-infected ART-treated mother-infant pairs. Thirteen women received prenatal ART containing ZDV; three received ART without ZDV. All infants received ZDV for 6 weeks postpartum. Venous blood was obtained from women at delivery and from infants at 1-3 days, 4-6 weeks, and 4-6 months of life; cord blood was collected immediately after delivery. Ten cord blood samples (controls) were obtained from infants of HIV-uninfected women who did not receive ART. %MN-RET was measured using a single laser 3-color flow cytometric system. Tenfold increases in %MN-RET were seen in women and infants who received ZDV-containing ART prenatally; no increases were detected in three women and infants who received prenatal ART without ZDV. Specifically, mean %MN-RET in cord blood of ZDV-exposed infants was 1.67 +/- 0.34 compared with 0.16 +/- 0.06 in non-ZDV ART-exposed infants (P = 0.006) and 0.12 +/- 0.02 in control cord bloods (P < 0.0001). %MN-RET in ZDV-exposed newborns decreased over the first 6 months of life to levels comparable to cord blood controls. These results demonstrate that transplacentalZDV exposure is genotoxic in humans. Long-term monitoring of HIV-uninfected ZDV-exposed infants is recommended to ensure their continued health.     

Tenofovir disoproxil fumarate, emtricitabine, and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients: 144-week analysis

BACKGROUND: As antiretroviral regimens for the treatment of HIV infection improve, trials providing data on long-term follow-up are increasingly important. METHODS: A regimen of tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and efavirenz (EFV) demonstrated superior virologic, immunologic and morphologic effects compared with a regimen of fixed-dose zidovudine/lamivudine (ZDV/3TC) and EFV through 96 weeks in a randomized open-label trial. After 96 weeks, patients on TDF + FTC transitioned to fixed-dose combination TDF/FTC. RESULTS: Through 144 weeks, significantly more patients in the TDF/FTC arm reached and maintained an HIV RNA level <400 copies/mL (71% receiving TDF/FTC and EFV vs. 58% receiving ZDV/3TC and EFV; P = 0.004), with a trend toward greater CD4 cell increase in the TDF/FTC arm (312 vs. 271 cells/mm; P = 0.09). Over 144 weeks of follow-up, more patients in the ZDV/3TC arm discontinued therapy because of adverse events (11% vs. 5%; P = 0.01) and no patients discontinued because of renal events. Patients in the ZDV/3TC arm had significantly less limb fat than patients in the TDF/FTC arm (5.4 vs. 7.9 kg; P < 0.001) at 144 weeks. CONCLUSIONS: Cumulative results from 3 years of follow-up suggest that a regimen of TDF/FTC and EFV demonstrates superior durability of viral load suppression and an improved safety and morphologic profile compared with ZDV/3TC and EFV.     

Maternal characteristics associated with antenatal, intrapartum, and neonatal zidovudine use in four US cities, 1994-1998

OBJECTIVES: To evaluate implementation of 1994 United States Public Health Service guidelines for zidovudine (ZDV) use in HIV-infected women and their newborns by describing the prevalence of use of perinatal ZDV and other antiretrovirals and by investigating determinants of not receiving perinatal ZDV. DESIGN/METHODS: The Perinatal AIDS Collaborative Transmission Study is a prospective cohort study designed to collect information related to mother-to-child HIV transmission that was conducted in New York City (NY), Newark (NJ), Baltimore (MD), and Atlanta (GA), U.S.A. The current analysis was restricted to infants born between July 1994 and June 1998. RESULTS: Utilization rates for antenatal, intrapartum, and neonatal ZDV increased from 41% to 70% during the 4-year period. Use of combination antiretrovirals increased from fewer than 2% of women in 1994 to 1995 to 35% in 1997 to 1998. Antenatal and neonatal ZDV use increased each year, but intrapartum ZDV use reached a plateau after 1996. Mother-infant pairs with the following characteristics were less likely to have received a complete 3-part ZDV regimen: older maternal age, CD4 count >500 cells/microl, preterm birth, cocaine or heroin use during pregnancy, positive newborn drug screen test result, and smoking or alcohol use during pregnancy. By multivariate logistic regression adjusted for hospital and year of birth, cocaine or heroin use during pregnancy (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.6-3.3), maternal CD4 count (OR, 0.4; 95% CI, 0.2-0.8; comparing <200 with >500 cells/microl), and preterm birth (OR, 1.6; 95% CI, 1.1-2.5) remained independently associated with not receiving the complete ZDV regimen. CONCLUSIONS: ZDV use by pregnant HIV-infected women and their infants has increased dramatically since publication of the 1994 guidelines. Nevertheless, women who abuse substances, give birth preterm, or have less advanced immunosuppression, were at substantial risk of not receiving the complete ZDV regimen.     

Effect of prenatal zidovudine on disease progression in perinatally HIV-1-infected infants

OBJECTIVE: To determine the influence of prenatal zidovudine (ZDV) prophylaxis on the course of HIV- 1 infection in children by comparing the clinical outcome of infants born to HIV- 1-seropositive mothers who did versus those who did not receive ZDV during pregnancy. METHODS: Medical records of HIV-1-seropositive mothers and their infants were reviewed retrospectively. Participants were divided according to maternal ZDV use: no ZDV (n = 152); ZDV (n = 139). The main outcome measure was rapid disease progression (RPD) in the infant, defined as occurrence of a category C disease or AIDS-related death before 18 months of age. RESULTS: HIV vertical transmission rates were significantly different (no ZDV versus ZDV: 22.3% versus 12.2%; p = .034). Among infected infants, the RPD rate was 29.4% in the no ZDV group compared with 70.6% in the ZDV group (p = .012), and prematurity was significantly associated with a higher risk of RPD (p = .027). CONCLUSIONS: The rate of RPD was significantly higher among perinatally infected infants born to HIV-infected mothers treated with ZDV than among infected infants born to untreated mothers. The decreased proportion of infected infants with nonrapid disease progression in the former group might be related to the ability of ZDV to block intrapartum transmission preferentially and also to nonrapid disease progression resulting from intrapartum transmission.     

HIV-1 viral load and other risk factors for mother-to-child transmission of HIV-1 in a breast-feeding population in Cote d'Ivoire

Short-course antiretroviral regimens have been evaluated to reduce mother-to-child transmission of HIV in resource-limited settings. This report from Abidjan, Cote d'Ivoire, examines the risk factors for HIV transmission by 1 and 24 months among breast-feeding women. Eligible HIV-1-seropositive pregnant women enrolled in this randomized double-blind clinical trial were randomly assigned to receive either oral zidovudine (ZDV) (n = 126) prophylaxis or placebo (n = 124). Maternal prophylaxis began at 36 weeks of gestation (300 mg ZDV twice daily antepartum and 300 mg every 3 hours intrapartum); there was no neonatal prophylaxis component. The cumulative risk of transmission in the treatment group was 11.9% and 22.1% by 1 and 24 months, respectively. In adjusted analyses, viral load at enrollment was the strongest predictor of transmission (per log increment: odds ratio [OR] = 4.8, 95% confidence interval [CI]: 2.5-9.5 at 1 month; OR = 5.7; 95% CI: 3.1-10.8 at 24 months). Overall, ZDV prophylaxis was not significantly protective for infection at 1 or 24 months. Comparing ZDV with placebo following dichotomization of viral load (<50,000 vs. > or =50,000 copies/mL) at enrollment, however, there was a significant effect of ZDV seen only among those women with a low viral load at enrollment. The substantial risk of transmission despite ZDV prophylaxis, particularly among those with higher viral loads, underscores the need to find more effective regimens appropriate for use in resource-limited settings.     

Maternal diesel inhalation increases airway hyperreactivity in ozone-exposed offspring

Air pollutant exposure is linked with childhood asthma incidence and exacerbations, and maternal exposure to airborne pollutants during pregnancy increases airway hyperreactivity (AHR) in offspring. To determine if exposure to diesel exhaust (DE) during pregnancy worsened postnatal ozone-induced AHR, timed pregnant C57BL/6 mice were exposed to DE (0.5 or 2.0 mg/m(3)) 4 hours daily from Gestation Day 9-17, or received twice-weekly oropharyngeal aspirations of the collected DE particles (DEPs). Placentas and fetal lungs were harvested on Gestation Day 18 for cytokine analysis. In other litters, pups born to dams exposed to air or DE, or to dams treated with aspirated diesel particles, were exposed to filtered air or 1 ppm ozone beginning the day after birth, for 3 hours per day, 3 days per week for 4 weeks. Additional pups were monitored after a 4-week recovery period. Diesel inhalation or aspiration during pregnancy increased levels of placental and fetal lung cytokines. There were no significant effects on airway leukocytes, but prenatal diesel augmented ozone-induced elevations of bronchoalveolar lavage cytokines at 4 weeks. Mice born to the high-concentration diesel-exposed dams had worse ozone-induced AHR, which persisted in the 4-week recovery animals. Prenatal diesel exposure combined with postnatal ozone exposure also worsened secondary alveolar crest development. We conclude that maternal inhalation of DE in pregnancy provokes a fetal inflammatory response that, combined with postnatal ozone exposure, impairs alveolar development, and causes a more severe and long-lasting AHR to ozone exposure.     

Tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naive patients: virologic, immunologic, and morphologic changes--a 96-week analysis

BACKGROUND: In antiretroviral-naive patients, tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and efavirenz (EFV) demonstrated superior outcomes compared with fixed-dose zidovudine (ZDV)/lamivudine (3TC) and EFV through 48 weeks. Results through a 96-week extension phase are presented. METHODS: In this randomized, open-label, noninferiority trial, 517 antiretroviral-naive HIV-infected patients received TDF, FTC, and EFV (TDF + FTC + EFV) or ZDV/3TC and EFV (ZDV/3TC + EFV). The primary endpoint was the proportion of patients with an HIV RNA level <400 copies/mL in patients without baseline nonnucleoside resistance. RESULTS: Through week 96, significantly more patients receiving TDF + FTC + EFV achieved and maintained an HIV RNA level <400 copies/mL (75% receiving TDF + FTC + EFV vs. 62% receiving ZDV/3TC + EFV; P = 0.004). There was a trend toward greater virologic suppression to <50 copies/mL in the TDF + FTC + EFV group (67% vs. 61%; P = 0.16). The TDF + FTC + EFV group demonstrated a significantly greater increase in CD4 count (270 vs. 237 cells/mm; P = 0.036). No patient developed the K65R mutation. Limb fat at week 96 was significantly greater in the TDF + FTC + EFV group versus the ZDV/3TC + EFV group (7.7 vs. 5.5 kg; P < 0.001). CONCLUSION: Over 96 weeks, the combination of TDF, FTC, and EFV was superior to fixed-dose ZDV/3TC + EFV for achieving and maintaining an HIV RNA level <400 copies/mL and an increase in CD4 cells.     

Zidovudine use during pregnancy among HIV-infected women on Medicaid

OBJECTIVES: This study estimates the rate of zidovudine (ZDV) use during pregnancy among HIV-infected women receiving Medicaid. The rates of ZDV use during pregnancy are compared before (preperiod) and after (postperiod) the 1994 publication of US Public Service Task Force guidelines, recommending use of ZDV during pregnancy. The authors also compare and contrast the correlates of ZDV use during pregnancy in each of the preguideline and postguideline periods. METHODS: New Jersey AIDS/HIV surveillance data and paid Medicaid claims data between 1992 and 1996 were merged to examine ZDV use during pregnancy. Among ZDV users, the authors also examined persistence of ZDV use during the 3 months preceding delivery. In these analyses, the authors examined care received during pregnancy and differentiated routine medical care from pregnancy-specific care. Correlates of intrapregnancy ZDV use were examined using chi2 analysis and robust regression techniques that correct for correlation among repeated observations. RESULTS: Use of ZDV during pregnancy steadily increased from 13% in 1992 to 70% in 1996, with the upward trend beginning before the release of the guidelines. Averaged over the full preperiod (1992-1994), the rate was 29%, increasing to 57% during the full postperiod (1995-1996). Women with no health care during pregnancy did not receive any ZDV prophylaxis. Women who had some health care contacts, but did not receive pregnancy-specific care, had low rates of ZDV use that did not increase after the promulgation of the guidelines (21% in preperiod and 27% in postperiod). Women who received pregnancy-specific care, whether from obstetrician-gynecologists (OB-GYNs) or other providers, substantially increased their use of ZDV in the postguideline period (from 37% to 63% for those who saw OB-GYNS, and from 20% to 59% for those who received pregnancy-specific care from other providers). However, among users of ZDV, only a minority (24%) used ZDV persistently during the 3 months preceding delivery. African American women were less likely to be persistent ZDV users, even after controlling for other factors. CONCLUSIONS: The study highlights the underutilization of ZDV by women who did not receive pregnancy-related care, even after the publication of guidelines. Lack of pregnancy-specific medical care during pregnancy is an important barrier to ZDV prophylaxis. This study confirms that the receipt of prenatal care during pregnancy is a key intervening variable in the real world application of the PHS guidelines and underscores the importance of proactive efforts to provide prenatal care to pregnant women with HIV.     

Induction with abacavir/lamivudine/zidovudine plus efavirenz for 48 weeks followed by 48-week maintenance with abacavir/lamivudine/zidovudine alone in antiretroviral-naive HIV-1-infected patients

BACKGROUND: The ESS40013 study tested 4-drug induction followed by 3-drug maintenance as initial antiretroviral therapy (ART) to reduce HIV RNA rapidly and then to simplify to an effective yet more convenient and tolerable regimen. METHODS: Four hundred forty-eight antiretroviral-naive adults were treated with abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) and efavirenz (EFV) for the 48-week induction phase. Two hundred eighty-two patients were randomized in a 1:1 ratio to continue ABC/3TC/ZDV+EFV or to simplify to ABC/3TC/ZDV for the 48-week maintenance phase. RESULTS: The baseline median HIV RNA level and CD4 cell count were 5.08 log10 copies/mL (56%>or=100,000 copies/mL) and 210 cells/mm (48% <200 cells/mm), respectively. No significant differences were noted between ABC/3TC/ZDV+EFV and ABC/3TC/ZDV for an HIV RNA level <50 copies/mL (79% vs. 77% [intent to treat (ITT), missing=failure]; P=0.697) or time to treatment failure (P=0.75) at week 96. Drug-related adverse events were more commonly reported for ABC/3TC/ZDV+EFV than for ABC/3TC/ZDV (15% vs. 6%). Improvements in total cholesterol, low-density lipoprotein cholesterol, and triglycerides were observed in the ABC/3TC/ZDV group. Virologic failure occurred in 22 patients during induction and in 24 patients (16 in ABC/3TC/ZDV group and 8 in ABC/3TC/ZDV+EFV group; P=0.134) during maintenance. A greater proportion of patients receiving ABC/3TC/ZDV than ABC/3TC/ZDV+EFV reported perfect adherence at week 96 (88.8% vs. 79.6%; P=0.057). CONCLUSIONS: After induction with ABC/3TC/ZDV+EFV, simplification to ABC/3TC/ZDV alone maintained virologic control and immunologic response, reduced fasting lipids and ART-associated adverse events, and improved adherence.     

Prenatal exposure to LPS leads to long-lasting physiological consequences in male offspring

Growing evidence suggests that early life events are critical determinants for disorders later in life. According to a comprehensive number of epidemiological/animal studies, exposure to lipopolysaccharide, causes alteration in pro-inflammatory cytokine levels, hypothalamic-pituitary-adrenal functioning and the hormonal system which may contribute to behavioral and neurological injuries. In this study we investigated the effects of lipopolysaccharide administration on physiological parameters in pregnant dams and their male offspring aged 9 weeks. In gestational Day 10, pregnant mice were injected intrapritoneally with Salmonella enterica lipopolysaccharide to model prenatal exposure to infection. The following results were obtained for offspring from dams stressed during pregnancy: (a) reduced anxiety-related behavior in the elevated plus maze; (b) reduced food and water intake; (c) reduced body weight from birth up to postnatal Day 40. The observed data provide experimental evidence showing that prenatal stress can have complex and long-lasting physiological/behavioral consequences in offspring.     

基于人群监测和医院监测的高发地区出生缺陷流行病学特征比较

目的比较中国出生缺陷高发地区人群监测和医院监测出生缺陷流行病学特征的差异。方法在中国出生缺陷高发的山西省选择2个高发县作为研究地区,对该地区2002年1月1日至2004年12月31日孕满20周及以上胎儿及婴幼儿出生缺陷的发生水平进行分析。人群监测采用社区调查和医院登记相结合的方法,医院监测来自当地医院妇产科及B超检查的登记册,比较两种监测方法出生缺陷发生率及顺位,孕20周至生后7d或至3岁时的差异。结果 2002至2004年医院监测累积出生4855人,出生缺陷113例,出生缺陷发生率为232.7/万出生;人群监测累积出生6420人,出生缺陷223例,出生缺陷发生率为347.4/万出生,差异有显著统计学意义（P〈0.001）。在孕20周至生后7d的常规监测年龄段,医院和人群监测资料出生缺陷均以神经系统畸形为主,神经系统、耳部畸形、泌尿生殖系统以及皮肤缺陷发生率均为人群监测高于医院监测。人群与医院监测的前5位出生缺陷顺位一致,依次为无脑儿、脊柱裂、先天性脑积水、脑膨出、唇和（或）腭裂。当人群监测年龄延长至3岁时,出生缺陷发生率高达844.2/万出生,是孕20周至生后7d人群监测数据的2.43倍,是医院监测数据的3.63倍。人群监测孕20周至3岁时出生缺陷顺位变化较大,前5位依次为腹股沟疝、无脑畸形、先天性智力低下、先天性心脏病和脊柱裂。结论出生缺陷的水平和顺位与监测方法和时段密切相关,在常规人群出生缺陷监测基础上,可将部分出生缺陷监测时间延长至3岁,可发现更多常规监测以外的出生缺陷种类,为出生缺陷预防提供可靠依据。     

Prevention of mother-to-child transmission of HIV in Thailand: physicians' attitudes on zidovudine use, pregnancy termination, and willingness to provide care.

We administered a survey to Thai physicians, using regular mail, on their attitudes and practices regarding zidovudine (ZDV) use and pregnancy termination in HIV-infected pregnant women. We surveyed their willingness to care for these patients as well. In 1997, 79.5% of 480 respondents reported that they did not routinely use perinatal ZDV prophylaxis. Predictors of failure to use ZDV found to be significant in our logistic regression model included practice outside of Bangkok (odds ratio [OR] = 2.0), belief that ZDV is not cost effective (OR = 2.5), unfamiliarity with AIDS Clinical Trials Group (ACTG) 076 results (OR = 2.5), and failure to screen for HIV routinely (OR = 4.9). Elective abortion for HIV-infected women was advocated by 45.3% of respondents. Factors associated in multivariable analysis with this preference included specialty training in obstetrics/gynecology (OR = 1.8), practice inside Bangkok (OR = 2.0), male gender (OR = 1.9), and treatment of < or =2 HIV-infected patients yearly (OR = 1.8). A significant proportion of respondents described themselves as unwilling to perform pelvic examinations (19.2%), vaginal deliveries (30.7%), or cesarean deliveries (39.5%) on women who were known to be infected with HIV. We conclude that many Thai obstetric providers are reluctant to care for HIV-infected women, do not routinely use perinatal ZDV prophylaxis, and prefer to terminate pregnancies among HIV-infected patients. Physician education concerning the value of HIV screening and antiretroviral therapy in HIV-infected pregnant women is needed urgently in Thailand.     

Effects of prenatal exposure to the CB-1 receptor agonist WIN 55212-2 or CO on the GABAergic neuronal systems of rat cerebellar cortex

The aim of this study was to assess the effects of prenatal exposures to cannabinoids or carbon monoxide (CO) in an animal experimental model reproducing the environmental conditions in which a fetus develops whose mother, during pregnancy, ingests by smoking low doses of cannabinoids or CO. Particular attention was devoted to analyses of the long-term effects of the exposures at the level of the cerebellar cortex, where already during prenatal development the GABAergic neuronal systems may be modulated by both cannabinoids and CO. Three groups of rats were subjected to the following experimental conditions: exposure to cannabinoids by maternal treatment during pregnancy with the cannabinoid CB-1 receptor agonist WIN 55212-2 (WIN) (0.5 mg/kg/day, s.c.); exposure to CO by maternal exposure during pregnancy to CO (75 parts per million, by inhalation); and exposure to WIN+CO at the above doses and means of administration; a fourth group was used as control. The body weight of dams, length of pregnancy, litter size at birth, body weight and postnatal mortality of pups were monitored in order to evaluate possible effects of the exposures on reproduction and on prenatal and postnatal development. In the different groups, the long-term effects of the exposures were studied in adult rats (120-150 days) by light microscopy analyses of the structure of the cerebellar cortex and of the distribution in the cortex of markers of GABAergic neurons, such as GAD and GABA itself. Results. Exposures to WIN or CO did not affect reproduction or prenatal/postnatal development. Moreover, the exposed rats showed no structural alterations of the cerebellar cortex and displayed qualitative distribution patterns of GAD and GABA immunoreactivities similar to those of the controls. However, quantitative analyses indicated significant changes of both of these immunoreactivities: in comparison with the controls, they were significantly increased in WIN-exposed rats and reduced in CO-exposed rats, but not significantly different in WIN+CO-exposed rats. The changes were detected in the molecular and Purkinje neuron layers, but not in the granular layer. Prenatal exposures of rats to WIN or CO, at doses that do not affect reproduction, general processes of development and histomorphogenesis of the cerebellar cortex, cause significant changes of GAD and GABA immunoreactivities in some GABAergic neuronal systems of the adult rat cerebellar cortex, indicating selective up-regulation of GABA-mediated neurotransmission as a long-term consequence of chronic prenatal exposures to cannabinoids or CO. Because the changes consist of overexpression or, vice versa, underexpression of these immunoreactivities, functional alterations of opposite types in the GABAergic systems of the cerebellum following exposure to WIN or CO can be postulated, in agreement with the results of behavioral and clinical studies. No changes in immunoreactivities were detected after prenatal exposure to WIN and CO in association.     

Self‐reported illness and birth weight in the Philippines: Implications for hypotheses of adaptive fetal plasticity

It has been proposed that prenatal nutrition provides the fetus with a cue allowing it to adjust biological settings in anticipation of postnatal nutrition. To evaluate the reliability of fetal growth rate as a nutritional cue, this study assesses the extent to which a nonnutritional factor‐maternal illness symptoms during pregnancy‐predicts birth outcomes in a large, population‐based sample of Filipino women and their newborns (n = 2,887). Self‐reported illness symptoms were collected during pregnancy and used to predict weight, length, BMI, and gestational age at birth. Independent of potential confounders, number of reported symptoms predicted a significant dose‐response decrease in birth weight and BMI, but not length that reflected a combination of reduced fetal growth rate and reduced duration of gestation. These effects were comparable in male and female offspring, but tended to be stronger when reported closer to term. Among women interviewed at 32 weeks gestation or later, multiple symptoms predicted a 144 g birth weight reduction compared with no symptoms. These findings suggest an acute effect of maternal illness on fetal nutrition late in gestation when growth rate and fat deposition are most rapid. Although modest, the effect was larger than that of most pregnancy macronutrient supplementation trials. These findings using crosssectional, self‐reported illness symptoms highlight a nonnutritional maternal influence on fetal nutrition, which could attenuate its value as a cue of postnatal ecology. Am. J. Hum. Biol., 2008. © 2008 Wiley‐Liss, Inc.