Proximal tubular dysfunction in pregnant women receiving tenofovir disoproxil fumarate to prevent mother-to-child transmission of hepatitis B virus.

BACKGROUND: Data evaluating the risk of proximal tubular dysfunction in women receiving tenofovir disoproxil fumarate for the prevention of mother-to-child transmission (PMTCT) of HBV are scarce. OBJECTIVES: To assess the risk of proximal tubulopathy in pregnant women receiving tenofovir disoproxil fumarate for PMTCT of HBV. PATIENTS AND METHODS: We used urine samples collected from HBV monoinfected pregnant women who participated in a Phase III, multicentre, randomized, double-blind, placebo-controlled clinical trial assessing a tenofovir disoproxil fumarate short course from 28 weeks gestational age (28-wk-GA) to 2 months post-partum (2-months-PP) for PMTCT of HBV in Thailand. Markers of tubular dysfunction, including retinol binding protein, kidney injury molecule-1, α1-microglobuin and ß2-microglobulin, were assayed at 28- and 32-wk-GA and 2-months-PP visits. Proximal tubulopathy was defined as the presence of ≥2 of the following: tubular proteinuria, euglycaemic glycosuria and increased urinary phosphate. RESULTS: A total of 291 women participated in the study. No kidney-related adverse events were severe, and none led to tenofovir disoproxil fumarate discontinuation. At 2-months-PP, 3 of the 120 (3%) evaluated women in the tenofovir disoproxil fumarate group experienced proximal tubulopathy versus 3 of 125 (2%) in the placebo group (P = 1.00). None of the six women met the criteria for proximal tubulopathy at 12-months-PP but proteinuria persisted in three of them. No growth abnormalities were found at 1 year of age in infants born to mothers with proximal tubulopathy at 2-months-PP. CONCLUSIONS: In these HBV-infected pregnant and breastfeeding women, tenofovir disoproxil fumarate administered from 28-wk-GA to 2-months-PP was not associated with a higher risk of proximal tubulopathy.

Tenofovir versus Placebo to Prevent Perinatal Transmission of Hepatitis B.

BACKGROUND: Pregnant women with an elevated viral load of hepatitis B virus (HBV) have a risk of transmitting infection to their infants, despite the infants' receiving hepatitis B immune globulin. METHODS: In this multicenter, double-blind clinical trial performed in Thailand, we randomly assigned hepatitis B e antigen (HBeAg)-positive pregnant women with an alanine aminotransferase level of 60 IU or less per liter to receive tenofovir disoproxil fumarate (TDF) or placebo from 28 weeks of gestation to 2 months post partum. Infants received hepatitis B immune globulin at birth and hepatitis B vaccine at birth and at 1, 2, 4, and 6 months. The primary end point was a hepatitis B surface antigen (HBsAg)-positive status in the infant, confirmed by the HBV DNA level at 6 months of age. We calculated that a sample of 328 women would provide the trial with 90% power to detect a difference of at least 9 percentage points in the transmission rate (expected rate, 3% in the TDF group vs. 12% in the placebo group). RESULTS: From January 2013 to August 2015, we enrolled 331 women; 168 women were randomly assigned to the TDF group and 163 to the placebo group. At enrollment, the median gestational age was 28.3 weeks, and the median HBV DNA level was 8.0 log10 IU per milliliter. Among 322 deliveries (97% of the participants), there were 319 singleton births, two twin pairs, and one stillborn infant. The median time from birth to administration of hepatitis B immune globulin was 1.3 hours, and the median time from birth to administration of hepatitis B vaccine was 1.2 hours. In the primary analysis, none of the 147 infants (0%; 95% confidence interval [CI], 0 to 2) in the TDF group were infected, as compared with 3 of 147 (2%; 95% CI, 0 to 6) in the placebo group (P=0.12). The rate of adverse events did not differ significantly between groups. The incidence of a maternal alanine aminotransferase level of more than 300 IU per liter after discontinuation of the trial regimen was 6% in the TDF group and 3% in the placebo group (P=0.29). CONCLUSIONS: In a setting in which the rate of mother-to-child HBV transmission was low with the administration of hepatitis B immune globulin and hepatitis B vaccine in infants born to HBeAg-positive mothers, the additional maternal use of TDF did not result in a significantly lower rate of transmission. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT01745822 .).

Tenofovir Exposure during Pregnancy and Postpartum in Women Receiving Tenofovir Disoproxil Fumarate for the Prevention of Mother-to-Child Transmission of Hepatitis B Virus.

We assessed tenofovir exposure during pregnancy and postpartum in hepatitis B virus (HBV)-infected HIV-uninfected women receiving tenofovir disoproxil fumarate (TDF) to prevent mother-to-child transmission of HBV. Data from 154 women who received TDF within a randomized controlled trial were included. Individual plasma tenofovir exposures (area under the concentration-time curve from 0 to 24 h [AUC0-24]) were estimated using a population pharmacokinetic approach. The estimated geometric mean tenofovir AUC0-24 was 20% (95% confidence interval [95% CI], 19 to 21%) lower during pregnancy than during postpartum; this modest reduction in the absence of HBV transmission suggests that no dose adjustment is needed.

Antibiotics for meconium-stained amniotic fluid in labour for preventing maternal and neonatal infections.

BACKGROUND: Chorioamnionitis is more likely to occur when meconium-stained amniotic fluid (MSAF) is present. Meconium may enhance the growth of bacteria in amniotic fluid by serving as a growth factor, inhibiting bacteriostatic properties of amniotic fluid. Many adverse neonatal outcomes related to MSAF result from meconium aspiration syndrome (MAS). MSAF is associated with both maternal and newborn infections. Antibiotics may be an effective option to reduce such morbidity. OBJECTIVES: The objective of this review is to assess the efficacy and side effects of prophylactic antibiotics for MSAF during labour in preventing maternal and neonatal infections. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2014).  SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing prophylactic antibiotics with placebo or no treatment during labour for women with MSAF. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. MAIN RESULTS: We included two studies with 362 pregnant women. Both studies compared ampicillin-sulbactam (N = 183) versus normal saline (N = 179) in pregnant women with MSAF. Prophylactic antibiotics appeared to have no statistically significant reduction in the incidence of neonatal sepsis (risk ratio (RR) 1.00, 95% CI 0.21 to 4.76), neonatal intensive care unit (NICU) admission (RR 0.83, 95% CI 0.39 to 1.78) and postpartum endometritis (RR 0.50, 95% CI 0.18 to 1.38). However, there was a significant decrease in the risk of chorioamnionitis (RR 0.36, 95% CI 0.21 to 0.62). No serious adverse effects were reported. Drug resistance, duration of mechanical ventilation and duration of admission to NICU/hospital were not reported. Most of the domains for risk of bias were at low risk of bias for one study and at unclear risk of bias for the other study. The quality of the evidence using GRADE was low for neonatal sepsis, postpartum endometritis, and neonatal mortality and morbidity prior to discharge (Neonatal intensive care admissions) and of moderate quality for chorioamnionitis. AUTHORS' CONCLUSIONS: Current evidence indicates that compared to placebo, antibiotics for MSAF in labour may reduce chorioamnionitis. There was no evidence that antibiotics could reduce postpartum endometritis, neonatal sepsis and NICU admission. This systematic review identifies the need for more well-designed, adequately powered RCTs to assess the effect of prophylactic antibiotics in the incidence of maternal and neonatal complications.

Antibiotics for meconium-stained amniotic fluid in labour for preventing maternal and neonatal infections.

BACKGROUND: Chorioamnionitis is more likely to occur when meconium-stained amniotic fluid (MSAF) is present. Meconium may enhance the growth of bacteria in amniotic fluid by serving as a growth factor, inhibiting bacteriostatic properties of amniotic fluid. Many adverse neonatal outcomes related to MSAF result from Meconium Aspiration Syndrome (MAS). MSAF is associated with both maternal and newborn infections. Antibiotics may be an effective option to reduce such morbidity. OBJECTIVES: The objective of this review is to assess the efficacy and side effects of prophylactic antibiotics for MSAF during labour in preventing maternal and neonatal infections. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2010).  SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing prophylactic antibiotics with placebo or no treatment during labour for women with MSAF. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the results of the only available trial and extracted data on maternal and neonatal outcomes. MAIN RESULTS: We included one study with 120 pregnant women. It compared ampicillin-salbactam (N = 60) versus normal saline (N = 60) in pregnant women with MSAF. Prophylactic antibiotics appeared to have no statistically significant reduction in the incidence of neonatal sepsis (risk ratio (RR) 1.00, 95% CI 0.21 to 4.76), neonatal intensive care unit (NICU) admission (RR 0.83, 95% CI 0.39 to 1.78) and postpartum endometritis (RR 0.50, 95% CI 0.18 to 1.38). However, significant decrease in the risk of chorioamnionitis (RR 0.29, 95% CI 0.10 to 0.82). No serious adverse effects were reported. AUTHORS' CONCLUSIONS: Current evidence indicates that compared to placebo, antibiotics for MSAF in labour may reduce chorioamnionitis. There was no evidence that antibiotics could reduce postpartum endometritis, neonatal sepsis and NICU admission. This systematic review identifies the need for more well-designed, adequately powered RCTs to assess the effect of prophylactic antibiotics in the incidence of maternal and neonatal complications.

Perinatal Antiretroviral Intensification to Prevent Intrapartum HIV Transmission When Antenatal Antiretroviral Therapy Is Initiated Less Than 8 Weeks Before Delivery.

INTRODUCTION: Infants born to women living with HIV initiating combination antiretroviral therapy (cART) late in pregnancy are at high risk of intrapartum infection. Mother/infant perinatal antiretroviral intensification may substantially reduce this risk. METHODS: In this single-arm Bayesian trial, pregnant women with HIV receiving standard of care antiretroviral prophylaxis in Thailand (maternal antenatal lopinavir-based cART; nonbreastfed infants 4 weeks' postnatal zidovudine) were offered "antiretroviral intensification" (labor single-dose nevirapine plus infant zidovudine-lamivudine-nevirapine for 2 weeks followed by zidovudine-lamivudine for 2 weeks) if their antenatal cART was initiated ≤8 weeks before delivery. A negative birth HIV-DNA polymerase chain reaction (PCR) followed by a confirmed positive PCR defined intrapartum transmission. Before study initiation, we modeled intrapartum transmission probabilities using data from 3738 mother/infant pairs enrolled in our previous trials in Thailand using a logistic model, with perinatal maternal/infant antiretroviral regimen and predicted viral load at delivery as main covariates. Using the characteristics of the women enrolled who received intensification, prior intrapartum transmission probabilities (credibility intervals) with/without intensification were estimated. After including the transmission data observed in the current study, the corresponding Bayesian posterior transmission probability was derived. RESULTS: No intrapartum transmission of HIV was observed among the 88 mother/infant pairs receiving intensification. The estimated intrapartum transmission probability was 2·2% (95% credibility interval 0·5-6·1) without intensification versus 0·3% (0·0-1·6) with intensification. The probability of superiority of intensification over standard of care was 94·4%. Antiretroviral intensification appeared safe. CONCLUSION: Mother/infant antiretroviral intensification was effective in preventing intrapartum transmission of HIV in pregnant women receiving ≤8 weeks antepartum cART.