Mom’s Diabetes May Affect Child’s Brain
Blood sugar may influence a critical period in the development of the hippocampus

by Nicky Penttila

September, 2007

The many pregnant women who have diabetes or develop it during pregnancy have another reason control their blood sugar: Abnormal glucose levels could affect their child’s memory, and damage might not be reversible.

A continuing study based at the University of Minnesota has tested children of diabetic mothers from day one through age 8 (and counting) and found consistent problems with their memory; specifically, their ability to recognize their mother’s voice (at birth), face (at 6 months), and sequences of actions (ages 3 and up). Researchers suspect that the impairment is caused by damage to the hippocampus, which rapidly develops during the third trimester of pregnancy.

“If the glucose levels in the mother fluctuate greatly … the fetus will also have high fluctuations in their glucose levels, which then leads to iron deficiency and oxygen deficiency” to the brain, says Tracy DeBoer of the University of California at Davis, one of the researchers. These deficiencies have been shown in animals to be especially damaging to hippocampus development, she says.

Much of our ability to remember the events we experience (called episodic memory) depends on the hippocampus, a small, metabolically active structure tucked deep into each hemisphere of the brain.

“Other research has shown that infants of diabetic mothers, when they do reach school age, have ‘poor cognitive outcomes,’ and that’s a very global term,” DeBoer says. “We’re really trying to be more neurally specific,” to pinpoint which aspects of memory might be affected.

A Battery of Tests

The study is part of a 20-year collaboration. Neonatologist Michael Georgieff at the University of Minnesota noticed that infants of diabetic mothers, who are often larger than average, often had lower stores of iron in their body than normal—and some had no reserve at all.

The researchers first studied sheep to discover what iron deficiency meant to the brain. “Ultimately, it sets up a competition for available iron coming from the mom” through the placenta, Georgieff says. Red blood cells win and get the iron they need, while the brain is deprived.

Using rats modified to have the same 40 percent reduction in iron as they found in at-risk infants of diabetic mothers, researchers found prioritization in the brain, as well—and the hippocampus is the first loser.

Charles A. Nelson III, then a colleague of Georgieff’s and now at Harvard Medical School, devised a way to study human babies. He started by using electrode-studded caps to capture event-related potential (ERP) recordings of sleeping newborns listening to recorded voices.

His team has continued with ERP recordings, using progressively more complex tasks, as the babies in the study have gotten older. DeBoer’s part of the research was to add behavioral testing to the electronic measurements starting at the 8-month stage.

They have found consistent, subtle memory deficiencies in children whose mothers had poorly controlled diabetes (of all types) during pregnancy. Newborns did not always distinguish their mother’s voice from another’s; 12-month-olds could build a rattle out of a marble and some blocks after seeing someone do it first, but they had forgotten how to do it a week later.

“The delayed-order recall was much more difficult for infants of diabetic mothers,” DeBoer says. And their trouble was related to how low their iron levels were at birth: “The greater the iron deficiency prenatally, the worse the memory performance.” That dose-response relationship is mirrored through all the tests, Nelson says, and echoes the animal findings.

But in most other respects, such as IQ levels, these children are just fine. Now that their subjects have reached school age, researchers are collecting their grades and other school records as more evidence of behavior, as well as using imaging and tests of other memory skills for more angles on what’s going on inside. They expect to finish this round of testing in two years.

All the children had normal levels of iron at 8 months old, so any memory difference would not be caused by a current lack in the hippocampus. Whether differences would be ameliorated if newborns were given extra iron is the subject of another study, now in the recruitment stage.

In animals, the equivalent prenatal damage is not remedied by more iron later, Georgieff says, which suggests that there is a critical period during hippocampal growth. There may be other ways to improve the faulty encoding, though, such as other nutrients, an enriched environment or more repetition. All would need to be tested. 

Effects on Body and Brain

From 5 percent to 10 percent of all pregnancies in the United States are complicated by diabetes, according to the Centers for Disease Control and Prevention (CDC). The vast majority are due to gestational diabetes, which develops during pregnancy and may disappear or diminish after delivery; the hormones of pregnancy are thought to cause insulin resistance or poor insulin secretion in women who are genetically predisposed to developing type 2 diabetes.

Type 2 diabetes accounts for 90 percent to 95 percent of all diabetes cases in North America, and its incidence has been increasing at such a rate that the CDC has declared it an epidemic. Diabetes damages all blood vessels, including those that supply the brain.

But a recent study done by Antonio Convit at the Nathan Kline Institute for Psychiatric Research in Orangeburg, N.Y., suggests that some damage is more closely targeted—and that the hippocampus may be affected first. Middle-aged adults who had been diagnosed with type 2 diabetes less than 10 years before testing showed deficits in hippocampal-based (recent or declarative) memory, while other aspects of memory (working and procedural), attention and executive function remained similar to that of a control group.

Using MRI scanners, the researchers could see atrophy of the hippocampus in their diabetic subjects, again with a dose-response relationship: the poorer the control of blood sugar levels, the lower the hippocampal volume.

Avoiding Early Damage

“Prevention, prevention, prevention” against iron deficiency is Georgieff’s advice to the more than 200,000 women each year who have diabetes during pregnancy and their caregivers. When blood sugar and iron were kept under tight control, infants of diabetic mothers had normal levels of iron at birth and have no memory troubles.

Obstetricians should screen for both diabetes and iron deficiency, which is the bigger problem worldwide, and then hand their observations over to pediatricians, Georgieff adds.

Nelson says that when a child looks big and healthy, pediatricians do not worry. “Our point is that they should be following these kids, particularly if the mother had poor prenatal care and the diabetes wasn’t controlled,” he says.