Exploration of IGF-1 L3 Treatment for Fetal Growth Restriction Yields Unexpected Results

Research study background

Building on decades of groundbreaking research on fetal development, neonatologists at Children’s Hospital Colorado and the University of Colorado School of Medicine’s Perinatal Research Center are breaking new ground. Their latest work explores whether targeted biological therapies have the potential to effectively treat fetal growth restriction (FGR).

FGR can be caused by placental insufficiency, which can lower levels of fetal insulin-like growth factor 1 (IGF-1) and insulin, both of which are critical for growth. It may also decrease glucose-stimulated insulin secretion (GSIS), potentially leading to neonatal glucose dysregulation and associated risks.

Previous research by this group showed that infusing normal fetal sheep with a high dose (6.6 µg·kg⁻¹·h⁻¹) of IGF-1 LR3, an analog for IGF-1, increased body weight while simultaneously reducing insulin levels and GSIS. These complex hormonal interactions prompted this current study, which hypothesized that a one-week, low-dose infusion of IGF-1 LR3 in a model of late gestation fetal sheep with FGR from placental insufficiency would promote growth without further lowering insulin levels or GSIS. After separating twin fetal sheep into two groups, researchers infused them with either IGF-1 LR3 or saline. Initially, the study planned to include increasing doses of IGF-1 LR3. However, after observing fetal demise in four animals who displayed signs of hypoglycemia and hypoxemia during the first dose increase, researchers decided to maintain the lowest dose (1.17 ± 0.12 µg·kg⁻¹·h⁻¹).

When the team compared results from the surviving animals to the control group, they found no difference in pancreatic weights, insulin-positive beta cell proportions or overall pancreatic vascularity. This indicates a lack of improvement in beta cell growth and function, critical factors for metabolic health during fetal development, especially in the context of FGR. Additionally, IGF-1 LR3 treatment did not decrease circulating insulin levels or GSIS. While glucose and oxygen concentrations did not vary between groups, IGF-1 LR3 treatment significantly reduced circulating amino acids, notably branched-chain amino acids, known to promote GSIS and protein accumulation to support fetal growth. While these findings suggest that IGF-1 LR3 may promote increased utilization of amino acids by the fetus, it did not correlate with enhanced fetal growth.

“These results likely reflect not a failure of the hormone, but of the environment. The chronic deprivation of oxygen and nutrients even limits the therapeutic potential of strong growth-promoting factors in fully restoring growth or beta cell function,” says Children’s Colorado neonatologist Alicia White, MD, lead author of the study.

Clinical implications

Study results, which contrast with the team’s findings in normal fetal sheep, suggest that FGR fetuses may respond differently to IGF-1 LR3, underscoring the need for a multipronged therapeutic approach.

Researchers concluded that to increase fetal growth in this population, it may be necessary to maintain circulating amino acid levels, or elevate insulin and oxygen levels, during low-dose treatment to match those typically found in normally-growing fetuses. While they acknowledged a higher dose of IGF-1 LR3 may have yielded data to support the hypothesis, future investigations should consider potential associations with increased fetal demise observed in this study.