RESUMEN
BACKGROUND: Seven days of antibiotics are recommended in the setting of preterm premature rupture of membranes (PPROM) to promote latency. Azithromycin has generally replaced a seven-day course of erythromycin in current clinical practice. Azithromycin clears from plasma quickly and concentrates in local tissue which is why daily dosing is not always needed and local tissue, rather than plasma, concentrations are used to determine dosing. Based on limited pharmacokinetic studies in pregnancy, 1g one time dose of azithromycin may not maintain local (amniotic fluid) drug concentrations above minimum inhibitory concentrations (MIC50) for common genitourinary pathogens (50-500ng/ml). OBJECTIVE: We aim to compare the pharmacokinetics of one-time vs daily dosing of azithromycin in the setting of preterm pre-labor rupture of membranes (PPROM) STUDY DESIGN: This is a randomized clinical trial of singletons with PPROM randomized to 1gram oral azithromycin once or 500mg oral azithromycin daily x7 days. Primary outcome was amniotic fluid azithromycin concentrations over 8 days. Secondary outcomes included plasma azithromycin trough concentrations. Plasma was collected at time points 1-4hrs and 12-24hrs after first dose, and then every 24hrs through 8 days. Amniotic fluid was collected opportunistically throughout the day noninvasively with Always Flex-foam pads. We aimed to enroll 20 participants to achieve N=5 still pregnant through 8 days in each group. Continuous variables compared with Mann Whitney U test and relationship between azithromycin concentration and time assessed with linear regression. RESULTS: The study was halted after N=6 enrolled due to lagging enrollment, with 3 in each group. The mean gestational age of enrollment was 27.1±1.7weeks in the 1g group and 31.0±1.4 weeks in the 500mg daily group. One participant in each group had latency to delivery >7days. Regarding amniotic fluid azithromycin concentration, there was a difference in change in amniotic fluid azithromycin concentration over time between groups (p<0.001). Amniotic fluid concentration of azithromycin was relatively stable in the 1g once group (B=-0.07 (-0.44 - 0.31), p=0.71), in contrast, amniotic fluid concentration (ng/ml) increased over time (hours) in the 500mg daily group (B=1.3 (0.7 - 1.9), p<0.001). By ≥96hours median amniotic fluid levels of azithromycin were lower in the 1g once dosing group (median 11[7-56]) compared to 500mg daily (median 46 [23-196]), with a median difference -27 (-154 to -1), p=0.03. In plasma, there was higher azithromycin concentration during the first 24hrs with 1g once vs 500mg daily (median difference 637ng/ml (101-1547), p=0.01), however by ≥96hrs plasma azithromycin declined and was virtually undetectable in the 1g once group, while trough plasma levels in the 500mg remained elevated (median difference -207ng/ml (-271 to -155), p=0.03). CONCLUSION: 500mg daily dosing of azithromycin maintains higher amniotic fluid concentrations, and more consistently greater than common MICs, over eight days compared to 1g once in the setting of PPROM.
RESUMEN
Methadone maintenance treatment for opioid dependent mothers is standard of care. Infants of methadone maintained opioid dependent (MMOD) mothers have better outcomes compared to infants of opioid dependent mothers without treatment. However, when compared to non-exposed infants, infants of MMOD mothers are associated with worse outcomes. We conducted a pilot study to examine genome wide differential DNA methylation using cord blood samples from sixteen term and near-term infants of MMOD and opioid naïve mothers, excluding Infants with chorioamnionitis. A total of 152 differentially methylated loci were identified at a difference > + 2, < - 2 and p-value < 0.05. There were 90 hypermethylated loci (59 annotated genes) and 62 hypomethylated loci (38 annotated genes) observed. The hypermethylated and hypomethylated DNA changes involved multiple genes, pathways and networks that may explain some of the changes seen in infants of MMOD mothers. Top hypermethylated and hypomethylated genes involved areas of cell growth, neurodevelopment, vision and xenobiotic metabolism functions. Our data may explain the role of key pathways and genes relevant to neonatal outcomes seen from methadone exposure in pregnancy. Functional studies on the identified pathways and genes could lead to improved understanding of the mechanisms and identify areas for intervention.
Asunto(s)
Metilación de ADN , Sangre Fetal , Metadona , Trastornos Relacionados con Opioides , Humanos , Femenino , Metadona/uso terapéutico , Sangre Fetal/metabolismo , Embarazo , Trastornos Relacionados con Opioides/genética , Recién Nacido , Adulto , Proyectos Piloto , Tratamiento de Sustitución de Opiáceos , Complicaciones del Embarazo/genética , Complicaciones del Embarazo/tratamiento farmacológico , Masculino , Analgésicos Opioides/uso terapéutico , MadresRESUMEN
OBJECTIVES: Our study evaluated if rapid inpatient titration of methadone for pregnant patients with opioid use disorder (OUD) improved outcomes without increasing the risk for overdose. METHODS: This is a retrospective cohort study of pregnant patients admitted for inpatient methadone titration from January 2020 to June 2022. Outcomes were compared between standard versus rapid titration protocols. Standard titration involved an initial methadone dose with additional doses every 6 hours if clinical opiate withdrawal score (COWS) is >9. Rapid titration involved an initial methadone dose with additional doses every 4 hours if COWS is >9. The primary outcome was time required to achieve stable dose. Secondary outcomes included elopement prior to achieving stable dose, methadone-related readmission, opioid overdose, and final dose. RESULTS: There were 97 patients in the standard titration (STP) and 97 patients in the rapid titration (RTP) groups. Demographic characteristics and substance use history did not differ between the 2 groups. Time to stable dose did not differ between the 2 groups (RTP, 5.0 days ±4.0; STP, 4.0 days ±3.0; P = 0.08). Patients in the rapid titration group were less likely to elope from the hospital prior to stabilization (RTP 23.0% vs STP 37.9%, P = 0.03) and had fewer methadone-related readmissions (P < 0.001). One patient (1.0%) in the RTP group required naloxone treatment while inpatient for concern for overdose, while none did in the STP group (P = 0.32). There was no difference in median final stable dose between the 2 groups (P = 0.07). CONCLUSIONS: Rapid titration of methadone for pregnant patients with OUD was associated with decreased medical elopement and methadone-related readmission, without increasing the risk for overdose.
RESUMEN
BACKGROUND: Both progestogens and cerclage are individually effective in preterm birth prevention in high risk pregnancies. However, national and international guidelines cite a lack of data available to comment on the potential benefit of concurrent progestogen therapy after cerclage has been placed. Studies to date have been small with mixed results regarding benefit of concurrent progestogen with cerclage leaving uncertainty regarding best clinical practice. OBJECTIVE: This study aimed to evaluate whether cerclage with progestogen therapy was superior to cerclage alone in the prevention of spontaneous preterm birth in singleton pregnancies. METHODS: This is an international retrospective cohort study of singleton pregnancies, without major anomaly or aneuploidy, and with cerclage placed at 10 different institutions in the United States and Colombia from June 2016 to June 2020. Exclusion criteria were lack of documentation regarding whether progestogen was prescribed, unavailable delivery outcome, and pregnancy termination (spontaneous or induced) before 16 weeks' gestation. The exposure of interest was progestogen use with cerclage placement, which included those who continued to use progestogen or who started progestogen after cerclage. The comparison group consisted of those without progestogen use after cerclage placement, which included those who had no progestogen use during the entire pregnancy or who initiated progestogen and then stopped it after cerclage placement. Progestogen type, cerclage indication, maternal baseline characteristics, and maternal/neonatal outcomes were collected. The primary outcome was spontaneous preterm birth at <37 weeks. The secondary outcomes were spontaneous preterm birth at <34 weeks, gestational age at delivery, and a composite neonatal outcome including ≥1 of the following: perinatal mortality, confirmed sepsis, grade III or IV intraventricular hemorrhage, retinopathy of prematurity, respiratory distress syndrome, and bronchopulmonary dysplasia. There were planned subgroup analyses by cerclage indication, progestogen type (vaginal progesterone vs 17-hydroxyprogesterone caproate), preterm birth history, and site. Continuous variables were compared in adjusted analyses with analysis of covariance, and categorical variables were compared with multivariable logistic regression, adjusting for potential confounders with adjusted odds ratio. A Cox regression survival curve was generated to compare latency to spontaneous delivery, censored after 37 weeks. RESULTS: During the study period, a total of 699 singletons met the inclusion criteria: 561 in the progestogen with cerclage group and 138 with cerclage alone. Baseline characteristics were similar, except the higher likelihood of previous spontaneous preterm birth in the progestogen group (61% vs 41%; P<.001). Within the progestogen group, 52% were on 17-hydroxyprogesterone caproate weekly, 44% on vaginal progesterone daily, and 3% on oral progesterone daily. Progestogen with cerclage was associated with a significantly lower frequency of spontaneous preterm birth <37 weeks (31% vs 39%; adjusted odds ratio, 0.59 [0.39-0.89]; P=.01) and <34 weeks (19% vs 27%; adjusted odds ratio, 0.55 [0.35-0.87]; P=.01), increased latency to spontaneous delivery (hazard ratio for spontaneous preterm birth <37 weeks, 0.66 [0.49-0.90]; P=.009), and lower frequency of perinatal death (7% vs 16%; adjusted odds ratio, 0.37 [0.20-0.67]; P=.001). In planned subgroup analyses, association with reduced odds of preterm birth <37 weeks persisted in those on vaginal progesterone, those without a previous preterm birth, those with ultrasound- or examination-indicated cerclage, those who started progestogen therapy before cerclage, and in sites restricted to the United States. CONCLUSION: Use of progestogen with cerclage was associated with reduced rates of spontaneous preterm birth and early spontaneous preterm birth compared with cerclage alone. Although this study was not sufficiently powered for subgroup analysis, the strength of evidence for benefit appeared greatest for those with ultrasound- or examination-indicated cerclage, and with vaginal progesterone. El resumen está disponible en Español al final del artículo.
Asunto(s)
Cerclaje Cervical , Nacimiento Prematuro , Progestinas , Humanos , Femenino , Cerclaje Cervical/métodos , Estudios Retrospectivos , Embarazo , Nacimiento Prematuro/prevención & control , Nacimiento Prematuro/epidemiología , Progestinas/administración & dosificación , Adulto , Estados Unidos/epidemiología , Colombia/epidemiología , Recién Nacido , Estudios de CohortesRESUMEN
Since the development of highly effective direct-acting antivirals, the WHO has set a goal of hepatitis C virus (HCV) elimination by 2030. Key to this strategy is increased screening and treatment. Pregnancy and the postpartum period represent a unique time when underserved populations have increased contact with the healthcare system. We propose using antenatal care to maximize case identification, treatment, and prevention. Pregnant individuals are an ideal sentinel population for HCV surveillance. Universal screening in pregnancy can provide population-level data. Once cases are identified, pregnancy presents an opportunity for intervention. Although not currently WHO approved, clinical trials are examining treatment during pregnancy. In the interim, identification of infection during pregnancy allows for optimization of the treatment cascade postpartum. Pregnancy can be used as a time for prevention. Taking advantage of patient engagement and existing infrastructure, pregnancy presents an opportunity to intervene in the fight for HCV eradication.
Asunto(s)
Hepatitis C Crónica , Hepatitis C , Humanos , Femenino , Embarazo , Hepacivirus , Antivirales/uso terapéutico , Hepatitis C Crónica/epidemiología , Hepatitis C/diagnóstico , Hepatitis C/tratamiento farmacológico , Hepatitis C/epidemiología , Atención PrenatalRESUMEN
BACKGROUND: Low dose aspirin is recommended for prevention of preeclampsia, however there is not consensus on the appropriate dose. Pregnancy specific changes have the potential to impact the pharmacology of aspirin in pregnancy, however there are very limited studies on aspirin pharmacokinetics in pregnancy and none linking pharmacokinetics (PK, drug dose and drug level) to pharmacodynamics (PD, drug dose and physiologic response) in pregnancy. As a result, we do not have a good understanding of the pharmacologic response to aspirin in pregnancy, which has important implications for clinical efficacy. We sought to describe the PK and PD of aspirin through pregnancy and to identify individual covariates that impacted aspirin PK/PD. OBJECTIVE: We sought to describe the PK and PD of aspirin through pregnancy (first and third trimester), to identify covariates that significantly impact aspirin PK and to identify the relationship between aspirin PK and PD. STUDY DESIGN: This is a prospective study of patients at high risk for preeclampsia recommended to take 81 mg aspirin daily. This study involved 3 visits as follows: (1) baseline, first trimester (10-16 weeks of gestation) 6-hour PK visit, done before initiation of aspirin; (2) follow-up 1: 2 to 4 weeks after aspirin initiation; and (3) follow-up 2: third trimester 6-hour PK visit (28-32 weeks of gestation). The following were assessed at each visit: weight or body mass index, platelet function analysis-100 (Siemens), urinary thromboxane B2, serum thromboxane B2, and plasma salicylic acid. The PK visits consisted of blood work done at baseline (predose), administration of 81 mg nonenteric coated aspirin, and then plasma blood level of salicylic acid assessed at 30 minutes and then hourly 1 to 6 hours after dose. Pearson correlation and multivariable regression were used to identify associations between parameters and identify relevant covariates. Log-adjusted values were used for regression analysis. P<.05 was considered statistically significant. RESULTS: Nineteen participants were included with first trimester data, and 16 with third trimester data. There was no statistically significant change in mean PK parameters between the first and third trimester, although there was a trend to lower peak concentration in the third than in the first trimester (P=.08). In multivariable regression, baseline obesity and current body mass index as a continuous measures were negatively associated with log-adjusted peak salicylic acid concentration (-0.28 [-0.46 to -0.11], P=.003 and -0.02 [-0.03 to -0.009], P=.001, respectively) and log-adjusted plasma salicylic acid area under the curve 0 to 6 hours postdose (-0.25 [-0.45 to 0.05], P=.02, -0.04 [-0.07 to -0.01], P=.008 respectively). There was a significant decrease in urinary thromboxane 2 to 4 weeks after aspirin initiation compared with baseline, which correlated with a concomitant increase in platelet function analysis-100 closure time. In multivariable regression model, there was a strong association between plasma salicylic acid concentration (area under the curve 0-6 hours postdose) and urinary thromboxane (B=-3.12 [-5.38 to -1.04], P=.006), and with urinary thromboxane suppression and platelet inhibition, platelet function analysis-100 (-0.23 [-0.31 to -0.14], P<.001). With progressive thromboxane suppression, platelet inhibition (platelet function analysis-100 closure time) increased. Individual comorbidities, including weight, hypertension, and pregestational diabetes (Type I or II), also impacted aspirin response. CONCLUSION: We have demonstrated the relationship between individual factors, plasma concentrations of salicylic acid, thromboxane suppression, and platelet inhibition at a single dose (81 mg) of aspirin taken through pregnancy. Our findings suggest that dose modification of aspirin in pregnancy may help to achieve the optimal response. Our results may be used to facilitate computational modeling to identify optimal dosing, taking into consideration individual factors.