Birth Defect Rates High in Youth-Onset Type 2 Diabetes Pregnancies

Miriam E Tucker

December 02, 2015

VANCOUVER, British Columbia — Congenital anomalies were "strikingly" high among the infants of young females with type 2 diabetes participating in a large clinical trial who became pregnant despite repeated counseling to use contraception.

The findings, from the multicenter Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study, were presented December 1 here at the World Diabetes Congress 2015 by Kristen Nareau, MD, associate professor of pediatrics, University of Colorado School of Medicine, Denver, and were simultaneously published in Diabetes Care.

The TODAY study, the largest intervention trial to date of youth with type 2 diabetes, randomized 699 overweight or obese youth aged 10 to 17 with type 2 diabetes to receive metformin alone, metformin plus rosiglitazone, or metformin plus an intensive family-based lifestyle program aimed at improving eating habits, increasing activity, and reducing weight.

Because rosiglitazone is a pregnancy class C medication, consent forms for all 452 females in the study specified that "an acceptable method of birth control" be used and diabetes education throughout the study included preconception counseling to defer pregnancy until an HbA1c of less than 6% was achieved.

Nonetheless, over a mean duration of study participation of nearly 4 years, 10.2% (46) of the females had 63 pregnancies. Among the 39 live births, six were preterm (15.4%) and eight (20.5%) had major congenital anomalies.

Also concerning was the fact that, despite repetition of the message regarding contraception and the importance of prepregnancy glycemic control at every study visit (every 2 months in year 1 and every 3 months for the rest of the study) only eight of the young women who became pregnant (13.3%) reported remembering that they had received such counseling.

"The message I would like to get out is the need to continuously remind teens and young adult women of the need to avoid pregnancy unless their diabetes is well controlled, the need to call their diabetes doctor as soon as they think they are pregnant, and to encourage long-acting contraception in those who may be at highest risk for an unexpected pregnancy," lead author Georgeanna J Klingensmith, MD, professor of pediatrics at the University of Colorado, told Medscape Medical News.

The congenital-anomaly rate was very high — three to four times greater even than that reported in adult women with type 1 and type 2 diabetes, Dr Klingensmith noted.

"We do not really have an explanation for the high congenital-anomaly rate. Severe obesity and a high-fat diet may play a role, as well as high A1c levels. Our numbers were too low to really sort it out," she said, adding that other pregnancy complications found in the TODAY group were similar to those seen in other reports of women with either type 1 or type 2 diabetes.

Session moderator and Diabetes Care editor William T Cefalu, MD, executive director, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, told Medscape Medical News, "When you do informed consent you talk about the risk of the study and you counsel the patient. The 10% pregnancy rate is surprising and suggests that what we do when we counsel individuals with diabetes, particularly adolescents, needs to be reevaluated."

Dr Cefalu also noted, "The large number of stillbirths and congenital abnormalities was just shocking. With type 2 diabetes on the rise in adolescents, this is really cause for concern."

Predictors of Pregnancy and Outcomes

Since pregnancy prevention wasn't a primary focus of the TODAY study, pregnancy information wasn't collected prospectively. Once it became clear that pregnancies and adverse outcomes were occurring, the investigators quickly put in place retrospective data collection from both maternal and infant records, Dr Nadeau explained.

Those who became pregnant were older at randomization (15 vs 13 years, P < .0001), more likely to be living away from their parent's home at the time of pregnancy (P = .008), and had a lower household income (P = .03). Other demographic characteristics didn't differ between those who became pregnant and those who didn't.

Of the 53 pregnancies that were not electively terminated and for which follow-up information was available, there were 14 pregnancy losses, including two stillbirths (at 27 and 37 weeks).

The median body mass index closest to conception was 35.2 kg/m2, and the median HbA1c was 7.0%. The HbA1c level close to delivery, available for 35 pregnancies, was over 7.5% in nearly half (48.5%) and over 8% in more than a third (37.1%).

Among the 53 full-term pregnancies, there were no differences in HbA1c closest to conception between the 27 with a healthy infant and the 26 with miscarriage, stillbirth, prematurity, or congenital anomaly.

Nearly three-quarters of the young women were receiving prenatal care, and those girls were more likely to have a term, live-born infant than were those who reported no prenatal care or did not provide that information (P = .0002).

Of the 44 women who reported taking medication during their pregnancies, 6.8% reported taking metformin and 72.7% reported taking insulin, but none reported taking rosiglitazone, a statin, or an ACE inhibitor. Just over a quarter reported taking other medications during the pregnancy.

Four mothers had preeclampsia during pregnancy, all of whom had hypertension prior to pregnancy.

Nine (23%) of the 39 live-born infants required a longer hospitalization than did the mother, including all eight with congenital anomalies. These anomalies included four cardiac anomalies and four other anomalies (polycystic kidney disease, microcephaly, cleft palate, and jejunal atresia). Six infants had hypoglycemia (16.7%), three had respiratory-distress syndrome (8.3%), and one had hypocalcemia (2.8%). None had shoulder dystocia.

There was no significant difference in pregnancy outcome by maternal BMI. Half (50%) of those with adverse pregnancy outcomes were current or prior smokers, whereas only 29.6% of those with healthy infants reported smoking. This did not reach statistical significance, though (P = .1296).

Dr Klingensmith told Medscape Medical News that since the TODAY study ended in 2011 (it began in 2004), some of the 15 study sites now encourage long-acting reversible contraceptives among young female patients with type 2 diabetes.

Dr. Cefalu commented, "I think the authors did a very good job in carefully wording this paper….They were able to go back retroactively and obtain the information and describe it, providing us a lot of good information to move forward. These findings suggest that we need to go back and question what we need to do with preconception counseling in adolescents. It's still a major problem."

The TODAY study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. None of the study authors have relevant financial relationships. Dr. Cefalu is a consultant for Intarcia Therapeutics and Sanofi and has been a principal investigator of studies for GlaxoSmithKline, AstraZeneca, and Janssen.

Diabetes Care. Published online December 1, 2015. Article

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