A new study from the Hebrew University of Jerusalem revealed that maternal stress during pregnancy can alter newborns’ molecular biology, with significant differences between boys and girls.
Published in Molecular Psychiatry, the study focused on the effects of perceived prenatal stress (PPS) and found that it can "reprogram" key molecular pathways in the fetus, particularly the cholinergic system, which regulates stress and inflammation responses.
"We found that even before babies take their first breath, the stress their mothers experienced during pregnancy can shape how their bodies respond to stress later in life, and we observed clear differences between boys and girls," said Prof. Hermona Soreq, who conducted the study with doctoral student Shani Vaknin from the Edmond and Lily Safra Center for Brain Sciences.
Sex-specific changes identified
The team analyzed blood samples from newborns whose mothers reported high stress levels during the third trimester. Mothers completed the Perceived Stress Scale (PSS-10), and those scoring above 19 were classified into the stress group.
Samples were collected from over 120 mother-infant pairs, recruited in Germany between 2016 and 2018. Blood was drawn from the umbilical cord and the mothers’ veins during labor, centrifuged and frozen at extremely low temperatures (down to −80°C or −112°F) before being analyzed at Hebrew University laboratories.
Researchers focused on small RNA molecules known as tRNA fragments (tRFs), which regulate gene expression similarly to micro-RNAs. Of all the samples, 35 met the biological quality criteria and were selected for RNA sequencing after filtering for normal births.
The findings were striking: maternal stress affected not just individual molecules but entire families of tRFs — particularly those originating from mitochondrial DNA, responsible for cellular energy production.
The changes varied by sex. Female newborns showed the most dramatic shifts, including a near-complete drop in levels of specific mitochondrial tRFs, termed "CholinotRFs," which regulate genes responsible for producing acetylcholine, a key neurotransmitter involved in brain function and immune regulation.
Researchers also measured levels of acetylcholinesterase (AChE), an enzyme that breaks down acetylcholine. Newborns of stressed mothers — especially boys — had higher AChE levels, suggesting an imbalance in their stress response system from birth. This points to a possible protective role of the strong RNA effects seen in girls.
Could CholinotRF profiles become diagnostic tools?
"Developing a practical diagnostic tool requires further testing on larger populations and regulatory approval," Vaknin said. "To our knowledge, using CholinotRFs to diagnose prenatal stress is entirely new, so more studies on larger cord blood datasets are needed before clinical application."
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Expanding the study
When asked whether the study would be expanded to high-risk pregnancies or women with clinical depression, Vaknin said that widening the sample would naturally cover a broader range of clinical symptoms.
"Our goal was specifically to address women experiencing high stress levels without clinical diagnoses of depression or anxiety, who might not otherwise receive monitoring that could predict effects on them or their infants," she explained.
Why are girls seemingly more protected?
Vaknin cautioned that since the study captures only a single time point — birth — it’s hard to definitively say the observed effects are protective. However, she noted that male infants are known to be more vulnerable in their first year of life.
Some theories attribute this to placental differences: male placentas prioritize fetal growth over maternal well-being, while female placentas maintain a more balanced relationship. Since the placenta is composed of fetal cells, it reflects chromosomal differences — XX for girls, XY for boys.
Shani VakninPhoto: Yael FrilozkyVaknin added that male newborns showed stronger activation of cholinergic proteins that promote inflammation by breaking down acetylcholine, while females had stronger tRF responses that inhibit these proteins and potentially prevent inflammation.
Potential long-term psychological effects
These molecular shifts could help explain why children exposed to high maternal stress during pregnancy face elevated risks for neurodevelopmental and psychiatric issues later in life.
Using machine-learning algorithms, the researchers could predict with 95% accuracy whether girls had been exposed to maternal stress, based solely on their CholinotRF profiles — a finding that could pave the way for early diagnostics and preventive treatments.
"This study offers a rare glimpse into how a mother’s mental state during pregnancy shapes her baby’s stress response, even as early as labor," Vaknin said. "It underscores the critical importance of maternal mental health and offers a potential early diagnostic point to support affected infants from the very beginning."
Applications for intervention
Could these findings lead to treatments to mitigate maternal stress effects?
Vaknin said that question would require separate research by clinicians and psychologists. "Our findings focus on molecular responses in cord blood to maternal stress," she explained. "We saw much weaker effects in maternal blood, likely because it was drawn earlier during labor rather than after birth like the cord blood."
Thus, the results suggest interventions could be developed to support affected infants after birth, rather than during pregnancy itself — a process she described as inherently more complex and potentially risky.
"Our goal was to identify newborns impacted by maternal stress at the earliest possible stage — birth — so that monitoring and support could be provided to promote healthy development," she added.
What are the key messages for pregnant women and healthcare providers?
"The main takeaway is that maternal stress during pregnancy can reach the fetus and should be considered even after birth," said Vaknin. "But some degree of psychological stress during pregnancy is inevitable. We are not telling mothers not to feel stress — doing so would only increase anxiety and guilt."
"Rather, our aim is to raise awareness so that women experiencing unusually high stress can get the help they need during pregnancy, while also creating early identification tools for affected newborns to enable timely intervention and support."