Chiriboga Claudia A, Kuhn Louise, Wasserman Gail A
Division of Pediatric Neurology, Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, USA ; Sergievsky Center, Columbia University, New York, NY, USA ; Harlem Hospital Center, New York, NY, USA.
Sergievsky Center, Columbia University, New York, NY, USA.
J Neurol Psychol. 2014 Nov;2(3). doi: 10.13188/2332-3469.1000015.
In experimental models, prenatal cocaine exposure has been found to perturb GABA and dopamine development. Clinically, abnormalities in tone, posture and state regulation are noted in early infancy but the evolution of these findings over time is not well described. The current study assesses the longitudinal effects of prenatal cocaine exposure in dose-dependent fashion on developmental & behavioral and neurological trajectories over the first 2 years of life.
Three hundred and eighty infants, 113 cocaine-exposed, were enrolled at birth from an urban hospital from 2000 to 2004. Exposure was determined by maternal interview, segmental hair analyses (RIAH) in all, and meconium and urine in a subset. Developmental, behavioral and neurological assessments were carried out blind to drug exposure at 6, 12 and 24 months of age in the 306 children who returned in follow-up. Mixed-effects linear modeling (developmental growth curve) assessed change in outcome over time.
The mental developmental growth curve showed a negative slope (2.2 points) in adjusted analyses among cocaine-exposed children over the first 2 years of life. (p=.04), while the slope of the motor development growth curve did not. Adjusting for microcephaly at 6 months diminished the strength of the association between cocaine exposure and mental developmental growth curve (effect modification). Cocaine exposure was marginally associated with behavioral outcomes in adjusted analyses. Total Behavior scores and Orientation/Engagement scores improved with age. At 1 year of age, prenatal cocaine exposure was significantly associated with lower motor development scores. High rates of hypertonia (global and diparesis) identified at the 6-month visit dropped dramatically in the first 2 years of life: cocaine-exposed children showed a more rapid rate of resolution of hypertonia than unexposed children, with hypertonia improving 2.2 times faster among those with heavy cocaine exposure.
We found differences in mental performance over the first 2 years of life associated with prenatal cocaine exposure that was mediated by microcephaly implying that cocaine exerts a sustained teratogenic effect on brain development. Early neurological (hypertonia) and behavioral findings associated with prenatal cocaine exposure improved over time. Hypertonia did not predict long-term development impairments. Conceivably, the transient nature of neurobehavioral manifestations reflects postnatally a tendency towards homeostasis of cocaine-related embryopathic perturbations of GABA and dopaminergic systems.
在实验模型中，已发现产前可卡因暴露会干扰γ-氨基丁酸（GABA）和多巴胺的发育。在临床上，婴儿早期会出现肌张力、姿势和状态调节异常，但这些发现随时间的演变情况并未得到充分描述。本研究以剂量依赖方式评估产前可卡因暴露对生命最初2年发育、行为和神经轨迹的纵向影响。
2000年至2004年，从一家城市医院招募了380名婴儿，其中113名有产前可卡因暴露史。通过产妇访谈确定暴露情况，全部进行分段毛发分析（RIAH），部分进行胎粪和尿液检测。对随访回来的306名儿童在6、12和24月龄时进行发育、行为和神经学评估，评估时对药物暴露情况设盲。采用混合效应线性模型（发育生长曲线）评估随时间变化的结果。
在调整分析中，产前可卡因暴露儿童在生命的头2年中，智力发育生长曲线呈负斜率（2.2分）（p = 0.04），而运动发育生长曲线的斜率则没有。校正6个月时的小头畸形后，可卡因暴露与智力发育生长曲线之间的关联强度减弱（效应修正）。在调整分析中，可卡因暴露与行为结果存在边缘关联。总行为得分和定向/参与得分随年龄增长而改善。1岁时，产前可卡因暴露与较低的运动发育得分显著相关。6个月时发现的高肌张力（全身性和双瘫性）发生率在生命的头2年中大幅下降：产前可卡因暴露儿童的高肌张力缓解速度比未暴露儿童更快，重度可卡因暴露儿童的高肌张力改善速度快2.2倍。
我们发现生命最初2年中与产前可卡因暴露相关的智力表现存在差异，这种差异由小头畸形介导，这意味着可卡因对大脑发育具有持续的致畸作用。与产前可卡因暴露相关的早期神经学（高肌张力）和行为表现随时间改善。高肌张力并不能预测长期发育障碍。可以想象，神经行为表现的短暂性在出生后反映了与可卡因相关的GABA和多巴胺能系统胚胎病变扰动的内稳态倾向。
