In collaboration with Danish colleagues, researchers at the March of Dimes Prematurity Research Center at Stanford have found that pregnant women with slightly elevated blood sugar levels that fall below the diagnostic level for gestational diabetes are at greater risk for preterm birth compared to pregnant women whose blood sugar levels are not elevated.
In addition, the team, which recently published a paper in the journal Epidemiology on the findings, observed that the preterm birth risk is even higher for women who are obese and have elevated blood sugar levels - even if they too fall below the diagnostic level for gestational diabetes.
The findings point to the potential need to expand screening for women whose blood sugar levels during pregnancy are within normal range according to medical and diagnostic standards—at least both in the US and Denmark, the origin country of the paper’s cohort—but still face an increased, and seemingly invisible, risk for preterm birth.
Women in the study with elevated, but not diagnosable, blood sugar levels saw their preterm birth risk increase by 20%; and those with elevated, but not diagnosable, blood sugar levels and obesity saw their preterm birth risk increase by 30%.
While gestational diabetes is a well-known risk factor for preterm birth, only women diagnosed with the condition can be flagged for additional care. The Stanford paper shows that there exists a group of at-risk women who are being overlooked because their blood sugar does not currently raise clinical red flags.
“Increased blood sugar levels, below the levels for [gestational diabetes], appear to increase the risk of preterm birth,” said Richard Liang, an epidemiology medical student at Stanford who is the paper’s first author. Stanford PRC investigators Dr. David Stevenson and Dr. Gary Shaw were also key players on the work, as was Danish scientist and senior paper author Dr. Lars Pedersen.
“Where obesity comes into play is that we observed that this risk of preterm birth due to increased blood sugar levels was even greater among women with [body mass index] levels in the obese category, as compared to women with [body mass index] levels in the normal category. In other words, obesity appears to additionally increase the strength of association that blood sugar levels have on risk of preterm birth.”
To look at the link between blood sugar and preterm birth, the team studied 11,337 Danish pregnancies from 2004-2018 that were part of a targeted gestational diabetes screening. Study participants had undergone an oral glucose test where they had their blood sugar taken two hours after drinking 75 grams of glucose.
The team found that the average blood sugar value in the cohort was 120 mg/dL, and women whose value was just 25 points past that average, at 145 mg/dL (still below the 162 mg/dL cutoff for gestational diabetes in Denmark), saw their preterm birth risk increase by 20%. Obese women with that same blood sugar value of 145 mg/dL, again, below diagnostic standards, saw their preterm birth risk jump to 30%.
The higher the blood sugar reading, the team found, the higher the risk for preterm birth. For example, women whose blood sugar reading was 162 mg/dL, which qualifies as gestational diabetes in Denmark, had a 34% increased risk of preterm birth compared to women whose blood sugar was 120 mg/dL. And obese women whose blood sugar was 162 mg/dL faced a 50% increased preterm birth risk.
There is no global diagnostic standard for gestational diabetes, and in the US, several standards are used. One of them is the two hour, 75-gram glucose test, in which gestational diabetes is diagnosed at 153 mg/dL—higher than the ‘safe’ average of 120 mg/dL identified in the study.
“This is all to say, regardless of which guideline we look at, increased levels of glucose below any of the cut-off values for [gestational diabetes] appear to increase the risk of preterm birth,” said Mr. Liang. “What we hope to show through our research is that there is a continuum, or spectrum, of blood glucose levels that increase risk of preterm birth, even before blood sugar levels reach the levels for [gestational diabetes.]
One of the reasons existing blood sugar cut-off levels appear to miss a significant chunk of at-risk women, Mr. Liang said, is because they were never formulated as a screening test for preterm birth; instead, they were made to identify women at risk of having babies that were too large.
“These guidelines were not made to prevent other adverse outcomes, such as preterm birth,” he said. “By having a single standard without taking into consideration other factors such as [body mass index] and obesity, we might be missing some at-risk groups.”
He added that a more targeted “precision health” approach could be an improvement over the current protocol, especially considering the compounding effect of obesity on blood sugar in the context of preterm birth risk.
The team plans to validate their findings in larger, more diverse populations outside of Denmark, and to investigate the link between obesity, blood sugar, and preterm birth in finer detail.
“The next steps include replicating these findings in other populations to understand whether there is a joint effect of obesity and blood sugar levels on the risk of preterm birth, as well as other adverse pregnancy outcomes,” Mr. Liang said. “I do encourage other clinician researchers to think about ways to revise and improve [gestational diabetes] screening guidelines, and to think outside of a one-size-fits-all approach.”