We report cortisol stress reactivity in school aged children with prenatal cocaine exposure. We found that cortisol reactivity to stress was more likely to be blunted in children with prenatal cocaine exposure. These effects were also related to domestic violence but they were independent of other covariates including prenatal and postnatal drug exposures. Thus, more children with prenatal cocaine exposure and exposure to domestic violence showed the blunted cortisol response than children with prenatal cocaine exposure or exposure to to show the blunted cortisol response than children domestic violence alone. We also found that children with heavy prenatal cocaine exposure were more likely with no cocaine exposure. These effects were independent of covariates including domestic violence suggesting that there is no association between cortisol reactivity and domestic violence in children with heavy cocaine exposure.
The association between stress and activation of the HPA axis, ultimately resulting in an increased secretion of cortisol from the adrenal glands has been well documented since the work of Selye. [42
] However, a growing literature suggests that the adrenal is hypoactive in some stress-related states, resulting in suppression of the HPA axis. [43
] Examples of such hypocortisolism include low cortisol levels, flat daytime (e.g. morning to evening) production patterns and a blunted cortisol response to stress.[37
] Hypocortisolism is related to prenatal stress and early adversity in animal models. The exposure of infant rats to stress, such as daily handling, results in decreased basal corticosterone levels, reduced adrenocortical responses to acute stressors and enhanced suppression of stress-induced HPA activation by dexamethasone in adult life. [46
] Administration of ACTH to pregnant rats results in decreased basal corticosterone levels, reduced adrenocortical reactivity and decreased adrenal volumes in the offspring.[13
In human studies, hypocortisolism has been reported in adults with post-traumatic stress disorder,[49
] patients suffering from bodily disorders, such as burnout with physical complaints, chronic fatigue syndrome, fibromyalgia, chronic pelvic pain and asthma among others, [50
] in very low-income women with high levels of depressive symptoms[55
] and in healthy individuals who lived under conditions of ongoing stress. [56
] In children, hypocortisolism has been reported in at risk populations of children,[37
] including children with chronic stress,[43
] children reared in institutions,[61
] or in foster care, [62
] boys with attention problems, [64
] clinically depressed maltreated school aged children,[65
] boys of low income depressed mothers,[67
] post-traumatic stress disorder,[68
] boys with antisocial behavior [69
] and autism.[76
] Blunting specifically has been found in children with psychosocial dwarfism,[77
] atopic dermatitis,[35
] Oppositional Defiant Disorder (ODD),[78
] juvenile delinquents with ODD and Conduct Disorder (CD),[79
] early onset or adolescent onset CD,[80
] sexually abused girls,[81
] and maltreated children.[12
Hypocortisolism is one form of neurobiological dysregulation of the HPA axis and there are a number of potential mechanisms involved including reduced biosynthesis at various levels of the HPA axis, hypersecretion of CRH in the hypothalamus, increased and enhanced sensitivity to the negative feedback of developmental perspective it has been suggested that early experience can affect adult health in at least two glucocorticoids, and morphological changes such as structural changes of the adrenal gland.[13
] From a ways, by the biological embedding of insults during sensitive developmental periods and by accumulating damage over time due to chronic stress.[82
] It is likely that the combination of biological embedding and cumulative stress resulted in the hypocortisolism that we observed.
We speculate that the biological embedding in our study is due to the insult of prenatal cocaine exposure that could have affected the intrauterine neuroendocrine environment. As a toxin, the teratogenic effects of cocaine have been described along two major pathways but there may be a third pathophysiology in which cocaine affects the HPA system. The first pathway is the direct effects of cocaine on neurotransmitter turnover in the brain and peripheral nervous system sites. Preclinical studies suggest effects of prenatal cocaine exposure on the developing monoaminergic system, resulting in both structural and functional changes to circuitry subserving functions such as arousal, regulation and reactivity.[83
] The second pathway is through vasoconstrictive effects on arteries in the uterus resulting in increased plasma catecholamine concentrations and marked secondary effects such as fetal hypoxemia and possibly ischemic injury.[85
] Elsewhere, we[86
] have suggested a third neuroendocrine pathophysiology. In this model, cocaine acts as an intrauterine stressor altering the expression of key placental genes, specifically the norepinephrine transporter (NET) and 11ß-HSD-2 which protect the fetus from excess catecholamines and glucocorticoids. 11ß-HSD-2 in particular converts maternal cortisol to inert cortisone protecting the developing fetus from exposure to maternal cortisol.[87
] Epigenetic mechanisms such as DNA methylation downregulate 11ß-HSD-2, increasing fetal exposure to cortisol and shifting the set points for HPA axis responses to the extrauterine environment.[86
] Prenatal stressors other than cocaine including other substances such as tobacco or other types of insults such as low birthweight could have similar affects. This could result in dysregulation, e.g., hyperactivity of the HPA axis, which becomes hypoactive with cumulative exposure to postnatal stress.
Hypocortisolism is one pattern that can result from the long-term effect of the physiologic response to stress. This has been referred to as “allostatic load” or the wear and tear of the body produced by the repeated activation of the HPA axis and related biological stress systems.[88
] This prolonged activation of the neuroendocrine stress axes has been related to physical disease and behavioral disorders.[90
] The children in our study are growing up in largely impoverished, high risk environments and the children with blunted cortisol response. As mentioned earlier, hypocortisolism has been related to chronic stress in prenatal cocaine exposure who were also exposed to domestic violence were the most likely to show the children.[43
] Other studies have documented the associations between adverse environments and cortisol reactivity, [5
] including violence [14
] and violence has also been associated with the effects of prenatal cocaine exposure on child outcome.[19
] Our findings also relate to those of Eiden et al [18
] who found that cortisol reactivity in cocaine exposed infants was moderated by caregiving instability suggesting that postnatal environmental factors can exacerbate the effects of prenatal cocaine exposure supporting a dual hazard vulnerability model.[18
] We suggest that the cumulative exposure to stress experienced by the children in our study could have resulted in allostatic load leading to downregulation of the HPA axis and the hypocortisolemic blunted cortisol response.
Parental substance use and family violence are major risk factors included under the description of toxic stress developed by the National Scientific Council on the Developing Child[91
] that refers to chronic activation of the HPA and related stress response systems resulting in stress related disorders. The notion of toxic stress is also important because of our finding related to heavy cocaine exposure. At this more “toxic” dose, there was no effect of domestic violence on cortisol reactivity which could suggest that at high levels of prenatal cocaine exposure the physiological pathways that were altered in utero
may have been affected by the overall chronic adversity endemic in the sample as a whole.
One limitation of this study is that genetic factors were not measured. Also, cortisol was measured from saliva rather than blood. However, the correlation between salivary and plasma cortisol in serum or plasma is very high (r>.90)[92
] and saliva sampling has the advantage of being a non-invasive technique. On the other hand blood sampling would have enabled us to also sample ACTH which is “higher up” on the HPA axis and is the principle tropic hormone for cortisol. The design of our study could be considered both a weakness and strength. The limitation is that there is no group without prenatal drug exposure or adversity in the postnatal caregiving environment. Therefore it is impressive that effects such as those reported here can be detected between two groups of essentially high risk children. The fact that these differences can be detected suggests that these are robust effects. It may be useful to include other physiological measures that are part of the activation of the HPA axis response to stress, such as blood pressure or heart rate. Of the methodological factors we examined, only time of day was associated with baseline cortisol level. However, time of day was not associated with cocaine exposure group or cortisol reactivity. Therefore, it is unlikely that our results were affected by time of day. We also ruled out potential effects of steroid medication, food or beverage consumption or exercise. Of course, it is possible that there are factors that we did not measure that could have affected our findings. A final limitation is sample size. Only approximately half of the subjects from the original sample were included. However, there were no clinically significant differences between those included and those not included (). The cell size was also small (n=37) for children with heavy prenatal exposure.
Most of the literature on the effects of prenatal cocaine exposure is focused on behavioral outcomes. In other populations activity of the HPA system, specifically hypocortisolism, is related to psychopathology [94
] and adult disease.[4
] Although the children in our study are certainly at risk for poor developmental outcome, [23
] these findings suggest that they may also be at greater risk for adult disease. Prenatal cocaine exposure, including effects on the neuroendocrine system, could contribute to allostatic load which could result in cocaine not only affecting behavior but also the development of stress related medical problems. It is important that these children continue to be followed to determine the possible long term effects of prenatal cocaine exposure on the later development of behavioral disorders and adult disease.