Use of Insulin Glargine During Pregnancy in a Type 1 Diabetic Woman

The patient was a 37-year-old registered nurse recently followed during her second pregnancy complicated by diabetes. Type 1 diabetes was diagnosed at age 9 years. She was initially referred to us for management of her first diabetic pregnancy in June 1998 at 10 weeks’ gestation with twins. She was on a multiple daily insulin injection (MDI) regimen with human regular insulin (three times daily before meals) and NPH insulin at bedtime. Her initial HbA_1c at the time of referral was 7.6%. She was free of any clinical signs of diabetic retinopathy or peripheral neuropathy, and her urine microalbumin tests were negative. She had a prior history of hypoglycemia unawareness with recurrent episodes of severe hypoglycemia.

She was converted to lispro (Humalog) insulin before the evening meal, and her glycemic control was progressively improved throughout the remainder of her pregnancy, with sequential HbA_1c results of 7.2, 6.1, and 5.8%. She was found on ultrasound to have lost one of her twins at 13 weeks’ gestation, but she then went on to deliver a healthy baby girl by spontaneous vaginal delivery at 36 weeks’ gestation. Other than transient neonatal hypoglycemia (nadir 25 mg/dl), and transient neonatal jaundice, the patient and infant did well postpartum. She was seen once during the postpartum period and was subsequently followed by her primary care physician.

She was referred back to us for management of her second pregnancy in May 2001, in the 9th week of gestation. She was taking regular insulin before breakfast, lispro insulin before her noon and evening meals, and NPH insulin at bedtime. Her HbA_1c was 5.5% and remained below 6.6% throughout the remainder of her pregnancy. Her pregnancy was complicated by nausea and dizziness during the daytime, and she was having frequent hypoglycemic reactions during the night. Her husband repeatedly found her unresponsive and diaphoretic between 1 a.m. and 3 a.m., despite reductions in her bedtime NPH insulin dose, and despite having an adequate bedtime snack. She required intramuscular glucagon injections on repeated occasions (as many as three times in 1 week) when her husband was unable to arouse her from sleep. She had normal blood pressure (132/70 mmHg) and heart rate (72 bpm), and her electrolytes were normal (K⁺ 4.4 mEq/l). Although a random serum cortisol was low (4.6 g/dl) in the late afternoon, she was reluctant to undergo an ACTH stimulation test during her pregnancy.

Although insulin glargine had only recently been approved for use in the U.S., its use during pregnancy has not been studied and it is considered to be in Pregnancy Category C (1). Despite the lack of safety data in pregnancy, we made the decision to substitute evening glargine for her bedtime NPH insulin. It was deemed that the risks of repeated severe hypoglycemia and the potential for repeated glucagon injections, with resultant elevations in serum ketone levels, would likely have deleterious effects on the mother and fetus (2). She was therefore converted to insulin glargine in the evening during her 14th week of pregnancy, and NPH insulin was discontinued. Her subsequent diabetic control remained excellent, with HbA_1c levels <6% and serum fructosamine levels between 234 and 296 mol/l (normal range 0–285). She had no episodes of severe hypoglycemia requiring assistance or glucagon injection throughout the remainder of her pregnancy. Dilated eye exams during and after her pregnancy did not show signs of retinopathy. She was induced and delivered vaginally a healthy baby boy at 36 weeks’ gestation. The birth weight was 7 lb 12 oz, and the baby did not appear macrosomic. The postpartum period was uneventful except for transient neonatal hypoglycemia requiring tube feedings for <48 h.

Insulin glargine has several potential advantages in the management of pregnancies complicated by type 1 diabetes. As in this case, nocturnal hypoglycemia may be a significant clinical problem in women attempting to maintain the stringent glycemic targets recommended for diabetic pregnancies (3). Because nocturnal hypoglycemia is less common with bedtime insulin glargine– versus bedtime NPH–based MDI insulin regimens (4), it may offer clear advantages in this clinical setting. Potential concerns of insulin glargine use during pregnancy are a report of increased mitogenicity of glargine versus human insulin in a malignant cell line (osteosarcoma Saos/B10) (5), and the observation of a three-grade progression of retinopathy in some patients with type 2 diabetes treated with insulin glargine for ≤1 year (6). Further studies are clearly needed to better define the efficacy and safety of insulin glargine use during pregnancy.