High HbA1c in Type 1 Diabetes Ups Risk of Heart Defects in Baby

Elevated glycated hemoglobin (HbA_1c) levels at or around the time of conception significantly increase the risk of major cardiac defects in infants born to mothers with type 1 diabetes compared with children born to nondiabetic women, a representative nationwide Swedish study indicates.

Indeed, even mothers with HbA_1c levels that meet the recommended target of less than 6.5% have a two-fold increased risk of giving birth to an infant with a heart defect compared with infants born to mothers without diabetes, the same study indicates.

"This confirms previous findings that there is a higher risk of birth defects, primarily of the heart, [in infants born to mothers with type 1 diabetes]," said lead author Jonas Ludvigsson, MD, PhD, of the Karolinska Institute, Stockholm, Sweden in a statement by the institution.

"The risk of birth defects is especially sensitive to factors during early pregnancy, and here blood glucose plays a vital part," he added.

The study was published online July 5 in BMJ.

The Higher the HbA_1c, the Greater the Risk

As the researchers note, type 1 diabetes in pregnancy has been associated with heart defects in offspring, but data specifically on glycemic control and birth defects are limited.

For this analysis, they linked information from the Swedish National Diabetes Register with data from 1,162,323 pregnancies to evaluate the risk of major birth defects according to HbA_1c levels in the period around conception.

This periconceptional period was defined as any time between 90 days before to 91 days after conception.

"HbA_1c was categorized as < 6.5%, 6.5% to < 7.8%, 7.8 to < 9.1%, and ≥ 9.1%," the researchers note.

"[And] our two main outcomes were major cardiac and noncardiac birth defects recorded during the first year of life," they add.

The final cohort consisted of 2458 infants born to mothers with type 1 diabetes and 1,159,865 infants born to mothers without diabetes. Mean age at conception for both groups was 30 years.

Among mothers with type 1 diabetes, investigators documented 122 major cardiac defects.

And the risk of giving birth to an infant with a major cardiac defect in general increased as periconceptional glycemic control worsened.

Risk of major cardiac defects in infants born to mothers with type 1 diabetes

Result	No diabetes	HbA_1c <6.5%	HbA_1c 6.5% to 7.8%	HbA_1c 7.8% to <9.1%	HbA_1c ≥9.1%
Adjusted risk ratio	—	2.17	3.17	2.79	6.23
Major cardiac defects/1000 infants	15	33	49	44	101

In the HbA_1c category of 9.1% or higher, "the risk of the baby having a heart defect was as much as 10.1% — or one in every 10 babies," Ludvigsson observed.

It is thought that hyperglycemia induces the expression of genes whose products may adversely affect fetal heart development, he noted.

Time to Change the Target HbA_1c in Pregnancy?

The investigators then restricted their analysis to 1068 mothers who had an HbA_1c measurement within 31 to 91 days after conception.

In this cohort, they found an "even more pronounced" increase in the risk of major cardiac defects with worsening glycemic control.

This ranged from an adjusted relative risk of 1.53 for mothers with a periconceptional HbA_1c < 6.5%; 3.78 for those with an HbA_1c between 6.5% to < 7.8%; 4.63 for those with levels between 7.8% to < 9.1%; and to 8.43 for those with a level of 9.1% or greater.

In contrast, they did not observe an elevated risk of noncardiac defects in any of the predefined HbA_1c categories.

"Alternative measures of poor glycemic control and severity of diabetes were also associated with an increased risk of major cardiac, but not noncardiac, birth defects," they add.

The rate of hospital admissions for diabetic acidosis in the past year, for example, was associated with a 10-fold increased risk of major cardiac defects in the babies, and the risk of hospital admission for any condition related to diabetes increased the risk of heart defects in the infant by 6.5 fold.

And both the presence of macroalbuminuria and an estimated glomerular filtration rate of less than 60 mL/min/1.73m²were each associated with a greater than six-fold increased risk of major cardiac defects in the baby.

"These findings may indicate that yet lower target HbA_1c levels than [are] currently recommended might be advisable [in pregnancy]," the authors suggest.

"However, before any changes to practice guidelines are implemented, the totality of evidence regarding other adverse pregnancy, fetal, and infant outcomes in relation to poor glycemic control — in particular the specific HbA_1c levels at which these events occur — need to be carefully considered and weighed against the risks associated with intensified insulin therapy, such as hypoglycemia," they caution.

The study was supported by a grant from the Swedish Diabetes Foundation. Ludvigsson has reported no relevant financial relationships. Disclosures for the other authors are listed in the article.

BMJ. Published online July 5, 2018. Full text

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