Monitoring In Utero Drug Exposure

与一般人口相比，吸毒妇女的妊娠并发症发生率较高，婴儿出生体重较轻的发生率较高，先天畸形和死亡率较高。此外，由于新生儿禁欲综合征而延长住院时间的流行率也有所增加。药物暴露的婴儿不良事件的风险可直接受到剂量、滥用物质的类别和宫内暴露时间的影响。此外，多种药物的使用也可能对胎儿的发育结果产生影响。为了更好地了解非法和合法物质对发育中的胎儿的作用，我们有必要开发改进的检测方法，并更好地了解药物穿过胎盘膜的转运过程。关于母体血浆、尿液、唾液、汗液和毛发中的药物浓度与羊水、脐带血、胎尿、胎粪和胎毛之间的关系的数据有限。我们设计了几项研究，以调查母体和胎儿药物处置在各种生物液体和组织。每个母体样本提供了妊娠不同阶段的药物暴露史。 胎儿标本提供了关于产前药物暴露的独特信息。 胎粪在妊娠的第13周开始形成，毛发在妊娠的最后三个月开始形成。每个矩阵都提供了确定不同矩阵中药物浓度是否与孕产妇和新生儿结局指标相关的机会。此外，由于胎儿基质中药物浓度低，因此有必要开发灵敏和选择性的方法来检测这些化合物。正在改进分析方法，以提供更灵敏、更可靠的方法来检测各种产妇和婴儿样本中的阿片类药物的母体药物和代谢物，包括丁丙诺啡和美沙酮、可卡因、甲基苯丙胺、大麻素和尼古丁。子宫内暴露后药物测量的分析挑战之一是新生儿样本中的药物和代谢产物谱可能与成人生物体液中的药物和代谢产物谱完全不同。这对于早产儿来说可能尤其如此。 对我们来说，一个重要的新举措是与儿科艾滋病毒/艾滋病队列研究（PHACS）一起量化胎粪中的抗逆转录病毒药物。儿科HIV/AIDS队列研究（PHACS）是一项纵向研究，开始于2007年，评估在宫内和/或出生后前两个月内暴露于抗逆转录病毒（ARV）的异常发生率，包括婴儿期和青春期的代谢、生长、心脏、神经系统、神经发育、行为、语言和听力领域。在PHACS队列中，ARV毒性监测（SMARTT）研究正在检查HIV感染妇女所生的未感染HIV的儿童的临床和实验室数据，以评估与妊娠期ARV暴露相关的不良事件的潜在信号。一些新生儿在妊娠期接触抗逆转录病毒药物的潜在毒性引起了人们的关注，包括线粒体功能障碍、骨孔隙率增加以及听力和语言障碍。非常需要准确地量化胎儿的抗逆转录病毒暴露。我们正在与该小组合作，提供胎粪中20种分析物的ARV测量结果;胎粪中的浓度可能更好地预测可能发生ARV相关毒性的婴儿。目的是确定胎粪ARV分析是否比母体药物史更能预测发育异常。 目前，我们还在研究胎粪中乙基葡萄糖醛酸苷、硫酸乙酯和脂肪酸乙酯浓度的效用，以检测妊娠期间母亲的饮酒情况。关于哪种标志物最能预测母亲的饮酒行为，以及哪种标志物应用于筛查婴儿潜在的酒精相关问题，该领域存在很大的争议。我们正在与大型临床研究合作，包括PHACS和SIDS产前酒精和死产（PASS，安全通道）研究，以评估这些目标。

Drug-abusing women have higher rates of pregnancy complications and an increased incidence of infants with lower birth weights and higher rates of congenital malformations and mortality than are seen within the general population. In addition, there is an increased prevalence for longer hospitalization due to neonatal abstinence syndrome. The risk of adverse events in drug-exposed infants can be directly influenced by dose, class of abused substance and time of intrauterine exposure. In addition, poly-drug use may also have an effect on the developmental outcome of the fetus. To better understand the role illicit and licit substances have on the developing fetus, it is necessary that we develop improved methods of detection and gain a better understanding of the transport process involved in the transfer of drug across the placental membrane. Limited data are available correlating the relationships between maternaldrug concentration in plasma, urine, saliva, sweat and hair to amniotic fluid, cord blood, fetal urine, meconium and fetal hair. We have designed several studies to investigate maternal and fetal drug disposition in a variety of biological fluid and tissues. Each maternal specimen provides a history of drug exposure at different stages of gestation. Fetal specimens offer unique information about prenatal drug exposure. Meconium begins to be formed in the 13th week of gestation and hair in the last trimester. Each matrix offers the opportunity to determine if drug concentrations in different matrices relate to maternal and neonatal outcome measures. In addition, due to the low concentrations of drugs in fetal matrices, it is necessary to develop sensitive and selective methods for detecting these compounds. Analytical methods are being improved to offer more sensitive and reliable methods of detecting the parent drug and metabolites of opiates, including buprenorphine and methadone, cocaine, methamphetamine, cannabinoids and nicotine in a variety of maternal and infant specimens. One of the analytical challenges in measurement of drugs following in utero exposure is that drug and metabolite profiles in neonatal specimens may be quite different than those found in adult biological fluids. This may be especially true for premature infants. A major new inititative for us is the quantification of anti-retroviral drugs in meconium in conjunction with the Pediatric HIV/AIDS Cohort Study (PHACS). The Pediatric HIV/AIDS Cohort Study (PHACS) is a longitudinal study, beginning in 2007, assessing occurrences of abnormalities from antiretroviral (ARV) exposure in utero and/or in the first two months of life in multiple domains, including metabolic, growth, cardiac, neurologic, neurodevelopmental, behavior, language, and hearing domains, during infancy and adolescence. Within the PHACS cohort, the Surveillance Monitoring for ARV Toxicities (SMARTT) study is examining clinical and laboratory data from HIV-uninfected children born to HIV-infected women to assess potential signals for adverse events related to gestational ARV exposure. Concerns are being raised about the potential toxicity in some neonates to gestational ARV exposure, including mitochondrial dysfunction, increased bone porosity, and hearing and language impairment. There is a strong need to accurately quantify fetal ARV exposure. We are collaborating with this group to provide meconium ARV measurements of 20 analytes; concentrations in meconium may better predict infants likely to develop ARV-related toxicities. The goal is to determine if meconium ARV analysis better predicts developmental abnormalities than maternal drug history. Currently we are also investigating the utility of ethyl glucuronide, ethyl sulfate and fatty acid ethyl ester concentrations in meconium to detect maternal alcohol consumption during pregnancy. There is great debate in the field about which marker(s) best predict maternal drinking behavior and which marker(s) should be used to screen infants for potential alcohol-related problems. We are collaborating with large clinical studies including PHACS and Prenatal Alcohol in SIDS and Stillbirth (PASS, Safe Passage) study to evaluate these objectives.