How Does Intrauterine Stress Affect Offspring Telomere Length?

Previously in this blog, I summarized some of the clinical findings on the association between chronic stress and telomere length as well as the research into the impact of stress mitigation techniques. However a growing body of literature is beginning to look at how our telomere length is impacted by things that happen before we are even born, while still in our mother’s womb. I wanted to round out this series that on stress and telomere length with a review of what the literature says about how intrauterine stress exposure can impact progeny average telomere length.

Fetal development is an exquisitely complex process in which environmental factors in utero can have lasting consequences for the offspring into adulthood and potentially into future generations. This effect is called fetal programming, a process whereby the environment in the womb, during sensitive periods for certain outcomes, can alter the development of the fetus with a permanent effect on the child. Some well know negative instances of fetal programming are fetal alcohol syndrome or microcephaly due to exposure to the Zika virus. Some other causes of fetal programming from maternal nutrition or stress levels are more subtle and can show up later in the child’s life. Indeed there is research that implicates fetal programming in cholesterol levels, heart disease, cancer, obesity and mood disorders. For example, adult onset heart disease and diabetes is associated with smaller head circumference and body length at birth but the exact mechanism for this association is not fully understood. Research however has been underway to look at how offspring telomeres are affected by maternal stress in an attempt to understand the well established link between prenatal stress and disease.

In 2011 while working with Drs. Pathik D. Wadhwa and Sonja Entringer at University of California, Irvine and other colleagues, we tested the hypothesis that stress exposure during intrauterine life is associated with shorter telomeres in adult life. We recruited a group of young adults in Trier, Germany whose mothers experienced a high level of psychosocial stress during pregnancy and compared them with a group of subjects whose mothers had not been exposed to negative life events during pregnancy. The subjects were asked if their mother had any of the following major negative life events during her pregnancy: death or sudden severe illness of an immediate family member or loss of primary residence. This information was then confirmed by reviewing it with their mother. Prenatal medical record was obtained from each participant. From this record, information about maternal age, medical complications during pregnancy (e.g., gestational diabetes, hypertension/preeclampsia, infection), birth outcomes (length of gestation/preterm birth and birth weight/small-for-gestational-age birth, height, and head circumference at birth) and newborn complications were obtained. Telomere length was measured from whole blood by the quantitative PCR method (the same assay principle is used in TeloYears test). Participants whose mother had a major stressful event during pregnancy has shorter telomere length than the comparison group whose mother did not experience major psychosocial stress by 178 bp, equivalent to 3.5 years of biological aging. This was after adjusting potential confounders in the participants (not the mothers) including age, BMI , sex, birth weight percentile, postnatal early-life adversity (e.g., early trauma, maternal care), and exposure to concurrent life stress (e.g., chronic stress, depressive symptoms). This is the first human study that demonstrated that exposure to maternal psychosocial stress during pregnancy is associated with significantly shorter LTL in young adulthood. This result provides one possible mechanistic explanation for the well-established link between prenatal stress and disease risk.

In a separate study conducted by the same group, the authors asked how early the negative effect of prenatal stress on telomere length can be detected. In a group of 27 mother-newborn dyads, maternal pregnancy-specific stress was assessed in early gestation and cord blood peripheral blood mononuclear cells were subsequently collected and analyzed for telomere length measurement. The participants were from a predominantly Medicaid-insured, low-income population in Pittsburgh, PA. At enrollment (on average at 9.2 weeks’gestation), the participants filled a 4-item pregnancy-specific stress scale that assesses their feelings about being pregnant, concerns about the health of the unborn baby and about labor and delivery. Peripheral blood mononuclear cells (PBMCs) were isolated from newborn’s cord blood and telomere length was measured by quantitative PCR. After accounting for the effects of potential determinants of newborn TL (gestational age at birth, weight, sex, and exposure to antepartum obstetric complications), pregnancy-specific stress was correlated with shorter newborn telomeres. This study shows that effects of exposure to prenatal stress on telomere length are already evident at birth.

In 2016, Marchetto et al, replicated the findings of our study with a prospective study that looked at 24 mother-child pairs in an urban teaching hospital. All mothers were screened for normal, healthy pregnancies and given a stress screening survey, the Holmes and Rahe Stress Scale, a 43-item
survey assesses whether the mothers had experienced life events within the past year that
were likely to initiate a physiological stress response. Newborn telomere length was measured using Southern blot analysis at delivery using cord blood. The authors found a significant negative correlation between maternal stress and newborn telomere length. In other words, the higher the mother’s stress, the lower the newborn’s telomere length.

Beyond stress exposure, there have been other studies that have correlated shorter newborn telomere length with maternal BMI, tobacco exposure and arterial hypertension. While these studies are preliminary, a picture is emerging suggesting that our telomere length is affected not just by our choices and health, but by those of our mothers as well.