Prenatal Programming

Cecelia Ky-Lan Do
Jun 15
13 min read

by Farrah Emam

art by Qingyang Meng

In the final winter of World War II, Allied forces began liberating German-occupied territories across Europe. After four years under German control, resistance fighters in the Netherlands launched a railroad strike to disrupt German troop movements in support of the Allies. In retaliation, German authorities blocked food rations, causing daily caloric intake to drop as low as 500 calories per person [1].

This blockade lasted six months and plunged the Dutch population into what became known as the Hunger Winter. Among those hit the hardest were thousands of pregnant women. Their unborn children, sustained by little more than scraps of bread and tulip bulbs, would become the focus of one of the most pivotal studies in developmental biology: the Dutch Hunger Winter Study [2].

Although the famine ended with the Netherlands’ liberation in May 1945, its effects endured, particularly for those exposed in utero. In 1994, researchers at the Academic Medical Center in Amsterdam launched the Dutch Famine Birth Cohort, consisting of adults whose gestation overlapped with the six-month famine [1]. The findings were striking.

Fetal exposure to famine during early gestation, when vital organs and brain structures develop, was associated with increased risks of obesity, cardiovascular disease, cognitive impairments, and mental health disorders [1]. Both men and women showed altered stress responses, metabolic changes, and signs of accelerated brain aging. However, men exposed in early gestation had smaller brain volumes and performed worse on cognitive tests at age 58 [3]. All these effects were unique to those exposed in utero. Compared to their siblings not in the womb during the famine, the famine cohort showed higher mortality rates and a greater risk of psychotic incidence [1].

Neuroimaging and cognitive assessments revealed significant structural and functional changes in the brain, including reduced volume and an elevated risk of psychiatric disorders. The famine cohort exhibited higher rates of conditions like schizophrenia and anatomical differences in key brain regions [4].

How could a relatively brief period of starvation, experienced before birth, lead to such persistent and widespread health effects across generations?

Before Birth: Developmental Origins of Health and Disease (DOHaD)

This question lies at the core of the Developmental Origins of Health and Disease (DOHaD) paradigm, a field of research sparked by epidemiologist David Barker in the 1990s. The Barker Hypothesis, also known as the fetal origins hypothesis, asserts that the environment in the womb can “program” a fetus in ways that profoundly influence long-term health. In other words, our prenatal experiences help shape our lifelong health trajectory [5].

In the 1980s, Barker and C. Osmond published a landmark study linking maternal malnutrition to a higher risk of heart disease in offspring. Echoing findings from the Dutch Famine Study, they concluded that a single maternal factor—nutrition—could have lasting, systemic effects on fetal development [6]. Their revolutionary insight: the roots of adult disease may stretch back to fetal life.

The Dutch Famine findings exemplify this hypothesis as in utero exposure to extreme malnutrition and stress translated into elevated risks of chronic disease, mental illness, and cognitive deficits decades later [4]. Today, researchers recognize that maternal factors like stress, nutrition, and illness can leave lasting biological “imprints” on a developing fetus. At the heart of DOHaD lies the idea that the intrauterine environment can shape not only our brains and bodies but potentially even those of future generations [7].

One key factor in this environment is maternal prenatal stress—the psychological and physiological stress a mother experiences during pregnancy. Before we explore how stress affects fetal brain development and becomes biologically encoded, we must address a deceptively simple question: What exactly is stress? And is it always harmful?

Stress: The Good, The Bad, and the Biological

Ask people what stress is, and you’ll likely get various answers. For you, it might be running late to an event. For me, it’s pulling an all-nighter in Butler’s stacks. The word stress often carries a negative connotation.

But stress isn’t inherently good or bad. It’s biological. Stress is simply the body’s response to a challenge or demand.

Picture Roar-ee the Lion strolling down Broadway at 116th Street when Millie suddenly jumps out and startles him. In an instant, Roar-ee’s body launches into a stress response: his heart begins to race, his breathing quickens, his muscles tense up—Roar-ee is now primed to sprint. This rapid reaction, known as the fight-or-flight response, is driven by the sympathetic nervous system, a branch of the autonomic nervous system responsible for regulating functions and parts of the body in response to physical danger or stress.

The nervous system has two main divisions: the central nervous system (the brain and spinal cord) and the peripheral nervous system (a network of nerves connecting the brain and spinal cord to the rest of the body). The peripheral nervous system has two branches: the somatic system, which controls voluntary movements, and the autonomic system, which controls involuntary functions like heart rate, digestion, and breathing [8].

Before this encounter, Roar-ee was walking calmly, his body in a “rest and digest” state governed by the parasympathetic branch of the autonomic nervous system. But the second Millie jumped out and frightened him, the sympathetic branch took over. His muscles activated for running, and his heart pumped faster to send oxygen-rich blood to critical organs. Roar-ee’s nervous system orchestrated these changes to help him respond to a perceived threat.

Two major systems are activated in this stress response. First, the SAM axis (Sympathetic Adrenomedullary) releases adrenaline (epinephrine), which acts like a gas pedal, ramping up heart rate and energy output. Second, the HPA axis (hypothalamic-pituitary-adrenal axis) kicks in, producing cortisol, often called the “stress hormone.” Unlike adrenaline, cortisol acts more slowly, helping the body stay alert and manage prolonged challenges. Together, these systems are essential for survival [9].

Adapting to stress is known as allostasis or “stability through change” [10]. However, when stress systems stay activated too long or are triggered too often, problems arise. Chronic stress, from circumstances like ongoing trauma, poverty, or illness, keeps the body in a constant state of activation. The resulting wear and tear is called allostatic load, the cumulative toll on the body when it doesn’t get a chance to recover [10].

Some systems, like the immune system, become suppressed. Others get overworked. Take finals week, for example. Elevated cortisol can temporarily suppress your immune system. When the stress lifts, cortisol levels drop, and your immune system rebounds, sometimes with a surge of inflammation. That’s why you might naturally feel sick right after finals (just in time for break). It’s your body’s way of revealing how overextended it’s been. Over time, a high allostatic load can disrupt brain function, impair mood regulation, and increase vulnerability to conditions like anxiety and PTSD [11].

So, stress isn’t inherently harmful. It’s critical for survival. But when it’s chronic or unrelenting, it can shift from helpful and adaptive to harmful and maladaptive. Now, what happens when a pregnant person experiences chronic stress? How does that affect a developing baby? After all, a fetus doesn’t see or feel stress directly. So why do maternal stress effects show up in the child years, even decades later? The answer lies in our genes!

Every cell in the human body contains the same DNA—the same set of genes—but a brain cell functions entirely differently from a skin or liver cell. How is that possible? Gene regulation. Our bodies use a range of mechanisms to control gene expression at the DNA, mRNA, and protein levels. One crucial mechanism involves switching genes “on” or “off” through chemical modifications [12].

Think of a gene like a lamp. The lamp stays the same, but you can switch it on (activate it) or off (deactivate it). This control over whether or how strongly a gene is expressed is the foundation of epigenetics.

The word epigenetics means “above the genome,” and refers to molecular tags influencing how we read or express the genetic code. You can picture DNA as a long thread wrapped around spool-like proteins called histones. For a gene to be active, the DNA must be accessible—unwound enough to be transcribed into RNA and eventually translated into proteins. Epigenetic tags determine how open or closed different regions of DNA are, which influences whether a gene gets expressed [12].

One common type of epigenetic modification is DNA methylation, where a small chemical group called a methyl group is added to the DNA. This usually acts like a red light, signaling to the cell not to read that section. In contrast, some histone modifications loosen the DNA structure, making genes more accessible, similar to a green light. These changes do not alter the DNA sequence itself. Instead, they control how much of a gene is expressed, which is essential for maintaining balance in the body. These regulators are responsive to internal and external signals, meaning they can adjust gene activity depending on environmental cues [12].

So, what does this relationship between the environment and epigenetics look like in the context of stress and prenatal development?

You can imagine a conversation between genes and the environment, something like the following: The gene says, “I have instructions for regulating cortisol.” The environment responds, “Turn that gene up; we need it,” or “Dial it down, we’re overwhelmed.” This back-and-forth leads to changes in how stress hormones are produced. Epigenetics helps relay environmental signals to the genome; in some cases, these changes can also be passed down to the next generation.

A groundbreaking study in rats showed that stress can affect a mother’s epigenetic patterns as well as those of her offspring. A 2004 study examined how maternal care in rats influenced their pups’ stress responses [13]. Some mother rats licked and groomed their pups frequently, while others did not. Pups that received less maternal care, an early-life stressor, developed increased DNA methylation on the glucocorticoid receptor (GR) gene, encoding a protein that helps shut down the stress response [13].

As a result, these pups had fewer glucocorticoid receptors in their brains, making it harder for them to regulate their stress. This caused higher levels of stress hormones and a more reactive stress response. These changes emerged during the first week of life and lasted into adulthood, well beyond the period of maternal care[14].

Although this study was done in rats, humans have demonstrated similar effects. A 2008 study investigated the impact of maternal depression and anxiety during pregnancy in a similar way [15]. Here, experimenters studied newborns’ cord blood and found increased DNA methylation of the NR3C1 gene, the human equivalent of the glucocorticoid receptor gene studied in rats.

Infants whose mothers experienced higher levels of anxiety or depression, especially in the third trimester, showed greater methylation of NR3C1. At three months old, the babies were exposed to a mild stressor, such as a brief separation from their mothers. The infants with more methylation had stronger cortisol responses, indicating a heightened sensitivity to stress.

These epigenetic changes in early life can affect the development of the entire nervous system. Over time, they may increase vulnerability to mood disorders and anxiety. Experimenters concluded that NR3C1 methylation is “sensitive to prenatal maternal mood and may offer a potential epigenetic link between antenatal maternal mood and altered HPA stress reactivity” [16].

In other words, a mother’s emotional state during pregnancy may shape her child’s biology in ways that affect how they handle stress for the rest of their life.

We now understand how chronic stress can wear down the body generationally. But what exactly happens in the developing brain?

Stress and the Developing Brain

Think of the developing brain in the womb as playdough. In the earliest stages, the basic mold is being formed. Later, details are added and refined. The timing of stress exposure during pregnancy plays a critical role in determining its impact on the child. Research suggests that stress in the first trimester may be linked to outcomes like earlier birth or alterations in immune system development. In contrast, stress in the late second and third trimesters tends to have more potent effects on brain development and behavior.

A notable study tracked maternal stress trajectories across pregnancy and examined infant brain connectivity after birth [17]. Mothers who experienced peak stress in late pregnancy—especially in the third trimester—had infants with stronger connectivity between the amygdala (a brain region involved in emotion and threat processing) and the prefrontal cortex (involved in regulation and control) [17]. Specifically, heightened third-trimester stress was associated with stronger connectivity between the amygdala, insula, and prefrontal cortex—regions central to emotion regulation. In their first year, these babies also showed more negative effects (e.g., increased irritability or difficulty calming).

Another study explored different types of prenatal stress, ranging from psychological distress to adverse life events [18]. They found that both the type and timing of stress mattered. For instance, early gestational stress was linked to outcomes like lower birth weight and altered fetal sex ratios, while later stress had more influence on brain development and emotional functioning [17]. These findings support the idea that stress at different developmental stages sends distinct biological signals: early stress may tell the fetus, “the world is dangerous—prioritize survival,” while stress later in gestation may signal “prepare for emotional challenges ahead.”

By the time the baby is born, researchers have observed a range of outcomes if their mother experienced significant stress during these key periods. Some are neuroanatomical, such as reduced volume in the hippocampus (which plays a central role in memory and stress regulation) or abnormalities in cortical development. Others involve functional connectivity, like altered patterns in the amygdala-prefrontal circuitry, which may influence how the child experiences and responds to stress. Still others emerge as behavioral or psychiatric conditions later in life, including increased risks for anxiety disorders, ADHD, or mood disorders [19].

A 2021 meta-analysis concluded that prenatal exposure to trauma or chronic stress is consistently associated with a higher risk of psychiatric conditions during adolescence and adulthood. Children of mothers who experienced high stress or depression during pregnancy were more likely to develop anxiety, depression, and attention difficulties, even after controlling for postnatal factors. Some studies also observed slightly lower cognitive scores and executive functioning issues among children exposed to high levels of prenatal stress [20].

Call to Action

The science of Developmental Origins of Health and Disease (DOHaD) and prenatal stress gives us a new perspective on fetal development: where we once saw the womb as a sterile, one-way incubator, we now see an active, dynamic environment where a baby prepares for life based on the signals it receives. These signals might reflect warmth, stability, and nourishment or hardship, scarcity, and stress. This period of immense plasticity shapes developing brains and bodies in lasting ways, for better or worse.

If stress and adversity during pregnancy can “program” developing systems in negative ways, then supporting maternal mental health and reducing chronic stress should lead to better developmental outcomes for children. Studies show that social support during pregnancy can buffer the effects of stress. One study found that women who received higher levels of support during pregnancy had children with better cognitive outcomes at age eight [21]. Interventions like therapy for depression or anxiety, stress-reduction techniques (e.g., mindfulness, gentle physical activity), and programs that address external stressors, such as housing insecurity, food access, or domestic violence, are not just beneficial for the mother; they are biological investments in the baby’s future [19].

Effective policy can support these goals. Paid parental leave, access to affordable mental health care, nutritional assistance, and safe community spaces are examples of upstream public health interventions. Researcher Kieran O’Donnell is among the first to advocate for a broader public health response to maternal stress [22]. O’Donnell argues that maternal mood and stress should be recognized as key predictors of child health, and healthcare systems should be structured to screen and respond accordingly. His research supplements this call to action, finding that maternal anxiety during pregnancy was associated with behavioral outcomes in children that persisted into adolescence [19]. As we continue to unravel how the prenatal environment shapes who we become, one truth becomes clear: the path to healthier brains and bodies begins before birth. By supporting pregnant women, we support our children. In doing so, we build a foundation not only for one life but for generations to come!

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Prenatal Programming

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