Are Nocebo Effects in Adulthood Linked to Prenatal Maternal Cortisol Levels?

Abstract

Objective: Placebo-induced adverse events, or nocebo effects, occur when doctor-patient communication anticipates the onset of negative symptoms. They have been found to correlate with the anxiety-related activity of the hypothalamic-pituitary-adrenal system. Here we try to determine if prenatal hyperactivity of this system, as assessed through plasma cortisol, may influence nocebo effects in adulthood.

Method: We investigated the rate and magnitude of nocebo effects in 378 adults whose prenatal maternal plasma cortisol was measured during the first, second and third trimester of pregnancy. The healthy subjects underwent a nocebo oxygen challenge. This consisted of the inhalation of fake (placebo) oxygen and assessment of the following adverse events: headache, chest pain, abdominal pain, and cough. Plasma cortisol responses during the nocebo adverse events were also measured.

Results: 41 out of 46 (89.1%) subjects who reported 3 adverse events, and 37 out of 37 (100%) subjects who reported 4 adverse events had prenatal maternal cortisol above normal levels. By contrast, only 10 out of 143 (7%) subjects who reported 0 adverse events showed prenatal maternal cortisol above the normal range. Moreover, whereas subjects who reported 3 and 4 adverse events showed a significant increase in plasma cortisol following the nocebo challenge, subjects who reported 0 adverse events showed no changes.

Conclusions: These findings emphasize the importance of the doctor-patient communication in perceiving symptoms like pain, and suggest that those subjects with high prenatal maternal cortisol may be more sensitive to the effects of a negative communication in adulthood.

Keywords: adverse events; cortisol; hyperalgesia; nocebo; oxygen; placebo; prenatal.

Figure 1.

Workflow and selection of the study participants. BMI=body mass index

Figure 2.

A) The number of adverse events is shown in relation to prenatal maternal cortisol in the 1^st, 2^nd, 3^rd trimester of pregnancy. Horizontal broken lines show the upper limit of the normal range of maternal plasma cortisol. Error bars are standard deviations. B) Increase in maternal plasma cortisol over the 3 trimesters of pregnancy in relation to no adverse events reported in adulthood (0AE), 1 adverse event (1AE), 2 adverse events (2AE), 3 adverse events (3AE), 4 adverse events (4AE). C) Adverse events profile for 0AE, 1AE, 2AE, 3AE, 4AE, whereby the magnitude of adverse events is measured by means of a numerical rating scale from 0 to 10 for headache pain, chest pain, abdominal pain, and by considering the number of coughs for cough. Error bars are standard deviations.

Figure 3.

A) Cortisol response in the NH group shows no efect by merely wearing the oxygen mask. B) In the NOC group, whereas cortisol response to the nocebo oxygen challenge was absent for groups 0AE and 1AE, an increase in cortisol occurred after nocebo administration in groups 2AE, 3AE and 4AE. In addition, cortisol response in 2AE difered significantly from both 3AE and 4AE, suggesting a gradual increase in cortisol secretion as the number of reported adverse events increased. The diferences of the means and their 95% confidence intervals are also shown (significant differences are in bold). Error bars are standard deviations

Figure 4.

Regression lines and 95% CI of prenatal maternal cortisol (trimesters 1, 2, 3) versus baseline cortisol before (left) and after (right) the nocebo challenge in all the 378 subjects of the NOC group analyzed