A condition that begins in the womb can have health consequences that unfold over decades. Research led by scientists at the University of Colorado Anschutz is offering new insights into how fetal growth restriction (FGR) affects health – in the womb as well as across the lifespan – that could lead to much-needed treatments.
FGR affects approximately 5-8% of pregnancies in the U.S. (10-15% worldwide) and is a leading cause of stillbirth, making careful monitoring during pregnancy essential. Preterm delivery is another complication. Laura D. Brown, MD, professor of pediatrics-neonatology at the CU Anschutz School of Medicine, cares for these premature babies in the neonatal intensive care unit (NICU).
In the lab, Brown is investigating why babies with FGR develop less skeletal muscle and whether those early changes help explain their increased risk of metabolic and cardiovascular disease as adults. Her goal is to identify ways to improve muscle growth during pregnancy or after birth.
Finding effective treatments for FGR has proven difficult. Researchers have explored approaches ranging from bed rest and oxygen supplementation to dietary changes and medications designed to improve blood flow, but none has demonstrated success in treating FGR.
“Right now, when an expectant mom asks what she can do to help her baby, we don't have great answers,” Brown said. “But what's hopeful and promising is that there is a huge amount of research happening in the area of poor fetal growth during pregnancy. Lots of people are investing time and effort to really try to improve the whole lifespan for individuals affected by FGR."
What is fetal growth restriction?
FGR is a pathological condition in which a baby does not grow as expected. It’s typically diagnosed during the second half of pregnancy, sometimes as early as 23 or 24 weeks.
During routine prenatal visits, clinicians measure the mother’s abdomen. If the fundal height (distance between the pubic bone to the top of the uterus) is smaller than expected, ultrasounds may be recommended to estimate the baby’s weight.
A Doppler ultrasound can then be used to evaluate blood flow between the fetus and placenta – the temporary organ that connects the fetus to the uterus. If this ultrasound shows abnormal blood flow, the baby is likely not receiving adequate oxygen and nutrients.
If the blood is flowing properly, the baby may just be small for its gestational age.
“It’s important to understand that in babies with FGR, there is a pathological reduction in the transport of nutrients and oxygen from placenta to fetus that then limits the fetus’s ability to reach their genetic growth potential. With our advanced ability to detect this problem during the pregnancy, the diagnosis of FGR is usually made when the baby is still in the womb. Small for gestational age babies have a birthweight that is less than the 10th percentile based on population definitions. They may have suffered from pathological FGR, or they may just be small genetically.”
It’s an important distinction, Brown said, because the clinical decisions and long-term outcomes associated with pathological growth restriction can differ from those of a baby who is simply small.
What causes fetal growth restriction?
One of the most common reasons for FGR is placental insufficiency, a condition in which the placenta does not adequately supply the nutrients and oxygen the fetus needs for optimal growth. Essentially, Brown said, the fetus adapts to this “adverse intrauterine environment” by slowing its growth rate in order to survive.
There are multiple risk factors associated with FGR, including drug use, smoking, chronic maternal conditions such as high blood pressure or diabetes, maternal infection, and multiple gestation (twins or triplets). Issues within the placenta itself can also impact blood flow, such as preeclampsia and placental abruption, when the placenta separates in part or fully from the uterus. FGR is also associated with genetic abnormalities in the fetus, such as trisomy 13 or trisomy 18.
Many cases don’t have an identifiable cause, Brown said.
“A mother may be perfectly healthy and have what otherwise appears to be a healthy pregnancy, yet the fetus is growth restricted.”
How fetal growth restriction impacts baby
“One of the most important adaptations to an adverse intrauterine environment is a phenomenon called ‘brain sparing,’” Brown said, adding that babies born with FGR may have a relatively normal-sized head compared with the rest of the body. Yet in severe cases, brain sparing may not be sufficient to protect normal brain development and result in poor neurodevelopmental outcomes.
When FGR is suspected or known, clinicians will monitor the baby’s growth and placental blood flow closely. When the risk of remaining in the uterus becomes greater than the risks associated with being born prematurely, early delivery is recommended.
“This means an infant with FGR may face complications associated with both growth restriction and prematurity,” Brown said. Immediate complications FGR babies may face include difficulties breathing, increased risk of infection, low blood glucose, difficulty maintaining body temperature and continued poor growth after birth.
Can fetal growth restriction affect health later in life?
The effects of FGR can extend well beyond infancy and childhood, Brown said. Even when “catch up” growth occurs after birth, children who experienced FGR may have difficulty achieving their growth potential.
There’s also an association between fetal growth restriction and an increased risk of metabolic disorders. Known as “fetal origins of adult disease,” both worldwide epidemiologic studies and research using animal models have confirmed that individuals who experienced FGR are at higher risk of developing diabetes, obesity and cardiovascular disease, including hypertension, heart disease and stroke.
“The reasons are likely multifactorial,” Brown said. “We think it may involve changes in how the liver produces glucose, how the pancreas secretes insulin and how tissues such as skeletal muscle and fat respond to insulin.”
Brown's research focuses on skeletal muscle, which plays a critical role in regulating blood sugar. Studies in humans and animal models have shown that growth-restricted newborns have reduced muscle and fat mass, raising questions about how these early changes may contribute to metabolic disorders later in life.
“When the body prioritizes blood flow to the brain and heart, skeletal muscle is particularly vulnerable. As a result, skeletal muscle of the baby experiences a significant reduction in oxygen and blood flow delivery while in the womb.”
How FGR impacts skeletal muscle development
Brown's laboratory has identified several changes in skeletal muscle development associated with FGR:
- Smaller skeletal muscles relative to overall body size.
- Smaller individual muscle fibers and fewer fibers within the muscle.
- Slower multiplication of cells involved in muscle development.
“These findings are particularly important because the number of skeletal muscle fibers is established at birth. After birth, muscle fibers don’t increase in number – they increase in size. So if a growth-restricted baby is born with fewer muscle fibers, the muscle may not be able to fully catch up after birth, even when those existing fibers grow larger.”
This change in muscle size may be playing a role in how individuals with FGR regulate blood sugar – the body’s primary source of energy.
“When a person eats, the body produces insulin to help move glucose into cells. Approximately 80% of this insulin-stimulated glucose disposal occurs in skeletal muscle,” Brown said, explaining that these changes could be contributing to hyperglycemia and insulin resistance, features of diabetes.
Another predictor of cardiovascular disease is having less muscle mass relative to fat mass. In babies born with FGR, muscle and fat mass are both reduced.
“We suspect, however, that fat mass may ‘catch up’ more effectively than muscle mass because of the abnormalities that developed in the skeletal muscle during fetal life,” Brown said.
Understanding long-term impacts can lead to interventions
As Brown continues to investigate how fetal growth restriction affects skeletal muscle development, she hopes her findings will lead to strategies that improve muscle growth and function during pregnancy or after birth.
“It’s possible there are nutritional strategies after birth that could help increase muscle mass while reducing accelerated fat accumulation, resulting in a healthier body composition.”
While effective treatments remain elusive, Brown hopes a better understanding of these early developmental changes will help researchers identify opportunities to reduce health risks throughout life.
Key points:
Fetal growth restriction (FGR) affects approximately 5-8% of pregnancies in the U.S. and occurs when a fetus cannot reach its expected growth potential.
Placental insufficiency is a common cause of FGR, limiting the oxygen and nutrients available to the developing baby.
FGR can increase the risk of complications during pregnancy and after birth, including preterm delivery and difficulties with breathing, blood sugar regulation and growth during the neonatal period.
People who experienced FGR have an increased risk of metabolic and cardiovascular conditions later in life.
CU Anschutz researcher Laura D. Brown, MD, is investigating how changes in skeletal muscle development could inform future strategies to improve long-term health.
