Insulin-Treated Diabetes Tied to LGA and Preterm Birth

Veronica Hackethal, MD

March 08, 2019

Newborns of women with insulin-treated diabetes have the highest risk for prematurity and for being large for gestational age (LGA), according to a large study published online February 25 in JAMA Pediatrics.

The study also found that having type 2 diabetes before pregnancy, even when not treated with insulin, can increase the risk for LGA and prematurity. Although the effect is smaller than for insulin-treated diabetes, the risk rises among women who are overweight.

The study is the largest and most comprehensive to date to evaluate the risk for LGA and prematurity in newborns of mothers with diabetes treated with insulin before pregnancy and to investigate the effect of body mass index (BMI) on these variables.

"In this cohort study of 649,043 births, maternal diabetes treated with insulin was associated with a high risk for the offspring to be large and/or preterm at birth, regardless of prepregnancy body mass index, whereas type 2 diabetes not treated with insulin was associated with a mild to moderate, albeit statistically significant, risk that was stronger in mothers who were obese or severely obese," write Linghua Kong, MSc, of Karolinska Institutet, Stockholm, Sweden, and colleagues.

Previous studies suggest that the babies of women who are obese and have type 1 diabetes or gestational diabetes are at increased risk for LGA and preterm birth, which can increase the risk for birth complications both to the mother and the newborn.

During pregnancy, women experience an increase in insulin resistance that helps ensure that the fetus receives enough energy to grow. Prepregnancy diabetes can exacerbate the already heightened insulin resistance of pregnancy. Insulin also serves as a growth hormone to the fetus. Yet little is known about how in utero exposure to insulin treatment affects newborns.

To investigate the question, researchers conducted a nationwide cohort study in Finland. They analyzed data from a national medical records database on children born from January 2004 through December 2014. They adjusted their models for maternal BMI, birth year, smoking, and other maternal factors, such as age and country of birth.

The rate of LGA was highest among newborns born to mothers with insulin-treated diabetes, at 39.6%, compared with 1.5% among those born to women of normal weight who did not have diabetes (adjusted odds ratio [aOR], 43.80). The risk was also elevated among those whose mothers had type 2 diabetes (12.8%; aOR, 9.57) and among newborns of mothers with gestational diabetes (5.4%; aOR, 3.80).

The likelihood of LGA did not change substantially with increasing BMI among women with insulin-treated diabetes. However, infants of insulin-treated women with moderate obesity (BMI, 30 – 34) still had the highest odds of LGA compared to normal weight women without diabetes (aOR, 45.04).

The steepest increase in risk for LGA occurred in women with type 2 diabetes who were moderately obese. In this group, 16.4% had an LGA infant, compared to 1.5% of normal-weight women without diabetes (aOR, 12.44), which was more than three times higher than in women with type 2 diabetes who were of normal weight (aOR, 3.85).

The rate of prematurity was likewise high among mothers with insulin-treated diabetes, at 37.1%, compared with 5.0% among women who were of normal weight and who did not have diabetes (aOR, 11.17). The rate of prematurity was also increased among mothers with type 2 diabetes, irrespective of insulin treatment (10.1%, aOR 2.12). By contrast, gestational diabetes was not linked to prematurity (prematurity rate, 5.1%).

Increasing BMI appeared to have less influence on risk for prematurity. Newborns of women with moderate obesity and insulin-treated diabetes were found to have the highest rate for prematurity (39.2%, aOR, 11.12).

"[H]igh risk pregnant women requiring insulin during pregnancy or with type 2 diabetes and a high body mass index should be carefully monitored throughout pregnancy," Monique Hedderson, PhD, commented to Medscape Medical News via email. Hedderson is a researcher at Kaiser Permanente Northern California Division of Research in Oakland and was not involved in the study.

She noted that the study could not evaluate the adequacy of blood sugar control during pregnancy in women treated with insulin.

"It is possible that these adverse outcomes can be mitigated by maintaining proper glycemic control throughout pregnancy, but this will require further study," she added.

"There is nothing fundamentally new here other than that the aORs for LGA among insulin-treated women are crazy high compared to everything else in the literature," Michael Greene, MD, commented to Medscape Medical News via email. Green, professor of obstetrics, gynecology, and reproductive biology at Harvard Medical School and Massachusetts General Hospital in Boston, was not involved in the study.

He explained that that may be because the study used a broader range of measurements to define LGA and being small for gestational age (SGA) than most people use.

"The authors have chosen 2 SD above or below the mean for LGA and SGA, respectively. Most of the literature uses above the 90th percentile and below the 10th percentile, respectively, for these definitions," he added.

The study has several limitations, among them the fact that it used self-reported data for prepregnancy maternal BMI and that it did not account for weight gain during pregnancy.

The study was funded by the THL National Institute for Health and Welfare, the Swedish Research Council, the Stockholm County Council, the Karolinska Institutet Stockholm County Council, the China Scholarship Council, and the Swedish Brain Foundation. One or more authors have received grants from one or more of the following: the China Scholarship Council, the Swedish Research Council, the Swedish Brain Foundation, and the Stockholm County Council. Hedderson has disclosed no relevant financial relationships.

JAMA Pediatr. Published online February 25, 2019. Abstract

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