Human Placenta Buffers the Fetus from Adverse Effects of Perceived Maternal Stress

Abstract

Maternal stress during pregnancy is linked to several negative birth outcomes. The placenta, a unique pregnancy-specific organ, not only nourishes and protects the fetus but is also the major source of progesterone and estrogens. As the placenta becomes the primary source of maternal progesterone (P4) and estradiol between 6–9 weeks of gestation, and these hormones are critical for maintaining pregnancy, maternal stress may modulate levels of these steroids to impact birth outcomes. The objective was to test whether maternal perceived stress crosses the placental barrier to modulate fetal steroids, including cortisol, which is a downstream indicator of maternal hypothalamic–pituitary–adrenal (HPA) axis regulation and is associated with negative fetal outcomes. Nulliparous women, 18 years or older, with no known history of adrenal or endocrine illness were recruited during their third trimester of pregnancy at the University of California San Francisco (UCSF) Mission Bay hospital obstetrics clinics. Simultaneous measurement of 10 steroid metabolites in maternal (plasma and hair) and fetal (cord blood and placenta) samples was performed using tandem mass spectrometry along with assessment of the perceived stress score and sociodemographic status. While the maternal perceived stress score (PSS) and sociodemographic status were positively associated with each other and each with the body mass index (BMI) (r = 0.73, p = 0.0008; r = 0.48, p = 0.05; r = 0.59, p = 0.014, respectively), PSS did not correlate with maternal or fetal cortisol, cortisone levels, or fetal birth weight. Regardless of maternal PSS or BMI, fetal steroid levels remained stable and unaffected. Progesterone was the only steroid analyte quantifiable in maternal hair and correlated positively with PSS (r = 0.964, p = 0.003), whereas cord estradiol was negatively associated with PSS (r = −0.94, p = 0.017). In conclusion, hair progesterone might serve as a better marker of maternal stress than cortisol or cortisone and maternal PSS negatively impacts fetal estradiol levels. Findings have implications for improved biomarkers of stress and targets for future research to identify factors that buffer the fetus from adverse effects of maternal stress.

Steroidomics of Pregnant Women at Advanced Age

“…We found placental P4 was 15-fold higher than cortisone in ordinary pregnant women and 5.88-fold in CB. Similarly, Vuppaladhadiam’s group also reported that placental P4 was ~13-fold higher than cortisone levels ( 10 ). These results support the theory that the placenta is the primary source of P4 during pregnancy ( 11 ).…”

“…Once the balance is broken, it will lead to adverse pregnancy and poor fetal outcomes. Vuppaladhadiam’s group ( 10 ) detected 10 types of steroid metabolites in P and CB using ultra-pure liquid chromatography (UPLC) MS, and they described a schematic of steroidogenesis in the maternal-fetal compartments. This diagram intuitively showed the synthesis, transport, and regulation of steroid hormones in the maternal-fetal interface ( Supplementary Figure 1 ).…”

Association between maternal adversity, DNA methylation, and cardiovascular health of offspring: a longitudinal analysis of the ALSPAC cohort study

“…Thus, this measure of adversity may not have captured all stressors during pregnancy, which may conceal a legitimate association and in part explain the null findings. Lastly, emerging evidence has suggested that the human placenta may buffer the effects of maternal stress and protect the developing fetus,5 which could provide a biological explanation for apparent absent effects of maternal stress in this cohort.…”

“…A recent review of maternal prenatal stress and infant DNA methylation identified several candidate genes implicated in the maternal central stress response that may be critical in driving phenotype changes for offspring 4. However, recent evidence also suggests that perhaps the placenta may buffer the effects of the maternal stress response 5…”

Examination of cord blood at birth in women with SARS-CoV-2 exposure and/or vaccination during pregnancy and relationship to fetal complete blood count, cortisol, ferritin, vitamin D, and CRP

“…Vitamin D is frequently placental in origin, and cortisol levels in the mother are known to be partially placentally transferred to the fetus ( 19 – 21 ). In addition, stressors of either the mother, neonatal infection, or the birthing process itself may also cause the neonate to generate cortisol on its own ( 22 , 23 ). This suggests that the bi-directional effect within the maternal/fetal dyad on cortisol has a vital role in the maintenance of neonatal homeostasis.…”