Researchers analyzed data from linked Swedish national registers and found that higher A1C levels were also associated with risks for hypoglycemia, large gestational age infants, macrosomia, neonatal death, respiratory distress and stillbirth.
Higher Blood Sugar in Women With T1D Tied to Preterm Birth Risk
As HbA1c levels rose, so did risk of preterm birth
Pregnant women with type 1 diabetes (T1D) and higher blood sugar levels around the time of conception were at a progressively increased risk for preterm birth, according to a population-based Swedish study.
Compared to pregnant women without type 1 diabetes, those with T1D were significantly more likely to be at risk for preterm birth (<37 weeks gestation), even if they met target HbA1c levels, reported Jonas Ludvigsson, MD, PhD, of the Karolinska Institutet in Stockholm, Sweden, and colleagues.
Women with T1D who met target HbA1c levels (<6.5%) had a significantly higher risk of preterm birth (adjusted risk ratio 2.83, 95% CI 2.28-3.52), and this risk increased with rising HbA1c levels in pregnancy, the authors wrote in Annals of Internal Medicine.
"A number of smaller studies have indicated that type 1 diabetes increases the risk of adverse pregnancy outcomes but the importance of blood sugar levels has been unclear," Ludvigsson told MedPage Today in an email. "This is important because if we show that high blood sugar increases this risk, this allows women and healthcare personnel to reduce the risk of preterm birth through better control of blood sugar."
American Diabetes Association guidelines recommend pregnant women with diabetes maintain A1c levels below 6.5% because of the risk for congenital anomalies like heart disease or diabetic embryopathy that can occur during the first 10 weeks of the term. However, they specify that this test, which measures the percentage of glycated hemoglobin in the blood, "represents an integrated measure of glucose," and is recommended to be taken secondarily, in addition to other measures of glycemic control.
Ludvigsson and his team said because the increased risk for preterm birth was similar in women with HbA1c levels less than 6% and below 6.5%, that type 1 diabetes might be "independently linked to preterm birth, and increasing HbA1c levels may add to the risk" for pregnant women with type 1 diabetes.
"Type 1 diabetes is not only high blood sugar, it is also indirectly a disease that affects blood vessels, kidneys, etc., and numerous papers have shown that chronic diseases in the mother are linked to preterm birth in the newborn, so probably another mechanism than the blood sugar [is behind this association]," Ludvigsson told MedPage Today.
Researchers examined data from linked Swedish national registers, including the National Diabetes Register, the National Patient Register, and the Medical Birth Register. They identified Swedish women with liveborn singleton births from 2003 through 2014, as well as pregnant women with type 1 diabetes (present before conception and up to 91 days after conception).
Overall, there were 2,474 infants born to mothers with diabetes as well as 1,165,216 infants in a control group whose mothers did not have diabetes. Women in the sample were an average age of 30 and about 7% were smokers. Women with T1D were more likely to be of Nordic origin, overweight or obese, and have diabetes-related autoimmune disease versus women without diabetes, the authors reported.
As HbA1c levels increased among women with T1D, younger maternal age, less education, higher BMI, and smoking tended to be more prevalent, Ludvigsson and colleagues added.
Risk for preterm birth increased with rising HbA1c levels in this population:
- Level of 6.5% to <7.8% (aRR 4.22, 95% CI 3.74-4.75)
- Level of 7.8% to <9.1% (aRR 5.56, 95% CI 4.84-6.38)
- Level of ≥9.1% (aRR 6.91, 95% CI 5.85-8.17)
Of the 552 preterm births in women with T1D, the authors found that 320 were medically indicated, 223 were spontaneous preterm births, and 9 could not be identified. Risk for spontaneous preterm birth was linked to periconceptional HbA1c levels, they said, though "the largest risk increase was observed for medically indicated preterm birth."
Secondary outcomes included risks for neonatal death and stillbirth, which were "significantly increased only at HbA1c levels of 7.8% and above," though the authors noted this was based on a small number of cases. Risk increases for large gestational age infants (>2 standard deviations above mean gestational age), macrosomia, hypoglycemia, respiratory distress, and low Apgar score seemed to plateau at the second (6.5% to <7.8%) and third (7.8% to <9.1%) HbA1c category, the authors said.
Ludvigsson and his team acknowledged the possibility of residual confounding due to this study's observational nature. Additional limitations include an inability to access data on physical activity, race and ethnicity, or other lifestyle factors that could have played a role in the analysis. HbA1c levels were not available for all pregnant women with T1D in this study either, they added.
The study was funded by the Swedish Diabetes Foundation.
Ludvigsson disclosed no conflicts of interest.
Other co-authors were supported by the Strategic Research Area Epidemiology Program at the Karolinska Institutet, the Swedish Research Council, the Stockholm County Council, Pfizer, AstraZeneca, Itrim, and the Novo Nordisk Foundation.
Annals of Internal MedicineSource Reference: Ludvigsson J, et al "Maternal glycemic control in type 1 diabetes and the risk for preterm birth" Annals of Internal Medicine 2019; DOI: 10.7326/M18-1974.
Maternal Glycemic Control in Type 1 Diabetes and the Risk for Preterm Birth: A Population-Based Cohort Study
Jonas F. Ludvigsson, MD, PhD; Martin Neovius, PhD; Jonas Söderling, PhD; Soffia Gudbjörnsdottir, MD, PhD; Ann-Marie Svensson, PhD; Stefan Franzén, PhD; Olof Stephansson, MD, PhD; Björn Pasternak, MD, PhD
Maternal type 1 diabetes (T1D) has been linked to preterm birth and other adverse pregnancy outcomes. How these risks vary with glycated hemoglobin (or hemoglobin A1c [HbA1c]) levels is unclear.
To examine preterm birth risk according to periconceptional HbA1c levels in women with T1D.
Population-based cohort study.
Sweden, 2003 to 2014.
2474 singletons born to women with T1D and 1 165 216 reference infants born to women without diabetes.
Risk for preterm birth (<37 gestational weeks). Secondary outcomes were neonatal death, large for gestational age, macrosomia, infant birth injury, hypoglycemia, respiratory distress, 5-minute Apgar score less than 7, and stillbirth.
Preterm birth occurred in 552 (22.3%) of 2474 infants born to mothers with T1D versus 54 287 (4.7%) in 1 165 216 infants born to mothers without diabetes. The incidence of preterm birth was 13.2% in women with a periconceptional HbA1c level below 6.5% (adjusted risk ratio [aRR] vs. women without T1D, 2.83 [95% CI, 2.28 to 3.52]), 20.6% in those with a level from 6.5% to less than 7.8% (aRR, 4.22 [CI, 3.74 to 4.75]), 28.3% in those with a level from 7.8% to less than 9.1% (aRR, 5.56 [CI, 4.84 to 6.38]), and 37.5% in those with a level of 9.1% or higher (aRR, 6.91 [CI, 5.85 to 8.17]). The corresponding aRRs for medically indicated preterm birth (n = 320) were 5.26 (CI, 3.83 to 7.22), 7.42 (CI, 6.21 to 8.86), 11.75 (CI, 9.72 to 14.20), and 17.51 (CI, 14.14 to 21.69), respectively. The corresponding aRRs for spontaneous preterm birth (n = 223) were 1.81 (CI, 1.31 to 2.52), 2.86 (CI, 2.38 to 3.44), 2.88 (CI, 2.23 to 3.71), and 2.80 (CI, 1.94 to 4.03), respectively. Increasing HbA1c levels were associated with the study's secondary outcomes: large for gestational age, hypoglycemia, respiratory distress, low Apgar score, neonatal death, and stillbirth.
Because HbA1c levels were registered annually at routine visits, they were not available for all pregnant women with T1D.
The risk for preterm birth was strongly linked to periconceptional HbA1c levels. Women with HbA1c levels consistent with recommended target levels also were at increased risk.
Primary Funding Source:
Swedish Diabetes Foundation.
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