Our original study found that women with prenatal antidepressant treatment had babies who were born at a reduced gestational age and were at a higher risk for preterm birth compared to two groups of untreated women. This follow-up study found an association between antidepressants and increased mean saliva estriol levels in the second half of pregnancy, as well as a steeper rise in saliva estriol across gestation. The differences in estriol levels were significant, even when controlling for active maternal depression and anxiety. Our previous study (15
) reported a mean gestational age for the preterm infants of 35.6 weeks (SD=1.1). Our current findings of elevated estriol levels in antidepressant treated women is consistent with the literature that elevated estriol appears to be predictive of late preterm birth (8
). Though preliminary, our data suggests a relationship between antidepressant dose and estriol levels. While our sample size was too small to meaningfully examine the direct relationship between estriol and gestational age for each group, we did find a significant negative correlation between these two variables in the second trimester for all subjects combined.
To our knowledge, this is the first prospective study to demonstrate an elevation in a previously described, biologic marker for preterm birth (8
) in antidepressant exposed women who subsequently delivered at a shorter gestational age and had a higher rate of prematurity. While the pathophysiologic processes involved in preterm birth are unclear, studies have shown that the pattern of rise in maternal saliva estriol concentrations, which reflect unbound, unconjugated maternal serum levels (20
), during the latter part of pregnancy correlate with duration of pregnancy (5
). Other biochemical markers that have also been associated with preterm birth include fetal fibronectin and corticotropin releasing hormone (CRH) (23
Estriol is produced almost entirely from precursors derived from the fetal adrenal gland and liver (24
), serving as a direct marker for the activity of the fetal adrenal gland. Levels of estriol demonstrate a characteristic, exponential increase two to four weeks before the onset of spontaneous labor. Goodwin (24
) proposed a possible mechanism by which an estrogen dominant milieu could have a positive influence on labor. He suggested that increased estriol in late pregnancy increases the activity of 11 beta hydroxysteroid dehydrogenase, which metabolizes maternal cortisol to inactive cortisone, thereby decreasing the suppression of the fetal hypothalamic-pituitary-adrenal (HPA) axis. The resulting increased DHEAS from the fetal zone of the adrenal gland would lead to increased estriol, further stimulating 11 beta hydroxysteroid dehydrogenase. Further positive feedback could also result as increased cortisol from the definitive zone of the fetal gland competes with progesterone for sites on placental glucocorticoid receptors, removing the potential inhibitory effect of progesterone on placental CRH release (25
), and increasing stimulation of the fetal pituitary. The estrogen dominant milieu created by the increase in estriol would result in conditions favoring labor, including the induction of uterine oxytocin receptors, myometrial gap junction proteins, and prostaglandin synthetases (26
The elevation of estriol levels in our study supports literature demonstrating an effect of antidepressants on the duration of pregnancy and suggests a potential endocrine mechanism. How or where antidepressants may interact with the pathways elucidated above remains to be further explored. Our study does not allow us to determine whether treatment with antidepressants increased estriol levels which then resulted in earlier birth, or whether antidepressants shortened gestational age through another mechanism, with higher estriol levels being a marker of this effect. Chronic treatment with antidepressants has been shown to decrease CRH mRNA and CRH concentrations in the hypothalamus of rats (29
), supporting clinical evidence that successful pharmacologic treatment is associated with normalization of dysregulated CRH levels (32
). It is not implausible to consider that antidepressant treatment may also result in changes in estriol levels, though a causal relationship remains to be further investigated.
It is possible that women in this study who chose not to be treated with antidepressants were different in some respect that could reflect on estriol levels. During pregnancy, total and free plasma cortisol levels increase steadily, peaking during the third trimester and maintaining a diurnal variation. For patients with major depression, hyperactivity of the HPA axis has been repeatedly demonstrated (33
), with increased 24-hour urine free cortisol, elevated plasma and CSF concentrations of cortisol, and nonsuppression of cortisol, beta-endorphin and ACTH following desamethasone administration. Exogenous corticosteroids have been shown to decrease estriol levels, and, thus, the hyperactivity of the HPA axis in our depressed subjects could have influenced estriol levels. However, a recent study of the effect of depression on the cortisol awakening response during pregnancy did not find a significant difference between women who were depressed and normal controls (36
). In addition, both groups of subjects in our study with a history of depression (on and off antidepressants) had a similar degree and duration of depression. Subjects in the antidepressant treated group included those who attempted to decrease or discontinue medication, switched to a different medication, or chose partial improvement with a lower dose. Active symptoms of depression were comparable between these two groups and did not significantly influence estriol results.
Several factors can influence saliva estriol levels, including diurnal variations, corticosteroids, activity, food consumption, and oral lesions or gingivitis. None of the women in our study were taking steroids, and time of day was not a significant variable. While women were given explicit instructions regarding collection procedures, including food consumption, activity level, and concurrent medication use, oral lesions and hygiene was not assessed.
Despite study limitations, our results suggest an association between prenatal antidepressant use and elevated saliva estriol levels in the second half of pregnancy. Whether the effect of antidepressants on pregnancy duration is mediated by estriol levels or is due to as yet undetermined other factors remains unknown. Further study of the biologic mechanisms involved is warranted.